Antisense oligomer formulations

Abstract

Provided herein are pharmaceutical formulations, kits and methods of their use for treating a disease or condition by modulating the expression of NaV1.1 protein in a cell of a subject in need thereof wherein the ASO modulates splicing of a non-sense mediated mRNA decay-inducing exon from a precursor mRNA in the cell of the subject, thereby modulating the expression of the NaV1.1 protein in the subject.

Description

Cross-referencing related applications

[0001] This application claims the benefits of U.S. Provisional Application No. 63 / 625,171, filed January 25, 2024, and U.S. Provisional Application No. 63 / 484,890, filed February 14, 2023, which are incorporated herein by reference in their entirety. Background Technology

[0002] Neurological disorders are often associated with channelopathies, characterized by impairment of ion channels that mediate neuronal excitability, neuronal interactions, and extensive brain function. (This is in contrast to wild-type Na+.) V Compared to protein 1.1, it belongs to the α-pore-forming subunit encoding neuronal voltage-gated sodium channels. SCN1A - SCN2A - SCN3A part of a gene cluster SCN1A Mutations in genes can cause reduced Na+ function. V 1.1 Protein (also known as "Na+") V The expression of 1.1"), Na V 1.1 expression decreased or both. SCN1A Mutations in genes are associated with the development of a variety of diseases and symptoms, such as Dravet Syndrome (DS) (Miller et al., 1993–2015, Gene Reviews, Pagon RA et al., eds., Seattle (WA): University of Washington, NBK1318; and Mulley et al., 2005, Human Mutat. 25: 535–542). Summary of the Invention

[0003] SCN1A Alternative splicing events in genes can produce nonproductive mRNA transcripts, which in turn can lead to aberrant protein expression and targeted protein expression. SCN1A Therapeutic agents targeting alternative splicing events in genes can modulate the expression levels of functional proteins and / or inhibit the expression of abnormal proteins in patients with Dlaivé syndrome. These therapeutic agents can be used to treat symptoms caused by deficiencies in SCN1A, SCN8A, or SCN5A proteins.

[0004] Choosing the right formulation, dosage, dosing regimen, and patient population for a drug is a critical step in drug development. For example, a physician cannot prescribe a drug without sufficient dosage information. Similarly, a drug cannot be medically useful or commercially viable if the permissible safe and predictable dosage or dosage range cannot be identified. Therefore, determining the correct drug dosage is a critical problem that needs to be addressed in clinical practice. Discovering the therapeutically effective dosage and dosing regimen of a drug requires balancing patient compliance, therapeutic efficacy, and side effects; this demands considerable skill. For example, appropriate dosages and dosing regimens can be discovered through clinical trials that form part of the approval process, requiring significant input of intellectual and financial resources from various parties and are not part of the routine for practicing physicians. For example, patient compliance can be critical for optimal treatment of various conditions. The higher the required dosage or the more difficult the treatment plan, the lower the likelihood of patient compliance. While healthcare agents have the ability to improve patients' quality of life (QOL), they can only do so when the drug is used correctly. Therefore, it is evident that choosing the right dosage, formulation, dosing regimen, and patient population for a drug is complex and unpredictable. Structurally similar compounds differ significantly in their solubility, toxicity, activity, stability, and pharmacological properties. Furthermore, significant physiological differences exist between animal models and human subjects. Therefore, translating preclinical information into clinically effective therapies is an unpredictable and challenging task.

[0005] This article provides characteristics of Na for treating subjects in need. V 1.1 Appropriate drug formulations, dosages, dosing regimens, and patient populations for diseases or conditions that reduce the expression or function of a protein or for reducing the likelihood of the subject developing such diseases or conditions.

[0006] This document provides a pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition comprising: i) an antisense oligomer (ASO), and ii) a pharmaceutically acceptable diluent; wherein the liquid composition is not buffered; and wherein: (a) the liquid composition comprises calcium, magnesium, and / or potassium ions, (b) the pharmaceutical formulation is formulated for or suitable for administration to the intrathecal space, cerebrospinal fluid, or brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

[0007] This document also provides a pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition comprising: (i) an antisense oligomer (ASO), and (ii) a pharmaceutically acceptable diluent, wherein (a) the ASO is stable in the pharmaceutical formulation after being stored at -20°C or at a certain temperature and relative humidity for a certain period of time; (b) the pharmaceutical formulation has a shelf life after being stored at -20°C or at a certain temperature and relative humidity for a certain period of time; (c) after being stored at -20°C or at a certain temperature and relative humidity for a certain period of time, the percentage of impurities in the pharmaceutical formulation does not exceed 2.5% based on an HPLC relative retention time of 0.92; and (d) after being stored at -20°C or at a certain temperature and relative humidity for a certain period of time, the percentage of impurities in the pharmaceutical formulation does not exceed 2.5% based on an HPLC relative retention time of 0.92. (e) An HPLC relative retention time of 0.98, wherein the percentage of impurities in the pharmaceutical formulation does not exceed 3.5%; (f) After storing the pharmaceutical formulation at -20°C or a certain temperature and relative humidity for a certain period of time, the percentage of any unspecified impurities in the pharmaceutical formulation does not exceed 1.8% according to HPLC; (g) After storing the pharmaceutical formulation at -20°C or a certain temperature and relative humidity for a certain period of time, the percentage of total impurities in the pharmaceutical formulation does not exceed 10% according to HPLC; (h) After storing the pharmaceutical formulation at -20°C or a certain temperature and relative humidity for a certain period of time, the pH of the pharmaceutical composition is 6.6 to 7.6; (h) After storing the pharmaceutical formulation at -20°C or a certain temperature and relative humidity for a certain period of time, the osmotic pressure of the pharmaceutical composition is 310. mOsm / kg to 360 mOsm / kg; and / or (i) no observable particulate formation was observed after storing the pharmaceutical formulation at -20°C or at a certain temperature and relative humidity for a certain period of time. In some embodiments, the temperature is 4°C, 25°C, 30°C, 37°C, or 40°C. In some embodiments, the relative humidity is about 55%, 60%, 65%, 70%, or 75%.In some embodiments, the time period is at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, and 34 weeks. Weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years.

[0008] In some embodiments, (a) the liquid composition comprises calcium ions, magnesium ions and / or potassium ions, (b) the pharmaceutical formulation is formulated for or suitable for administration into the intrathecal space, cerebrospinal fluid or brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

[0009] This document also provides a pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition comprising: (i) an antisense oligomer (ASO), and (ii) a pharmaceutically acceptable diluent; wherein the liquid composition is deficient in Na2HPO4 and / or NaH2PO4; and wherein: (a) the liquid composition contains calcium ions, magnesium ions and / or potassium ions, (b) the pharmaceutical formulation is formulated for or suitable for administration to the intrathecal space, cerebrospinal fluid or brain of a human subject, and / or (c) each nucleobase of the ASO contains a modified sugar moiety.

[0010] In some embodiments, the liquid composition is deficient in phosphate ions.

[0011] In some embodiments, the liquid composition comprises calcium ions, magnesium ions, and / or potassium ions.

[0012] This article also provides a pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition comprising: (i) an antisense oligomer (ASO), and (ii) a pharmaceutically acceptable diluent consisting of: a) NaCl, b) KCl, c) MgCl2 or MgCl2 6H2O, and d) CaCl2 or CaCl2 2H2O.

[0013] In some embodiments, the liquid composition comprises 0.1-50 mM CaCl2 or CaCl2 2H2O.

[0014] In some embodiments, the liquid composition comprises 1-2 mM CaCl2 or CaCl2 2H2O.

[0015] In some embodiments, the liquid composition comprises about 1.4 mM CaCl2 or CaCl2 2H2O.

[0016] In some embodiments, the liquid composition comprises 0.1-50 mM MgCl2 or MgCl2 6H2O.

[0017] In some embodiments, the liquid composition comprises 0.5-1.5 mM MgCl2 or MgCl2 6H2O.

[0018] In some embodiments, the liquid composition comprises about 0.79 mM MgCl2 or MgCl2 6H2O.

[0019] In some embodiments, the liquid composition comprises 5-250 mM NaCl, 0.1-20 mM KCl, 0.1-50 mM CaCl2 or CaCl2 2H2O, and 0.1-50 mM MgCl2 or MgCl2 6H2O.

[0020] This document also provides a pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition comprising: (i) an antisense oligomer (ASO), and (ii) a pharmaceutically acceptable diluent; wherein the liquid composition is deficient in calcium and / or magnesium ions; and wherein: (a) the liquid composition contains potassium ions, (b) the pharmaceutical formulation is formulated for or suitable for administration to the intrathecal space, cerebrospinal fluid, or brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

[0021] In some embodiments, the liquid composition contains a buffer.

[0022] In some embodiments, the buffer has a pKa of about 4.75; about 5.64; about 1.70, about 6.04 and about 9.09; about 3.1, about 4.7 and about 6.4; or about 6.50 at 25°C.

[0023] In some embodiments, the buffer is an effective buffer solution with a pH range of about 3.6 to 5.6, about 5.5 to 6.5, about 5.5 to 7.4, about 3.0 to 6.2, or about 5.8 to 7.2.

[0024] In some embodiments, the buffer is selected from the group consisting of: acetate, succinate, histidine, citrate, 2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3-diol (Bis-Tris), and any combination thereof.

[0025] In some embodiments, the liquid composition is formulated for application to the intrathecal space, cerebrospinal fluid, or brain of a human subject.

[0026] In some embodiments, the liquid composition is formulated for application to the cerebrospinal fluid in the brain of a human subject.

[0027] In some embodiments, the ASO comprises at least one modified sugar moiety.

[0028] In some embodiments, each nucleotide of the antisense oligomer contains a modified sugar moiety.

[0029] This document also provides a kit comprising: (i) a concentrate comprising an antisense oligomer (ASO); and (ii) a pharmaceutically acceptable diluent, wherein the concentrate is miscible with the pharmaceutically acceptable diluent; and wherein mixing the ASO with the pharmaceutically acceptable diluent produces a liquid composition comprising the ASO, and wherein the liquid composition is not buffered; and wherein: (a) the liquid composition comprises calcium, magnesium, and / or potassium ions, (b) the pharmaceutical formulation is formulated for or suitable for administration to the intrathecal space, cerebrospinal fluid, or brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

[0030] In some embodiments, the kit comprises: (i) a concentrate comprising an antisense oligomer (ASO); and (ii) a pharmaceutically acceptable diluent, wherein the concentrate is miscible with the pharmaceutically acceptable diluent; and wherein mixing the ASO with the pharmaceutically acceptable diluent produces a liquid composition comprising the ASO, and wherein (a) the ASO is stable in the pharmaceutical formulation after storage at -20°C or a certain temperature and relative humidity for a certain period of time; (b) the pharmaceutical formulation has a shelf life after storage at -20°C or a certain temperature and relative humidity for a certain period of time; (c) after storage of the pharmaceutical formulation at -20°C or a certain temperature and relative humidity for a certain period of time, the percentage of impurities in the pharmaceutical formulation does not exceed 2.5% based on an HPLC relative retention time of 0.92; and (d) after storage of the pharmaceutical formulation at... (e) After storage at -20°C or a certain temperature and relative humidity for a certain period of time, the percentage of impurities in the pharmaceutical formulation does not exceed 3.5% according to an HPLC relative retention time of 0.98; (f) After storage of the pharmaceutical formulation at -20°C or a certain temperature and relative humidity for a certain period of time, the percentage of any unspecified impurities in the pharmaceutical formulation does not exceed 1.8% according to HPLC; (g) After storage of the pharmaceutical formulation at -20°C or a certain temperature and relative humidity for a certain period of time, the percentage of total impurities in the pharmaceutical formulation does not exceed 10% according to HPLC; (g) After storage of the pharmaceutical formulation at -20°C or a certain temperature and relative humidity for a certain period of time, the pH of the pharmaceutical composition is 6.6 to 7.6; (h) After storage of the pharmaceutical formulation at -20°C or a certain temperature and relative humidity for a certain period of time, the osmotic pressure of the pharmaceutical composition is 310. mOsm / kg to 360 mOsm / kg; and / or (i) no observable particulate formation was observed after storing the pharmaceutical formulation at -20°C or at a certain temperature and relative humidity for a certain period of time. In some embodiments, the temperature is 4°C, 25°C, 30°C, 37°C, or 40°C. In some embodiments, the relative humidity is about 55%, 60%, 65%, 70%, or 75%.In some embodiments, the time period is at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, and 34 weeks. Weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years.

[0031] In some embodiments, (a) the liquid composition comprises calcium ions, magnesium ions and / or potassium ions, (b) the pharmaceutical formulation is formulated for or suitable for administration into the intrathecal space, cerebrospinal fluid or brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

[0032] In some embodiments, the kit comprises: (i) a concentrate comprising an antisense oligomer (ASO); and (ii) a pharmaceutically acceptable diluent, wherein the concentrate is miscible with the pharmaceutically acceptable diluent; and wherein mixing the ASO with the pharmaceutically acceptable diluent produces a liquid composition comprising the ASO, wherein the liquid composition is deficient in Na2HPO4 and / or NaH2PO4; and wherein: (a) the liquid composition comprises calcium, magnesium, and / or potassium ions, (b) the pharmaceutical formulation is formulated for or suitable for administration to the intrathecal space, cerebrospinal fluid, or brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

[0033] In some embodiments, the liquid composition is deficient in phosphate ions.

[0034] In some embodiments, the liquid composition comprises calcium ions, magnesium ions, and / or potassium ions.

[0035] In some embodiments, the kit comprises: (i) a concentrate comprising an antisense oligomer (ASO); and (ii) a pharmaceutically acceptable diluent comprising: a) NaCl, b) KCl, c) MgCl2 or MgCl2 6H2O, and d) CaCl2 or CaCl2 2H2O, wherein the concentrate is miscible with the pharmaceutically acceptable diluent; and wherein mixing the ASO with the pharmaceutically acceptable diluent produces a liquid composition comprising the ASO.

[0036] In some embodiments, the liquid composition comprises 0.1-50 mM CaCl2 or CaCl2 2H2O.

[0037] In some embodiments, the liquid composition comprises 1-2 mM CaCl2 or CaCl2 2H2O.

[0038] In some embodiments, the liquid composition comprises about 1.4 mM CaCl2 or CaCl2 2H2O.

[0039] In some embodiments, the liquid composition comprises 0.1-50 mM MgCl2 or MgCl2 6H2O.

[0040] In some embodiments, the liquid composition comprises 0.5-1.5 mM MgCl2 or MgCl2 6H2O.

[0041] In some embodiments, the liquid composition comprises about 0.79 mM MgCl2 or MgCl2 6H2O.

[0042] In some embodiments, the liquid composition comprises 5-250 mM NaCl, 0.1-20 mM KCl, 0.1-50 mM CaCl2 or CaCl2 2H2O, and 0.1-50 mM MgCl2 or MgCl2 6H2O.

[0043] This document also provides a kit comprising: (i) a concentrate comprising an antisense oligomer (ASO); and (ii) a pharmaceutically acceptable diluent, wherein the concentrate is miscible with the pharmaceutically acceptable diluent; wherein mixing the ASO with the pharmaceutically acceptable diluent produces a liquid composition comprising the ASO, wherein the liquid composition is deficient in calcium and / or magnesium ions; and wherein: (a) the liquid composition comprises potassium ions, (b) the pharmaceutical formulation is formulated for or suitable for administration to the intrathecal space, cerebrospinal fluid, or brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

[0044] In some embodiments, the liquid composition contains a buffer.

[0045] In some embodiments, the buffer has a pKa of about 4.75; about 5.64; about 1.70, about 6.04 and about 9.09; about 3.1, about 4.7 and about 6.4; or about 6.50 at 25°C.

[0046] In some embodiments, the buffer is an effective buffer solution with a pH range of about 3.6 to 5.6, about 5.5 to 6.5, about 5.5 to 7.4, about 3.0 to 6.2, or about 5.8 to 7.2.

[0047] In some embodiments, the buffer is selected from the group consisting of: acetate, succinate, histidine, citrate, 2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3-diol (Bis-Tris), and any combination thereof.

[0048] In some embodiments, the liquid composition is formulated for application to the intrathecal space, cerebrospinal fluid, or brain of a human subject.

[0049] In some embodiments, the liquid composition is formulated for application to the cerebrospinal fluid in the brain of a human subject.

[0050] In some embodiments, the ASO comprises at least one modified sugar moiety.

[0051] In some embodiments, each nucleotide of the antisense oligomer contains a modified sugar moiety.

[0052] In some embodiments, the kit further comprises: (iii) instructions for diluting or dissolving the ASO in a pharmaceutically acceptable diluent.

[0053] In some embodiments, the liquid composition contains 25-250 mM NaCl.

[0054] In some embodiments, the liquid composition contains 0.1-20 mM KCl.

[0055] In some embodiments, the liquid composition contains 2-4 mM KCl.

[0056] In some embodiments, the liquid composition contains about 3 mM KCl.

[0057] In some embodiments, the liquid composition contains 100-160 mM NaCl.

[0058] In some embodiments, the liquid composition contains 125-145 mM NaCl.

[0059] In some embodiments, the liquid composition contains about 130 mM NaCl.

[0060] In some embodiments, the liquid composition comprises a buffer (pH 6.6-7.6) solution.

[0061] In some embodiments, the liquid composition contains 0.1-50 mM Na2HPO4.

[0062] In some embodiments, the liquid composition contains 0.1-50 mM NaH2PO4.

[0063] In some embodiments, the liquid composition comprises 5-250 mM NaCl, 0.1-20 mM KCl, 0.1-50 mM Na2HPO4, and 0.1-50 mM NaH2PO4.

[0064] In some embodiments, the ASO is dissolved in a pharmaceutically acceptable diluent.

[0065] In some embodiments, the pharmaceutically acceptable diluent is an isotonic solution.

[0066] In some embodiments, the ASO is not substantially multidistributed.

[0067] In some embodiments, the osmotic pressure of the liquid composition is less than 150 mM.

[0068] In some embodiments, the osmotic pressure of the liquid composition is about 130 mM.

[0069] In some embodiments, the liquid composition further comprises carbohydrates.

[0070] In some embodiments, the carbohydrate comprises D-glucose.

[0071] In some embodiments, the liquid composition further comprises 1-100 mM D-glucose.

[0072] In some embodiments, the liquid composition further comprises an antioxidant.

[0073] In some embodiments, the antioxidant is tert-butylhydroxyquinoline (TBHQ), butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E, or any combination thereof.

[0074] In some embodiments, the liquid composition does not contain preservatives.

[0075] In some embodiments, the liquid composition is packaged in a single-use vial.

[0076] In some embodiments, the liquid composition is formulated for or adapted to be administered (i) by bolus injection; (ii) by infusion using a delivery pump; (iii) by intraventricular injection; and / or (iv) by intrathecal injection.

[0077] In some embodiments, the ASO comprises a T-methoxyethyl sugar moiety.

[0078] In some embodiments, the T-methoxyethyl sugar moiety is the T-2'-methoxyethyl sugar moiety.

[0079] In some embodiments, the ASO comprises a 2'-O-methoxyethyl moiety.

[0080] In some embodiments, the ASO comprises thymidine including a 2'-O-methoxyethyl moiety.

[0081] In some embodiments, each nucleobase of the ASO comprises a 2'-O-methoxyethyl moiety.

[0082] In some embodiments, the ASO consists of 8 to 50 nucleobases.

[0083] In some embodiments, the ASO consists of fewer than 35 nucleobases.

[0084] In some embodiments, the ASO consists of 16 to 20 nucleobases.

[0085] In some embodiments, the ASO consists of 12 to 20 nucleobases.

[0086] In some embodiments, the ASO consists of 8 to 20 nucleobases.

[0087] In some embodiments, the ASO comprises 5'-methylcytosine (5'-MeC).

[0088] In some embodiments, each cytosine of the ASO is 5'-methylcytosine (5'-MeC).

[0089] In some embodiments, the ASO comprises a thiophosphate bond.

[0090] In some embodiments, each nucleoside bond of the ASO is a thiophosphate bond.

[0091] In some embodiments, the ASO comprises locked nucleic acid (LNA).

[0092] In some embodiments, the liquid composition comprises 1 mL to 20 mL of the pharmaceutically acceptable diluent, 2 mL to 10 mL of the pharmaceutically acceptable diluent, or 1 mL to 5 mL of the pharmaceutically acceptable diluent.

[0093] In some embodiments, the liquid composition comprises 0.1 mL to 50 mL of the pharmaceutically acceptable diluent.

[0094] In some embodiments, the liquid composition comprises about 0.1 mL, 0.5 mL, 1 mL, 2 mL, 2.5 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, 10 mL, 11 mL, 12 mL, 13 mL, 14 mL, 15 mL, 16 mL, 17 mL, 18 mL, 19 mL, 20 mL, 25 mL, 30 mL, 35 mL, 40 mL, 45 mL, or 50 mL of the pharmaceutically acceptable diluent.

[0095] In some embodiments, the liquid composition comprises about 0.5 mg to about 500 mg of the ASO.

[0096] In some embodiments, the liquid composition comprises 0.1 mg, 0.5 mg, 1 mg, 2.5 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg, 40 mg, 42.5 mg, 45 mg, 47.5 mg, 50 mg, 52.5 mg, 55 mg, 57.5 mg, 60 mg, 62.5 mg, 65 mg, 67.5 mg, 70 mg, 72.5 mg, 75 mg, 77.5 mg, 80 mg, 82.5 mg, 85 mg, 87.5 mg, 90 mg, 92.5 mg, 95 mg, 97.5 mg, 10 ... 102.5 mg mg, 150 mg, 152.5 mg, 155 mg, 157.5 mg, 160 mg, 162.5 mg, 165 mg, 167.5 mg, 170 mg, 172.5 mg, 175 mg, 177.5 mg, 180 mg, 182.5 mg, 185 mg, 187.5 mg, 190 mg, 192.5 mg, 195 mg, 197.5 mg, 200 mg, 202.5 mg, 205 mg, 207.5 mg, 210 mg, 212.5 mg, 215 mg, 217.5 mg, 220mg, 222.5 mg, 225 mg, 227.5 mg, 230 mg, 232.5 mg, 235 mg, 237.5 mg, 240 mg, 242.5 mg, 245 mg, 247.5 mg or 250 mg of the ASO.

[0097] In some embodiments, the ASO is present in the liquid composition at a concentration of 0.1-500 mg / mL.

[0098] In some embodiments, the ASO is present in the liquid composition at a concentration of 0.1 mg / mL to 250 mg / mL.

[0099] In some embodiments, the ASO is present in the pharmaceutical formulation at a concentration of 6.7 mg / mL to 188 mg / mL or 6.8 mg / mL to 187 mg / mL.

[0100] In some embodiments, the ASO is present in the liquid composition at concentrations of about 0.1 mg / mL, 0.5 mg / mL, 1 mg / mL, 2 mg / mL, 2.5 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, or 20 mg / mL.

[0101] In some embodiments, the ASO is present in the liquid composition at concentrations of 11 mg / mL, 22 mg / mL, 33 mg / mL, 44 mg / mL, 55 mg / mL, 66 mg / mL, 77 mg / mL, 88 mg / mL, 99 mg / mL, or 100 mg / mL.

[0102] In some embodiments, the ASO is present in the liquid composition at a concentration of about 22.5 mg / mL, 25 mg / mL, 27.5 mg / mL, 30 mg / mL, 32.5 mg / mL, 35 mg / mL, 37.5 mg / mL, 40 mg / mL, 42.5 mg / mL, 45 mg / mL, 47.5 mg / mL, 50 mg / mL, 52.5 mg / mL, 55 mg / mL, 57.5 mg / mL, 60 mg / mL, 62.5 mg / mL, 65 mg / mL, 67.5 mg / mL, 70 mg / mL, 72.5 mg / mL, 75 mg / mL, 77.5 mg / mL, 80 mg / mL, 82.5 mg / mL, 85 mg / mL, 87.5 mg / mL, 90 mg / mL, 92.5 mg / mL, 95 mg / mL, 97.5 mg / mL, 100 mg / mL, 102.5 mg / mL, 105 mg / mL, 107.5 mg / mL, 110 mg / mL, 112.5 mg / mL, 115 mg / mL, 117.5 mg / mL, 120 mg / mL, 122.5 mg / mL, 125 mg / mL, 127.5 mg / mL, 130 mg / mL, 132.5 mg / mL, 135 mg / mL, 137.5 mg / mL, 140 mg / mL, 142.5 mg / mL, 145 mg / mL, 147.5 mg / mL, 150 mg / mL, 152.5 mg / mL, 155 mg / mL, 157.5 mg / mL, 160 mg / mL, 162.5 mg / mL, 165 mg / mL, 167.5 mg / mL, 170 mg / mL, 172.5 mg / mL, 175 mg / mL, 177.5 mg / mL, 180 mg / mL, 182.5 mg / mL, 185 mg / mL, 187.5 mg / mL, 190 mg / mL, 192.5 mg / mL, 195 mg / mL, 197.5 mg / mL, 200 mg / mL, 202.5 mg / mL, 205 mg / mL, 207.5 mg / mL, 210 mg / mL, 212.5 mg / mL, 215 mg / mL, 217.5 mg / mL, 220 mg / mL, 222.5 mg / mL, 225 mg / mL, 227.5 mg / mL, 230 mg / mL, 232.5 mg / mL, 235 mg / mL, 237.5 mg / mL, 240 mg / mL, 242.5 mg / mL, 245 mg / mL, 247.5 mg / mL or 250 mg / mL.

[0103] In some embodiments, the ASO comprises a sequence having at least about 80% sequence identity with any of SEQ ID NO: 21-67, 210-256 or 304-1099.

[0104] In some embodiments, the ASO comprises a sequence having at least 83%, 88%, 94%, or 100% sequence identity with any of SEQ ID NO: 21-67, 210-256, or 304-1099.

[0105] In some embodiments, the ASO consists of a sequence having at least 83%, 88%, 94%, or 100% sequence identity with any of SEQ ID NO: 21-67, 210-256, or 304-1099.

[0106] In some embodiments, the ASO is a compound with the following chemical structure: .

[0107] In some embodiments, the ASO is a compound with the following chemical structure: .

[0108] In some respects, this document provides a liquid pharmaceutical formulation that is substantially composed of: (a) an antisense oligomer (ASO) at a concentration of about 0.1 mg / mL to about 500 mg / mL, wherein the ASO is a compound with the following chemical structure:

[0109] (i) or its salts; (b) calcium chloride dihydrate (CaCl2 2H2O) at a concentration of about 0.1 mM to about 50 mM; (c) magnesium chloride hexahydrate (MgCl2 6H2O) at a concentration of about 0.1 mM to about 50 mM; (d) potassium chloride (KCl) at a concentration of about 0.1 mM to about 20 mM; (e) sodium chloride (NaCl) at a concentration of about 25 mM to about 250 mM; and (f) water.

[0110] In some aspects, the pharmaceutical formulation further comprises an amount of sodium hydroxide (NaOH) and / or hydrochloric acid (HCl) providing a pH of 6.6 to 7.6 for the pharmaceutical formulation. In some aspects, the pharmaceutical formulation further comprises sodium hydroxide (NaOH) at a concentration of about 0.1 mM to about 20 mM and / or hydrochloric acid (HCl) at a concentration of about 0.1 mM to about 20 mM. In some aspects, a liquid pharmaceutical formulation is provided herein, which is substantially composed of: (a) an antisense oligomer (ASO) at a concentration of about 0.1 mg / mL to about 500 mg / mL, wherein the ASO is a compound according to the following chemical structure:

[0111] (i) or its salts; (b) calcium chloride dihydrate (CaCl2 2H2O) at a concentration of about 0.1 mM to about 50 mM; (c) magnesium chloride hexahydrate (MgCl2 6H2O) at a concentration of about 0.1 mM to about 50 mM; (d) potassium chloride (KCl) at a concentration of about 0.1 mM to about 20 mM; (e) sodium chloride (NaCl) at a concentration of about 25 mM to about 250 mM; (f) sodium hydroxide (NaOH) at a concentration of about 0.1 mM to about 20 mM and / or hydrochloric acid (HCl) at a concentration of about 0.1 mM to about 20 mM; and (g) water.

[0112] In some aspects, the concentration of the ASO is from about 0.1 mg / mL to about 250 mg / mL. In some aspects, the concentration of the ASO is from 6.7 mg / mL to 188 mg / mL, from 6.8 mg / mL to 187 mg / mL, from 3 mg / mL to 100 mg / mL, or from 3 mg / mL to 33 mg / mL. In some aspects, the concentration of the ASO is about 0.1 mg / mL, 0.5 mg / mL, 1 mg / mL, 2 mg / mL, 2.5 mg / mL, 3 mg / mL, 4 mg / mL, 4.5 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 22 mg / mL, 25 mg / mL, 28 mg / mL, or 33 mg / mL. In some aspects, the concentration of the ASO is 11 mg / mL, 22 mg / mL, 33 mg / mL, 44 mg / mL, 55 mg / mL, 66 mg / mL, 77 mg / mL, 88 mg / mL, 99 mg / mL, or 100 mg / mL. In some aspects, the concentration of the ASO is about 3 mg / mL, 4 mg / mL, 4.5 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 22.5 mg / mL, 25 mg / mL, 27.5 mg / mL, 30 mg / mL, 32.5 mg / mL, 35 mg / mL, 37.5 mg / mL, 40 mg / mL, 42.5 mg / mL, 45 mg / mL, 47.5 mg / mL, 50 mg / mL, 52.5 mg / mL, 55 mg / mL, 57.5 mg / mL, 60 mg / mL, 62.5 mg / mL, 65mg / mL, 67.5 mg / mL, 70 mg / mL, 72.5 mg / mL, 75 mg / mL, 77.5 mg / mL, 80 mg / mL, 82.5 mg / mL, 85 mg / mL, 87.5 mg / mL, 90 mg / mL, 92.5 mg / mL, 95 mg / mL, 97.5 mg / mL, 100 mg / mL, 102.5 mg / mL, 105 mg / mL, 107.5 mg / mL, 110 mg / mL, 112.5 mg / mL, 115 mg / mL, 117.5 mg / mL, 120 mg / mL, 122.5 mg / mL, 125 mg / mL, 127.5 mg / mL, 130 mg / mL, 132.5 mg / mL, 135 mg / mL, 137.5 mg / mL, 140 mg / mL, 142.5 mg / mL, 145 mg / mL, 147.5 mg / mL, 150 mg / mL, 152.5 mg / mL, 155 mg / mL, 157.5 mg / mL, 160 mg / mL, 162.5 mg / mL, 165 mg / mL, 167.5 mg / mL, 170 mg / mL, 172.5 mg / mL, 175 mg / mL, 177.5 mg / mL, 180 mg / mL, 182.5 mg / mL, 185 mg / mL, 187.5 mg / mL, 190 mg / mL, 192.5 mg / mL, 195 mg / mL, 197.5 mg / mL, 200 mg / mL, 202.5 mg / mL, 205 mg / mL, 207.5 mg / mL, 210 mg / mL, 212.5 mg / mL, 215 mg / mL, 217.5 mg / mL, 220 mg / mL, 222.5 mg / mL, 225 mg / mL, 227.5 mg / mL, 230 mg / mL, 232.5 mg / mL, 235 mg / mL, 237.5 mg / mL, 240 mg / mL, 242.5 mg / mL, 245 mg / mL, 247.5 mg / mL or 250 mg / mL.

[0113] In some aspects, the concentration of calcium chloride dihydrate is 0.2 mM to 25 mM, 0.5 mM to 10 mM, 0.75 mM to 5 mM, or 1 mM to 2 mM. In some aspects, the concentration of calcium chloride dihydrate is about 1 mM to about 2 mM. In some aspects, the concentration of calcium chloride dihydrate is about 1.4 mM. In some aspects, the concentration of magnesium chloride hexahydrate is 0.2 mM to 25 mM, 0.3 mM to 15 mM, 0.4 mM to 5 mM, 0.5 mM to 1.5 mM, or 0.6 mM to 1 mM. In some aspects, the concentration of magnesium chloride hexahydrate is about 0.6 mM to about 1 mM. In some aspects, the concentration of magnesium chloride hexahydrate is about 0.79 mM. In some aspects, the concentration of potassium chloride is 0.5 mM to 10 mM, 1 mM to 7.5 mM, or 2 mM to 5 mM. In some aspects, the concentration of potassium chloride is about 2 mM to about 5 mM. In some aspects, the concentration of potassium chloride is about 3 mM. In some aspects, the concentration of sodium chloride is 25 mM to 250 mM, 100 mM to 160 mM, 110 mM to 140 mM, or 130 mM to 160 mM. In some aspects, the concentration of sodium chloride is about 125 mM to 145 mM. In some aspects, the concentration of sodium chloride is about 130 mM. In some aspects, the concentration of sodium chloride is about 140 mM to 160 mM. In some aspects, the concentration of sodium chloride is about 150 mM. In some aspects, the concentration of calcium chloride dihydrate is about 0.5 mM to about 5 mM; the concentration of magnesium chloride hexahydrate is about 0.3 mM to about 1.25 mM; the concentration of potassium chloride is about 1 mM to about 10 mM; and the concentration of sodium chloride is about 100 mM to 180 mM. In some aspects, the concentration of calcium chloride dihydrate is about 1 mM to about 2 mM; the concentration of magnesium chloride hexahydrate is about 0.6 mM to about 1 mM; the concentration of potassium chloride is about 2 mM to about 5 mM; and the concentration of sodium chloride is about 120 mM to 160 mM. In some aspects, the concentration of ASO is about 3 mg / mL, about 4.5 mg / mL, about 7 mg / mL, or about 33 mg / mL; the concentration of calcium chloride dihydrate is about 1.4 mM; the concentration of magnesium chloride hexahydrate is about 0.79 mM; the concentration of potassium chloride is about 3 mM; and the concentration of sodium chloride is about 150 mM. In some aspects, the pH of the pharmaceutical composition is about 6.6 to about 7.6. In some aspects, the pH of the pharmaceutical composition is about 6.8 to about 7.2. In some aspects, the pH of the pharmaceutical composition is about 6.9 to about 7.1. In some respects, the volume of the pharmaceutical composition is about 5 mL, about 6 mL, about 7 mL, about 8 mL, about 9 mL, about 10 mL, about 12 mL, about 15 mL, about 20 mL, or about 25 mL.In some respects, the volume of the pharmaceutical composition is about 10 mL.

[0114] In some respects, this document provides a liquid pharmaceutical formulation that is substantially composed of: (a) an antisense oligomer (ASO) at a concentration of about 0.1 mg / mL to about 500 mg / mL, wherein the ASO is a compound with the following chemical structure:

[0115] (i) or its salts; (b) calcium ions (Ca) at a concentration of about 0.1 mM to about 50 mM. 2+ (c) Magnesium ions (Mg) at concentrations of approximately 0.1 mM to approximately 50 mM. 2+ (d) Potassium ions (K) at concentrations of approximately 0.1 mM to approximately 20 mM. + (e) Sodium ions (Na+) at a concentration of approximately 25 mM to approximately 250 mM. + (f) Chloride ions (Cl) at concentrations of approximately 25 mM to approximately 250 mM. - ); and (g) water.

[0116] In some respects, this document provides a liquid pharmaceutical formulation that is substantially composed of: (a) an antisense oligomer (ASO) at a concentration of about 0.1 mg / mL to about 500 mg / mL, wherein the ASO is a compound with the following chemical structure:

[0117] (i) or its salt; (b) calcium ions at a concentration of approximately 1.4 mM (Ca 2+ (c) Magnesium ions (Mg) at a concentration of approximately 0.79 mM. 2+ (d) Potassium ions (K) at a concentration of approximately 3 mM + (e) Sodium ions at a concentration of approximately 160 mM (Na) + (f) Chloride ions (Cl) at a concentration of approximately 160 mM - ); and (g) water.

[0118] In some respects, this document provides a pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition comprising: i) an active pharmaceutical ingredient (API), and ii) a pharmaceutically acceptable diluent; wherein the liquid composition is not buffered; and wherein: (a) the liquid composition comprises calcium ions, magnesium ions and / or potassium ions, and / or (b) the pharmaceutical formulation is formulated for or suitable for administration into the intrathecal space, cerebrospinal fluid or brain of a human subject.

[0119] In some aspects, this document also provides a pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition comprising: (i) an active pharmaceutical ingredient (API), and (ii) a pharmaceutically acceptable diluent; wherein the liquid composition is deficient in Na₂HPO₄ and / or NaH₂PO₄; and wherein: (a) the liquid composition contains calcium ions, magnesium ions, and / or potassium ions, and / or (b) the pharmaceutical formulation is formulated for or suitable for administration into the intrathecal space, cerebrospinal fluid, or brain of a human subject. In some embodiments, the liquid composition is deficient in phosphate ions. In some embodiments, the liquid composition contains calcium ions, magnesium ions, and / or potassium ions.

[0120] In some aspects, this document also provides a pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition comprising: (i) an active pharmaceutical ingredient (API), and (ii) a pharmaceutically acceptable diluent consisting of: a) NaCl, b) KCl, c) MgCl2 or MgCl2 6H2O, and d) CaCl2 or CaCl2 2H2O. In some embodiments, the liquid composition is deficient in phosphate ions. In some embodiments, the liquid composition comprises calcium ions, magnesium ions, and / or potassium ions.

[0121] In some embodiments, the pharmaceutically acceptable diluents provided herein are suitable for preparing any pharmaceutical formulation for intrathecal administration. For example, any active pharmaceutical ingredient suitable for intrathecal administration can be formulated using the pharmaceutically acceptable diluents provided herein. The active pharmaceutical ingredient may be a small molecule or biological agent, such as an organic chemical compound, antisense oligonucleotide, DNA, antibody or any other protein or polypeptide, a living organism such as bacteria or fungi, a viral vector or virus-like particle, or any combination thereof.

[0122] This article provides a method for treating a disease or condition in a subject in need or for reducing the likelihood of the subject having the disease or condition, the method comprising administering to the subject a pharmaceutical composition disclosed herein.

[0123] In some embodiments, the subject is a human subject.

[0124] In some embodiments, the human subject is up to 18 years of age when the first dose of the pharmaceutical composition is administered.

[0125] In some embodiments, the method includes administering the ASO at a first dose of about 0.5 mg to about 500 mg.

[0126] In some embodiments, the method includes administering multiple doses of the ASO.

[0127] In some embodiments, the disease or symptom is characterized by the subject's Na V 1.1 Decreased protein expression or function.

[0128] In some embodiments, the disease or symptom is Delaware syndrome.

[0129] In some embodiments, the subject is characterized by having the following: a. Seizures occurring before 12 months of age, with recurrent focal motor or hemiconvulsive or generalized tonic-clonic seizures, which are usually prolonged and triggered by high fever; b. No history of causally related lesions on magnetic resonance imaging; c. Other known causes besides Delaware syndrome, without any disease or symptom; d. Normal development during epileptic seizures; e. SCN1A Pathogenic variants or variants with uncertain significance in genes; f. At least two prior epilepsy treatments, either of which failed to provide adequate seizure control; g. Four or more convulsive seizures during the 28 days prior to administration, wherein the convulsive seizures are selected from any of the following: hemiclonic, focal with motor signs, focal to bilateral tonic-clonic seizures, generalized tonic-clonic seizures, tonic, tonic or atonic (falling seizures), and clonic. h. Current interventions for epilepsy or medications containing at least one antiepileptic drug at a stable dose for at least 4 weeks, wherein the epilepsy intervention is a ketogenic diet, vagus nerve stimulants, or cannabinoids or cannabis-derived products; or i. Any combination thereof.

[0130] In some embodiments, the subject is characterized by not having one or more of the following: a. The aforementioned SCN1A One of the following mutations in the gene: Thr226Met, Leu263Val, Val422Leu, Thr1174Ser, Trp1204Arg, Pro1345Ser, Gln1489Lys, Phe1499Leu, Arg1575Cys, Val1611Phe, Leu1624Pro, Arg1648Cys, Leu1649Gln, Leu1670Trp, Gly1674Arg, and Asp1866Tyr; b. Another known pathogenic mutation in a gene that causes epilepsy, wherein the pathogenic mutation is homozygous in the case of a known recessive disease; c. Sodium channel blockers are currently used as maintenance therapy and anticoagulants, wherein the sodium channel blockers are phenytoin, carbamazepine, oxcarbazepine, lamotrigine, lacosamide, or rufinamide, and wherein the anticoagulant is not aspirin. d. Clinically significant and unstable medical conditions other than epilepsy; e. Clinically relevant symptoms or clinically significant diseases other than epilepsy within 4 weeks prior to administration; f. History of brain or spinal cord disease other than epilepsy, Delaware syndrome, or bacterial meningitis or brain malformation; g. Spinal deformities or other conditions that alter the free flow of cerebrospinal fluid (CSF) or the presence of an implanted CSF drainage shunt; h. Clinically significant abnormal laboratory values ​​prior to administration; i. Aspartate aminotransferase or alanine aminotransferase > 2.5 times the upper limit of normal, serum creatinine > the upper limit of normal, or platelet count < the lower limit of normal; j. Clinically relevant abnormalities in the 12-lead electrocardiogram (ECG) measured prior to administration; k. Mental or behavioral disorders; l. Currently or within the past 4 weeks, medications containing an anticoagulant, wherein the anticoagulant is not aspirin; or m. Any combination thereof.

[0131] In some embodiments, the subjects are aged 1 to 18 years, 2 to 18 years, 3 to 18 years, 4 to 18 years, 5 to 18 years, 6 to 18 years, 7 to 18 years, 8 to 18 years, 9 to 18 years, 10 to 18 years, 11 to 18 years, 12 to 18 years, 13 to 18 years, 14 to 18 years, 15 to 18 years, 16 to 18 years, or 17 to 18 years.

[0132] In some embodiments, the subjects are individuals aged 1 to 17 years, 1 to 16 years, 1 to 15 years, 1 to 14 years, 1 to 13 years, 1 to 12 years, 1 to 11 years, 1 to 10 years, 1 to 9 years, 1 to 8 years, 1 to 7 years, 1 to 6 years, 1 to 5 years, 1 to 4 years, 1 to 3 years, or 1 to 2 years.

[0133] In some embodiments, the subject is under one year old or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 years old.

[0134] In some embodiments, the pharmaceutical composition is administered into the intrathecal space of the subject.

[0135] In some embodiments, the pharmaceutical composition is administered to the cerebrospinal fluid of the subject.

[0136] In some embodiments, the pharmaceutical composition is administered to the brain of the subject.

[0137] In some embodiments, the pharmaceutical composition is administered to the cerebrospinal fluid in the brain of the subject.

[0138] In some embodiments, the pharmaceutical composition is administered via bolus injection.

[0139] In some embodiments, the method comprises administering the pharmaceutical composition by bolus injection over a period of 1 to 60 minutes, 1 to 50 minutes, 1 to 40 minutes, 1 to 30 minutes, 1 to 20 minutes, 1 to 10 minutes, 1 to 5 minutes, or 1 to 3 minutes.

[0140] In some embodiments, the pharmaceutical composition is administered by infusion using a delivery pump.

[0141] In some embodiments, the pharmaceutical composition is administered via intraventricular injection.

[0142] In some embodiments, the pharmaceutical composition is administered via intrathecal injection.

[0143] In some embodiments, the method reduces or improves at least one symptom of Drave syndrome in the human subject.

[0144] In some embodiments, the symptoms of the Delaware syndrome are epileptic seizures.

[0145] In some embodiments, the application reduces or improves the frequency, intensity, or duration of seizures.

[0146] In some embodiments, the method further includes evaluating the tolerability or efficacy of the pharmaceutical composition.

[0147] In some embodiments, the method further comprises administering a pharmaceutical composition to the subject, the pharmaceutical composition comprising a subsequent dose of about 0.5 mg to about 500 mg of the ASO.

[0148] In some embodiments, the subsequent doses are 0.1 mg, 0.5 mg, 1 mg, 2.5 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg, 40 mg, 42.5 mg, 45 mg, 47.5 mg, 50 mg, 52.5 mg, 55 mg, 57.5 mg, 60 mg, 62.5 mg, 65 mg, 67.5 mg, 70 mg, 72.5 mg, 75 mg, 77.5 mg, 80 mg, 82.5 mg, 85 mg, 87.5 mg, 90 mg, 92.5 mg, 95 mg, 97.5 mg, 10 ... 102.5 mg mg, 150 mg, 152.5 mg, 155 mg, 157.5 mg, 160 mg, 162.5 mg, 165 mg, 167.5 mg, 170 mg, 172.5 mg, 175 mg, 177.5 mg, 180 mg, 182.5 mg, 185 mg, 187.5 mg, 190 mg, 192.5 mg, 195 mg, 197.5 mg, 200 mg, 202.5 mg, 205 mg, 207.5 mg, 210 mg, 212.5 mg, 215 mg, 217.5 mg, 220mg, 222.5 mg, 225 mg, 227.5 mg, 230 mg, 232.5 mg, 235 mg, 237.5 mg, 240 mg, 242.5 mg, 245 mg, 247.5 mg or 250 mg.

[0149] In some embodiments, the subsequent dose is lower than the previous dose after indicating intolerance to the previous dose.

[0150] In some embodiments, after indication of tolerance to the previous dose, the subsequent dose is the same as the previous dose.

[0151] In some embodiments, after indication of tolerance to the previous dose, the subsequent dose is higher than the previous dose.

[0152] In some embodiments, after indicating that the previous dose has been effective, the subsequent dose is the same as the previous dose.

[0153] In some embodiments, the subsequent dose is lower than the previous dose after it has been indicated that the previous dose was effective.

[0154] In some embodiments, the subsequent dose is higher than the previous dose after an indication that the previous dose was ineffective.

[0155] In some embodiments, the subsequent dose is administered at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months after the previous dose is administered.

[0156] In some embodiments, the dose frequency is maintained or reduced after indicating that the previous dose is ineffective.

[0157] In some embodiments, the dose frequency is increased after indicating that the previous dose was ineffective.

[0158] In some embodiments, the method further comprises administering at least one additional therapeutic agent or therapy.

[0159] In some embodiments, the at least one additional therapeutic agent or therapy is administered simultaneously with the dose.

[0160] In some embodiments, the at least one additional therapeutic agent or therapy is administered prior to the administration of the dose.

[0161] In some embodiments, the at least one additional therapeutic agent or therapy is administered after the administration of the dose.

[0162] In some embodiments, Na V 1.1 Decreased protein expression or function is associated with exons containing nonsense-mediated RNA decay-induced exons and encoding Na+. V 1.1 Splicing-related changes in NMD exons of protein precursor mRNA.

[0163] In some embodiments, the ASO facilitates the extraction of NMD exons and encoding the Na V The NMD exon is excluded from the precursor mRNA of the protein.

[0164] In some embodiments, the ASO contains the NMD exon and encodes the Na V 1.1 Binding to the target portion of the protein's precursor mRNA.

[0165] In some embodiments, the ASO facilitates the extraction of NMD exons and encoding the Na V The NMD exon is excluded from the precursor mRNA of the protein.

[0166] In some embodiments, when the ASO is introduced into cells, the ASO increases the encoding of Na+. V 1.1 Levels of treated mRNA of the protein.

[0167] In some embodiments, when the ASO is introduced into the cells, the ASO increases the Na+ content. V 1.1 Protein levels.

[0168] In some embodiments, the targeting portion is located within an intron sequence adjacent to the NMD exon.

[0169] In some embodiments, the targeting portion comprises at least one nucleotide of the NMD exon.

[0170] In some embodiments, the targeting portion is located within the NMD exon.

[0171] This document also provides a method for preparing the pharmaceutical composition described herein, the method comprising diluting the antisense oligomer (ASO) in a pharmaceutically acceptable diluent, thereby preparing the liquid composition.

[0172] In some embodiments, the ASO is at 3 mg / mL, 4 mg / mL, 4.5 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 22 mg / mL, 25 mg / mL, 28 mg / mL, 30 mg / mL, 44 mg / mL, 55 mg / mL, 66 mg / mL, 77 mg / mL, 88 mg / mL, 99 mg / mL, 100 mg / mL, 22.5 mg / mL, 25 mg / mL, 27.5 mg / mL, 30 mg / mL, 32.5 mg / mL, 35 mg / mL, 37.5 mg / mL, 40 mg / mL, 42.5 mg / mL, 45 mg / mL, 47.5 mg / mL, 50 mg / mL, 52.5 mg / mL, 55 mg / mL, 57.5 mg / mL, 60 mg / mL, 62.5 mg / mL, 65 mg / mL, 67.5 mg / mL, 70 mg / mL, 72.5 mg / mL, 75 mg / mL, 77.5 mg / mL, 80 mg / mL, 82.5 mg / mL, 85 mg / mL, 87.5 mg / mL, 90 mg / mL, 92.5 mg / mL, 95 mg / mL, 97.5 mg / mL, 100 mg / mL, 102.5 mg / mL, 105 mg / mL, 107.5 mg / mL, 110 mg / mL, 112.5 mg / mL, 115 mg / mL, 117.5 mg / mL, 120 mg / mL, 122.5 mg / mL, 125 mg / mL, 127.5 mg / mL, 130 mg / mL, 132.5 mg / mL, 135 mg / mL, 137.5 mg / mL, 140 mg / mL, 142.5 mg / mL, 145 mg / mL, 147.5 mg / mL, 150 mg / mL, 152.5 mg / mL, 155 mg / mL, 157.5 mg / mL, 160 mg / mL, 162.5 mg / mL, 165 mg / mL, 167.5 mg / mL, 170 mg / mL, 172.5 mg / mL, 175 mg / mL, 177.5 mg / mL, 180 mg / mL, 182.5 mg / mL, 185 mg / mL, 187.5 mg / mL, 190 mg / mL, 192.The liquid composition is present at concentrations of 5 mg / mL, 195 mg / mL, 197.5 mg / mL, 200 mg / mL, 202.5 mg / mL, 205 mg / mL, 207.5 mg / mL, 210 mg / mL, 212.5 mg / mL, 215 mg / mL, 217.5 mg / mL, 220 mg / mL, 222.5 mg / mL, 225 mg / mL, 227.5 mg / mL, 230 mg / mL, 232.5 mg / mL, 235 mg / mL, 237.5 mg / mL, 240 mg / mL, 242.5 mg / mL, 245 mg / mL, 247.5 mg / mL, or 250 mg / mL.

[0173] In some embodiments, the method further comprises diluting the liquid composition with an additional volume of the pharmaceutically acceptable diluent, thereby preparing the liquid composition.

[0174] In some embodiments, the ASO is in the form of 0.1-500 mg / mL, 0.1 mg / mL to 250 mg / mL, 6.7 mg / mL to 188 mg / mL, 6.8 mg / mL to 187 mg / mL, 3 mg / mL to 100 mg / mL, or 3 mg / mL to 33 mg / mL, or about 0.1 mg / mL, 0.5 mg / mL, 1 mg / mL, 2 mg / mL, 2.5 mg / mL, 3 mg / mL, 4 mg / mL, 4.5 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, or 20 mg / mL, 22 mg / mL, 25 mg / mL, 28 mg / mL. The concentrations of mg / mL, 30 mg / mL, or 33 mg / mL present in the liquid composition are present in the liquid composition.

[0175] In some embodiments, the method further comprises filtering the liquid composition.

[0176] In some embodiments, filtration includes filtering the liquid composition at least twice or filtering the liquid composition through at least two membranes.

[0177] In some embodiments, filtration includes filtering the liquid composition through 0.45 μm membranes and 0.2 μm membranes.

[0178] In some embodiments, the at least two membranes, the 0.45 μm membrane, and / or the 0.2 μm membrane comprise polyethersulfone membranes.

[0179] In some embodiments, the method further comprises filling a vial with the liquid composition.

[0180] In some embodiments, the vial is sterile and / or depyrogenated.

[0181] In some embodiments, the method further includes assembling the vial with a stopper.

[0182] In some embodiments, the stopper is sterilized and / or depyrogenated.

[0183] In some embodiments, the method further includes capping the vial with a seal.

[0184] In some embodiments, the seal is sterile and / or depyrogenated.

[0185] In some embodiments, the method is performed aseptically.

[0186] In some embodiments, the method further includes storing the vial at a certain temperature for a certain period of time.

[0187] In some embodiments, the temperature is -20 ± 5°C.

[0188] In some embodiments, the time period does not exceed 36 months.

[0189] In some embodiments, the time period does not exceed 24 months.

[0190] In some embodiments, the method further includes administering the liquid composition to a human subject after storage. By incorporating references

[0191] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each individual publication, patent or patent application were specifically and individually indicated to be incorporated by reference. Attached Figure Description

[0192] The features of this disclosure are specifically set forth in the appended claims. A better understanding of the features and advantages of this disclosure will be obtained by referring to the following detailed description of illustrative embodiments, which utilize the principles of this disclosure, and the accompanying drawings: Figures 1A-1BA schematic diagram of a target precursor mRNA is depicted, which contains nonsense-mediated RNA decay-inducing exons (NMD exon mRNA) and a therapeutic agent-mediated process to remove nonsense-mediated mRNA decay-inducing exons from the precursor mRNA to increase the expression of full-length target proteins or functional RNA. Figure 1A The image shows a cell divided into a nuclear compartment and a cytoplasmic compartment. In the nucleus, the precursor mRNA transcript of the target gene undergoes splicing to generate treated mRNA, which is then exported to the cytoplasm and translated into the target protein. For this target gene, a portion of the treated mRNA contains nonsense-mediated decay-inducible exons (NMD exon mRNAs) that degrade in the cytoplasm, thus preventing the production of the target protein. Figure 1B An example of the same cell divided into a nuclear compartment and a cytoplasmic compartment is shown. Treatment with therapeutic agents such as antisense oligomers (ASO) promotes the elimination of nonsense-mediated mRNA decay-induced exons from precursor mRNA and increases the amount of treated mRNA, which is then translated into higher levels of target proteins.

[0193] Figure 1C This is a schematic diagram of therapeutic ASO-mediated exclusion of nonsense-mediated mRNA decay-induced exons from precursor mRNA, which reduces nonproductive treated mRNA (e.g., with NMD exons) and increases productive mRNA (e.g., without NMD exons) and increases the expression of full-length target proteins from productive mRNA.

[0194] Figure 1D It shows SCN1A Identification of exemplary sequences in genes encoding nonsense-mediated mRNA decay (NMD)-induced exons. The use of comparative genomics is illustrated. SCN1A The sequence identification of exons encoding NMD in genes was visualized in the UCSC Genome Explorer. The top inset shows a scaled-down representation. SCN1A Graphical representation of the gene. Conservation levels across 100 vertebrate species are shown as peaks. The highest peak corresponds to exons (black boxes), while no peaks were observed in most introns (lines with arrows). A peak of conservation was identified in intron 20 (NM_006920) shown in the middle inset. Examination of conserved sequences identified a 64 bp exon-like sequence flanked by 3' and 5' splice sites (underlined sequences) (bottom inset, sequence highlighted in gray). The inclusion of this exon caused a box shift and introduced an premature stop codon in exon 21, making the transcript a target of NMD.

[0195] Figure 2The study design timeline for monitoring wild-type (WT) and Dravei syndrome (DS) mice is shown, along with the Kaplan-Meier survival curve, which shows the survival of DS and WT littermates monitored up to 14 weeks.

[0196] Figure 3 The experimental design for monitoring EEG seizures in DS mice and their WT littermates is shown.

[0197] Figures 4A-4E The results of monitoring seizures in mice administered ASO-22 or phosphate-buffered saline (PBS) are shown. Figure 4A An exemplary EEG record from a DS mouse is shown. Figure 4B The number of seizures occurring in various brain regions is shown in both mouse groups. *Indicates p < 0.05. Figure 4C The total number of spontaneous seizures (generalized and focal) recorded between P22 and P46 in DS mice administered PBS (n = 21) or ASO-22 (n = 21) was summarized. *Indicates p < 0.05. Figure 4D The number of mice that had multiple seizures in each group is shown. Figure 4E The effect of ASO-22 on the latency of the first recorded seizure between P22 and P46 in DS mice administered with PBS (n = 21) or ASO-22 (n = 21) is shown.

[0198] Figures 5A-5G This study demonstrated that a single ICV injection of 20 μg ASO-22 at P2 reduced the incidence of sudden epileptic death (SUDEP) and Na+ in DS mice. V 1.1 Increased protein expression. Figure 5A This is a schematic diagram of the experimental design. Figure 5B , 5C Figures 5D, 5E, 5F, and 5G represent the concentrations of ASO-22 in brain tissue at 7 or 14 weeks after a single ICV injection of ASO-22 (20 μg) or PBS at P2, respectively. Scn1a fold change in gene expression and Na V 1.1 Expression.

[0199] Figures 6A-6B The percentage of survival in DS and WT mice after a single ICV injection of ASO-22 (60 μg) or PBS at P14 is shown.

[0200] Figures 7A-7FThe ASO-22 exposure in brain tissue at P35 and P90 following a single ICV injection of ASO-22 (60 μg) or PBS at P14 is shown. Scn1a Expression and Na V 1.1 Expression.

[0201] Figure 8 The experimental conditions and the number of monkeys used in each group are shown.

[0202] Figures 9A-9B The levels of ASO-22 in different regions of the cynomolgus monkey brain were shown on days 3 and 29 of the study.

[0203] Figures 10A-10B The figures show the Na+ concentrations in different regions of the cynomolgus monkey brain on days 3 and 29 of the study. V 1.1 Protein levels.

[0204] Figures 11A-11B Productivity of the evaluation of target engagement in cynomolgus monkeys on days 3 and 29 is shown. SCN1A Genes relative to total SCN1A Percentage of genes.

[0205] Figure 12A Plasma pharmacokinetics in cynomolgus monkeys at different time points following intrathecal administration of ASO-22 are shown. Figure 12B The levels of ASO-22 in the cerebrospinal fluid (CSF) of cynomolgus monkeys were shown on days 3 and 29 of the study.

[0206] Figures 13A-13D Describes the generation of NMD SCN1A Identification of variable splicing events in [the context]. Figure 13A This illustrates the inclusion or exclusion of alternative exons in ReNcells. SCN1A Splicing homoisoforms, as confirmed by RT-PCR. Figure 13B The images show the cerebral cortex of four species. SCN1A Evaluation of gene alternative splicing events. Figure 13C The results show the amplification of total RNA extracted from the brains of WT C57BL / 6J mice at P0 to P20 and at 10 months. Scn1a Images of TBE PAGE gels of productive (bottom band, 498 bp) and non-productive transcripts (top band, 562 bp) corresponding to RT-PCR products. Mice... Gapdh Used as a sample loading control. Figure 13D A summary of the brain tissue of mice after birth Scn1a Expression of productive and non-productive transcripts, using Figure 13C The optical density of the PCR products shown is calculated.

[0207] Figures 14A-14E The selected ASO demonstrated that it suppressed NMD splicing events and increased productivity in ReNcell. SCN1A mRNA expression.

[0208] Figures 15A-15C The ASO-22 effect on ReN cells is shown. SCN1A The dose-dependent effects of mRNA splicing and expression.

[0209] Figures 16A-16H The study demonstrated that ASO-22 ICV injection induced productive activity in the mouse brain. Scn1a mRNA and Na V 1.1 Dose-dependent and sustained increase in protein expression.

[0210] Figure 17 The effects of ASO-22 on the brains of newborn mice injected with ICV were demonstrated. Scn1a Dose-dependent effects of mRNA expression (§ = nonproductive; * = productive).

[0211] Figure 18 This demonstrates the effect of ASO-22 on Na+ in the brains of newborn mice injected with ICV. V The dose-dependent effect of expression in 1.1.

[0212] Figure 19 The figures show the brain activity of mice at different days after injection. Scn1a mRNA expression (§ = nonproductive; * = productive).

[0213] Figure 20 The figure shows the Na levels in the mouse brain at different days after injection. V The expression in 1.1.

[0214] Figure 21 Two types of Na-resistant antibodies used in the examples are shown. V 1.1 Antibody validation. Using antibodies developed by... Scn1a - / - Total protein samples prepared from mouse brains (middle lane) and brains from two WT littermates (left and right lanes) were tested for two anti-Na antibodies. V 1.1 Specificity of antibodies Alomone ASC-001 and NeuroMab 75-023.

[0215] Figure 22A schematic diagram illustrating the clinical presentation and relative incidence of Dlaivide syndrome according to age is shown. AA: Atypical absent; AE: Acute encephalopathy; CG: Crouching gait; CPS: Complex partial seizures; DD: Developmental delay; DS: Dlaivide syndrome; EEG: Electroencephalogram; FSz: Complex febrile seizures; GMS: Generalized motor seizures; HS: Hyperthermia; m: Month; MSz: Myoclonic seizures; OS: Lethargic state; SE: Status epilepticus; SUDEP: Sudden epileptic death; y: Year; *60% of moderate fever is primarily clonic generalized and unilateral motor seizures; **AA and CPS are difficult to distinguish in the absence of sudden EEG recordings, therefore their precise incidence is unknown. See, for example, Gataullina and Dulac, 2017, the entire contents of which are incorporated herein by reference.

[0216] Figure 23 TANGO (targeted enhancement of nuclear gene output) is shown as a potential treatment for Delaware syndrome.

[0217] Figure 24 This demonstrates the transformative potential of TANGO technology in Delaware syndrome.

[0218] Figure 25 The study design is shown. It is a two-part, phase 1 / 2a open-label study conducted at approximately 20 sites in the United States.

[0219] Figure 26 A schematic diagram of the research design is shown.

[0220] Figure 27 The patient inclusion and exclusion criteria are shown.

[0221] Figure 28 The research evaluation is shown.

[0222] Figure 29 The effect of phosphate on the pH of the ASO-1 formulation is shown.

[0223] Figure 30 The self-buffering capacity of the oligonucleotide ASO-1 relative to pH is shown in the titrations at 33 mg / mL and 5 mg / mL.

[0224] Figure 31 The Fourier transform infrared spectroscopy (FTIR) readings are shown.

[0225] Figure 32 The scanning electron microscopy-energy dispersive X-ray spectroscopy (SEM-EDS) method is shown.

[0226] Figure 33These are representative photographs of fibrous particles present in the ASO formulation after 1 month and 3 months of storage at 25°C. This exemplary formulation contains 4.58 mM ASO-1, 1.4 mM CaCl2, 0.79 mM MgCl2, 3 mM KCl, 150 mM NaCl, 0.70 mM Na2HPO4·2H2O, and 0.3 mM NaH2PO4·2H2O at pH 7.0 to 7.5.

[0227] Figure 34 These are representative photographs of large waxy flakes observed in stability tests of formulations containing 4.58 mM ASO₄⁻, 1.4 mM CaCl₂, 0.79 mM MgCl₂, 3 mM KCl, 0.70 mM Na₂HPO₄·2H₂O, and 0.3 mM NaH₂PO₄·2H₂O; or containing 4.58 mM ASO₄⁻, 1.4 mM CaCl₂, 0.79 mM MgCl₂, 3 mM KCl, 150 mM NaCl, 0.70 mM Na₂HPO₄·2H₂O, and 0.3 mM NaH₂PO₄·2H₂O without pH adjustment. These large waxy flakes were present under all stability conditions (2–8 °C; 25 °C / 60% RH; and 40 °C / 75% RH). Detailed Implementation

[0228] Certain specific details have been set forth in this specification to provide a thorough understanding of the various embodiments. However, those skilled in the art will understand that this disclosure can be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments.

[0229] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. While methods and materials similar to or equivalent to those described herein may be used to practice or test this disclosure, suitable methods and materials are described below.

[0230] Definitions As used in this specification and the appended claims, unless the context clearly indicates otherwise, the singular forms “an,” “an,” and “the” include plural references.

[0231] It should be noted that, unless the context explicitly indicates otherwise, the term “or” is generally used to include the meaning of “and / or”. As used herein, the terms “and / or” and “any combination thereof” and their grammatical equivalents are used interchangeably. These terms can convey a specific consideration of any combination. For illustrative purposes only, the phrases “A, B and / or C” or “A, B, C or any combination thereof” can mean “A alone; B alone; C alone; A and B; B and C; A and C; and A, B and C.” The term “or” can be used together or separately unless the context specifically indicates separate use.

[0232] The terms "about" or "approximately" can mean within an acceptable margin of error for a particular value, as determined by a person skilled in the art, which will depend in part on how the value was measured or determined, i.e., the limitations of the measurement system. For example, according to practice in the art, "about" can mean within one or more standard deviations. Alternatively, "about" can mean a range of up to 20%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, particularly for biological systems or processes, the term can mean within orders of magnitude of the value, i.e., within 5 times, and more preferably within 2 times. When specific values ​​are described in this application and claims, unless otherwise indicated, it should be assumed that the term "about" means within an acceptable margin of error for the specific value.

[0233] As used in this specification and one or more claims, the terms “comprising” (and any form of inclusion, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of inclusion, such as “includes” and “include”), or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional unlisted elements or method steps. It is contemplated that any embodiments discussed in this specification can be implemented with respect to any method or composition of this disclosure, and vice versa. Furthermore, the compositions of this disclosure can be used to implement the methods of this disclosure.

[0234] In this specification, references to "embodiment," "some embodiments," "an embodiment," "one embodiment," "certain embodiments," or "other embodiments" indicate that a particular feature, structure, or characteristic described in connection with the embodiments is included in at least some embodiments, but not necessarily all embodiments of this disclosure. To facilitate understanding of this disclosure, several terms and phrases are defined below.

[0235] The terms “oligonucleotide sequence,” “nucleic acid sequence,” “polynucleotide sequence,” “nucleotide sequence,” and “nucleotide sequence” are used interchangeably in the broadest sense herein and have the same meaning herein, and preferably refer to DNA or RNA. A nucleic acid sequence is a sequence comprising nucleotide monomers or polymers composed of nucleotide monomers covalently linked to each other by phosphodiester bonds of a sugar / phosphate backbone. The term “nucleic acid sequence” also encompasses modified nucleic acid sequences, such as DNA or RNA modified by base modifications, sugar modifications, or backbone modifications.

[0236] The term "fragment" or "fragment of sequence," which has the same meaning herein, refers, for example, a shorter portion of the full-length sequence of a nucleic acid molecule or protein, such as DNA or RNA. Thus, a fragment typically consists of a sequence identical to its corresponding segment within the full-length sequence. In the context of this invention, a preferred fragment of a sequence consists of a contiguous segment entity, such as a nucleotide or amino acid corresponding to a contiguous segment entity in the molecule from which the fragment originates, said contiguous segment entity representing at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, at least 99.5%, or even 100% of the total (i.e., full-length) molecule from which the fragment originates. For example, a "fragment" or "functional fragment" of a polynucleotide or polypeptide is a fragment of a polynucleotide or polypeptide shorter than the full length, immature or mature, and having at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, at least 99.5%, or even 100% or more of the activity of a full-length mature reference polynucleotide or polypeptide. The fragment of interest can be prepared by recombinant, synthetic, or digestive methods.

[0237] When used in relation to, for example, cells, nucleic acids, proteins, or vectors, the term "recombinant" indicates that the cell, nucleic acid, protein, or vector has been modified by laboratory methods or is the result of laboratory methods. Thus, for example, the term "recombinant polynucleotide" can refer to a polynucleotide that is not naturally occurring and is synthesized or manipulated in vitro, such as a polynucleotide produced by laboratory methods. Recombinant polynucleotides can be synthesized in the laboratory and / or prepared by using recombinant DNA techniques through enzymatic modification of DNA, such as enzyme restriction digestion, ligation, and cloning. Recombinant polypeptides can be prepared by in vitro transcription of recombinant DNA, followed by in vitro translation of the resulting messenger RNA (mRNA). Alternatively, under suitable conditions, recombinant polynucleotides or RNA can be incorporated into cells, and recombinant polypeptides can be expressed intracellularly. Recombinant proteins may include amino acid residues not found in the native (non-recombinant) form of the protein, or may include modified, for example, labeled amino acid residues.

[0238] The term "isolated" means separated from components such as cells, where polynucleotides, polypeptides, proteins, or fragments thereof are normally associated with said components in nature. For example, with respect to polynucleotides, an isolated polynucleotide is a polynucleotide separated from the 5' and 3' ends to which the polynucleotide normally associates in its naturally occurring sequence. As will be apparent to those skilled in the art, non-natural polynucleotides, polypeptides, proteins, or fragments thereof do not require "isolation" to distinguish them from their naturally occurring counterparts. Furthermore, "concentrated," "isolated," or "diluted" polynucleotides, polypeptides, proteins, or fragments thereof are distinguishable from their naturally occurring counterparts because their concentration or number of molecules per volume is greater than or less than that of their naturally occurring counterparts.

[0239] As used herein, “nucleotide” means a nucleoside that further comprises a phosphate ester linking group. As used herein, “linked nucleosides” may be linked by a phosphate ester bond or may not be linked by a phosphate ester bond, and therefore include, but are not limited to, “linked nucleotides”. As used herein, “linked nucleosides” are nucleosides linked in a continuous sequence (i.e., there are no other nucleosides between those linked).

[0240] As used herein, "nucleobase" refers to a set of atoms that can be linked to a sugar moiety to produce a nucleoside that can be incorporated into an oligonucleotide, and wherein said set of atoms can bond to a complementary, naturally occurring nucleobase of another oligonucleotide or nucleic acid. Nucleobases may be naturally occurring or modified.

[0241] As used herein, "nucleoside" refers to a compound comprising a nucleobase moiety and a sugar moiety. Nucleosides include, but are not limited to, naturally occurring nucleosides (such as those found in DNA and RNA) and modified nucleosides. Nucleosides may be linked to a phosphate moiety.

[0242] As used in this article, “naturally occurring sugar moieties” means, for example, riboflavin found in naturally occurring RNA or riboflavin found in naturally occurring DNA.

[0243] As used in this article, "sugar moiety" refers to the naturally occurring sugar moiety of a nucleoside or the modified sugar moiety.

[0244] As used in this article, "modified sugar moiety" means a substituted sugar moiety, a bicyclic or tricyclic sugar moiety, or a sugar substitute.

[0245] As used herein, the term "antisense oligonucleotide" refers to a synthetic antinucleotide oligonucleotide (ASO) or antisense oligonucleotide analogue, typically between 12 and 30 nucleotides in length, designed to hybridize with RNA via Watson-Crick base pairing. ASOs can be programmed to bind to both protein-coding RNAs (mRNAs) and non-coding RNAs, such as microRNAs or large non-coding RNAs. Upon binding to a target RNA, ASOs can modulate the function of the target RNA through several different mechanisms, including degradation of precursor mRNA in the nucleus or mature RNA in the cytoplasm by RNase H1, and degradation of cytoplasmic RNA by the RISC complex (Ago2) or by ribozymes or DNases. ASOs can also modulate RNA function through non-degradation mechanisms, such as splicing or polyadenylation in the nucleus, and regulate protein translation in the cytoplasm.

[0246] The term "hybridization" refers to the formation of hydrogen bonds between complementary nucleosides or nucleotide bases, which can be formed through Watson-Crick, Hoogsteen, or reverse Hoogsteen hydrogen bonding. As used herein, "complementarity" refers to the ability of two nucleotides to pair precisely. Oligonucleotides and DNA or RNA are complementary when a sufficient number of corresponding positions in each molecule are occupied by nucleotides that can hydrogen bond with each other.

[0247] In the context of two or more nucleic acid or polypeptide sequences, the term "identical" or "percentage of identity" refers to two or more sequences or subsequences that are identical or have a specified percentage of identical nucleotide or amino acid residues when compared and aligned against the maximum correspondence in a comparison window or designated region (i.e., 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, 99.5%, 99.8%, 99.9%, or 100% identity, for example, in a designated region of a single domain of the polypeptide of the present invention, such as using sequence comparison algorithms or by manual alignment and visual inspection). Such sequences that are at least about 80% identical are referred to as "substantially identical." In some embodiments, the two sequences are 100% identical. In some embodiments, the two sequences are identical in one sequence (…). For example The sequence (where the shorter of two sequences of different lengths) is 100% identical over its entire length. In various embodiments, identity may refer to the complementary sequence of the test sequence.

[0248] In some embodiments, the identity exists in a region having a length of at least about 2 to about 400 amino acids or nucleotides. In some embodiments, the identity exists in a region having a length of at least about 2 to about 390, at least about 2 to about 380, at least about 2 to about 370, at least about 2 to about 360, at least about 2 to about 350, at least about 2 to about 340, at least about 2 to about 330, at least about 2 to about 320, at least about 2 to about 310, at least about 2 to about 300, at least about 2 to about 290, at least about 2 to about 280, at least about 2 to about 270, at least about 2 to about 260, at least about 2 to about 250, at least about 2 to about 200, at least about 2 to about 150, or at least about 2 to about 100 amino acids or nucleotides. In some embodiments, the identity exists in a region of length of at least about 2 to about 90, at least about 2 to about 85, at least about 2 to about 80, at least about 2 to about 75, at least about 2 to about 70, at least about 2 to about 65, at least about 2 to about 60, at least about 2 to about 55, at least about 2 to about 50, at least about 2 to about 45, at least about 2 to about 40, at least about 2 to about 35, at least about 2 to about 30, at least about 2 to about 25, at least about 2 to about 20, at least about 2 to about 10, or at least about 2 to about 5 amino acids or nucleotides.

[0249] In some embodiments, the identity exists in lengths of at least about 3 to about 400, about 4 to about 400, about 5 to about 400, about 6 to about 400, about 7 to about 400, about 8 to about 400, about 9 to about 400, about 10 to about 400, about 11 to about 400, about 12 to about 400, about 13 to about 400, about 14 to about 400, about 15 to about 400, about 16 to about 400, about 17 to about 400, about 18 to about 400, about 19 On a region containing approximately 400 amino acids or nucleotides, approximately 20 to approximately 400, approximately 21 to approximately 400, approximately 22 to approximately 400, approximately 23 to approximately 400, approximately 24 to approximately 400, approximately 25 to approximately 400, approximately 26 to approximately 400, approximately 27 to approximately 400, approximately 28 to approximately 400, approximately 29 to approximately 400, approximately 30 to approximately 400, approximately 31 to approximately 400, approximately 32 to approximately 400, approximately 33 to approximately 400, approximately 34 to approximately 400, approximately 35 to approximately 400. In some embodiments, the identity exists in lengths of at least about 40 to about 400, about 45 to about 400, about 50 to about 400, about 55 to about 400, about 60 to about 400, about 61 to about 400, about 62 to about 400, about 63 to about 400, about 64 to about 400, about 65 to about 400, about 66 to about 400, about 67 to about 400, about 68 to about 400, about 69 to about 400, about 70 On a region containing approximately 400 amino acids or nucleotides, approximately 71 to approximately 400, approximately 72 to approximately 400, approximately 73 to approximately 400, approximately 74 to approximately 400, approximately 75 to approximately 400, approximately 80 to approximately 400, approximately 85 to approximately 400, approximately 90 to approximately 400, approximately 100 to approximately 400, approximately 150 to approximately 400, approximately 200 to approximately 400, approximately 250 to approximately 400, approximately 300 to approximately 400, approximately 350 to approximately 400.

[0250] In some embodiments, the identity exists in lengths of at least about 2 to about 343, about 3 to about 343, about 4 to about 343, about 7 to about 343, about 9 to about 343, about 11 to about 343, about 15 to about 343, about 16 to about 343, about 20 to about 343, about 25 to about 343, about 62 to about 343, about 2 to about 317, about 3 to about 317, about 4 to about 317, about 7 to about 317, about 9 to about 317, about 11 to about 317, about 15 to about 317, about 16 to about 317, about 20 to about 317, about 25 to about On a region of 317, about 62 to about 317, about 2 to about 300, about 3 to about 300, about 4 to about 300, about 7 to about 300, about 9 to about 300, about 11 to about 300, about 15 to about 300, about 16 to about 300, about 20 to about 300, about 25 to about 300, about 62 to about 300, about 2 to about 62, about 3 to about 62, about 4 to about 62, about 7 to about 62, about 9 to about 62, about 11 to about 62, about 15 to about 62, about 16 to about 62, about 20 to about 62, about 25 to about 62 amino acids or nucleotides.

[0251] The term "genetically modified" means containing and / or expressing a foreign gene or nucleic acid sequence that subsequently modifies the genotype or phenotype of a cell or its progeny. In other words, the term refers to any addition, deletion, or disruption of endogenous nucleotides in a cell.

[0252] The term "operably linked" can refer to a functional relationship between two or more nucleic acid sequences, such as a transcriptional regulatory or signal sequence-transcriptional relationship. For example, if a target motif or nucleic acid encoding a target motif is expressed as a preprotein involved in targeting a polypeptide encoded by a coding sequence to a cell membrane, intracellular, or extracellular compartment, then the target motif or nucleic acid encoding the target motif is operably linked to the coding sequence. Similarly, if a signal peptide or nucleic acid encoding a signal peptide is expressed as a preprotein involved in the secretion of a polypeptide encoded by a coding sequence, then the signal peptide or nucleic acid encoding the signal peptide is operably linked to the coding sequence. Furthermore, if a promoter stimulates or regulates transcription of a coding sequence, then the promoter is operably linked.

[0253] The terms “subject” or “patient” encompass vertebrates or mammals. Examples of mammals include, but are not limited to, any member of the mammal class: humans, non-human primates such as chimpanzees and other ape and monkey species; farm animals such as cattle, horses, sheep, goats, pigs, etc.; domesticated animals such as rabbits, dogs, and cats, etc.; and laboratory animals, including rodents such as rats, mice, and guinea pigs. On one hand, mammals are humans. As used herein, the term “animal” includes both human and non-human animals. In one embodiment, a “non-human animal” is a mammal, for example, a rodent such as a rat or mouse. In one embodiment, a non-human animal is a mouse.

[0254] A "control" is a substitute subject or sample used in an experiment for comparative purposes. A control can be "positive" or "negative".

[0255] Pharmaceutical composition On the one hand, this article provides a pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition comprising: (i) an antisense oligomer (ASO), and (ii) a pharmaceutically acceptable diluent; wherein the liquid composition is not buffered by a buffer; and wherein: (a) the liquid composition comprises calcium ions, magnesium ions and / or potassium ions, (b) the pharmaceutical formulation is formulated for or suitable for administration to the intrathecal space, cerebrospinal fluid or brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

[0256] In some embodiments, the pharmaceutical formulation is a liquid composition comprising: (i) an antisense oligomer (ASO) and (ii) a pharmaceutically acceptable diluent, wherein the ASO is stable in the pharmaceutical formulation for at least 1 or 2 years at 4°C.

[0257] In some embodiments, (a) the liquid composition comprises calcium ions, magnesium ions and / or potassium ions, (b) the pharmaceutical formulation is formulated for or suitable for administration into the intrathecal space, cerebrospinal fluid or brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

[0258] On the other hand, this document also provides a pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition comprising: (i) an antisense oligomer (ASO), and (ii) a pharmaceutically acceptable diluent; wherein the liquid composition is deficient in Na2HPO4 and / or NaH2PO4; and wherein: (a) the liquid composition contains calcium ions, magnesium ions and / or potassium ions, (b) the pharmaceutical formulation is formulated for or suitable for administration to the intrathecal space, cerebrospinal fluid or brain of a human subject, and / or (c) each nucleobase of the ASO contains a modified sugar moiety.

[0259] In some embodiments, the liquid composition is deficient in phosphate ions.

[0260] In some embodiments, the liquid composition comprises calcium ions, magnesium ions, and / or potassium ions.

[0261] On the other hand, this article also provides a pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition comprising: (i) an antisense oligomer (ASO), and (ii) a pharmaceutically acceptable diluent consisting of: a) NaCl, b) KCl, c) MgCl2 or MgCl2 6H2O, and d) CaCl2 or CaCl2 2H2O.

[0262] In some embodiments, the liquid composition comprises 0.1-50 mM CaCl2 or CaCl2 2H2O.

[0263] In some embodiments, the liquid composition comprises 1-2 mM CaCl2 or CaCl2 2H2O.

[0264] In some embodiments, the liquid composition comprises about 1.4 mM CaCl2 or CaCl2 2H2O.

[0265] In some embodiments, the liquid composition comprises 0.1-50 mM MgCl2 or MgCl2 6H2O.

[0266] In some embodiments, the liquid composition comprises 0.5-1.5 mM MgCl2 or MgCl2 6H2O.

[0267] In some embodiments, the liquid composition comprises about 0.79 mM MgCl2 or MgCl2 6H2O.

[0268] In some embodiments, the liquid composition comprises 5-250 mM NaCl, 0.1-20 mM KCl, 0.1-50 mM CaCl2 or CaCl2 2H2O, and 0.1-50 mM MgCl2 or MgCl2 6H2O.

[0269] On the other hand, this document also provides a pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition comprising: (i) an antisense oligomer (ASO), and (ii) a pharmaceutically acceptable diluent; wherein the liquid composition is deficient in calcium and / or magnesium ions; and wherein: (a) the liquid composition contains potassium ions, (b) the pharmaceutical formulation is formulated for or suitable for administration to the intrathecal space, cerebrospinal fluid, or brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

[0270] In some embodiments, the liquid composition is formulated for application to the intrathecal space, cerebrospinal fluid, or brain of a human subject.

[0271] In some embodiments, the liquid composition is formulated for application to the cerebrospinal fluid in the brain of a human subject.

[0272] In some embodiments, the ASO comprises at least one modified sugar moiety.

[0273] In some embodiments, each nucleotide of the antisense oligomer contains a modified sugar moiety.

[0274] On the other hand, this document also provides a kit comprising: (i) a concentrate comprising an antisense oligomer (ASO); and (ii) a pharmaceutically acceptable diluent, wherein the concentrate is miscible with the pharmaceutically acceptable diluent; and wherein mixing the ASO with the pharmaceutically acceptable diluent produces a liquid composition comprising the ASO, and wherein the liquid composition is not buffered by a buffer; and wherein: (a) the liquid composition comprises calcium ions, magnesium ions and / or potassium ions, (b) the pharmaceutical formulation is formulated for or suitable for administration to the intrathecal space, cerebrospinal fluid or brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

[0275] In some embodiments, the kit comprises: (i) a concentrate containing an antisense oligomer (ASO); and (ii) a pharmaceutically acceptable diluent, wherein the concentrate is miscible with the pharmaceutically acceptable diluent; and wherein mixing the ASO with the pharmaceutically acceptable diluent produces a liquid composition containing the ASO, and wherein the ASO is stable in the liquid composition at 4°C for at least 1 or 2 years.

[0276] In some embodiments, (a) the liquid composition comprises calcium ions, magnesium ions and / or potassium ions, (b) the pharmaceutical formulation is formulated for or suitable for administration into the intrathecal space, cerebrospinal fluid or brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

[0277] In some embodiments, the kit comprises: (i) a concentrate comprising an antisense oligomer (ASO); and (ii) a pharmaceutically acceptable diluent, wherein the concentrate is miscible with the pharmaceutically acceptable diluent; and wherein mixing the ASO with the pharmaceutically acceptable diluent produces a liquid composition comprising the ASO, wherein the liquid composition is deficient in Na2HPO4 and / or NaH2PO4; and wherein: (a) the liquid composition comprises calcium, magnesium, and / or potassium ions, (b) the pharmaceutical formulation is formulated for or suitable for administration to the intrathecal space, cerebrospinal fluid, or brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

[0278] In some embodiments, the liquid composition is deficient in phosphate ions.

[0279] In some embodiments, the liquid composition comprises calcium ions, magnesium ions, and / or potassium ions.

[0280] In some embodiments, the kit comprises: (i) a concentrate comprising an antisense oligomer (ASO); and (ii) a pharmaceutically acceptable diluent comprising: a) NaCl, b) KCl, c) MgCl2 or MgCl2 6H2O, and d) CaCl2 or CaCl2 2H2O, wherein the concentrate is miscible with the pharmaceutically acceptable diluent; and wherein mixing the ASO with the pharmaceutically acceptable diluent produces a liquid composition comprising the ASO.

[0281] In some embodiments, the kit comprises: (i) a concentrate comprising an antisense oligomer (ASO); and (ii) a pharmaceutically acceptable diluent, wherein the concentrate is miscible with the pharmaceutically acceptable diluent; wherein mixing the ASO with the pharmaceutically acceptable diluent produces a liquid composition comprising the ASO, wherein the liquid composition is deficient in calcium and / or magnesium ions; and wherein: (a) the liquid composition comprises potassium ions, (b) the pharmaceutical formulation is formulated for or suitable for administration to the intrathecal space, cerebrospinal fluid, or brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

[0282] In some embodiments, the liquid composition is formulated for application to the intrathecal space, cerebrospinal fluid, or brain of a human subject.

[0283] In some embodiments, the liquid composition is formulated for application to the cerebrospinal fluid in the brain of a human subject.

[0284] In some embodiments, the ASO comprises at least one modified sugar moiety.

[0285] In some embodiments, each nucleotide of the antisense oligomer contains a modified sugar moiety.

[0286] In some embodiments, the kit further includes (iii) instructions for diluting or dissolving the ASO in a pharmaceutically acceptable diluent.

[0287] In some embodiments, the liquid composition contains 25-250 mM NaCl.

[0288] In some embodiments, the liquid composition contains 0.1-20 mM KCl.

[0289] In some embodiments, the liquid composition contains 2-4 mM KCl.

[0290] In some embodiments, the liquid composition contains about 3 mM KCl.

[0291] In some embodiments, the liquid composition contains 100-160 mM NaCl.

[0292] In some embodiments, the liquid composition contains 125-145 mM NaCl.

[0293] In some embodiments, the liquid composition contains about 130 mM NaCl.

[0294] In some embodiments, the liquid composition comprises a buffer (pH 6.6-7.6) solution.

[0295] In some embodiments, the liquid composition contains 0.1-50 mM Na2HPO4.

[0296] In some embodiments, the liquid composition contains 0.1-50 mM NaH2PO4.

[0297] In some embodiments, the liquid composition comprises 5-250 mM NaCl, 0.1-20 mM KCl, 0.1-50 mM Na2HPO4, and 0.1-50 mM NaH2PO4.

[0298] In some embodiments, the ASO is dissolved in a pharmaceutically acceptable diluent.

[0299] In some embodiments, the pharmaceutically acceptable diluent is an isotonic solution.

[0300] In some embodiments, the ASO is not substantially multidistributed.

[0301] In some embodiments, the osmotic pressure of the liquid composition is less than 150 mM.

[0302] In some embodiments, the osmotic pressure of the liquid composition is about 130 mM.

[0303] In some embodiments, the liquid composition further comprises carbohydrates.

[0304] In some embodiments, the carbohydrate comprises D-glucose.

[0305] In some embodiments, the liquid composition further comprises 1-100 mM D-glucose.

[0306] In some embodiments, the liquid composition further comprises an antioxidant.

[0307] In some embodiments, the antioxidant is tert-butylhydroxyquinoline (TBHQ), butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E, or any combination thereof.

[0308] In some embodiments, ASO as described herein is dissolved or diluted in an artificial cerebrospinal fluid (aCSF) solution. In some embodiments, ASO as described herein is dissolved or diluted in an isotonic solution.

[0309] As used herein, the term "artificial cerebrospinal fluid (aCSF)" refers to a biological buffer solution commonly used as a mediator solution for administering drugs to the central nervous system (CNS). For example, aCSF closely matches the electrolyte concentration and physiological compatibility of endogenous CSF to achieve an important environment for neuronal tissue by maintaining homeostasis, osmotic pressure, and pH at physiological levels.

[0310] As used herein, the term "isotonic solution" refers to a solution containing an electrolyte balance similar to that of plasma in the bloodstream. Administration of an isotonic solution to a subject or patient increases the fluid volume of the subject or patient without fluid displacement. Exemplary isotonic solutions include, but are not limited to, 0.9% saline, Ringer's solution, plasma-lyte, and 5% dextran / water (D5W).

[0311] As used herein, the term "hypotonic solution" refers to a solution in which the concentration of electrolytes is lower than that in plasma. For example, intravenous administration of a hypotonic solution can divert fluid from the bloodstream to areas of higher concentration in the interstitial and intracellular spaces. Exemplary hypotonic solutions include, but are not limited to, 0.45% physiological saline (semi-physiological saline), 0.33% NaCl solution, 0.225% NaCl solution, and 2.5% dextrose / water (D... 2.5 W).

[0312] As used herein, the term "hypertonic solution" refers to a solution in which the concentration of electrolytes is higher than that of plasma. For example, intravenous administration of a hypertonic solution can divert fluid from the interstitial and intracellular spaces into the bloodstream to dilute electrolytes. Exemplary hypertonic solutions include, but are not limited to, 3% NaCl solution, 5% dextrose / 0.45% NaCl (D5 ½ NS), 5% dextrose / 0.9% normal saline (D5NS), 5% dextrose / lactated Ringer's solution (D5LR), and 10% dextrose / water (D5NS). 10 W), 20% dextrose / water (D) 20 W) and 50% dextrose / water (D) 50 W).

[0313] In some embodiments, ASO as described herein is dissolved or diluted in a phosphate buffer solution (pH 6.6–7.6). In some embodiments, ASO as described herein is dissolved or diluted in a phosphate buffer solution (pH 6.0–8.0). In some embodiments, ASO as described herein is dissolved or diluted in a phosphate buffer solution (pH 5.0–8.0). In some embodiments, as described herein, ASO is dissolved or diluted at pH 4.5–8.5, pH 4.6–8.5, pH 4.7–8.5, pH 4.8–8.5, pH 4.9–8.5, pH 5.0–8.5, pH 5.1–8.5, pH 5.2–8.5, pH 5.3–8.5, pH 5.4–8.5, pH 5.5–8.5, pH 5.6–8.5, pH 5.7–8.5, pH 5.8–8.5, pH 5.9–8.5, pH 6.0–8.5, pH 6.1–8.5, pH 6.2–8.5, pH 6.3–8.5, pH 6.4–8.5, pH 6.5–8.5, pH 6.6–8.5, pH 6.7–8.5, pH In phosphate buffer solutions with pH values ​​of 6.8-8.5, 6.9-8.5, 7.0-8.5, 7.1-8.5, 7.2-8.5, 7.3-8.5, 7.4-8.5, 7.5-8.5, 7.6-8.5, 7.7-8.5, 7.8-8.5, 7.9-8.5, 8.0-8.5, 8.1-8.5, 8.2-8.5, 8.3-8.5, or 8.4-8.5.In some embodiments, as described herein, ASO is dissolved or diluted at pH 4.5–8.3, pH 4.5–8.2, pH 4.5–8.1, pH 4.5–8.0, pH 4.5–7.9, pH 4.5–7.8, pH 4.5–7.7, pH 4.5–7.6, pH 4.5–7.5, pH 4.5–7.4, pH 4.5–7.3, pH 4.5–7.2, pH 4.5–7.1, pH 4.5–7.0, pH 4.5–6.9, pH 4.5–6.8, pH 4.5–6.7, pH 4.5–6.6, pH 4.5–6.5, pH 4.5–6.4, pH 4.5–6.3, pH 4.5–6.2, pH 4.5–6.1, pH In phosphate buffer solutions with pH values ​​of 4.5-6.0, 4.5-5.9, 4.5-5.8, 4.5-5.7, 4.5-5.6, 4.5-5.5, 4.5-5.4, 4.5-5.3, 4.5-5.2, 4.5-5.1, 4.5-5.0, 4.5-4.9, 4.5-4.8, 4.5-4.7, or 4.5-4.6. In some embodiments, as described herein, ASO is dissolved or diluted in phosphate buffer solutions at pH 6.0–7.6, pH 6.1–7.6, pH 6.2–7.6, pH 6.3–7.6, pH 6.4–7.6, pH 6.5–7.6, pH 6.6–7.6, pH 6.7–7.6, pH 6.8–7.6, pH 6.9–7.6, pH 7.0–7.6, pH 7.1–7.6, pH 7.2–7.6, pH 7.3–7.6, pH 7.4–7.6, or pH 7.5–7.6. In some embodiments, as described herein, ASO is dissolved or diluted in phosphate buffer solutions at pH 6.6–8.0, pH 6.6–7.9, pH 6.6–7.8, pH 6.6–7.7, pH 6.6–7.6, pH 6.6–7.5, pH 6.6–7.4, pH 6.6–7.3, pH 6.6–7.2, pH 6.6–7.1, pH 6.6–7.0, pH 6.6–6.9, pH 6.6–6.8, or pH 6.6–6.7.In some embodiments, as described herein, ASO is dissolved or diluted in phosphate buffer solutions at pH 6.0–8.0, pH 6.1–8.0, pH 6.2–8.0, pH 6.3–8.0, pH 6.4–8.0, pH 6.5–8.0, pH 6.6–8.0, pH 6.7–8.0, pH 6.8–8.0, pH 6.9–8.0, pH 7.0–8.0, pH 7.1–8.0, pH 7.2–8.0, pH 7.3–8.0, pH 7.4–8.0, pH 7.5–8.0, pH 7.6–8.0, pH 7.7–8.0, pH 7.8–8.0, or pH 7.9–8.0. In some embodiments, as described herein, ASO is dissolved or diluted in phosphate buffer solutions at pH 6.0–7.9, pH 6.0–7.8, pH 6.0–7.7, pH 6.0–7.6, pH 6.0–7.5, pH 6.0–7.4, pH 6.0–7.3, pH 6.0–7.2, pH 6.0–7.1, pH 6.0–7.0, pH 6.0–6.9, pH 6.0–6.8, pH 6.0–6.7, pH 6.0–6.6, pH 6.0–6.5, pH 6.0–6.4, pH 6.0–6.3, pH 6.0–6.2, or pH 6.0–6.1. In some embodiments, ASO as described herein is dissolved or diluted in a phosphate buffer solution with pH 5.7–8.5, 5.8–8.4, 5.9–8.3, 6.0–8.2, 6.1–8.1, 6.2–8.0, 6.3–7.9, 6.4–7.8, 6.5–7.7, or 6.6–7.6. In some embodiments, ASO as described herein is dissolved or diluted in a phosphate buffer solution with pH about 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or 8.0. In some embodiments, as described herein, ASO is dissolved or diluted in a phosphate buffer solution at pH 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or 8.0.

[0314] In some embodiments, ASO, as described herein, is dissolved or diluted in a buffer solution containing 25-250 mM NaCl.

[0315] In some embodiments, as described herein, ASO is dissolved or diluted in solutions containing 25-250 mM, 30-250 mM, 35-250 mM, 40-250 mM, 45-250 mM, 50-250 mM, 55-250 mM, 60-250 mM, 65-250 mM, 70-250 mM, 75-250 mM, 80-250 mM, 85-250 mM, 90-250 mM, 95-250 mM, 100-250 mM, 105-250 mM, 110-250 mM, 115-250 mM, 120-250 mM, 125-250 mM, 130-250 mM, 135-250 mM, 140-250 mM, 145 ... 210-250 mM 215-250mM, 220-250mM, 225-250mM, 230-250mM, 235-250mM, 240-250mM or 245-250mMNaCl. In some embodiments, as described herein, ASO is dissolved or diluted in solutions containing 25-245 mM, 25-240 mM, 25-235 mM, 25-230 mM, 25-225 mM, 25-220 mM, 25-215 mM, 25-210 mM, 25-205 mM, 25-200 mM, 25-195 mM, 25-190 mM, 25-185 mM, 25-180 mM, 25-175 mM, 25-170 mM, 25-165 mM, 25-160 mM, 25-155 mM, 25-150 mM, 25-145 mM, 25-140 mM, 25-135 mM, 25-130 mM, 25-125 mM, 25-120 ... mm, 25-115 mm, 25-110 mm, 25-105 mm, 25-110 mm, 25-105 mm, 25-100 mm, 25-95 mm, 25-90 mm, 25-85 mm, 25-80 mm, 25-75 mm, 25-70 mm, 25-65 mm, 25-60 25-55mM, 25-50mM, 25-45mM, 25-40mM, 25-35mM or 25-30mM NaCl.In some embodiments, as described herein, ASO is dissolved or diluted in a buffer solution containing 30-245 mM, 35-240 mM, 40-235 mM, 45-230 mM, 50-225 mM, 55-220 mM, 60-215 mM, 65-210 mM, 70-205 mM, 75-200 mM, 80-195 mM, 85-190 mM, 90-185 mM, 95-180 mM, 100-175 mM, 105-170 mM, 110-165 mM, 115-160 mM, 120-155 mM, 125-150 mM, 130-145 mM, or 135-140 mM NaCl. In some embodiments, as described herein, ASO is dissolved or diluted in solutions containing 100-140 mM, 101-140 mM, 102-140 mM, 103-140 mM, 104-140 mM, 105-140 mM, 106-140 mM, 107-140 mM, 108-140 mM, 109-140 mM, 110-140 mM, 111-140 mM, 112-140 mM, 113-140 mM, 114-140 mM, 115-140 mM, 116-140 mM, 117-140 mM, 118-140 mM, 119-140 mM, 120-140 mM, 121-140 mM, 122-140 mM, etc. Buffers of NaCl at mM, 123-140 mM, 124-140 mM, 125-140 mM, 126-140 mM, 127-140 mM, 128-140 mM, 129-140 mM, 130-140 mM, 131-140 mM, 132-140 mM, 133-140 mM, 134-140 mM, 135-140 mM, 136-140 mM, 137-140 mM, 138-140 mM, or 139-140 mM.In some embodiments, as described herein, ASO is dissolved or diluted in amounts comprising 100-139 mM, 100-138 mM, 100-137 mM, 100-136 mM, 100-135 mM, 100-134 mM, 100-133 mM, 100-132 mM, 100-131 mM, 100-130 mM, 100-129 mM, 100-128 mM, 100-127 mM, 100-126 mM, 100-125 mM, 100-124 mM, 100-123 mM, 100-122 mM, 100-121 mM, 100-120 mM, 100-119 mM, 100-118 mM, 100-117 mM, etc. 100-116 mM, 100-115 mM, 100-114 mM, 100-113 mM, 100-112 mM, 100-111 mM, 100-110 mM, 100-109 mM, 100-108 mM, 100-107 mM, 100-106 mM, 100-105 mM, 100-104 100-103 mM, 100-102 mM or 100-101 mM NaCl in buffer. In some embodiments, as described herein, ASO is dissolved or diluted in a solution containing at least 90 mM, 91 mM, 92 mM, 93 mM, 94 mM, 95 mM, 96 mM, 97 mM, 98 mM, 99 mM, 100 mM, 101 mM, 102 mM, 103 mM, 104 mM, 105 mM, 106 mM, 107 mM, 108 mM, 109 mM, 110 mM, 111 mM, 112 mM, 113 mM, 114 mM, 115 mM, 116 mM, 118 mM, 119 mM, 120 mM, 121 mM, 122 mM, 123 mM, 124 mM, 125 mM, 126 mM, 127 mM, 128 mM, 129 mM, 130 mM, 131 mM, or 131 mM. In a buffer solution of NaCl at mM, 132mM, 133mM, 134mM, 135mM, 136mM, 137mM, 138mM, 139mM or 140mM.In some embodiments, as described herein, ASO is dissolved or diluted in solutions containing up to 90 mM, 91 mM, 92 mM, 93 mM, 94 mM, 95 mM, 96 mM, 97 mM, 98 mM, 99 mM, 100 mM, 101 mM, 102 mM, 103 mM, 104 mM, 105 mM, 106 mM, 107 mM, 108 mM, 109 mM, 110 mM, 111 mM, 112 mM, 113 mM, 114 mM, 115 mM, 116 mM, 118 mM, 119 mM, 120 mM, 121 mM, 122 mM, 123 mM, 124 mM, 125 mM, 126 mM, 127 mM, 128 mM, 129 mM, 130 mM, or more. In a buffer solution of NaCl at mM, 131 mM, 132 mM, 133 mM, 134 mM, 135 mM, 136 mM, 137 mM, 138, 139 mM or 140 mM. In some embodiments, ASO as described herein is dissolved or diluted in solutions containing 90 mM, 91 mM, 92 mM, 93 mM, 94 mM, 95 mM, 96 mM, 97 mM, 98 mM, 99 mM, 100 mM, 101 mM, 102 mM, 103 mM, 104 mM, 105 mM, 106 mM, 107 mM, 108 mM, 109 mM, 110 mM, 111 mM, 112 mM, 113 mM, 114 mM, 115 mM, 116 mM, 118 mM, 119 mM, 120 mM, 121 mM, 122 mM, 123 mM, 124 mM, 125 mM, 126 mM, 127 mM, 128 mM, 129 mM, 130 mM, 131 mM, 131 mM, 122 mM, 123 mM, 124 mM, 125 mM, 126 mM, 127 mM, 128 mM, 129 mM, 130 ... In a buffer solution of NaCl at mM, 132 mM, 133 mM, 134 mM, 135 mM, 136 mM, 137 mM, 138 mM, 139 mM or 140 mM.

[0316] In some embodiments, ASO, as described herein, is dissolved or diluted in a buffer solution containing 0.1-20 mM KCl.

[0317] In some embodiments, as described herein, ASO is dissolved or diluted in concentrations of 0.1-40 mM, 0.1-39 mM, 0.1-38 mM, 0.1-37 mM, 0.1-36 mM, 0.1-35 mM, 0.1-34 mM, 0.1-33 mM, 0.1-32 mM, 0.1-31 mM, 0.1-30 mM, 0.1-29 mM, 0.1-28 mM, 0.1-27 mM, 0.1-26 mM, 0.1-25 mM, 0.1-24 mM, 0.1-23 mM, 0.1-22 mM, 0.1-21 mM, 0.1-20 mM, 0.1-19 mM, 0.1-18 mM, 0.1-17 mM, 0.1-16 mM, 0.1-15 mM, etc. 0.1-14 mM, 0.1-13 mM, 0.1-12 mM, 0.1-10 mM, 0.1-9 mM, 0.1-8 mM, 0.1-7 mM, 0.1-6 mM, 0.1-5 mM, 0.1-4 mM, 0.1-3 mM, 0.1-2 mM or 0.1-1 mM KCl in buffer. In some embodiments, as described herein, ASO is dissolved or diluted in concentrations of 0.2-40 mM, 0.3-40 mM, 0.4-40 mM, 0.5-40 mM, 0.6-40 mM, 0.7-40 mM, 0.8-40 mM, 0.9-40 mM, 1-40 mM, 2-40 mM, 3-40 mM, 4-40 mM, 5-40 mM, 6-40 mM, 7-40 mM, 8-40 mM, 9-40 mM, 10-40 mM, 11-40 mM, 12-40 mM, 13-40 mM, 14-40 mM, 15-40 mM, 16-40 mM, 17-40 mM, 18-40 mM, 19-40 mM, 20-40 mM, 21-40 mM, etc. 37-40 mM 38-40 mM or 39-40 mM KCl in buffer.In some embodiments, ASO as described herein is dissolved or diluted in concentrations of 0.1-3.5 mM, 0.2-3.5 mM, 0.3-3.5 mM, 0.4-3.5 mM, 0.5-3.5 mM, 0.6-3.5 mM, 0.7-3.5 mM, 0.8-3.5 mM, 0.9-3.5 mM, 1.0-3.5 mM, 1.1-3.5 mM, 1.2-3.5 mM, 1.3-3.5 mM, 1.4-3.5 mM, 1.5-3.5 mM, 1.6-3.5 mM, 1.7-3.5 mM, 1.8-3.5 mM, 1.9-3.5 mM, 2.0-3.5 mM, 2.1-3.5 mM, 2.2-3.5 mM, and 2.3-3.5 mM. In buffer solutions of KCl at mM, 2.4-3.5 mM, 2.5-3.5 mM, 2.6-3.5 mM, 2.7-3.5 mM, 2.8-3.5 mM, 2.9-3.5 mM, 3.0-3.5 mM, 3.1-3.5 mM, 3.2-3.5 mM, 3.3-3.5 mM or 3.4-3.5 mM. In some embodiments, ASO is dissolved or diluted as described herein in concentrations of 0.1-3.4 mM, 0.1-3.3 mM, 0.1-3.2 mM, 0.1-3.1 mM, 0.1-3.0 mM, 0.1-2.9 mM, 0.1-2.8 mM, 0.1-2.7 mM, 0.1-2.6 mM, 0.1-2.5 mM, 0.1-2.4 mM, 0.1-2.3 mM, 0.1-2.2 mM, 0.1-2.1 mM, 0.1-2.0 mM, 0.1-1.9 mM, 0.1-1.8 mM, 0.1-1.7 mM, 0.1-1.6 mM, 0.1-1.5 mM, 0.1-1.4 mM, 0.1-1.3 mM, and 0.1-1.2 mM. In buffer solutions of KCl at mM, 0.1-1.1 mM, 0.1-1.0 mM, 0.1-0.9 mM, 0.1-0.8 mM, 0.1-0.7 mM, 0.1-0.6 mM, 0.1-0.5 mM, 0.1-0.4 mM, 0.1-0.3 mM, or 0.1-0.2 mM.In some embodiments, as described herein, ASO is dissolved or diluted in a buffer solution containing at least 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, 0.9 mM, 1.0 mM, 1.1 mM, 1.2 mM, 1.3 mM, 1.4 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM, 2.0 mM, 2.1 mM, 2.2 mM, 2.3 mM, 2.4 mM, 2.5 mM, 2.6 mM, 2.7 mM, 2.8 mM, 2.9 mM, 3.0 mM, 3.1 mM, 3.2 mM, 3.3 mM, 3.4 mM, or 3.5 mM KCl. In some embodiments, as described herein, ASO is dissolved or diluted in a buffer solution containing up to 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, 0.9 mM, 1.0 mM, 1.1 mM, 1.2 mM, 1.3 mM, 1.4 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM, 2.0 mM, 2.1 mM, 2.2 mM, 2.3 mM, 2.4 mM, 2.5 mM, 2.6 mM, 2.7 mM, 2.8 mM, 2.9 mM, 3.0 mM, 3.1 mM, 3.2 mM, 3.3 mM, 3.4 mM, or 3.5 mM KCl. In some embodiments, as described herein, ASO is dissolved or diluted in a buffer solution containing 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, 0.9 mM, 1.0 mM, 1.1 mM, 1.2 mM, 1.3 mM, 1.4 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM, 2.0 mM, 2.1 mM, 2.2 mM, 2.3 mM, 2.4 mM, 2.5 mM, 2.6 mM, 2.7 mM, 2.8 mM, 2.9 mM, 3.0 mM, 3.1 mM, 3.2 mM, 3.3 mM, 3.4 mM, or 3.5 mM KCl.

[0318] In some embodiments, ASO, as described herein, is dissolved or diluted in a buffer solution containing 0.1-50 mM Na2HPO4.

[0319] In some embodiments, as described herein, ASO is dissolved or diluted in concentrations of 0.01-100 mM, 0.02-100 mM, 0.03-100 mM, 0.04-100 mM, 0.05-100 mM, 0.06-100 mM, 0.07-100 mM, 0.08-100 mM, 0.09-100 mM, 0.1-100 mM, 0.2-100 mM, 0.3-100 mM, 0.4-100 mM, 0.5-100 mM, 0.6-100 mM, 0.7-100 mM, 0.8-100 mM, 0.9-100 mM, 1-100 mM, 2-100 mM, 3-100 mM, 4-100 mM, 5-100 mM, 6-100 mM, etc. mM, 7-100mM, 8-100mM, 9-100mM, 10-100mM, 15-100mM, 20-100mM, 25-100mM, 30-100mM, 35-100mM, 40-100mM, 45-100mM, 50-100mM, 55-100mM, 60-100 mM, 65-100mM, 70-100mM, 75-100mM, 80-100mM, 85-100mM, 90-100mM or 95-100mM Na2HPO4 buffer.In some embodiments, as described herein, ASO is dissolved or diluted in concentrations of 0.01-95 mM, 0.01-90 mM, 0.01-85 mM, 0.01-80 mM, 0.01-75 mM, 0.01-70 mM, 0.01-65 mM, 0.01-60 mM, 0.01-55 mM, 0.01-50 mM, 0.01-45 mM, 0.01-40 mM, 0.01-35 mM, 0.01-30 mM, 0.01-25 mM, 0.01-20 mM, 0.01-15 mM, 0.01-10 mM, 0.01-9 mM, 0.01-8 mM, 0.01-7 mM, 0.01-6 mM, 0.01-5 mM, 0.01-4 mm, 0.01-3 mm, 0.01-2 mm, 0.01-1 mm, 0.01-0.9 mm, 0.01-0.8 mm, 0.01-0.7 mm, 0.01-0.6 mm, 0.01-0.5 mm, 0.01-0.4 mm, 0.01-0.3 mm, 0.01-0.2 mm, 0.01-0.1 0.01-0.09 mM, 0.01-0.08 mM, 0.01-0.07 mM, 0.01-0.06 mM, 0.01-0.05 mM, 0.01-0.04 mM, 0.01-0.03 mM or 0.01-0.02 mM Na2HPO4 buffer. In some embodiments, ASO is dissolved or diluted as described herein in concentrations of 0.1-3.0 mM, 0.1-2.9 mM, 0.1-2.8 mM, 0.1-2.7 mM, 0.1-2.6 mM, 0.1-2.5 mM, 0.1-2.4 mM, 0.1-2.3 mM, 0.1-2.2 mM, 0.1-2.1 mM, 0.1-2.0 mM, 0.1-1.9 mM, 0.1-1.8 mM, 0.1-1.7 mM, 0.1-1.6 mM, 0.1-1.5 mM, 0.1-1.4 mM, 0.1-1.3 mM, 0.1-1.2 mM, 0.1-1.1 mM, 0.1-1.0 mM, 0.1-0.9 mM, and 0.1-0.8 mM. In buffer solutions of Na2HPO4 at mM, 0.1-0.7 mM, 0.1-0.6 mM, 0.1-0.5 mM, 0.1-0.4 mM, 0.1-0.3 mM or 0.1-0.2 mM.In some embodiments, ASO as described herein is dissolved or diluted in concentrations of 0.1-3.0 mM, 0.2-3.0 mM, 0.3-3.0 mM, 0.4-3.0 mM, 0.5-3.0 mM, 0.6-3.0 mM, 0.7-3.0 mM, 0.8-3.0 mM, 0.9-3.0 mM, 1.0-3.0 mM, 1.2-3.0 mM, 1.3-3.0 mM, 1.4-3.0 mM, 1.5-3.0 mM, 1.6-3.0 mM, 1.7-3.0 mM, 1.8-3.0 mM, 1.9-3.0 mM, 2.0-3.0 mM, 2.1-3.0 mM, 2.2-3.0 mM, 2.3-3.0 mM, and 2.4-3.0 mM. In buffer solutions of Na2HPO4 at mM, 2.5-3.0 mM, 2.6-3.0 mM, 2.7-3.0 mM, 2.8-3.0 mM or 2.9-3.0 mM. In some embodiments, as described herein, ASO is dissolved or diluted in a buffer solution containing at least 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, 0.9 mM, 1.0 mM, 1.1 mM, 1.2 mM, 1.3 mM, 1.4 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM, 2.0 mM, 2.1 mM, 2.2 mM, 2.3 mM, 2.4 mM, 2.5 mM, 2.6 mM, 2.7 mM, 2.8 mM, 2.9 mM, or 3.0 mM Na2HPO4. In some embodiments, as described herein, ASO is dissolved or diluted in a buffer solution containing up to 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, 0.9 mM, 1.0 mM, 1.1 mM, 1.2 mM, 1.3 mM, 1.4 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM, 2.0 mM, 2.1 mM, 2.2 mM, 2.3 mM, 2.4 mM, 2.5 mM, 2.6 mM, 2.7 mM, 2.8 mM, 2.9 mM, or 3.0 mM Na2HPO4.In some embodiments, as described herein, ASO is dissolved or diluted in a buffer solution containing 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, 0.9 mM, 1.0 mM, 1.1 mM, 1.2 mM, 1.3 mM, 1.4 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM, 2.0 mM, 2.1 mM, 2.2 mM, 2.3 mM, 2.4 mM, 2.5 mM, 2.6 mM, 2.7 mM, 2.8 mM, 2.9 mM, or 3.0 mM Na2HPO4.

[0320] In some embodiments, ASO, as described herein, is dissolved or diluted in a buffer solution containing 0.1-50 mM NaH2PO4.

[0321] In some embodiments, as described herein, ASO is dissolved or diluted in concentrations of 0.01-100 mM, 0.02-100 mM, 0.03-100 mM, 0.04-100 mM, 0.05-100 mM, 0.06-100 mM, 0.07-100 mM, 0.08-100 mM, 0.09-100 mM, 0.1-100 mM, 0.2-100 mM, 0.3-100 mM, 0.4-100 mM, 0.5-100 mM, 0.6-100 mM, 0.7-100 mM, 0.8-100 mM, 0.9-100 mM, 1-100 mM, 2-100 mM, 3-100 mM, 4-100 mM, 5-100 mM, 6-100 mM, etc. mM, 7-100mM, 8-100mM, 9-100mM, 10-100mM, 15-100mM, 20-100mM, 25-100mM, 30-100mM, 35-100mM, 40-100mM, 45-100mM, 50-100mM, 55-100mM, 60-100 mM, 65-100mM, 70-100mM, 75-100mM, 80-100mM, 85-100mM, 90-100mM or 95-100mM NaH2PO4 buffer.In some embodiments, as described herein, ASO is dissolved or diluted in concentrations of 0.01-95 mM, 0.01-90 mM, 0.01-85 mM, 0.01-80 mM, 0.01-75 mM, 0.01-70 mM, 0.01-65 mM, 0.01-60 mM, 0.01-55 mM, 0.01-50 mM, 0.01-45 mM, 0.01-40 mM, 0.01-35 mM, 0.01-30 mM, 0.01-25 mM, 0.01-20 mM, 0.01-15 mM, 0.01-10 mM, 0.01-9 mM, 0.01-8 mM, 0.01-7 mM, 0.01-6 mM, 0.01-5 mM, 0.01-4 mm, 0.01-3 mm, 0.01-2 mm, 0.01-1 mm, 0.01-0.9 mm, 0.01-0.8 mm, 0.01-0.7 mm, 0.01-0.6 mm, 0.01-0.5 mm, 0.01-0.4 mm, 0.01-0.3 mm, 0.01-0.2 mm, 0.01-0.1 0.01-0.09 mM, 0.01-0.08 mM, 0.01-0.07 mM, 0.01-0.06 mM, 0.01-0.05 mM, 0.01-0.04 mM, 0.01-0.03 mM or 0.01-0.02 mM NaH2PO4 buffer. In some embodiments, ASO is dissolved or diluted as described herein in concentrations of 0.1-3.0 mM, 0.1-2.9 mM, 0.1-2.8 mM, 0.1-2.7 mM, 0.1-2.6 mM, 0.1-2.5 mM, 0.1-2.4 mM, 0.1-2.3 mM, 0.1-2.2 mM, 0.1-2.1 mM, 0.1-2.0 mM, 0.1-1.9 mM, 0.1-1.8 mM, 0.1-1.7 mM, 0.1-1.6 mM, 0.1-1.5 mM, 0.1-1.4 mM, 0.1-1.3 mM, 0.1-1.2 mM, 0.1-1.1 mM, 0.1-1.0 mM, 0.1-0.9 mM, and 0.1-0.8 mM. In buffer solutions of NaH2PO4 at mM, 0.1-0.7 mM, 0.1-0.6 mM, 0.1-0.5 mM, 0.1-0.4 mM, 0.1-0.3 mM or 0.1-0.2 mM.In some embodiments, ASO as described herein is dissolved or diluted in concentrations of 0.1-3.0 mM, 0.2-3.0 mM, 0.3-3.0 mM, 0.4-3.0 mM, 0.5-3.0 mM, 0.6-3.0 mM, 0.7-3.0 mM, 0.8-3.0 mM, 0.9-3.0 mM, 1.0-3.0 mM, 1.2-3.0 mM, 1.3-3.0 mM, 1.4-3.0 mM, 1.5-3.0 mM, 1.6-3.0 mM, 1.7-3.0 mM, 1.8-3.0 mM, 1.9-3.0 mM, 2.0-3.0 mM, 2.1-3.0 mM, 2.2-3.0 mM, 2.3-3.0 mM, and 2.4-3.0 mM. In buffer solutions of NaH2PO4 at mM, 2.5-3.0 mM, 2.6-3.0 mM, 2.7-3.0 mM, 2.8-3.0 mM or 2.9-3.0 mM. In some embodiments, as described herein, ASO is dissolved or diluted in a buffer solution containing at least 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, 0.9 mM, 1.0 mM, 1.1 mM, 1.2 mM, 1.3 mM, 1.4 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM, 2.0 mM, 2.1 mM, 2.2 mM, 2.3 mM, 2.4 mM, 2.5 mM, 2.6 mM, 2.7 mM, 2.8 mM, 2.9 mM, or 3.0 mM NaH2PO4. In some embodiments, as described herein, ASO is dissolved or diluted in a buffer solution containing up to 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, 0.9 mM, 1.0 mM, 1.1 mM, 1.2 mM, 1.3 mM, 1.4 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM, 2.0 mM, 2.1 mM, 2.2 mM, 2.3 mM, 2.4 mM, 2.5 mM, 2.6 mM, 2.7 mM, 2.8 mM, 2.9 mM, or 3.0 mM NaH2PO4.In some embodiments, as described herein, ASO is dissolved or diluted in a buffer solution containing 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, 0.9 mM, 1.0 mM, 1.1 mM, 1.2 mM, 1.3 mM, 1.4 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM, 2.0 mM, 2.1 mM, 2.2 mM, 2.3 mM, 2.4 mM, 2.5 mM, 2.6 mM, 2.7 mM, 2.8 mM, 2.9 mM, or 3.0 mM NaH2PO4.

[0322] In some embodiments, ASO, as described herein, is dissolved or diluted in a buffer solution containing 0.1-50 mM CaCl2.

[0323] In some embodiments, as described herein, ASO is dissolved or diluted in concentrations of 0.1-50 mM, 0.2-50 mM, 0.3-50 mM, 0.4-50 mM, 0.5-50 mM, 0.6-50 mM, 0.7-50 mM, 0.8-50 mM, 0.9-50 mM, 1.0-50 mM, -50 mM, 1.1-50 mM, 1.2-50 mM, 1.3-50 mM, 1.4-50 mM, 1.5-50 mM, 1.6-50 mM, 1.7-50 mM, 1.8-50 mM, 1.9-50 mM, 2.0-50 mM, 2.1-50 mM, 2.2-50 mM, 2.3-50 mM, 2.4-50 mM, 2.5-50 mM, etc. 3.9-50 mM 30-50 mM CaCl2 in buffer solution.In some embodiments, ASO is dissolved or diluted as described herein in concentrations of 0.1-45 mM, 0.1-40 mM, 0.1-35 mM, 0.1-30 mM, 0.1-25 mM, 0.1-20 mM, 0.1-15 mM, 0.1-10 mM, 0.1-5 mM, 0.1-4 mM, 0.1-4.9 mM, 0.1-4.8 mM, 0.1-4.7 mM, 0.1-4.6 mM, 0.1-4.5 mM, 0.1-4.4 mM, 0.1-4.3 mM, 0.1-4.2 mM, 0.1-4.1 mM, 0.1-4.0 mM, 0.1-3.9 mM, 0.1-3.8 mM, 0.1-3.7 mM, and 0.1-3.6 mM. mM, 0.1-3.5 mm, 0.1-3.4 mm, 0.1-3.3 mm, 0.1-3.2 mm, 0.1-3.1 mm, 0.1-3.0 mm, 0.1-2.9 mm, 0.1-2.8 mm, 0.1-2.7 mm, 0.1-2.6 mm, 0.1-2.5 mm, 0.1-2.4 mm, 0.1-2.3 mM, 0.1-2.2 mm, 0.1-2.1 mm, 0.1-2.0 mm, 0.1-1.9 mm, 0.1-1.8 mm, 0.1-1.7 mm, 0.1-1.6 mm, 0.1-1.5 mm, 0.1-1.4 mm, 0.1-1.3 mm, 0.1-1.2 In buffer solutions of CaCl2 at concentrations of mM, 0.1-1.1 mM, 0.1-1.0 mM, 0.1-0.9 mM, 0.1-0.8 mM, 0.1-0.7 mM, 0.1-0.6 mM, 0.1-0.5 mM, 0.1-0.4 mM, 0.1-0.3 mM, or 0.1-0.2 mM. In some embodiments, as described herein, ASO is dissolved or diluted in a buffer solution containing at least 1.0 mM, 1.1 mM, 1.2 mM, 1.3 mM, 1.4 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM, 2.0 mM, 2.1 mM, 2.2 mM, 2.3 mM, 2.4 mM, 2.5 mM, 2.6 mM, 2.7 mM, 2.8 mM, 2.9 mM, 3.0 mM, 3.1 mM, 3.2 mM, 3.3 mM, 3.4 mM, 3.5 mM, 3.6 mM, 3.7 mM, 3.8 mM, 3.9 mM, or 4.0 mM CaCl2.In some embodiments, as described herein, ASO is dissolved or diluted in a buffer solution containing up to 1.0 mM, 1.1 mM, 1.2 mM, 1.3 mM, 1.4 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM, 2.0 mM, 2.1 mM, 2.2 mM, 2.3 mM, 2.4 mM, 2.5 mM, 2.6 mM, 2.7 mM, 2.8 mM, 2.9 mM, 3.0 mM, 3.1 mM, 3.2 mM, 3.3 mM, 3.4 mM, 3.5 mM, 3.6 mM, 3.7 mM, 3.8 mM, 3.9 mM, or 4.0 mM CaCl2. In some embodiments, as described herein, ASO is dissolved or diluted in a buffer solution containing 1.0 mM, 1.1 mM, 1.2 mM, 1.3 mM, 1.4 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM, 2.0 mM, 2.1 mM, 2.2 mM, 2.3 mM, 2.4 mM, 2.5 mM, 2.6 mM, 2.7 mM, 2.8 mM, 2.9 mM, 3.0 mM, 3.1 mM, 3.2 mM, 3.3 mM, 3.4 mM, 3.5 mM, 3.6 mM, 3.7 mM, 3.8 mM, 3.9 mM, or 4.0 mM CaCl2.

[0324] In some embodiments, ASO, as described herein, is dissolved or diluted in a buffer solution containing 0.1-50 mM MgCl2.

[0325] In some embodiments, as described herein, ASO is dissolved or diluted in concentrations of 0.1-50 mM, 0.2-50 mM, 0.3-50 mM, 0.4-50 mM, 0.5-50 mM, 0.6-50 mM, 0.7-50 mM, 0.8-50 mM, 0.9-50 mM, 1.0-50 mM, -50 mM, 1.1-50 mM, 1.2-50 mM, 1.3-50 mM, 1.4-50 mM, 1.5-50 mM, 1.6-50 mM, 1.7-50 mM, 1.8-50 mM, 1.9-50 mM, 2.0-50 mM, 2.1-50 mM, 2.2-50 mM, 2.3-50 mM, 2.4-50 mM, 2.5-50 mM, etc. 3.9-50 mM MgCl2 buffer solution.In some embodiments, ASO is dissolved or diluted as described herein in concentrations of 0.1-45 mM, 0.1-40 mM, 0.1-35 mM, 0.1-30 mM, 0.1-25 mM, 0.1-20 mM, 0.1-15 mM, 0.1-10 mM, 0.1-5 mM, 0.1-4 mM, 0.1-4.9 mM, 0.1-4.8 mM, 0.1-4.7 mM, 0.1-4.6 mM, 0.1-4.5 mM, 0.1-4.4 mM, 0.1-4.3 mM, 0.1-4.2 mM, 0.1-4.1 mM, 0.1-4.0 mM, 0.1-3.9 mM, 0.1-3.8 mM, 0.1-3.7 mM, and 0.1-3.6 mM. mM, 0.1-3.5 mm, 0.1-3.4 mm, 0.1-3.3 mm, 0.1-3.2 mm, 0.1-3.1 mm, 0.1-3.0 mm, 0.1-2.9 mm, 0.1-2.8 mm, 0.1-2.7 mm, 0.1-2.6 mm, 0.1-2.5 mm, 0.1-2.4 mm, 0.1-2.3 mM, 0.1-2.2 mm, 0.1-2.1 mm, 0.1-2.0 mm, 0.1-1.9 mm, 0.1-1.8 mm, 0.1-1.7 mm, 0.1-1.6 mm, 0.1-1.5 mm, 0.1-1.4 mm, 0.1-1.3 mm, 0.1-1.2 MgCl2 in buffer solutions of mM, 0.1-1.1 mM, 0.1-1.0 mM, 0.1-0.9 mM, 0.1-0.8 mM, 0.1-0.7 mM, 0.1-0.6 mM, 0.1-0.5 mM, 0.1-0.4 mM, 0.1-0.3 mM or 0.1-0.2 mM. In some embodiments, ASO is dissolved or diluted as described herein in concentrations of at least 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, 0.9 mM, 1.0 mM, 1.1 mM, 1.2 mM, 1.3 mM, 1.4 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM, 2.0 mM, 2.1 mM, 2.2 mM, 2.3 mM, 2.4 mM, 2.5 mM, 2.6 mM, 2.7 mM, 2.8 mM, 2.9 mM, 3.0 mM, 3.1 mM, 3.2 mM, 3.3 mM, 3.4 mM, 3.5 mM, 3.6 mM, 3.7 mM, 3.8 mM, 3.9 mM. In a buffer solution of mM or 4.0 mM MgCl2.In some embodiments, ASO is dissolved or diluted as described herein in concentrations of up to 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, 0.9 mM, 1.0 mM, 1.1 mM, 1.2 mM, 1.3 mM, 1.4 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM, 2.0 mM, 2.1 mM, 2.2 mM, 2.3 mM, 2.4 mM, 2.5 mM, 2.6 mM, 2.7 mM, 2.8 mM, 2.9 mM, 3.0 mM, 3.1 mM, 3.2 mM, 3.3 mM, 3.4 mM, 3.5 mM, 3.6 mM, 3.7 mM, 3.8 mM, 3.9 mM. In a buffer solution of mM or 4.0 mM MgCl2. In some embodiments, ASO is dissolved or diluted as described herein in concentrations of 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, 0.9 mM, 1.0 mM, 1.1 mM, 1.2 mM, 1.3 mM, 1.4 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM, 2.0 mM, 2.1 mM, 2.2 mM, 2.3 mM, 2.4 mM, 2.5 mM, 2.6 mM, 2.7 mM, 2.8 mM, 2.9 mM, 3.0 mM, 3.1 mM, 3.2 mM, 3.3 mM, 3.4 mM, 3.5 mM, 3.6 mM, 3.7 mM, 3.8 mM, 0.8 mM, 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, 0.8 mM, 0.8 mM, 0.7 mM, 0.8 mM, 0.8 mM, 0.8 mM, 0.8 mM, 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, 0.8 mM, 0.8 mM, 0.7 mM, 0.8 mM, 0.8 mM, 0.8 mM, 0.8 mM, 0.8 In a buffer solution of mM, 3.9mM or 4.0 mM MgCl2.

[0326] In some embodiments, ASO is dissolved or diluted in a buffer solution further comprising 1-100 mM NaHCO3, 1-100 mM KHCO3, or a combination thereof.

[0327] In some embodiments, ASO, as described herein, is dissolved or diluted in a buffer solution containing 1-100 mM NaHCO3.

[0328] In some embodiments, as described herein, ASO is dissolved or diluted in a buffer solution containing 1-99 mM, 1-95 mM, 1-90 mM, 1-85 mM, 1-80 mM, 1-75 mM, 1-70 mM, 1-65 mM, 1-60 mM, 1-55 mM, 1-50 mM, 1-45 mM, 1-40 mM, 1-35 mM, 1-30 mM, 1-25 mM, 1-20 mM, 1-15 mM, 1-10 mM, 1-9 mM, 1-8 mM, 1-7 mM, 1-6 mM, 1-5 mM, 1-4 mM, 1-3 mM, or 1-2 mM NaHCO3. In some embodiments, as described herein, ASO is dissolved or diluted in a buffer solution containing 2-100 mM, 3-100 mM, 4-100 mM, 5-100 mM, 6-100 mM, 7-100 mM, 8-100 mM, 9-100 mM, 10-100 mM, 15-100 mM, 20-100 mM, 25-100 mM, 30-100 mM, 35-100 mM, 40-100 mM, 45-100 mM, 50-100 mM, 55-100 mM, 60-100 mM, 65-100 mM, 70-100 mM, 75-100 mM, 80-100 mM, 85-100 mM, 90-100 mM, or 95-100 mM NaHCO3.In some embodiments, ASO is dissolved or diluted as described herein in concentrations of 24.0-28.0 mM, 24.0-27.9 mM, 24.0-27.8 mM, 24.0-27.7 mM, 24.0-27.6 mM, 24.0-27.5 mM, 24.0-27.4 mM, 24.0-27.3 mM, 24.0-27.2 mM, 24.0-27.1 mM, 24.0-27.0 mM, 24.0-26.9 mM, 24.0-26.8 mM, 24.0-26.7 mM, 24.0-26.6 mM, 24.0-26.5 mM, 24.0-26.4 mM, 24.0-26.3 mM, and 24.0-26.2 mM. 24.0-26.1 mM, 24.0-26.0mM, 24.0-25.9mM, 4.0-25.8mM, 24.0-25.7mM, 24.0-25.6mM, 24.0-25.5mM, 24.0-25.4mM, 24.0-25.3mM, 24.0-25.2 24.0-25.1mM, 24.0-25.0mM, 24.0-24.9mM, 24.0-24.8mM, 24.0-24.7mM, 24.0-24.6mM, 24.0-24.5mM, 24.0-24.4mM, 24.0-24.3 In a buffer solution of 24.0-24.2 mM or 24.0-24.1 mM NaHCO3.In some embodiments, ASO as described herein is dissolved or diluted in concentrations of 24.1-28.0 mM, 24.2-28.0 mM, 24.3-28.0 mM, 24.4-28.0 mM, 24.5-28.0 mM, 24.6-28.0 mM, 24.7-28.0 mM, 24.8-28.0 mM, 24.9-28.0 mM, 25.0-28.0 mM, 25.1-28.0 mM, 25.2-28.0 mM, 25.3-28.0 mM, 25.4-28.0 mM, 25.5-28.0 mM, 25.6-28.0 mM, 25.7-28.0 mM, 25.8-28.0 mM, and 25.9-28.0 mM. 26.0-28.0 mM, 26.1-28.0 mM, 26.2-28.0 mM, 26.3-28.0mM, 26.4-28.0mM, 26.5-28.0mM, 26.6-28.0mM, 26.7-28.0mM, 26.8-28.0 27.8-28.0 mM mM or 27.9-28.0 mM In NaHCO3 buffer solution. In some embodiments, as described herein, ASO is dissolved or diluted in solutions containing at least 24.0 mM, 24.1 mM, 24.2 mM, 24.3 mM, 24.4 mM, 24.5 mM, 24.6 mM, 24.7 mM, 24.8 mM, 24.9 mM, 25.0 mM, 25.1 mM, 25.2 mM, 25.3 mM, 25.4 mM, 25.5 mM, 25.6 mM, 25.7 mM, 25.8 mM, 25.9 mM, 26.0 mM, 26.1 mM, 26.2 mM, 26.3 mM, 26.4 mM, 26.5 mM, 26.6 mM, 26.7 mM, 26.8 mM, 26.9 mM, 27.0 mM, 27.1 mM, and 27.2 mM. In buffer solutions of 27.3 mM, 27.4 mM, 27.5 mM, 27.6 mM, 27.7 mM, 27.8 mM, 27.9 mM or 28.0 mM NaHCO3.In some embodiments, ASO is dissolved or diluted as described herein in concentrations of up to 24.0 mM, 24.1 mM, 24.2 mM, 24.3 mM, 24.4 mM, 24.5 mM, 24.6 mM, 24.7 mM, 24.8 mM, 24.9 mM, 25.0 mM, 25.1 mM, 25.2 mM, 25.3 mM, 25.4 mM, 25.5 mM, 25.6 mM, 25.7 mM, 25.8 mM, 25.9 mM, 26.1 mM, 26.2 mM, 26.3 mM, 26.4 mM, 26.5 mM, 26.6 mM, 26.7 mM, 26.8 mM, 26.9 mM, 27.0 mM, 27.1 mM, 27.2 mM, 27.3 mM. In buffer solutions of 27.4 mM, 27.5 mM, 27.6 mM, 27.7 mM, 27.8 mM, 27.9 mM or 28.0 mM NaHCO3. In some embodiments, ASO is dissolved or diluted as described herein in solutions containing 24.0 mM, 24.1 mM, 24.2 mM, 24.3 mM, 24.4 mM, 24.5 mM, 24.6 mM, 24.7 mM, 24.8 mM, 24.9 mM, 25.0 mM, 25.1 mM, 25.2 mM, 25.3 mM, 25.4 mM, 25.5 mM, 25.6 mM, 25.7 mM, 25.8 mM, 25.9 mM, 26.1 mM, 26.2 mM, 26.3 mM, 26.4 mM, 26.5 mM, 26.6 mM, 26.7 mM, 26.8 mM, 26.9 mM, 27.0 mM, 27.1 mM, 27.2 mM, and 27.3 mM. In buffer solutions of 27.4 mM, 27.5 mM, 27.6 mM, 27.7 mM, 27.8 mM, 27.9 mM or 28.0 mM NaHCO3.

[0329] In some embodiments, ASO, as described herein, is dissolved or diluted in a buffer solution containing 1-100 mM KHCO3.

[0330] In some embodiments, as described herein, ASO is dissolved or diluted in a buffer solution containing 1-99 mM, 1-95 mM, 1-90 mM, 1-85 mM, 1-80 mM, 1-75 mM, 1-70 mM, 1-65 mM, 1-60 mM, 1-55 mM, 1-50 mM, 1-45 mM, 1-40 mM, 1-35 mM, 1-30 mM, 1-25 mM, 1-20 mM, 1-15 mM, 1-10 mM, 1-9 mM, 1-8 mM, 1-7 mM, 1-6 mM, 1-5 mM, 1-4 mM, 1-3 mM, or 1-2 mM KHCO3. In some embodiments, as described herein, ASO is dissolved or diluted in a buffer solution containing 2-100 mM, 3-100 mM, 4-100 mM, 5-100 mM, 6-100 mM, 7-100 mM, 8-100 mM, 9-100 mM, 10-100 mM, 15-100 mM, 20-100 mM, 25-100 mM, 30-100 mM, 35-100 mM, 40-100 mM, 45-100 mM, 50-100 mM, 55-100 mM, 60-100 mM, 65-100 mM, 70-100 mM, 75-100 mM, 80-100 mM, 85-100 mM, 90-100 mM, or 95-100 mM KHCO3.In some embodiments, ASO is dissolved or diluted as described herein in concentrations of 24.0-28.0 mM, 24.0-27.9 mM, 24.0-27.8 mM, 24.0-27.7 mM, 24.0-27.6 mM, 24.0-27.5 mM, 24.0-27.4 mM, 24.0-27.3 mM, 24.0-27.2 mM, 24.0-27.1 mM, 24.0-27.0 mM, 24.0-26.9 mM, 24.0-26.8 mM, 24.0-26.7 mM, 24.0-26.6 mM, 24.0-26.5 mM, 24.0-26.4 mM, 24.0-26.3 mM, and 24.0-26.2 mM. 24.0-26.1 mM, 24.0-26.0mM, 24.0-25.9mM, 4.0-25.8mM, 24.0-25.7mM, 24.0-25.6mM, 24.0-25.5mM, 24.0-25.4mM, 24.0-25.3mM, 24.0-25.2 24.0-25.1mM, 24.0-25.0mM, 24.0-24.9mM, 24.0-24.8mM, 24.0-24.7mM, 24.0-24.6mM, 24.0-24.5mM, 24.0-24.4mM, 24.0-24.3 In a buffer solution of mM, 24.0-24.2mM or 24.0-24.1mM KHCO3.In some embodiments, ASO as described herein is dissolved or diluted in concentrations of 24.1-28.0 mM, 24.2-28.0 mM, 24.3-28.0 mM, 24.4-28.0 mM, 24.5-28.0 mM, 24.6-28.0 mM, 24.7-28.0 mM, 24.8-28.0 mM, 24.9-28.0 mM, 25.0-28.0 mM, 25.1-28.0 mM, 25.2-28.0 mM, 25.3-28.0 mM, 25.4-28.0 mM, 25.5-28.0 mM, 25.6-28.0 mM, 25.7-28.0 mM, 25.8-28.0 mM, and 25.9-28.0 mM. 26.0-28.0 mM, 26.1-28.0 mM, 26.2-28.0 mM, 26.3-28.0mM, 26.4-28.0mM, 26.5-28.0mM, 26.6-28.0mM, 26.7-28.0mM, 26.8-28.0 27.8-28.0 mM mM or 27.9-28.0 mM In a buffer solution containing KHCO3. In some embodiments, as described herein, ASO is dissolved or diluted in solutions containing at least 24.0 mM, 24.1 mM, 24.2 mM, 24.3 mM, 24.4 mM, 24.5 mM, 24.6 mM, 24.7 mM, 24.8 mM, 24.9 mM, 25.0 mM, 25.1 mM, 25.2 mM, 25.3 mM, 25.4 mM, 25.5 mM, 25.6 mM, 25.7 mM, 25.8 mM, 25.9 mM, 26.0 mM, 26.1 mM, 26.2 mM, 26.3 mM, 26.4 mM, 26.5 mM, 26.6 mM, 26.7 mM, 26.8 mM, 26.9 mM, 27.0 mM, 27.1 mM, and 27.2 mM. In a buffer solution of 27.3 mM, 27.4 mM, 27.5 mM, 27.6 mM, 27.7 mM, 27.8 mM, 27.9 mM or 28.0 mM KHCO3.In some embodiments, ASO is dissolved or diluted as described herein in concentrations of up to 24.0 mM, 24.1 mM, 24.2 mM, 24.3 mM, 24.4 mM, 24.5 mM, 24.6 mM, 24.7 mM, 24.8 mM, 24.9 mM, 25.0 mM, 25.1 mM, 25.2 mM, 25.3 mM, 25.4 mM, 25.5 mM, 25.6 mM, 25.7 mM, 25.8 mM, 25.9 mM, 26.1 mM, 26.2 mM, 26.3 mM, 26.4 mM, 26.5 mM, 26.6 mM, 26.7 mM, 26.8 mM, 26.9 mM, 27.0 mM, 27.1 mM, 27.2 mM, 27.3 mM. In buffer solutions of 27.4 mM, 27.5 mM, 27.6 mM, 27.7 mM, 27.8 mM, 27.9 mM or 28.0 mM KHCO3. In some embodiments, ASO is dissolved or diluted as described herein in solutions containing 24.0 mM, 24.1 mM, 24.2 mM, 24.3 mM, 24.4 mM, 24.5 mM, 24.6 mM, 24.7 mM, 24.8 mM, 24.9 mM, 25.0 mM, 25.1 mM, 25.2 mM, 25.3 mM, 25.4 mM, 25.5 mM, 25.6 mM, 25.7 mM, 25.8 mM, 25.9 mM, 26.1 mM, 26.2 mM, 26.3 mM, 26.4 mM, 26.5 mM, 26.6 mM, 26.7 mM, 26.8 mM, 26.9 mM, 27.0 mM, 27.1 mM, 27.2 mM, and 27.3 mM. In buffer solutions of 27.4 mM, 27.5 mM, 27.6 mM, 27.7 mM, 27.8 mM, 27.9 mM or 28.0 mM KHCO3.

[0331] In some embodiments, ASO, as described herein, is dissolved or diluted in a buffer solution containing 0-50 mM KH2PO4.

[0332] In some embodiments, as described herein, ASO is dissolved or diluted in solutions containing 0-100 mM, 0.01-100 mM, 0.02-100 mM, 0.03-100 mM, 0.04-100 mM, 0.05-100 mM, 0.06-100 mM, 0.07-100 mM, 0.08-100 mM, 0.09-100 mM, 0.1-100 mM, 0.2-100 mM, 0.3-100 mM, 0.4-100 mM, 0.5-100 mM, 0.6-100 mM, 0.7-100 mM, 0.8-100 mM, 0.9-100 mM, 1-100 mM, 2-100 mM, 3-100 mM, 4-100 mM, 5-100 mM, etc. 60-100 mM 100 mM KH2PO4 buffer solution. In some embodiments, ASO as described herein is dissolved or diluted in solutions containing 0-95 mM, 0-90 mM, 0-85 mM, 0-80 mM, 0-75 mM, 0-70 mM, 0-65 mM, 0-60 mM, 0-55 mM, 0-50 mM, 0-45 mM, 0-40 mM, 0-35 mM, 0-30 mM, 0-25 mM, 0-20 mM, 0-15 mM, 0-10 mM, 0-9 mM, 0-8 mM, 0-7 mM, 0-6 mM, 0-5 mM, 0-4 mM, 0-3 mM, 0-2 mM, 0-1 mM, 0-0.9 mM, 0-0.8 mM, 0-0.7 mM, 0-0.6 mM, 0-0.5 mM, 0-0.4 mM, 0-0.3 mM. In buffer solutions of KH2PO4 at mM, 0-0.2 mM, 0-0.1 mM, 0-0.09 mM, 0-0.08 mM, 0-0.07 mM, 0-0.06 mM, 0-0.05 mM, 0-0.04 mM, 0-0.03 mM or 0-0.02 mM.In some embodiments, as described herein, ASO is dissolved or diluted in concentrations of 0.01-95 mM, 0.01-90 mM, 0.01-85 mM, 0.01-80 mM, 0.01-75 mM, 0.01-70 mM, 0.01-65 mM, 0.01-60 mM, 0.01-55 mM, 0.01-50 mM, 0.01-45 mM, 0.01-40 mM, 0.01-35 mM, 0.01-30 mM, 0.01-25 mM, 0.01-20 mM, 0.01-15 mM, 0.01-10 mM, 0.01-9 mM, 0.01-8 mM, 0.01-7 mM, 0.01-6 mM, 0.01-5 mM, 0.01-4 mm, 0.01-3 mm, 0.01-2 mm, 0.01-1 mm, 0.01-0.9 mm, 0.01-0.8 mm, 0.01-0.7 mm, 0.01-0.6 mm, 0.01-0.5mM, 0.01-0.4 mm, 0.01-0.3 mm, 0.01-0.2 mm, 0.01-0.1 KH2PO4 buffer solution: In some embodiments, ASO as described herein is dissolved or diluted in concentrations comprising 0-3.0 mM, 0-2.9 mM, 0-2.8 mM, 0-2.7 mM, 0-2.6 mM, 0-2.5 mM, 0-2.4 mM, 0-2.3 mM, 0-2.2 mM, 0-2.1 mM, 0-2.0 mM, 0-1.9 mM, 0-1.8 mM, 0-1.7 mM, 0-1.6 mM, 0-1.5 mM, 0-1.4 mM, 0-1.3 mM, 0-1.2 mM, 0-1.1 mM, 0-1.0 mM, 0-0.9 mM, 0-0.8 mM, 0-0.7 mM, 0-0.6 mM, 0-0.5 mM, 0-0.4 mM, 0-0.3 mM, or 0-0.2 mM. In a buffer solution containing KH2PO4.In some embodiments, ASO is dissolved or diluted as described herein in concentrations of 0.1-3.0 mM, 0.1-2.9 mM, 0.1-2.8 mM, 0.1-2.7 mM, 0.1-2.6 mM, 0.1-2.5 mM, 0.1-2.4 mM, 0.1-2.3 mM, 0.1-2.2 mM, 0.1-2.1 mM, 0.1-2.0 mM, 0.1-1.9 mM, 0.1-1.8 mM, 0.1-1.7 mM, 0.1-1.6 mM, 0.1-1.5 mM, 0.1-1.4 mM, 0.1-1.3 mM, 0.1-1.2 mM, 0.1-1.1 mM, 0.1-1.0 mM, 0.1-0.9 mM, and 0.1-0.8 mM. In buffer solutions of mM, 0.1-0.7 mM, 0.1-0.6 mM, 0.1-0.5 mM, 0.1-0.4 mM, 0.1-0.3 mM or 0.1-0.2 mM KH2PO4. In some embodiments, ASO as described herein is dissolved or diluted in concentrations comprising 0-3.0 mM, 0.1-3.0 mM, 0.2-3.0 mM, 0.3-3.0 mM, 0.4-3.0 mM, 0.5-3.0 mM, 0.6-3.0 mM, 0.7-3.0 mM, 0.8-3.0 mM, 0.9-3.0 mM, 1.0-3.0 mM, 1.2-3.0 mM, 1.3-3.0 mM, 1.4-3.0 mM, 1.5-3.0 mM, 1.6-3.0 mM, 1.7-3.0 mM, 1.8-3.0 mM, 1.9-3.0 mM, 2.0-3.0 mM, 2.1-3.0 mM, 2.2-3.0 mM, and 2.3-3.0 mM. In buffer solutions of 2.4-3.0 mM, 2.5-3.0 mM, 2.6-3.0 mM, 2.7-3.0 mM, 2.8-3.0 mM or 2.9-3.0 mM KH2PO4. In some embodiments, as described herein, ASO is dissolved or diluted in a buffer solution containing at least 0 mM, 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, 0.9 mM, 1.0 mM, 1.1 mM, 1.2 mM, 1.3 mM, 1.4 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM, 2.0 mM, 2.1 mM, 2.2 mM, 2.3 mM, 2.4 mM, 2.5 mM, 2.6 mM, 2.7 mM, 2.8 mM, 2.9 mM, or 3.0 mM KH2PO4.In some embodiments, as described herein, ASO is dissolved or diluted in a buffer solution containing up to 0 mM, 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, 0.9 mM, 1.0 mM, 1.1 mM, 1.2 mM, 1.3 mM, 1.4 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM, 2.0 mM, 2.1 mM, 2.2 mM, 2.3 mM, 2.4 mM, 2.5 mM, 2.6 mM, 2.7 mM, 2.8 mM, 2.9 mM, or 3.0 mM KH2PO4. In some embodiments, as described herein, ASO is dissolved or diluted in a buffer solution containing 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, 0.9 mM, 1.0 mM, 1.1 mM, 1.2 mM, 1.3 mM, 1.4 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM, 2.0 mM, 2.1 mM, 2.2 mM, 2.3 mM, 2.4 mM, 2.5 mM, 2.6 mM, 2.7 mM, 2.8 mM, 2.9 mM, or 3.0 mM KH2PO4.

[0333] In some embodiments, ASO, as described herein, is dissolved or diluted in a buffer solution containing 0-50 mM NaH2PO4.

[0334] In some embodiments, ASO as described herein is dissolved or diluted in concentrations comprising 0-50 mM, 0-45 mM, 0-40 mM, 0-35 mM, 0-30 mM, 0-25 mM, 0-20 mM, 0-19 mM, 0-18 mM, 0-17 mM, 0-16 mM, 0-15 mM, 0-14 mM, 0-13 mM, 0-12 mM, 0-11 mM, 0-10 mM, 0-9 mM, 0-8 mM, 0-7 mM, 0-6 mM, 0-5 mM, 0-4 mM, 0-3 mM, 0-2 mM, 0-1 mM, 0-0.9 mM, 0-0.8 mM, 0-0.7 mM, 0-0.6 mM, 0-0.5 mM, 0-0.4 mM, 0-0.3 mM, or 0-0.2 mM. In a buffer solution containing mM NaH2PO4. In some embodiments, ASO as described herein is dissolved or diluted in concentrations of 0.1-50 mM, 0.1-45 mM, 0.1-40 mM, 0.1-35 mM, 0.1-30 mM, 0.1-25 mM, 0.1-20 mM, 0.1-19 mM, 0.1-18 mM, 0.1-17 mM, 0.1-16 mM, 0.1-15 mM, 0.1-14 mM, 0.1-13 mM, 0.1-12 mM, 0.1-11 mM, 0.1-10 mM, 0.1-9 mM, 0.1-8 mM, 0.1-7 mM, 0.1-6 mM, 0.1-5 mM, 0.1-4 mM, 0.1-3 mM, 0.1-2 mM, 0.1-1 mM, 0.1-0.9 mM. In buffer solutions of NaH2PO4 at mM, 0.1-0.8 mM, 0.1-0.7 mM, 0.1-0.6 mM, 0.1-0.5 mM, 0.1-0.4 mM, 0.1-0.3 mM or 0.1-0.2 mM.In some embodiments, as described herein, ASO is dissolved or diluted in solutions containing 0-50 mM, 0.1-50 mM, 0.2-50 mM, 0.3-50 mM, 0.4-50 mM, 0.5-50 mM, 0.6-50 mM, 0.7-50 mM, 0.8-50 mM, 0.9-50 mM, 1-50 mM, 2-50 mM, 3-50 mM, 4-50 mM, 5-50 mM, 6-50 mM, 7-50 mM, 8-50 mM, 9-50 mM, 1-50 mM, 11-50 mM, 12-50 mM, 13-50 mM, 14-50 mM, 15-50 mM, 16-50 mM, 17-50 mM, 18-50 mM, 19-50 mM, etc. In buffer solutions of 20-50 mM, 25-50 mM, 30-50 mM, 35-50 mM, 40-50 mM or 45-50 mM NaH2PO4. In some embodiments, ASO as described herein is dissolved or diluted in concentrations of 0-20 mM, 0.1-20 mM, 0.2-20 mM, 0.3-20 mM, 0.4-20 mM, 0.5-20 mM, 0.6-20 mM, 0.7-20 mM, 0.8-20 mM, 0.9-20 mM, 1-20 mM, 2-20 mM, 3-20 mM, 4-20 mM, 5-20 mM, 6-20 mM, 7-20 mM, 8-20 mM, 9-20 mM, 10-20 mM, 11-20 mM, 12-20 mM, 13-20 mM, 14-20 mM, 15-20 mM, 16-20 mM, 17-20 mM, 18-20 mM, or 19-20 mM. In some embodiments, ASO as described herein is dissolved or diluted in a buffer solution containing at least 0 mM, 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, 0.9 mM, 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, or 20 mM NaH2PO4.In some embodiments, as described herein, ASO is dissolved or diluted in a buffer solution containing up to 0 mM, 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, 0.9 mM, 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, or 20 mM NaH2PO4. In some embodiments, as described herein, ASO is dissolved or diluted in a buffer solution containing 0 mM, 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, 0.9 mM, 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, or 20 mM NaH2PO4.

[0335] In some embodiments, ASO is dissolved in a liquid composition that is not buffered by a buffer. The buffer in the liquid formulations described herein is a buffering agent that, other than the active pharmaceutical ingredient in the formulation (e.g., ASO as described herein), buffers the pH of the formulation.

[0336] In some embodiments, ASO is dissolved in a liquid composition comprising a buffer. In some embodiments, the buffer has a pKa of about 4.75; about 5.64; about 1.70, about 6.04 and about 9.09; about 3.1, about 4.7 and about 6.4; or about 6.50 at 25°C. In some embodiments, the buffer is an effective buffer solution with a pH range of about 3.6 to 5.6, about 5.5 to 6.5, about 5.5 to 7.4, about 3.0 to 6.2 or about 5.8 to 7.2. In some embodiments, the buffer is selected from the group consisting of acetate, succinate, histidine, citrate, 2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3-diol (Bis-Tris), and any combination thereof.

[0337] In some embodiments, ASO is stable in the pharmaceutical formulation for at least 1, 2, or 3 years at -20°C. In some embodiments, ASO is stable in the pharmaceutical formulation for at least 1, 2, or 3 years at 4°C. In some embodiments, ASO is stable in the pharmaceutical formulation for at least 1, 2, or 3 years at 25°C. In some embodiments, the pharmaceutical formulation is stable after being stored at -20°C for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 weeks. After 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or after 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or after 1 year, 2 years, 3 years, 4 years, or 5 years, the ASO is stable in the pharmaceutical formulation. In some embodiments, the ASO is stable in the pharmaceutical formulation after being stored at -20°C for at least 12 months. In some embodiments, the ASO is stable in the pharmaceutical formulation after being stored at -20°C for at least 24 months. In some embodiments, the ASO is stable in the pharmaceutical formulation after being stored at -20°C for at least 36 months. In some embodiments, the pharmaceutical preparation is stored at 4°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, and 35 weeks. ASO remains stable in pharmaceutical formulations after 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or after 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or after 1 year, 2 years, 3 years, 4 years, or 5 years.In some embodiments, the pharmaceutical preparation is stored at 25°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, and 35 weeks. ASO remains stable in pharmaceutical formulations after 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or after 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or after 1 year, 2 years, 3 years, 4 years, or 5 years. In some embodiments, the pharmaceutical preparation is stored at 30°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, and 35 weeks. ASO remains stable in pharmaceutical formulations after 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or after 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or after 1 year, 2 years, 3 years, 4 years, or 5 years. In some embodiments, the pharmaceutical preparation is stored at 37°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, and 35 weeks. ASO remains stable in pharmaceutical formulations after 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or after 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or after 1 year, 2 years, 3 years, 4 years, or 5 years.In some embodiments, the pharmaceutical preparation is stored at 40°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, and 35 weeks. ASO remains stable in pharmaceutical formulations after 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or after 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or after 1 year, 2 years, 3 years, 4 years, or 5 years. In some embodiments, the pharmaceutical formulation is stored at 4°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 32 weeks. ASO remains stable in pharmaceutical formulations after 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or after 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or after 1 year, 2 years, 3 years, 4 years, or 5 years. In some embodiments, the pharmaceutical formulation is stored at 25°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 32 weeks. ASO remains stable in pharmaceutical formulations after 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks, or after 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or after 1 year, 2 years, 3 years, 4 years, or 5 years.In some embodiments, the pharmaceutical formulation is stored at 30°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 32 weeks. ASO remains stable in pharmaceutical formulations after 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks, or after 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or after 1 year, 2 years, 3 years, 4 years, or 5 years. In some embodiments, the pharmaceutical formulation is stored at 37°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 32 weeks. ASO remains stable in pharmaceutical formulations after 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks, or after 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or after 1 year, 2 years, 3 years, 4 years, or 5 years. In some embodiments, the pharmaceutical formulation is stored at 40°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 32 weeks. ASO remains stable in pharmaceutical formulations after 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks, or after 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or after 1 year, 2 years, 3 years, 4 years, or 5 years.In some embodiments, ASO is stable in pharmaceutical formulations based on LC / MS identification of molecules with a molecular weight of 7197.2 ± 4.0 Da.

[0338] In some embodiments, when stored at -20°C, the shelf life of the pharmaceutical preparation is at least 1, 2, or 3 years. In some embodiments, when stored at 4°C, the shelf life of the pharmaceutical preparation is at least 1, 2, or 3 years. In some embodiments, when stored at 25°C, the shelf life of the pharmaceutical preparation is at least 1, 2, or 3 years. In some embodiments, when stored at -20°C, the shelf life of the pharmaceutical preparation is at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 32 weeks. Weeks 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52; or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months; or 1 year, 2 years, 3 years, 4 years, or 5 years. In some embodiments, ASO is stable in the pharmaceutical formulation after being stored at -20°C for at least 12 months. In some embodiments, when stored at 4°C, the shelf life of the pharmaceutical preparation is at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, and 32 weeks. 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks; or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months; or 1 year, 2 years, 3 years, 4 years, or 5 years.In some embodiments, when stored at 25°C, the shelf life of the pharmaceutical preparation is at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, and 32 weeks. 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years. In some embodiments, when stored at 30°C, the shelf life of the pharmaceutical preparation is at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, and 32 weeks. 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years. In some embodiments, when stored at 37°C, the shelf life of the pharmaceutical preparation is at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, and 32 weeks. 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years.In some embodiments, when stored at 40°C, the shelf life of the pharmaceutical preparation is at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, and 32 weeks. 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years. In some embodiments, when stored at 4°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75%, the shelf life of the pharmaceutical preparation is at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, or 29 weeks. 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years. In some embodiments, when stored at 25°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75%, the shelf life of the pharmaceutical preparation is at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, or 29 weeks. 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years.In some embodiments, when stored at 30°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75%, the shelf life of the pharmaceutical preparation is at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, or 29 weeks. 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years. In some embodiments, when stored at 37°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75%, the shelf life of the pharmaceutical preparation is at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, or 29 weeks. 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years. In some embodiments, when stored at 40°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75%, the shelf life of the pharmaceutical preparation is at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, or 29 weeks. 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years.

[0339] In some embodiments, the pharmaceutical preparation is stored at -20°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, and 38 weeks. After 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or 1 year, 2 years, 3 years, 4 years, or 5 years, the percentage of impurities in the pharmaceutical formulation, based on a HPLC relative retention time of 0.92, does not exceed 2.5%. In some embodiments, after storing the pharmaceutical formulation at -20°C for at least 12 months, the percentage of impurities in the pharmaceutical formulation, based on a HPLC relative retention time of 0.92, does not exceed 2.5%. In some embodiments, after storing the pharmaceutical formulation at -20°C for at least 24 months, the percentage of impurities in the pharmaceutical formulation, based on a HPLC relative retention time of 0.92, does not exceed 2.5%. In some embodiments, after storing the pharmaceutical formulation at -20°C for at least 36 months, the percentage of impurities in the pharmaceutical formulation does not exceed 2.5% based on an HPLC relative retention time of 0.92. In some embodiments, after storing the pharmaceutical formulation at 4°C for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, and 38 weeks... After 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of impurities in the drug formulation shall not exceed 2.5% based on a HPLC relative retention time of 0.92.In some embodiments, the pharmaceutical preparation is stored at 25°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, and 38 weeks. After 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of impurities in the drug formulation shall not exceed 2.5% based on a HPLC relative retention time of 0.92. In some embodiments, the pharmaceutical preparation is stored at 30°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, and 38 weeks. After 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of impurities in the drug formulation shall not exceed 2.5% based on a HPLC relative retention time of 0.92. In some embodiments, the pharmaceutical preparation is stored at 37°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, and 38 weeks. After 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of impurities in the drug formulation shall not exceed 2.5% based on a HPLC relative retention time of 0.92.In some embodiments, the pharmaceutical preparation is stored at 40°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, and 38 weeks. After 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of impurities in the drug formulation shall not exceed 2.5% based on a HPLC relative retention time of 0.92. In some embodiments, the pharmaceutical formulation is stored at 4°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, or 35 weeks. After 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of impurities in the drug formulation shall not exceed 2.5% based on a HPLC relative retention time of 0.92.In some embodiments, the pharmaceutical formulation is stored at 25°C and 55%, 60%, 65%, 70%, or 75% relative humidity for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, or 35 weeks. After 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of impurities in the drug formulation shall not exceed 2.5% based on a HPLC relative retention time of 0.92. In some embodiments, the pharmaceutical formulation is stored at 30°C and 55%, 60%, 65%, 70%, or 75% relative humidity for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, or 35 weeks. After 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of impurities in the drug formulation shall not exceed 2.5% based on a HPLC relative retention time of 0.92.In some embodiments, the pharmaceutical formulation is stored at 37°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, or 35 weeks. After 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of impurities in the drug formulation shall not exceed 2.5% based on a HPLC relative retention time of 0.92. In some embodiments, the pharmaceutical formulation is stored at 40°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, or 35 weeks. After 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of impurities in the drug formulation shall not exceed 2.5% based on a HPLC relative retention time of 0.92.

[0340] In some embodiments, the pharmaceutical preparation is stored at -20°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, and 38 weeks. After 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or 1 year, 2 years, 3 years, 4 years, or 5 years, the percentage of impurities in the pharmaceutical formulation, based on a HPLC relative retention time of 0.98, does not exceed 3.5%. In some embodiments, after storing the pharmaceutical formulation at -20°C for at least 12 months, the percentage of impurities in the pharmaceutical formulation, based on a HPLC relative retention time of 0.98, does not exceed 3.5%. In some embodiments, after storing the pharmaceutical formulation at -20°C for at least 24 months, the percentage of impurities in the pharmaceutical formulation, based on a HPLC relative retention time of 0.98, does not exceed 3.5%. In some embodiments, after storing the pharmaceutical formulation at -20°C for at least 36 months, the percentage of impurities in the pharmaceutical formulation does not exceed 3.5% based on an HPLC relative retention time of 0.98. In some embodiments, after storing the pharmaceutical formulation at 4°C for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, and 38 weeks... After 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of impurities in the drug formulation shall not exceed 3.5% based on a relative retention time of 0.98 on HPLC.In some embodiments, the pharmaceutical preparation is stored at 25°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, and 38 weeks. After 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of impurities in the drug formulation shall not exceed 3.5% based on a relative retention time of 0.98 on HPLC. In some embodiments, the pharmaceutical preparation is stored at 30°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, and 38 weeks. After 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of impurities in the drug formulation shall not exceed 3.5% based on a relative retention time of 0.98 on HPLC. In some embodiments, the pharmaceutical preparation is stored at 37°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, and 38 weeks. After 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of impurities in the drug formulation shall not exceed 3.5% based on a relative retention time of 0.98 on HPLC.In some embodiments, the pharmaceutical preparation is stored at 40°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, and 38 weeks. After 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of impurities in the drug formulation shall not exceed 3.5% based on a relative retention time of 0.98 on HPLC. In some embodiments, the pharmaceutical formulation is stored at 4°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, or 35 weeks. After 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of impurities in the drug formulation shall not exceed 3.5% based on a relative retention time of 0.98 on HPLC.In some embodiments, the pharmaceutical formulation is stored at 25°C and 55%, 60%, 65%, 70%, or 75% relative humidity for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, or 35 weeks. After 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of impurities in the drug formulation shall not exceed 3.5% based on a relative retention time of 0.98 on HPLC. In some embodiments, the pharmaceutical formulation is stored at 30°C and 55%, 60%, 65%, 70%, or 75% relative humidity for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, or 35 weeks. After 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of impurities in the drug formulation shall not exceed 3.5% based on a relative retention time of 0.98 on HPLC.In some embodiments, the pharmaceutical formulation is stored at 37°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, or 35 weeks. After 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of impurities in the drug formulation shall not exceed 3.5% based on a relative retention time of 0.98 on HPLC. In some embodiments, the pharmaceutical formulation is stored at 40°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, or 35 weeks. After 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of impurities in the drug formulation shall not exceed 3.5% based on a relative retention time of 0.98 on HPLC.

[0341] In some embodiments, the pharmaceutical preparation is stored at -20°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, and 37 weeks. After 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or after 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or after 1 year, 2 years, 3 years, 4 years, or 5 years, the percentage of any unspecified impurities in the pharmaceutical formulation does not exceed 1.8% according to HPLC. In some embodiments, after storing the pharmaceutical formulation at -20°C for at least 12 months, the percentage of any unspecified impurities in the pharmaceutical formulation does not exceed 1.8% according to HPLC. In some embodiments, after storing the pharmaceutical formulation at -20°C for at least 24 months, the percentage of any unspecified impurities in the pharmaceutical formulation does not exceed 1.8% according to HPLC. In some embodiments, after storing the pharmaceutical formulation at -20°C for at least 36 months, the percentage of any unspecified impurities in the pharmaceutical formulation does not exceed 1.8% according to HPLC. In some embodiments, after storing the pharmaceutical formulation at 4°C for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, and 37 weeks... After 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of any unspecified impurities in the drug formulation shall not exceed 1.8% according to HPLC.In some embodiments, the drug formulation is stored at 25°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, and 37 weeks. After 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of any unspecified impurities in the drug formulation shall not exceed 1.8% according to HPLC. In some embodiments, the drug formulation is stored at 30°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, and 37 weeks. After 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of any unspecified impurities in the drug formulation shall not exceed 1.8% according to HPLC. In some embodiments, the drug formulation is stored at 37°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, and 37 weeks. After 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of any unspecified impurities in the drug formulation shall not exceed 1.8% according to HPLC.In some embodiments, the drug formulation is stored at 40°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, and 37 weeks. After 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of any unspecified impurities in the drug formulation shall not exceed 1.8% according to HPLC. In some embodiments, the pharmaceutical formulation is stored at 4°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, or 34 weeks. After 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of any unspecified impurities in the drug formulation shall not exceed 1.8% according to HPLC.In some embodiments, the pharmaceutical formulation is stored at 25°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, or 34 weeks. After 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of any unspecified impurities in the drug formulation shall not exceed 1.8% according to HPLC. In some embodiments, the pharmaceutical formulation is stored at 30°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, or 34 weeks. After 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of any unspecified impurities in the drug formulation shall not exceed 1.8% according to HPLC.In some embodiments, the pharmaceutical formulation is stored at 37°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, or 34 weeks. After 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of any unspecified impurities in the drug formulation shall not exceed 1.8% according to HPLC. In some embodiments, the pharmaceutical formulation is stored at 40°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, or 34 weeks. After 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of any unspecified impurities in the drug formulation shall not exceed 1.8% according to HPLC.

[0342] In some embodiments, the pharmaceutical formulation is stored at -20°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, and 3... After 7 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or 1 year, 2 years, 3 years, 4 years, or 5 years, the percentage of total impurities in the pharmaceutical formulation does not exceed 10% according to HPLC. In some embodiments, after storing the pharmaceutical formulation at -20°C for at least 12 months, the percentage of total impurities in the pharmaceutical formulation does not exceed 10% according to HPLC. In some embodiments, after storing the pharmaceutical formulation at -20°C for at least 24 months, the percentage of total impurities in the pharmaceutical formulation does not exceed 10% according to HPLC. In some embodiments, after storing the pharmaceutical formulation at -20°C for at least 36 months, the percentage of total impurities in the pharmaceutical formulation does not exceed 10% according to HPLC. In some embodiments, after storing the pharmaceutical formulation at 4°C for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, and 37 weeks... After 1 week, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of total impurities in the drug formulation shall not exceed 10% according to HPLC.In some embodiments, the pharmaceutical preparation is stored at 25°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, and 3... After 7 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of total impurities in the drug formulation shall not exceed 10% according to HPLC. In some embodiments, the pharmaceutical preparation is stored at 30°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, and 37 weeks. After 1 week, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of any total impurities in the pharmaceutical formulation shall not exceed 10% according to HPLC. In some embodiments, the pharmaceutical preparation is stored at 37°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, and 3... After 7 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of total impurities in the drug formulation shall not exceed 10% according to HPLC.In some embodiments, the pharmaceutical formulation is stored at 40°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, and 3... After 7 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of total impurities in the drug formulation shall not exceed 10% according to HPLC. In some embodiments, the pharmaceutical formulation is stored at 4°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, or 3... After 4 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of total impurities in the drug formulation shall not exceed 10% according to HPLC.In some embodiments, the pharmaceutical formulation is stored at 25°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, or 3... After 4 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of total impurities in the drug formulation shall not exceed 10% according to HPLC. In some embodiments, the pharmaceutical formulation is stored at 30°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, or 3... After 4 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of total impurities in the drug formulation shall not exceed 10% according to HPLC.In some embodiments, the pharmaceutical formulation is stored at 37°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, or 3... After 4 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of total impurities in the drug formulation shall not exceed 10% according to HPLC. In some embodiments, the pharmaceutical formulation is stored at 40°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, or 3... After 4 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the percentage of total impurities in the drug formulation shall not exceed 10% according to HPLC.

[0343] In some embodiments, the pharmaceutical preparation is stored at -20°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, and 3 weeks. The pH of the pharmaceutical composition is 6.6 to 7.6 after 6 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks, or 1 month, 2 months, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or 1 year, 2 years, 3 years, 4 years, or 5 years. In some embodiments, the pH of the pharmaceutical composition is 6.6 to 7.6 after storing the pharmaceutical formulation at -20°C for at least 12 months. In some embodiments, the pH of the pharmaceutical composition is 6.6 to 7.6 after storing the pharmaceutical formulation at -20°C for at least 24 months. In some embodiments, the pH of the pharmaceutical composition is 6.6 to 7.6 after storing the pharmaceutical formulation at -20°C for at least 36 months. In some embodiments, the drug formulation is stored at 4°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, and 35 weeks. The pH of the pharmaceutical composition is 6.6 to 7.6 after 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years.In some embodiments, the drug formulation is stored at 25°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, and 35 weeks. The pH of the pharmaceutical composition is 6.6 to 7.6 after 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years. In some embodiments, the drug formulation is stored at 30°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, and 35 weeks. The pH of the pharmaceutical composition is 6.6 to 7.6 after 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years. In some embodiments, the drug formulation is stored at 37°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, and 35 weeks. The pH of the pharmaceutical composition is 6.6 to 7.6 after 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years.In some embodiments, the drug formulation is stored at 40°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, and 35 weeks. The pH of the pharmaceutical composition is 6.6 to 7.6 after 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years. In some embodiments, the pharmaceutical formulation is stored at 4°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 32 weeks. The pH of the pharmaceutical composition is 6.6 to 7.6 after 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years. In some embodiments, the pharmaceutical formulation is stored at 25°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 32 weeks. The pH of the pharmaceutical composition is 6.6 to 7.6 after 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or 1 year, 2 years, 3 years, 4 years, or 5 years.In some embodiments, the pharmaceutical formulation is stored at 30°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 32 weeks. The pH of the pharmaceutical composition is 6.6 to 7.6 after 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or 1 year, 2 years, 3 years, 4 years, or 5 years. In some embodiments, the pharmaceutical formulation is stored at 37°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 32 weeks. The pH of the pharmaceutical composition is 6.6 to 7.6 after 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or 1 year, 2 years, 3 years, 4 years, or 5 years.In some embodiments, the pharmaceutical formulation is stored at 40°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 32 weeks. The pH of the pharmaceutical composition is 6.6 to 7.6 after 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or 1 year, 2 years, 3 years, 4 years, or 5 years.

[0344] In some embodiments, the pharmaceutical preparation is stored at -20°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, and 3... After 5 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or 1 year, 2 years, 3 years, 4 years, or 5 years, the osmotic pressure of the pharmaceutical composition is from 310 mOsm / kg to 360 mOsm / kg. In some embodiments, after storing the pharmaceutical formulation at -20°C for at least 12 months, the osmotic pressure of the pharmaceutical composition is from 310 mOsm / kg to 360 mOsm / kg. In some embodiments, after storing the pharmaceutical formulation at -20°C for at least 24 months, the osmotic pressure of the pharmaceutical composition is 310 mOsm / kg to 360 mOsm / kg. In some embodiments, after storing the pharmaceutical formulation at -20°C for at least 36 months, the osmotic pressure of the pharmaceutical composition is 310 mOsm / kg to 360 mOsm / kg. In some embodiments, after storing the pharmaceutical formulation at 4°C for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, and 35 weeks... After 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the osmotic pressure of the pharmaceutical composition is 310 mOsm / kg to 360 mOsm / kg.In some embodiments, the pharmaceutical preparation is stored at 25°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, and 35 weeks. After 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the osmotic pressure of the pharmaceutical composition is 310 mOsm / kg to 360 mOsm / kg. In some embodiments, the pharmaceutical preparation is stored at 30°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, and 35 weeks. After 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the osmotic pressure of the pharmaceutical composition is 310 mOsm / kg to 360 mOsm / kg. In some embodiments, the pharmaceutical preparation is stored at 37°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, and 35 weeks. After 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the osmotic pressure of the pharmaceutical composition is 310 mOsm / kg to 360 mOsm / kg.In some embodiments, the pharmaceutical preparation is stored at 40°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, and 35 weeks. After 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the osmotic pressure of the pharmaceutical composition is 310 mOsm / kg to 360 mOsm / kg. In some embodiments, the pharmaceutical formulation is stored at 4°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 32 weeks. After 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the osmotic pressure of the pharmaceutical composition is 310 mOsm / kg to 360 mOsm / kg.In some embodiments, the pharmaceutical formulation is stored at 25°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 3... After 2 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the osmotic pressure of the pharmaceutical composition is 310 mOsm / kg to 360 mOsm / kg. In some embodiments, the pharmaceutical formulation is stored at 30°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 3... After 2 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the osmotic pressure of the pharmaceutical composition is 310 mOsm / kg to 360 mOsm / kg.In some embodiments, the pharmaceutical formulation is stored at 37°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 3... After 2 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the osmotic pressure of the pharmaceutical composition is 310 mOsm / kg to 360 mOsm / kg. In some embodiments, the pharmaceutical formulation is stored at 40°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 3... After 2 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years, the osmotic pressure of the pharmaceutical composition is 310 mOsm / kg to 360 mOsm / kg.

[0345] In some embodiments, the pharmaceutical preparation is stored at -20°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, and 3 weeks. No observable particle formation or particle formation larger than 50 µm was observed after 6 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or 1 year, 2 years, 3 years, 4 years, or 5 years. In some embodiments, no observable particle formation or particle formation larger than 50 µm was observed after storing the pharmaceutical preparation at -20°C for at least 12 months. In some embodiments, no observable particle formation or particle formation larger than 50 µm was observed after storing the pharmaceutical preparation at -20°C for at least 24 months. In some embodiments, after storing the pharmaceutical preparation at -20°C for at least 36 months, no observable particle formation or particle formation with a size greater than 50 µm was observed. In some embodiments, after storing the pharmaceutical preparation at 4°C for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, and 36 weeks, no observable particle formation or particle formation with a size greater than 50 µm was observed. No observable particle formation or particle formation larger than 50 µm was observed after 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years.In some embodiments, the pharmaceutical preparation is stored at 25°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, and 3 weeks. No observable particle formation or particle formation larger than 50 µm was observed after 6 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or 1 year, 2 years, 3 years, 4 years, or 5 years. In some embodiments, the pharmaceutical preparation is stored at 30°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, and 3 weeks. No observable particle formation or particle formation larger than 50 µm was observed after 6 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or 1 year, 2 years, 3 years, 4 years, or 5 years. In some embodiments, the pharmaceutical formulation is stored at 37°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, and 3 weeks. No observable particle formation or particle formation larger than 50 µm was observed after 6 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or 1 year, 2 years, 3 years, 4 years, or 5 years.In some embodiments, the pharmaceutical preparation is stored at 40°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, and 3 weeks. No observable particle formation or particle formation larger than 50 µm was observed after 6 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or 1 year, 2 years, 3 years, 4 years, or 5 years. In some embodiments, the pharmaceutical formulation is stored at 4°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 32 weeks. No observable particle formation or particle formation larger than 50 µm was observed after 3 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or 1 year, 2 years, 3 years, 4 years, or 5 years.In some embodiments, the pharmaceutical formulation is stored at 25°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 32 weeks. No observable particle formation or particle formation larger than 50 µm was observed after 3 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or 1 year, 2 years, 3 years, 4 years, or 5 years. In some embodiments, the pharmaceutical formulation is stored at 30°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, or 3... No observable particle formation or particle formation larger than 50 µm was observed after 3 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or 1 year, 2 years, 3 years, 4 years, or 5 years.In some embodiments, the pharmaceutical formulation is stored at 37°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 32 weeks. No observable particle formation or particle formation larger than 50 µm was observed after 3 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or 1 year, 2 years, 3 years, 4 years, or 5 years. In some embodiments, the pharmaceutical formulation is stored at 40°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 32 weeks. No observable particle formation or particle formation larger than 50 µm was observed after 3 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or 1 year, 2 years, 3 years, 4 years, or 5 years.

[0346] In some embodiments, the pharmaceutical preparation is stored at -20°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, and 35 weeks. No observable particulate formation was observed after 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or after 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or after 1 year, 2 years, 3 years, 4 years, or 5 years. In some embodiments, no observable particulate formation was observed after the pharmaceutical preparation was stored at -20°C for at least 12 months. In some embodiments, no observable particulate formation was observed after the pharmaceutical preparation was stored at -20°C for at least 24 months. In some embodiments, no observable particulate formation was observed after the pharmaceutical preparation was stored at -20°C for at least 36 months. In some embodiments, the pharmaceutical preparation is stored at 4°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, and 35 weeks. No observable particle formation was observed after 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years.In some embodiments, the pharmaceutical preparation is stored at 25°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, and 35 weeks. No observable particle formation was observed after 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years. In some embodiments, the pharmaceutical preparation is stored at 30°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, and 35 weeks. No observable particle formation was observed after 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years. In some embodiments, the pharmaceutical preparation is stored at 37°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, and 35 weeks. No observable particle formation was observed after 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years.In some embodiments, the pharmaceutical preparation is stored at 40°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, and 35 weeks. No observable particle formation was observed after 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years. In some embodiments, the pharmaceutical formulation is stored at 4°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 32 weeks. No observable particle formation was observed after 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or 1 year, 2 years, 3 years, 4 years, or 5 years. In some embodiments, the pharmaceutical formulation is stored at 25°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 32 weeks. No observable particle formation was observed after 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or 1 year, 2 years, 3 years, 4 years, or 5 years.In some embodiments, the pharmaceutical formulation is stored at 30°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 32 weeks. No observable particle formation was observed after 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or 1 year, 2 years, 3 years, 4 years, or 5 years. In some embodiments, the pharmaceutical formulation is stored at 37°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 32 weeks. No observable particle formation was observed after 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or 1 year, 2 years, 3 years, 4 years, or 5 years. In some embodiments, the pharmaceutical formulation is stored at 40°C and at a relative humidity of 55%, 60%, 65%, 70%, or 75% for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 32 weeks. No observable particle formation was observed after 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or 1 year, 2 years, 3 years, 4 years, or 5 years.

[0347] In some embodiments, ASO is dissolved in a buffer solution free of Na2HPO4 and / or NaH2PO4.

[0348] In some embodiments, ASO is dissolved or diluted in a buffer solution further containing carbohydrates. In some embodiments, the carbohydrates contain D-glucose. In some embodiments, ASO is dissolved or diluted in a buffer solution further containing 1-100 mM D-glucose.

[0349] In some embodiments, ASO, as described herein, is dissolved or diluted in a buffer containing 1-100 mM D-glucose.

[0350] In some embodiments, as described herein, ASO is dissolved or diluted in solutions containing 1-100 mM, 1-95 mM, 1-90 mM, 1-85 mM, 1-80 mM, 1-75 mM, 1-70 mM, 1-65 mM, 1-60 mM, 1-55 mM, 1-50 mM, 1-45 mM, 1-40 mM, 1-35 mM, 1-30 mM, 1-29 mM, 1-28 mM, 1-27 mM, 1-26 mM, 1-25 mM, 1-24 mM, 1-23 mM, 1-22 mM, 1-21 mM, 1-20 mM, 1-19 mM, 1-18 mM, 1-17 mM, 1-16 mM, 1-15 mM, 1-14 mM, 1-13 mM, 1-12 mM, 1-12 mM, 1-12 mM, 1-13 mM, 1-14 mM, 1-15 mM, 1-14 mM, 1-13 mM, 1-15 mM, 1-16 mM, 1-15 mM, 1-14 mM, 1-13 mM, 1-15 mM, 1-16 mM, 1-17 ...7 mM, 1-16 mM, 1-17 mM, 1-16 mM, 1-17 mM, 1-16 D-glucose in buffer solutions of mM, 1-11 mM, 1-10 mM, 1-9 mM, 1-8 mM, 1-7 mM, 1-6 mM, 1-5 mM, 1-4 mM, 1-3 mM or 1-2 mM. In some embodiments, as described herein, ASO is dissolved or diluted in solutions containing 2-100 mM, 3-100 mM, 4-100 mM, 5-100 mM, 6-100 mM, 7-100 mM, 8-100 mM, 9-100 mM, 10-100 mM, 11-100 mM, 12-100 mM, 13-100 mM, 14-100 mM, 15-100 mM, 16-100 mM, 17-100 mM, 18-100 mM, 19-100 mM, 20-100 mM, 21-100 mM, 22-100 mM, 23-100 mM, 24-100 mM, 25-100 mM, 26-100 mM, 29-100 mM, 28-100 mM, etc. D-glucose in buffer solutions of 29-100 mM, 30-100 mM, 35-100 mM, 40-100 mM, 45-100 mM, 50-100 mM, 55-100 mM, 60-100 mM, 65-100 mM, 70-100 mM, 75-100 mM, 80-100 mM, 85-100 mM, 90-100 mM, or 95-100 mM.In some embodiments, as described herein, ASO is dissolved or diluted in a buffer solution containing 2-30 mM, 3-30 mM, 4-30 mM, 5-30 mM, 6-30 mM, 7-30 mM, 8-30 mM, 9-30 mM, 10-30 mM, 11-30 mM, 12-30 mM, 13-30 mM, 14-30 mM, 15-30 mM, 16-30 mM, 17-30 mM, 18-30 mM, 19-30 mM, 20-30 mM, 21-30 mM, 22-30 mM, 23-30 mM, 24-30 mM, 25-30 mM, 26-30 mM, 27-30 mM, 28-30 mM, or 29-30 mM D-glucose. In some embodiments, ASO as described herein is dissolved or diluted in a buffer containing at least 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, 20 mM, 21 mM, 22 mM, 23 mM, 24 mM, 25 mM, 26 mM, 27 mM, 28 mM, 29 mM, or 30 mM D-glucose. In some embodiments, ASO as described herein is dissolved or diluted in a buffer containing up to 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, 20 mM, 21 mM, 22 mM, 23 mM, 24 mM, 25 mM, 26 mM, 27 mM, 28 mM, 29 mM, or 30 mM D-glucose. In some embodiments, as described herein, ASO is dissolved or diluted in a buffer solution containing 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, 20 mM, 21 mM, 22 mM, 23 mM, 24 mM, 25 mM, 26 mM, 27 mM, 28 mM, 29 mM, or 30 mM D-glucose.

[0351] In some embodiments, as described herein, ASO is dissolved or diluted in solutions containing 1-100 mM, 1-95 mM, 1-90 mM, 1-85 mM, 1-80 mM, 1-75 mM, 1-70 mM, 1-65 mM, 1-60 mM, 1-55 mM, 1-50 mM, 1-45 mM, 1-40 mM, 1-35 mM, 1-30 mM, 1-29 mM, 1-28 mM, 1-27 mM, 1-26 mM, 1-25 mM, 1-24 mM, 1-23 mM, 1-22 mM, 1-21 mM, 1-20 mM, 1-19 mM, 1-18 mM, 1-17 mM, 1-16 mM, 1-15 mM, 1-14 mM, 1-13 mM, 1-12 mM, 1-12 mM, 1-12 mM, 1-13 mM, 1-14 mM, 1-15 mM, 1-14 mM, 1-13 mM, 1-15 mM, 1-16 mM, 1-15 mM, 1-14 mM, 1-13 mM, 1-15 mM, 1-16 mM, 1-17 ...7 mM, 1-16 mM, 1-17 mM, 1-16 mM, 1-17 mM, 1-16 In a glucose buffer solution of 1-11 mM, 1-10 mM, 1-9 mM, 1-8 mM, 1-7 mM, 1-6 mM, 1-5 mM, 1-4 mM, 1-3 mM or 1-2 mM. In some embodiments, as described herein, ASO is dissolved or diluted in solutions containing 2-100 mM, 3-100 mM, 4-100 mM, 5-100 mM, 6-100 mM, 7-100 mM, 8-100 mM, 9-100 mM, 10-100 mM, 11-100 mM, 12-100 mM, 13-100 mM, 14-100 mM, 15-100 mM, 16-100 mM, 17-100 mM, 18-100 mM, 19-100 mM, 20-100 mM, 21-100 mM, 22-100 mM, 23-100 mM, 24-100 mM, 25-100 mM, 26-100 mM, 29-100 mM, 28-100 mM, etc. In a glucose buffer solution of 29-100 mM, 30-100 mM, 35-100 mM, 40-100 mM, 45-100 mM, 50-100 mM, 55-100 mM, 60-100 mM, 65-100 mM, 70-100 mM, 75-100 mM, 80-100 mM, 85-100 mM, 90-100 mM or 95-100 mM.In some embodiments, as described herein, ASO is dissolved or diluted in a buffer solution containing 2-30 mM, 3-30 mM, 4-30 mM, 5-30 mM, 6-30 mM, 7-30 mM, 8-30 mM, 9-30 mM, 10-30 mM, 11-30 mM, 12-30 mM, 13-30 mM, 14-30 mM, 15-30 mM, 16-30 mM, 17-30 mM, 18-30 mM, 19-30 mM, 20-30 mM, 21-30 mM, 22-30 mM, 23-30 mM, 24-30 mM, 25-30 mM, 26-30 mM, 27-30 mM, 28-30 mM, or 29-30 mM glucose. In some embodiments, as described herein, ASO is dissolved or diluted in a buffer solution containing at least 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, 20 mM, 21 mM, 22 mM, 23 mM, 24 mM, 25 mM, 26 mM, 27 mM, 28 mM, 29 mM, or 30 mM glucose. In some embodiments, ASO as described herein is dissolved or diluted in a buffer solution containing up to 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, 20 mM, 21 mM, 22 mM, 23 mM, 24 mM, 25 mM, 26 mM, 27 mM, 28 mM, 29 mM, or 30 mM glucose. In some embodiments, as described herein, ASO is dissolved or diluted in a buffer solution containing 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, 20 mM, 21 mM, 22 mM, 23 mM, 24 mM, 25 mM, 26 mM, 27 mM, 28 mM, 29 mM, or 30 mM glucose.

[0352] In some embodiments, ASO is dissolved or diluted in a buffer solution containing 25-250 mM NaCl, 0.1-20 mM KCl, 0.1-50 mM Na2HPO4, 0.1-50 mM NaH2PO4, 0.1-50 mM CaCl2 and 0.1-50 mM MgCl2.

[0353] In some embodiments, ASO is dissolved or diluted in a buffer solution containing 150 mM NaCl, 3.0 mM KCl, 0.7 mM Na2HPO4, 0.3 mM NaH2PO4, 0.79 mM MgCl2 and 1.4 mM CaCl2.

[0354] In some embodiments, ASO is dissolved or diluted in a buffer solution further containing an antioxidant. In some embodiments, the antioxidant is tert-butylhydroxyquinoline (TBHQ), butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E, or any combination thereof. In some embodiments, ASO is dissolved or diluted in a buffer solution further containing an antioxidant, wherein the antioxidant is ascorbic acid (vitamin C), glutathione, lipoic acid, uric acid, carotene, α-tocopherol (vitamin E), panthenol (coenzyme Q), or any combination thereof.

[0355] In some embodiments, as described herein, ASO is dissolved or diluted in a buffer solution containing 25-250 mM NaCl, 0.1-20 mM KCl, 0-50 mM KH2PO4, 1-100 mM NaHCO3, 0-50 mM Na2HPO4, 1-100 mM D-glucose, 0.1-50 mM CaCl2, 0.1-50 mM MgCl2, or any combination thereof.

[0356] In some embodiments, as described herein, ASO is dissolved or diluted in a buffer solution containing 25-250 mM NaCl, 0.1-20 mM KCl, 0-50 mM KH2PO4, 1-100 mM NaHCO3, 0-50 mM Na2HPO4, 1-100 mM D-glucose, 0.1-50 mM CaCl2, and 0.1-50 mM MgCl2.

[0357] In some embodiments, ASO as described herein is dissolved or diluted in a buffer solution containing 127 mM NaCl, 1.0 mM KCl, 1.2 mM KH2PO4, 26 mM NaHCO3, 10 mM D-glucose, 2.4 mM CaCl2 and 1.3 mM MgCl2.

[0358] In some embodiments, ASO as described herein is dissolved or diluted in a buffer solution containing 119 mM NaCl, 26.2 mM NaHCO3, 2.5 mM KCl, 1 mM NaH2PO4, 1.3 mM MgCl2, 10 mM glucose and 2.5 mM CaCl2.

[0359] In some embodiments, the pharmaceutical composition does not contain a preservative. In some embodiments, the pharmaceutical composition contains a preservative.

[0360] In some embodiments, ASO as described herein is present in the pharmaceutical composition at a concentration of 5-250 mg / mL.

[0361] In some embodiments, the ASO as described herein is at 5 - 250 mg / mL, 5 - 247.5 mg / mL, 5 - 245 mg / mL, 5 - 242.5 mg / mL, 5 - 240 mg / mL, 5 - 237.5 mg / mL, 5 - 235 mg / mL, 5 - 232.5 mg / mL, 5 - 230 mg / mL, 5 - 227.5 mg / mL, 5 - 225 mg / mL, 5 - 225.5 mg / mL, 5 - 220 mg / mL, 5 - 217.5 mg / mL, 5 - 215 mg / mL, 5 - 212.5 mg / mL, 5 - 210 mg / mL, 5 - 205.5 mg / mL, 5 - 205 mg / mL, 5 - 202.5 mg / mL, 5 - 200 mg / mL, 5 - 197.5 mg / mL, 5 - 195 mg / mL, 5 - 192.5 mg / mL, 5 - 190 mg / mL, 5 - 187.5 mg / mL, 5 - 185 mg / mL, 5 - 182.5 mg / mL, 5 - 180 mg / mL, 5 - 177.5 mg / mL, 5 - 175 mg / mL, 5 - 172.5 mg / mL, 5 - 170 mg / mL, 5 - 167.5 mg / mL, 5 - 165 mg / mL, 5 - 162.5 mg / mL, 5 - 160 mg / mL, 5 - 157.5 mg / mL, 5 - 155 mg / mL, 5 - 152.5 mg / mL, 5 - 150 mg / mL, 5 - 147.5 mg / mL, 5 - 145 mg / mL, 5 - 142.5 mg / mL, 5 - 140 mg / mL, 5 - 137.5 mg / mL, 5 - 135 mg / mL, 5 - 132.5 mg / mL, 5 - 130 mg / mL, 5 - 127.5 mg / mL, 5 - 125 mg / mL, 5 - 122.5 mg / mL, 5 - 120 mg / mL, 5 - 117.5 mg / mL, 5 - 115 mg / mL, 5 - 112.5 mg / mL, 5 - 110 mg / mL, 5 - 107.5 mg / mL, 5 - 105 mg / mL, 5 - 102.5 mg / mL, 5 - 100 mg / mL, 5 - 97.5 mg / mL, 5 - 95 mg / mL, 5 - 92.5 mg / mL, 5 - 90 mg / mL, 5 - 87.5 mg / mL, 5 - 85 mg / mL, 5 - 82.5 mg / mL, 5 - 80 mg / mL, 5 - 77.5 mg / mL, 5 - 75 mg / mL, 5 - 72.5 mg / mL, 5 - 70 mg / mL, 5 - 67.5 mg / mL, 5 - 65 mg / mL, 5 - 6The concentrations of 5-55 mg / mL, 5-52.5 mg / mL, 5-50 mg / mL, 5-47.5 mg / mL, 5-45 mg / mL, 5-42.5 mg / mL, 5-40 mg / mL, 5-37.5 mg / mL, 5-35 mg / mL, 5-32.5 mg / mL, 5-30 mg / mL, 5-27.5 mg / mL, 5-25 mg / mL, 5-22.5 mg / mL, 5-20 mg / mL, 5-17.5 mg / mL, 5-15 mg / mL, 5-12.5 mg / mL, or 5-10 mg / mL are present in the pharmaceutical composition. In some embodiments, as described herein, ASO is expressed in concentrations of 10-250 mg / mL, 15-250 mg / mL, 20-250 mg / mL, 25-250 mg / mL, 30-250 mg / mL, 35-250 mg / mL, 40-250 mg / mL, 45-250 mg / mL, 50-250 mg / mL, 55-250 mg / mL, 60-250 mg / mL, 65-250 mg / mL, 70-250 mg / mL, 75-250 mg / mL, 80-250 mg / mL, 85-250 mg / mL, 90-250 mg / mL, 95-250 mg / mL, 100-250 mg / mL, 105-250 mg / mL, 110-250 mg / mL, 115-250 mg / mL, 120-250 mg / mL. mg / mL, 125-250 mg / mL, 130-250 mg / mL, 135-250 mg / mL, 140-250 mg / mL, 145-250mg / mL, 150-250 mg / mL, 155-250 mg / mL, 160-250 mg / mL, 165-250 mg / mL, 170-250 mg / mL, 175-250 mg / mL, 180-250 mg / mL, 185-250 mg / mL, 190-250 mg / mL, or 195-250 mg / mL, 200-250 mg / mL, 205-250 mg / mL, 210-250 mg / mL, 215-250 mg / mL, 220-250 mg / mL, 225-250 mg / mL, 230-250 235-250 mg / mL, 240-250 mg / mL, or 245-250 mg / mL are present in the pharmaceutical composition at concentrations of 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, or 7 mg / mL. In some embodiments, ASO as described herein is present in concentrations of at least 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, or 7 mg / mL.mg / mL、8 mg / mL、9 mg / mL、10 mg / mL、11 mg / mL、12 mg / mL、13 mg / mL、14 mg / mL、15 mg / mL、16 mg / mL、17 mg / mL、18 mg / mL、19 mg / mL、20 mg / mL、21 mg / mL、22mg / mL、23 mg / mL、24 mg / mL、25 mg / mL、26 mg / mL、27 mg / mL、28 mg / mL、29 mg / mL、30 mg / mL、31 mg / mL、32 mg / mL、33 mg / mL、34 mg / mL、35 mg / mL、36 mg / mL、37 mg / mL、38 mg / mL、39mg / mL、40 mg / mL、41 mg / mL、42 mg / mL、43 mg / mL、44 mg / mL、45 mg / mL、46 mg / mL、47 mg / mL、48 mg / mL、49 mg / mL、50 mg / mL、51 mg / mL、52 mg / mL、53 mg / mL、54 mg / mL、55 mg / mL、56mg / mL、57 mg / mL、58 mg / mL、59 mg / mL、60 mg / mL、61 mg / mL、62 mg / mL、63 mg / mL、64 mg / mL、65 mg / mL、66 mg / mL、67 mg / mL、68 mg / mL、69 mg / mL、70 mg / mL、71 mg / mL、72 mg / mL、73mg / mL、74 mg / mL、75 mg / mL、76 mg / mL、77 mg / mL、78 mg / mL、79 mg / mL、80 mg / mL、81 mg / mL、82 mg / mL、83 mg / mL、84 mg / mL、85 mg / mL、86 mg / mL、87 mg / mL、88 mg / mL、89 mg / mL、90mg / mL、91 mg / mL、92 mg / mL、93 mg / mL、94 mg / mL、95 mg / mL、96 mg / mL、97 mg / mL、98 mg / mL、99 mg / mL、100 mg / mL、101 mg / mL、102 mg / mL、103 mg / mL、104 mg / mL、105 mg / mL、106mg / mL、107 mg / mL、108 mg / mL、109 mg / mL、110 mg / mL、111 mg / mL、112 mg / mL、113 mg / mL、114 mg / mL、115 mg / mL、116 mg / mL、117mg / mL、118 mg / mL、119 mg / mL、120 mg / mL、121 mg / mL、122 mg / mL、123 mg / mL、124 mg / mL、125 mg / mL、126 mg / mL、127 mg / mL、128 mg / mL、129mg / mL、130 mg / mL、131 mg / mL、132 mg / mL、133 mg / mL、134 mg / mL、135 mg / mL、136 mg / mL、137 mg / mL、138 mg / mL、139 mg / mL、140 mg / mL、141 mg / mL、142 mg / mL、143 mg / mL、144 mg / mL、145 mg / mL、146 mg / mL、147 mg / mL、148 mg / mL、149 mg / mL、150 mg / mL、151 mg / mL、152mg / mL、153 mg / mL、154 mg / mL、155 mg / mL、156 mg / mL、157 mg / mL、158 mg / mL、159 mg / mL、160 mg / mL、161 mg / mL、162 mg / mL、163 mg / mL、164 mg / mL、165 mg / mL、166 mg / mL、167 mg / mL、168 mg / mL、169 mg / mL、170 mg / mL、171 mg / mL、172 mg / mL、173 mg / mL、174 mg / mL、175mg / mL、176 mg / mL、177 mg / mL、178 mg / mL、179 mg / mL、180 mg / mL、181 mg / mL、182 mg / mL、183 mg / mL、184 mg / mL、185 mg / mL、186 mg / mL、187 mg / mL、188 mg / mL、189 mg / mL、190 mg / mL、191 mg / mL、192 mg / mL、193 mg / mL、194 mg / mL、195 mg / mL、196 mg / mL、197 mg / mL、198mg / mL、199 mg / mL、200 mg / mL、210 mg / mL、211 mg / mL、212 mg / mL、213 mg / mL、214 mg / mL、215 mg / mL、216 mg / mL、217 mg / mL、218 mg / mL、219 mg / mL、220 mg / mL、221 mg / mL、222 mg / mL、223 mg / mL、224 mg / mL、225 mg / mL、226Concentrations of mg / mL, 227 mg / mL, 228 mg / mL, 229 mg / mL, 230 mg / mL, 231 mg / mL, 232 mg / mL, 233 mg / mL, 234 mg / mL, 235 mg / mL, 236 mg / mL, 237 mg / mL, 238 mg / mL, 239 mg / mL, 240 mg / mL, 241 mg / mL, 242 mg / mL, 243 mg / mL, 244 mg / mL, 245 mg / mL, 246 mg / mL, 247 mg / mL, 248 mg / mL, 249 mg / mL or 250 mg / mL are present in the pharmaceutical composition. In some embodiments, the ASO as described herein is at a concentration of up to 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 21 mg / mL, 22 mg / mL, 23 mg / mL, 24 mg / mL, 25 mg / mL, 26 mg / mL, 27 mg / mL, 28 mg / mL, 29 mg / mL, 30 mg / mL, 31 mg / mL, 32 mg / mL, 33 mg / mL, 34 mg / mL, 35 mg / mL, 36 mg / mL, 37 mg / mL, 38 mg / mL, 39 mg / mL, 40 mg / mL, 41 mg / mL, 42 mg / mL, 43 mg / mL, 44 mg / mL, 45 mg / mL, 46 mg / mL, 47 mg / mL, 48 mg / mL, 49 mg / mL, 50 mg / mL, 51 mg / mL, 52 mg / mL, 53 mg / mL, 54 mg / mL, 55 mg / mL, 56 mg / mL, 57 mg / mL, 58 mg / mL, 59 mg / mL, 60 mg / mL, 61 mg / mL, 62 mg / mL, 63 mg / mL, 64 mg / mL, 65 mg / mL, 66 mg / mL, 67 mg / mL, 68 mg / mL, 69 mg / mL, 7mg / mL、82mg / mL、83 mg / mL、84 mg / mL、85 mg / mL、86 mg / mL、87 mg / mL、88 mg / mL、89 mg / mL、90 mg / mL、91 mg / mL、92 mg / mL、93 mg / mL、94 mg / mL、95 mg / mL、96 mg / mL、97 mg / mL、98 mg / mL、99mg / mL、100 mg / mL、101 mg / mL、102 mg / mL、103 mg / mL、104 mg / mL、105 mg / mL、106 mg / mL、107 mg / mL、108 mg / mL、109 mg / mL、110 mg / mL、111 mg / mL、112 mg / mL、113 mg / mL、114 mg / mL、115 mg / mL、116 mg / mL、117 mg / mL、118 mg / mL、119 mg / mL、120 mg / mL、121 mg / mL、122mg / mL、123 mg / mL、124 mg / mL、125 mg / mL、126 mg / mL、127 mg / mL、128 mg / mL、129 mg / mL、130 mg / mL、131 mg / mL、132 mg / mL、133 mg / mL、134 mg / mL、135 mg / mL、136 mg / mL、137 mg / mL、138 mg / mL、139 mg / mL、140 mg / mL、141 mg / mL、142 mg / mL、143 mg / mL、144 mg / mL、145mg / mL、146 mg / mL、147 mg / mL、148 mg / mL、149 mg / mL、150 mg / mL、151 mg / mL、152 mg / mL、153 mg / mL、154 mg / mL、155 mg / mL、156 mg / mL、157 mg / mL、158 mg / mL、159 mg / mL、160 mg / mL、161 mg / mL、162 mg / mL、163 mg / mL、164 mg / mL、165 mg / mL、166 mg / mL、167 mg / mL、168mg / mL、169 mg / mL、170 mg / mL、171 mg / mL、172 mg / mL、173 mg / mL、174 mg / mL、175 mg / mL、176 mg / mL、177 mg / mL、178 mg / mL、179 mg / mL、180 mg / mL、181 mg / mL、182 mg / mL、183Concentrations of mg / mL, 184 mg / mL, 185 mg / mL, 186 mg / mL, 187 mg / mL, 188 mg / mL, 189 mg / mL, 190 mg / mL, 191 mg / mL, 192 mg / mL, 193 mg / mL, 194 mg / mL, 195 mg / mL, 196 mg / mL, 197 mg / mL, 198 mg / mL, 199 mg / mL, 200 mg / mL, 210 mg / mL, 211 mg / mL, 212 mg / mL, 213 mg / mL, 214 mg / mL, 215 mg / mL, 216 mg / mL, 217 mg / mL, 218 mg / mL, 219 mg / mL, 220 mg / mL, 221 mg / mL, 222 mg / mL, 223 mg / mL, 224 mg / mL, 225 mg / mL, 226 mg / mL, 227 mg / mL, 228 mg / mL, 229 mg / mL, 230 mg / mL, 231 mg / mL, 232 mg / mL, 233 mg / mL, 234 mg / mL, 235 mg / mL, 236 mg / mL, 237 mg / mL, 238 mg / mL, 239 mg / mL, 240 mg / mL, 241 mg / mL, 242 mg / mL, 243 mg / mL, 244 mg / mL, 245 mg / mL, 246 mg / mL, 247 mg / mL, 248 mg / mL, 249 mg / mL or 250 mg / mL are present in the pharmaceutical composition. In some embodiments, the ASO as described herein is at 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 21 mg / mL, 22 mg / mL, 23 mg / mL, 24 mg / mL, 25 mg / mL, 26 mg / mL, 27 mg / mL, 28 mg / mL, 29 mg / mL, 30 mg / mL, 31 mg / mL, 32 mg / mL, 33 mg / mL, 34 mg / mL, [35 mg / mL, 36 mg / mL, 37 mg / mL, 38 mg / mL, 39 mg / mL, 40 mg / mL, 41 mg / mL, 42 mg / mL, 43 mg / mL, 44 mg / mL, 45mg / mL、46 mg / mL、47 mg / mL、48 mg / mL、49 mg / mL、50 mg / mL、51 mg / mL、52 mg / mL、53 mg / mL、54 mg / mL、55 mg / mL、56 mg / mL、57 mg / mL、58mg / mL、59 mg / mL、60 mg / mL、61 mg / mL、62 mg / mL、63 mg / mL、64 mg / mL、65 mg / mL、66 mg / mL、67 mg / mL、68 mg / mL、69 mg / mL、70 mg / mL、71 mg / mL、72 mg / mL、73 mg / mL、74 mg / mL、75mg / mL、76 mg / mL、77 mg / mL、78 mg / mL、79 mg / mL、80 mg / mL、81 mg / mL、82 mg / mL、83 mg / mL、84 mg / mL、85 mg / mL、86 mg / mL、87 mg / mL、88 mg / mL、89 mg / mL、90 mg / mL、91 mg / mL、92mg / mL、93 mg / mL、94 mg / mL、95 mg / mL、96 mg / mL、97 mg / mL、98 mg / mL、99 mg / mL、100 mg / mL、101 mg / mL、102 mg / mL、103 mg / mL、104 mg / mL、105 mg / mL、106 mg / mL、107 mg / mL、108mg / mL、109 mg / mL、110 mg / mL、111 mg / mL、112 mg / mL、113 mg / mL、114 mg / mL、115 mg / mL、116 mg / mL、117 mg / mL、118 mg / mL、119 mg / mL、120 mg / mL、121 mg / mL、122 mg / mL、123 mg / mL、124 mg / mL、125 mg / mL、126 mg / mL、127 mg / mL、128 mg / mL、129 mg / mL、130 mg / mL、131mg / mL、132 mg / mL、133 mg / mL、134 mg / mL、135 mg / mL、136 mg / mL、137 mg / mL、138 mg / mL、139 mg / mL、140 mg / mL、141 mg / mL、142 mg / mL、143 mg / mL、144 mg / mL、145 mg / mL、146 mg / mL、147 mg / mL、148 mg / mL、149 mg / mL、150 mg / mL、151Concentrations of mg / mL, 152 mg / mL, 153 mg / mL, 154 mg / mL, 155 mg / mL, 156 mg / mL, 157 mg / mL, 158 mg / mL, 159 mg / mL, 160 mg / mL, 161 mg / mL, 162 mg / mL, 163 mg / mL, 164 mg / mL, 165 mg / mL, 166 mg / mL, 167 mg / mL, 168 mg / mL, 169 mg / mL, 170 mg / mL, 171 mg / mL, 172 mg / mL, 173 mg / mL, 174 mg / mL, 175 mg / mL, 176 mg / mL, 177 mg / mL, 178 mg / mL, 179 mg / mL, 180 mg / mL, 181 mg / mL, 182 mg / mL, 183 mg / mL, 184 mg / mL, 185 mg / mL, 186 mg / mL, 187 mg / mL, 188 mg / mL, 189 mg / mL, 190 mg / mL, 191 mg / mL, 192 mg / mL, 193 mg / mL, 194 mg / mL, 195 mg / mL, 196 mg / mL, 197 mg / mL, 198 mg / mL, 199 mg / mL, 200 mg / mL, 210 mg / mL, 211 mg / mL, 212 mg / mL, 213 mg / mL, 214 mg / mL, 215 mg / mL, 216 mg / mL, 217 mg / mL, 218 mg / mL, 219 mg / mL, 220 mg / mL, 221 mg / mL, 222 mg / mL, 223 mg / mL, 224 mg / mL, 225 mg / mL, 226 mg / mL, 227 mg / mL, 228 mg / mL, 229 mg / mL, 230 mg / mL, 231 mg / mL, 232 mg / mL, 233 mg / mL, 234 mg / mL, 235 mg / mL, 236 mg / mL, 237 mg / mL, 238 mg / mL, 239 mg / mL, 240 mg / mL, 241 mg / mL, 242 mg / mL, 243 mg / mL, 244 mg / mL, 245 mg / mL, 246 mg / mL, 247 mg / mL, 248 mg / mL, 249 mg / mL or 250 mg / mL are present in the pharmaceutical composition.

[0362] In some embodiments, ASO as described herein is present in the pharmaceutical composition at concentrations from 0.1 mg / mL to 250 mg / mL. In some embodiments, ASO as described herein is present in the pharmaceutical composition at concentrations of about 0.1 mg / mL, 0.5 mg / mL, 1 mg / mL, 2 mg / mL, 2.5 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, or 20 mg / mL. In some embodiments, the ASO as described herein is present in the pharmaceutical composition at concentrations of about 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, 150 mg / mL, 160 mg / mL, 170 mg / mL, 180 mg / mL, 190 mg / mL, or 200 mg / mL. In some embodiments, the ASO as described herein is present in the pharmaceutical composition at concentrations of about 11 mg / mL, 22 mg / mL, 33 mg / mL, 44 mg / mL, 55 mg / mL, 66 mg / mL, 77 mg / mL, 88 mg / mL, 99 mg / mL, or 100 mg / mL in a diluent.

[0363] In some embodiments, as described herein, ASO is administered at doses of 0.1 mg / mL to 250 mg / mL, 0.2 mg / mL to 250 mg / mL, 0.3 mg / mL to 250 mg / mL, 0.4 mg / mL to 250 mg / mL, 0.5 mg / mL to 250 mg / mL, 0.6 mg / mL to 250 mg / mL, 0.7 mg / mL to 250 mg / mL, 0.8 mg / mL to 250 mg / mL, 0.9 mg / mL to 250 mg / mL, 1.0 mg / mL to 250 mg / mL, 1.1 mg / mL to 250 mg / mL, 1.2 mg / mL to 250 mg / mL, 1.3 mg / mL to 250 mg / mL, 1.4 mg / mL to 250 mg / mL, 1.5 mg / mL to 250 mg / mL, 1.6 mg / mL to 250 mg / mL, and 1.7 mg / mL to 250 mg / mL. mg / mL, 1.8 mg / mL to 250 mg / mL, 1.9 mg / mL to 250 mg / mL, 2.0 mg / mL to 250 mg / mL, 2.1 mg / mL to 250 mg / mL, 2.2 mg / mL to 250 mg / mL, 2.3 mg / mL to 250 mg / mL, 2.4 mg / mL to 250mg / mL, 2.5 mg / mL to 250 mg / mL, 2.6 mg / mL to 250 mg / mL, 2.7 mg / mL to 250 mg / mL, 2.8 mg / mL to 250 mg / mL, 2.9 mg / mL to 250 mg / mL, 3.0 mg / mL to 250 mg / mL, 3.1 mg / mL to 250 mg / mL, 3.2 mg / mL to 250 mg / mL, 3.3 mg / mL to 250 mg / mL, 3.4 mg / mL to 250 mg / mL, 3.5 mg / mL to 250 mg / mL, 3.6 mg / mL to 250 mg / mL, 3.7 mg / mL to 250 mg / mL, 3.8 mg / mL to 250 mg / mL, 3.9 mg / mL to 250 mg / mL, 4.0 mg / mL to 250 mg / mL, 5.0 mg / mL to 250 mg / mL, 6.0 mg / mL to 250 mg / mL, 7.0 mg / mL to 250 mg / mL, 8.0 mg / mL to 250 mg / mL, 9.0 mg / mL to 250 mg / mL, 10 mg / mL to 250 mg / mL, 15 mg / mL to 250 mg / mL, 20 mg / mL to 250 mg / mL, 25 mg / mL to 250 mg / mL, 30 mg / mL to 250 mg / mL, 35 mg / mL to 250 mg / mL, 40 mg / mL to 250 mg / mL, 45 mg / mL to 250 mg / mL, 50 mg / mL to 250 mg / mL, 55 mg / mL to 250 mg / mL, 60 mg / mL to 250 mg / mL, 65 mg / mL to 250 mg / mL, 70 mg / mL to 250 mg / mL, 75 mg / mL to 250 mg / mL, 80 mg / mL to 250 mg / mL, 85 mg / mL to 250 mg / mL, 90 mg / mL to 250 mg / mL, 95 mg / mL to 250 mg / mL mg / mL, 100 mg / mL to 250 mg / mL, 105 mg / mL to 250 mg / mL, 110 mg / mL to 250 mg / mL, 115 mg / mL to 250 mg / mL, 120 mg / mL to 250 mg / mL, 125 mg / mL to 250 mg / mL, 130 mg / mL to 250 mg / mL, 135 mg / mL to 250 mg / mL, 140 mg / mL to 250 mg / mL, 145 mg / mL to 250 mg / mL, 150 mg / mL to 250 mg / mL, 155 mg / mL to 250 mg / mL, 160 mg / mL to 250 mg / mL, 165 mg / mL to 250 mg / mL, 170 mg / mL to 250 mg / mL, 175 mg / mL to 250 mg / mL, 180 mg / mL to 250 mg / mL, 185 Concentrations of 190 mg / mL to 250 mg / mL, 195 mg / mL to 250 mg / mL, 200 mg / mL to 250 mg / mL, 205 mg / mL to 250 mg / mL, 210 mg / mL to 250 mg / mL, 215 mg / mL to 250 mg / mL, 220 mg / mL to 250 mg / mL, 225 mg / mL to 250 mg / mL, 230 mg / mL to 250 mg / mL, 235 mg / mL to 250 mg / mL, 240 mg / mL to 250 mg / mL, or 245 mg / mL to 250 mg / mL are present in the pharmaceutical composition.

[0364] In some embodiments, as described herein, ASO is administered at doses ranging from 0.1 mg / mL to 250 mg / mL, 0.1 mg / mL to 245 mg / mL, 0.1 mg / mL to 240 mg / mL, 0.1 mg / mL to 235 mg / mL, 0.1 mg / mL to 230 mg / mL, 0.1 mg / mL to 225 mg / mL, 0.1 mg / mL to 220 mg / mL, 0.1 mg / mL to 215 mg / mL, 0.1 mg / mL to 210 mg / mL, 0.1 mg / mL to 205 mg / mL, 0.1 mg / mL to 200 mg / mL, 0.1 mg / mL to 195 mg / mL, 0.1 mg / mL to 190 mg / mL, 0.1 mg / mL to 185 mg / mL, 0.1 mg / mL to 180 mg / mL, 0.1 mg / mL to 175 mg / mL, and 0.1 mg / mL to 170 mg / mL. mg / mL, 0.1 mg / mL to 165 mg / mL, 0.1 mg / mL to 160 mg / mL, 0.1 mg / mL to 155 mg / mL, 0.1 mg / mL to 150 mg / mL, 0.1 mg / mL to 145 mg / mL, 0.1 mg / mL to 140 mg / mL, 0.1 mg / mL to 135mg / mL, 0.1 mg / mL to 130 mg / mL, 0.1 mg / mL to 125 mg / mL, 0.1 mg / mL to 120 mg / mL, 0.1 mg / mL to 115 mg / mL, 0.1 mg / mL to 110 mg / mL, 0.1 mg / mL to 100 mg / mL, 0.1 mg / mL to 95 mg / mL, 0.1 mg / mL to 90 mg / mL, 0.1 mg / mL to 85 mg / mL, 0.1 mg / mL to 80 mg / mL, 0.1 mg / mL to 75 mg / mL, 0.1 mg / mL to 70 mg / mL, 0.1 mg / mL to 65 mg / mL, 0.1 mg / mL to 60 mg / mL, 0.1 mg / mL to 55 mg / mL, 0.1 mg / mL to 50 mg / mL, 0.1 mg / mL to 45 mg / mL, 0.1 mg / mL to 40 mg / mL, 0.1 mg / mL to 35 mg / mL, 0.1 mg / mL to 30 mg / mL, 0.1 mg / mL to 25 mg / mL, 0.1 mg / mL to 20 mg / mL, 0.1 mg / mL to 15 mg / mL, 0.1 mg / mL to 10 mg / mL, 0.1 mg / mL to 9 mg / mL, 0.1 mg / mL to 8 mg / mL, 0.1 mg / mL to 7 mg / mL, 0.1 mg / mL to 6 mg / mL, 0.1 mg / mL to 5 mg / mL, 0.1 mg / mL to 4 mg / mL, 0.1 mg / mL to 3.9 mg / mL, 0.1 mg / mL to 3.8 mg / mL, 0.1 mg / mL to 3.7 mg / mL, 0.1 mg / mL to 3.6 mg / mL, 0.1 mg / mL to 3.5 mg / mL, 0.1 mg / mL to 3.4 mg / mL, 0.1 mg / mL to 3.3 mg / mL, 0.1 mg / mL to 3.2 mg / mL, 0.1 mg / mL to 3.1 mg / mL, 0.1 mg / mL to 3.0 mg / mL, 0.1 mg / mL to 2.9 mg / mL, 0.1 mg / mL to 2.8 mg / mL, 0.1 mg / mL to 2.7 mg / mL, 0.1 mg / mL to 2.6 mg / mL, 0.1 mg / mL to 2.5 mg / mL, 0.1 mg / mL to 2.4 mg / mL, 0.1 mg / mL to 2.3 mg / mL, 0.1 mg / mL to 2.2 mg / mL, 0.1 mg / mL to 2.1 mg / mL, 0.1 mg / mL to 2.0 mg / mL, 0.1 mg / mL to 1.9 mg / mL, 0.1 mg / mL to 1.8 mg / mL, 0.1 mg / mL to 1.7 mg / mL, 0.1 mg / mL to 1.6 mg / mL, 0.1 mg / mL to 1.5 mg / mL, 0.1 mg / mL to 1.4 mg / mL, 0.1 mg / mL to 1.3 mg / mL, 0.1 mg / mL to 1.2 mg / mL, 0.1 mg / mL to 1.1 mg / mL, 0.1 mg / mL to 1.0 mg / mL, 0.1 mg / mL to 0.9 mg / mL, 0.1 mg / mL to 0.8 The drug composition is present at concentrations of 0.1 mg / mL to 0.7 mg / mL, 0.1 mg / mL to 0.6 mg / mL, 0.1 mg / mL to 0.5 mg / mL, 0.1 mg / mL to 0.4 mg / mL, 0.1 mg / mL to 0.3 mg / mL, or 0.1 mg / mL to 0.2 mg / mL.

[0365] In some embodiments, the ASO as described herein is at least 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1.0 mg / mL, 1.1 mg / mL, 1.2 mg / mL, 1.3 mg / mL, 1.4 mg / mL, 1.5 mg / mL, 1.6 mg / mL, 1.7 mg / mL, 1.8 mg / mL, 1.9 mg / mL, 2.0 mg / mL, 2.1 mg / mL, 2.2 mg / mL, 2.3 mg / mL, 2.4 mg / mL, 2.5 mg / mL, 2.6 mg / mL, 2.7 mg / mL, 2.8 mg / mL, 2.9 mg / mL, 3.0 mg / mL, 3.1 mg / mL, 3.2 mg / mL, 3.3 mg / mL, 3.4 mg / mL, 3.5 mg / mL, 3.6 mg / mL, 3.7 mg / mL, 3.8 mg / mL, 3.9 mg / mL, 4.0 mg / mL, 4.1 mg / mL, 4.2 mg / mL, 4.3 mg / mL, 4.4 mg / mL, 4.5 mg / mL, 4.6 mg / mL, 4.7 mg / mL, 4.8 mg / mL, 4.9 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 21 mg / mL, 22 mg / mL, 23 mg / mL, 24 mg / mL, 25 mg / mL, 26 mg / mL, 27 mg / mL, 28 mg / mL, 29 mg / mL, 30 mg / mL, 31 mg / mL, 32 mg / mL, 33 mg / mL, 34 mg / mL, 35 mg / mL, 36 mg / mL, 37 mg / mL, 38 mg / mL, 39 mg / mL, 40 mg / mL, 41 mg / mL, 42 mg / mL, 43 mg / mL, 44 mg / mL, 45 mg / mL, 46 mg / mL, 47 mg / mL, 48 mg / mL, 49 mg / mL, 50 mg / mL, 51 mg / mL, 52 mg / mL, 53 mg / mL, 54 mg / mL, 55 mg / mL, 56 mg / mL, 57 mg / mL, 58 mg / mL, 59mg / mL、60 mg / mL、61 mg / mL、62 mg / mL、63 mg / mL、64mg / mL、65 mg / mL、66 mg / mL、67 mg / mL、68 mg / mL、69 mg / mL、70 mg / mL、71 mg / mL、72 mg / mL、73 mg / mL、74 mg / mL、75 mg / mL、76 mg / mL、77 mg / mL、78 mg / mL、79 mg / mL、80 mg / mL、81mg / mL、82 mg / mL、83 mg / mL、84 mg / mL、85 mg / mL、86 mg / mL、87 mg / mL、88 mg / mL、89 mg / mL、90 mg / mL、91 mg / mL、92 mg / mL、93 mg / mL、94 mg / mL、95 mg / mL、96 mg / mL、97 mg / mL、98mg / mL、99 mg / mL、100 mg / mL、101 mg / mL、102 mg / mL、103 mg / mL、104 mg / mL、105 mg / mL、106 mg / mL、107 mg / mL、108 mg / mL、109 mg / mL、110 mg / mL、111 mg / mL、112 mg / mL、113 mg / mL、114 mg / mL、115 mg / mL、116 mg / mL、117 mg / mL、118 mg / mL、119 mg / mL、120 mg / mL、121mg / mL、122 mg / mL、123 mg / mL、124 mg / mL、125 mg / mL、126 mg / mL、127 mg / mL、128 mg / mL、129 mg / mL、130 mg / mL、131 mg / mL、132 mg / mL、133 mg / mL、134 mg / mL、135 mg / mL、136 mg / mL、137 mg / mL、138 mg / mL、139 mg / mL、140 mg / mL、141 mg / mL、142 mg / mL、143 mg / mL、144mg / mL、145 mg / mL、146 mg / mL、147 mg / mL、148 mg / mL、149 mg / mL、150 mg / mL、151 mg / mL、152 mg / mL、153 mg / mL、154 mg / mL、155 mg / mL、156 mg / mL、157 mg / mL、158 mg / mL、159 mg / mL、160 mg / mL、161 mg / mL、162 mg / mL、163Concentrations of mg / mL, 164 mg / mL, 165 mg / mL, 166 mg / mL, 167 mg / mL, 168 mg / mL, 169 mg / mL, 170 mg / mL, 171 mg / mL, 172 mg / mL, 173 mg / mL, 174 mg / mL, 175 mg / mL, 176 mg / mL, 177 mg / mL, 178 mg / mL, 179 mg / mL, 180 mg / mL, 181 mg / mL, 182 mg / mL, 183 mg / mL, 184 mg / mL, 185 mg / mL, 186 mg / mL, 187 mg / mL, 188 mg / mL, 189 mg / mL, 190 mg / mL, 191 mg / mL, 192 mg / mL, 193 mg / mL, 194 mg / mL, 195 mg / mL, 196 mg / mL, 197 mg / mL, 198 mg / mL, 199 mg / mL, 200 mg / mL, 210 mg / mL, 211 mg / mL, 212 mg / mL, 213 mg / mL, 214 mg / mL, 215 mg / mL, 216 mg / mL, 217 mg / mL, 218 mg / mL, 219 mg / mL, 220 mg / mL, 221 mg / mL, 222 mg / mL, 223 mg / mL, 224 mg / mL, 225 mg / mL, 226 mg / mL, 227 mg / mL, 228 mg / mL, 229 mg / mL, 230 mg / mL, 231 mg / mL, 232 mg / mL, 23३ mg / mL, 234 mg / mL, 235 mg / mL, 236 mg / mL, 237 mg / mL, 238 mg / mL, 239 mg / mL, 240 mg / mL, 241 mg / mL, 242 mg / mL, 243 mg / mL, 244 mg / mL, 245 mg / mL, 246 mg / mL, 247 mg / mL, 248 mg / mL, 249 mg / mL or 250 mg / mL are present in the pharmaceutical composition. In some embodiments, the ASO as described herein is at most 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1.0 mg / mL, 1.1 mg / mL, 1.2 mg / mL, 1.3 mg / mL, 1.4 mg / mL, 1.5 mg / mL, 1.6 mg / mL, 1.7 mg / mL, 1.8mg / mL、1.9 mg / mL、2.0 mg / mL、2.1 mg / mL、2.2 mg / mL、2.3 mg / mL、2.4 mg / mL、2.5 mg / mL、2.6mg / mL、2.7 mg / mL、2.8 mg / mL、2.9 mg / mL、3.0 mg / mL、3.1 mg / mL、3.2 mg / mL、3.3 mg / mL、3.4 mg / mL、3.5 mg / mL、3.6 mg / mL、3.7 mg / mL、3.8 mg / mL、3.9 mg / mL、4.0 mg / mL、4.1 mg / mL、4.2 mg / mL、4.3 mg / mL、4.4 mg / mL、4.5 mg / mL、4.6 mg / mL、4.7 mg / mL、4.8 mg / mL、4.9mg / mL、5 mg / mL、6 mg / mL、7 mg / mL、8 mg / mL、9 mg / mL、10 mg / mL、11 mg / mL、12 mg / mL、13mg / mL、14 mg / mL、15 mg / mL、16 mg / mL、17 mg / mL、18 mg / mL、19 mg / mL、20 mg / mL、21 mg / mL、22 mg / mL、23 mg / mL、24 mg / mL、25 mg / mL、26 mg / mL、27 mg / mL、28 mg / mL、29 mg / mL、30mg / mL、31 mg / mL、32 mg / mL、33 mg / mL、34 mg / mL、35 mg / mL、36 mg / mL、37 mg / mL、38 mg / mL、39 mg / mL、40 mg / mL、41 mg / mL、42 mg / mL、43 mg / mL、44 mg / mL、45 mg / mL、46 mg / mL、47mg / mL、48 mg / mL、49 mg / mL、50 mg / mL、51 mg / mL、52 mg / mL、53 mg / mL、54 mg / mL、55 mg / mL、56 mg / mL、57 mg / mL、58 mg / mL、59 mg / mL、60 mg / mL、61 mg / mL、62 mg / mL、63 mg / mL、64mg / mL、65 mg / mL、66 mg / mL、67 mg / mL、68 mg / mL、69 mg / mL、70 mg / mL、71 mg / mL、72 mg / mL、73 mg / mL、74 mg / mL、75 mg / mL、76 mg / mL、77 mg / mL、78 mg / mL、79 mg / mL、80 mg / mL、81mg / mL、82mg / mL、83 mg / mL、84 mg / mL、85 mg / mL、86 mg / mL、87 mg / mL、88 mg / mL、89 mg / mL、90 mg / mL、91 mg / mL、92 mg / mL、93 mg / mL、94 mg / mL、95 mg / mL、96 mg / mL、97 mg / mL、98mg / mL、99 mg / mL、100 mg / mL、101 mg / mL、102 mg / mL、103 mg / mL、104 mg / mL、105 mg / mL、106 mg / mL、107 mg / mL、108 mg / mL、109 mg / mL、110 mg / mL、111 mg / mL、112 mg / mL、113 mg / mL、114 mg / mL、115 mg / mL、116 mg / mL、117 mg / mL、118 mg / mL、119 mg / mL、120 mg / mL、121mg / mL、122 mg / mL、123 mg / mL、124 mg / mL、125 mg / mL、126 mg / mL、127 mg / mL、128 mg / mL、129 mg / mL、130 mg / mL、131 mg / mL、132 mg / mL、133 mg / mL、134 mg / mL、135 mg / mL、136 mg / mL、137 mg / mL、138 mg / mL、139 mg / mL、140 mg / mL、141 mg / mL、142 mg / mL、143 mg / mL、144mg / mL、145 mg / mL、146 mg / mL、147 mg / mL、148 mg / mL、149 mg / mL、150 mg / mL、151 mg / mL、152 mg / mL、153 mg / mL、154 mg / mL、155 mg / mL、156 mg / mL、157 mg / mL、158 mg / mL、159 mg / mL、160 mg / mL、161 mg / mL、162 mg / mL、163 mg / mL、164 mg / mL、165 mg / mL、166 mg / mL、167mg / mL、168 mg / mL、169 mg / mL、170 mg / mL、171 mg / mL、172 mg / mL、173 mg / mL、174 mg / mL、175 mg / mL、176 mg / mL、177 mg / mL、178 mg / mL、179 mg / mL、180 mg / mL、181 mg / mL、182 mg / mL、183 mg / mL、184Concentrations of mg / mL, 185 mg / mL, 186 mg / mL, 187 mg / mL, 188 mg / mL, 189 mg / mL, 190 mg / mL, 191 mg / mL, 192 mg / mL, 193 mg / mL, 194 mg / mL, 195 mg / mL, 196 mg / mL, 197 mg / mL, 198 mg / mL, 199 mg / mL, 200 mg / mL, 210 mg / mL, 211 mg / mL, 212 mg / mL, 213 mg / mL, 214 mg / mL, 215 mg / mL, 216 mg / mL, 217 mg / mL, 218 mg / mL, 219 mg / mL, 220 mg / mL, 221 mg / mL, 222 mg / mL, 223 mg / mL, 224 mg / mL, 225 mg / mL, 226 mg / mL, 227 mg / mL, 228 mg / mL, 229 mg / mL, 230 mg / mL, 231 mg / mL, 232 mg / mL, 233 mg / mL, 234 mg / mL, 235 mg / mL, 236 mg / mL, 237 mg / mL, 238 mg / mL, 239 mg / mL, 240 mg / mL, 241 mg / mL, 242 mg / mL, 243 mg / mL, 244 mg / mL, 245 mg / mL, 246 mg / mL, 247 mg / mL, 248 mg / mL, 249 mg / mL or 250 mg / mL are present in the pharmaceutical composition. In some embodiments, the ASO as described herein is at 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1.0 mg / mL, 1.1 mg / mL, 1.2 mg / mL, 1.3 mg / mL, 1.4 mg / mL, 1.5 mg / mL, 1.6 mg / mL, 1.7 mg / mL, 1.8 mg / mL, 1.9 mg / mL, 2.0 mg / mL, 2.1 mg / mL, 2.2 mg / mL, 2.3 mg / mL, 2.4 mg / mL, 2.5 mg / mL, 2.6 mg / mL, 2.7 mg / mL, 2.8 mg / mL, 2.9 mg / mL, 3.0 mg / mL, 3.1 mg / mL, 3.2 mg / mL, 3.3 mg / mL, 3.4 mg / mL, 3.5 mg / mL, 3.6 mg / mL, 3.7 mg / mL, 3.8 mg / mL, 3.9 mg / mL, 4.0mg / mL、4.1 mg / mL、4.2mg / mL、4.3 mg / mL、4.4 mg / mL、4.5 mg / mL、4.6 mg / mL、4.7 mg / mL、4.8 mg / mL、4.9 mg / mL、5mg / mL、6 mg / mL、7 mg / mL、8 mg / mL、9 mg / mL、10 mg / mL、11 mg / mL、12 mg / mL、13 mg / mL、14mg / mL、15 mg / mL、16 mg / mL、17 mg / mL、18 mg / mL、19 mg / mL、20 mg / mL、21 mg / mL、22 mg / mL、23 mg / mL、24 mg / mL、25 mg / mL、26 mg / mL、27 mg / mL、28 mg / mL、29 mg / mL、30 mg / mL、31mg / mL、32 mg / mL、33 mg / mL、34 mg / mL、35 mg / mL、36 mg / mL、37 mg / mL、38 mg / mL、39 mg / mL、40 mg / mL、41 mg / mL、42 mg / mL、43 mg / mL、44 mg / mL、45 mg / mL、46 mg / mL、47 mg / mL、48mg / mL、49 mg / mL、50 mg / mL、51 mg / mL、52 mg / mL、53 mg / mL、54 mg / mL、55 mg / mL、56 mg / mL、57 mg / mL、58 mg / mL、59 mg / mL、60 mg / mL、61 mg / mL、62 mg / mL、63 mg / mL、64 mg / mL、65mg / mL、66 mg / mL、67 mg / mL、68 mg / mL、69 mg / mL、70 mg / mL、71 mg / mL、72 mg / mL、73 mg / mL、74 mg / mL、75 mg / mL、76 mg / mL、77 mg / mL、78 mg / mL、79 mg / mL、80 mg / mL、81 mg / mL、82mg / mL、83 mg / mL、84 mg / mL、85 mg / mL、86 mg / mL、87 mg / mL、88 mg / mL、89 mg / mL、90 mg / mL、91 mg / mL、92 mg / mL、93 mg / mL、94 mg / mL、95 mg / mL、96 mg / mL、97 mg / mL、98 mg / mL、99mg / mL、100 mg / mL、101 mg / mL、102 mg / mL、103 mg / mL、104 mg / mL、105mg / mL、106 mg / mL、107 mg / mL、108 mg / mL、109 mg / mL、110 mg / mL、111 mg / mL、112 mg / mL、113 mg / mL、114 mg / mL、115 mg / mL、116 mg / mL、117 mg / mL、118 mg / mL、119 mg / mL、120 mg / mL、121 mg / mL、122mg / mL、123 mg / mL、124 mg / mL、125 mg / mL、126 mg / mL、127 mg / mL、128 mg / mL、129 mg / mL、130 mg / mL、131 mg / mL、132 mg / mL、133 mg / mL、134 mg / mL、135 mg / mL、136 mg / mL、137 mg / mL、138 mg / mL、139 mg / mL、140 mg / mL、141 mg / mL、142 mg / mL、143 mg / mL、144 mg / mL、145mg / mL、146 mg / mL、147 mg / mL、148 mg / mL、149 mg / mL、150 mg / mL、151 mg / mL、152 mg / mL、153 mg / mL、154 mg / mL、155 mg / mL、156 mg / mL、157 mg / mL、158 mg / mL、159 mg / mL、160 mg / mL、161 mg / mL、162 mg / mL、163 mg / mL、164 mg / mL、165 mg / mL、166 mg / mL、167 mg / mL、168mg / mL、169 mg / mL、170 mg / mL、171 mg / mL、172 mg / mL、173 mg / mL、174 mg / mL、175 mg / mL、176 mg / mL、177 mg / mL、178 mg / mL、179 mg / mL、180 mg / mL、181 mg / mL、182 mg / mL、183 mg / mL、184 mg / mL、185 mg / mL、186 mg / mL、187 mg / mL、188 mg / mL、189 mg / mL、190 mg / mL、191mg / mL、192 mg / mL、193 mg / mL、194 mg / mL、195 mg / mL、196 mg / mL、197 mg / mL、198 mg / mL、199 mg / mL、200 mg / mL、210 mg / mL、211 mg / mL、212 mg / mL、213 mg / mL、214mg / mL, 215 mg / mL, 216 mg / mL, 217 mg / mL, 218 mg / mL, 219 mg / mL, 220 mg / mL, 221 mg / mL, 222 mg / mL, 223mg / mL, 224 mg / mL, 225 mg / mL, 226 mg / mL, 227 mg / mL, 228 mg / mL, 229 mg / mL, 230 mg / mL, 231 mg / mL, 232 mg / mL, 233 mg / mL, 234 mg / mL, 235 mg / mL, 236 mg / mL, 237 mg / mL, 238 mg / mL, 239 mg / mL, 240 mg / mL, 241 mg / mL, 242 mg / mL, 243 mg / mL, 244 mg / mL, 245 mg / mL, 246mg / mL, 247 mg / mL, 248 mg / mL, 249 The pharmaceutical composition is present at a concentration of mg / mL or 250 mg / mL.

[0366] Pharmaceutical agents comprising the described compositions (e.g., antisense oligonucleotides or antisense oligomers) and pharmaceutical compositions used in any of the methods described herein can be prepared according to conventional techniques well known in the pharmaceutical industry and described in published literature. In some embodiments, a pharmaceutical composition for treating a subject comprises an effective amount of any antisense oligomer as described herein or a pharmaceutically acceptable salt, solvate, hydrate, or ester thereof. In some embodiments, the pharmaceutical compositions described herein further comprise pharmaceutically acceptable excipients, carriers, or diluents.

[0367] Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate the processing of active compounds into pharmaceutically usable formulations. Appropriate formulations depend on the chosen route of administration, and summaries of pharmaceutical compositions can be found, for example, in *Remington: The Science and Practice of Pharmacy*, 19th edition (Easton, Pa.: Mack Publishing Company, 1995); *Remington's Pharmaceutical Sciences*, Hoover, Easton, Pa., Mack Publishing Company, 1975; *Pharmaceutical Dosage Forms*, edited by Liberman, HA and Lachman, L., Marcel Decker, New York, NY, 1980; and *Pharmaceutical Dosage Forms and Drug Delivery Systems*, 7th edition (Lippincott Williams & Wilkins). (1999), the referenced document is incorporated herein by reference. In some embodiments, the pharmaceutical composition facilitates the administration of the compound to a living organism.

[0368] Such compositions may contain buffers, such as neutral buffered saline, phosphate buffered saline, etc.; carbohydrates, such as glucose, mannose, sucrose or dextran, mannitol; proteins; peptides or amino acids, such as glycine; antioxidants; chelating agents, such as EDTA or glutathione; adjuvants (e.g., aluminum hydroxide); and preservatives.

[0369] The terms “pharmaceutical composition” and “pharmaceutical formulation” (or “formulation”) are used interchangeably and refer to a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient and one or more pharmaceutically acceptable excipients to be administered to a subject (e.g., a person in need).

[0370] The term "pharmaceutically acceptable" refers to the properties of materials that can be used to prepare pharmaceutical compositions that are generally safe and non-toxic, and are not biologically or otherwise undesirable and are acceptable for veterinary and human use. "Pharmaceutically acceptable" can refer to materials such as carriers or diluents that do not impair the biological activity or properties of the compound and are relatively non-toxic; that is, the material can be administered to an individual without causing undesirable biological effects or interacting in a harmful manner with any component of the composition contained in the material.

[0371] The terms “pharmaceuticalally acceptable excipient,” “pharmaceuticalally acceptable carrier,” and “therapeutically inert excipient” are used interchangeably and refer to any pharmaceutically acceptable component in a pharmaceutical composition that is not therapeutically active and is non-toxic to the subject to which it is administered, such as disintegrants, binders, fillers, solvents, buffers, tension agents, stabilizers, antioxidants, surfactants, carriers, diluents, excipients, preservatives, or lubricants used in the formulation of pharmaceutical products.

[0372] In some embodiments, the composition is prepared together with a carrier that protects the components of the composition from rapid elimination from the body, such as a controlled-release formulation comprising implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations will be readily apparent to those skilled in the art. The materials are also commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposome suspensions (including liposomes targeting infected cells with monoclonal antibodies against viral antigens) can also be used as pharmaceutically acceptable carriers. These materials can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811, the entire contents of which are incorporated herein by reference.

[0373] Pharmaceutical agents comprising the described compositions (e.g., antisense oligonucleotides) and pharmaceutical compositions or formulations used in any of the described methods can be prepared according to conventional techniques well known in the pharmaceutical industry and described in published literature. In examples, pharmaceutical compositions or formulations for treating a subject comprise an effective amount of any antisense oligomer as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or ester thereof. Pharmaceutical formulations comprising antisense oligomers may further comprise pharmaceutically acceptable excipients, carriers, or diluents.

[0374] Pharmaceutically acceptable salts are suitable for contact with tissues in humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and are proportionate to a reasonable benefit / risk ratio. (See, for example, SM Berge et al., *Journal of Pharmaceutical Sciences*, 66: 1-19 (1977), which is incorporated herein by reference for this purpose). Salts can be prepared in situ during the final isolation and purification of the compound, or by reacting the free base functional group with a suitable organic acid. Examples of pharmaceutically acceptable, non-toxic acid addition salts are those formed by the amino group with acids or by other methods described in the literature, such as ion exchange: inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid; or organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-heptate, glyceryl phosphate, gluconate, hemisulfate, heptaate, hydroiodate, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations that resist counterion formation, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0375] In some embodiments, this document provides a method for producing a pharmaceutical composition as described herein.

[0376] Pharmaceutical formulation In some aspects, this document provides a pharmaceutical formulation comprising: an antisense oligomer (as described herein, ASO), wherein the ASO as described herein comprises a sequence having at least 80% sequence identity with any one of SEQ ID NO: 21-67, 210-256, or 304-1099; and a pharmaceutically acceptable diluent; wherein approximately 0.1 mg, 0.5 mg, 1 mg, 2.5 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg, 40 mg, 42.5 mg, 45 mg, 47.5 mg, 50 mg, 52.5 mg, 55 mg, 57.5 mg, 60 mg, etc. mg, 62.5mg, 65 mg, 67.5 mg, 70 mg, 72.5 mg, 75 mg, 77.5 mg, 80 mg, 82.5 mg, 85 mg, 87.5 mg, 90mg, 92.5 mg, 95 mg, 97.5 mg, 100 mg, 102.5 mg, 105 mg, 107.5 mg, 110 mg, 112.5 mg, 115mg, 117.5 mg, 120 mg, 122.5 mg, 125 mg, 127.5 mg, 130 mg, 132.5 mg, 135 mg, 137.5 mg, 140 mg, 142.5 mg, 145 mg, 147.5 mg, 150 mg, 152.5 mg, 155 mg, 157.5 mg, 160 mg, 162.5mg, 165 mg, 167.5 ASO as described herein is dissolved or suspended in solution at concentrations ranging from 0.1 to 250 mg / mL. (The table lists various ASO concentrations, including 170 mg, 172.5 mg, 175 mg, 177.5 mg, 180 mg, 182.5 mg, 185 mg, 187.5 mg, 190 mg, 192.5 mg, 195 mg, 197.5 mg, 200 mg, 202.5 mg, 205 mg, 207.5 mg, 210 mg, 212.5 mg, 215 mg, 217.5 mg, 220 mg, 222.5 mg, 225 mg, 227.5 mg, 230 mg, 232.5 mg, 235 mg, 237.5 mg, 240 mg, 242.5 mg, 245 mg, 247.5 mg, or 250 mg.)In some embodiments, the ASO as described herein includes a sequence that has at least 80% sequence identity with any of the sequences listed in Tables 4A, 4B, 5A, 5B, 6A, 6B, 7, 8A and 8B.

[0377] In some embodiments, the ASO as described herein comprises a sequence having at least 60%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 884%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.8%, 99.9%, or 100% sequence identity with any of SEQ ID NO: 21-67, 210-256, or 304-1099. In some embodiments, the ASO as described herein consists of a sequence having at least 60%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 884%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.8%, 99.9%, or 100% sequence identity with any of SEQ ID NO: 21-67, 210-256, or 304-1099. In some embodiments, an ASO as described herein consists of a sequence having at least 60%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 884%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.8%, 99.9%, or 100% sequence identity with any of the sequences listed in Tables 4A, 4B, 5A, 5B, 6A, 6B, 7, 8A, and 8B.

[0378] In some embodiments, ASO as described herein is a compound having the structure depicted in formula (I) (free acid): .

[0379] In some embodiments, ASO as described herein is a compound having the structure depicted in formula (II) (sodium salt): .

[0380] In any of the structural formulas (graphical representations of chemical compounds) presented herein, the two curves and the straight line between them connect a phosphorus atom (“P”) and an oxygen atom (“O”). These two curves and the straight line should be considered as a single, complete segment representing a covalent bond between the phosphorus and oxygen atoms, which is part of the backbone bond (e.g., a phosphodiester bond or a thiophosphate bond) between two adjacent nucleotides. Any vertex (corner) in any structural formula connected by the curves and the straight line does not indicate the presence of a carbon atom or the associated position of -CH2- in the compound represented by the structural formula.

[0381] In some cases, the ASO described in this article is Full P-ambo- 2'- O-( 2-Methoxyethyl)- P- Thioadenosyl-(3'→5')-2'- O-( 2-Methoxyethyl)- P- Thioguanosine-(3'→5')-2'- O-( 2-Methoxyethyl)-5-methyl- P- Thiouridine-(3'→5')-2'- O-( 2-Methoxyethyl)-5-methyl- P- Thiouridine-(3'→5')-2'- O-( 2-Methoxyethyl)- P- Thioguanosine-(3'→5')-2'- O-( 2-Methoxyethyl)- P- Thioguanosine-(3'→5')-2'- O-( 2-Methoxyethyl)- P- Thioadenosyl-(3'→5')-2'- O-( 2-Methoxyethyl)- P- Thioguanosine-(3'→5')-2'- O-( 2-Methoxyethyl)-5-methyl- P- Thiocytidine-(3'→5')-2'- O-( 2-Methoxyethyl)- P- Thioadenosyl-(3'→5')-2'- O-( 2-Methoxyethyl)- P- Thioadenosyl-(3'→5')-2'- O- ( 2-Methoxyethyl)- P- Thioguanosine-(3'→5')-2'- O-( 2-Methoxyethyl)-P- Thioadenosyl-(3'→5')-2'- O-( 2-Methoxyethyl)-5-methyl- P- Thiouridine-(3'→5')-2'- O-( 2-Methoxyethyl)-5-methyl- P- Thiouridine-(3'→5')-2'- O-( 2-Methoxyethyl)- P- Thioadenosyl-(3'→5')-2'- O-( 2-Methoxyethyl)-5-methyl- P- Thiouridine-(3'→5')-2'- O-( 2-Methoxyethyl)-5-methylcytidine or its salt.

[0382] In some cases, the ASO described in this article is Full P-ambo- 2'- O-( 2-Methoxyethyl)- P- Thioadenosyl-(3'→5')-2'- O-( 2-Methoxyethyl)- P- Thioguanosine-(3'→5')-2'- O-( 2-Methoxyethyl)-5-methyl- P- Thiouridine-(3'→5')-2'- O-( 2-Methoxyethyl)-5-methyl- P- Thiouridine-(3'→5')-2'- O-( 2-Methoxyethyl)- P- Thioguanosine-(3'→5')-2'- O-( 2-Methoxyethyl)- P- Thioguanosine-(3'→5')-2'- O-( 2-Methoxyethyl)- P- Thioadenosyl-(3'→5')-2'- O-( 2-Methoxyethyl)- P- Thioguanosine-(3'→5')-2'- O-( 2-Methoxyethyl)-5-methyl- P- Thiocytidine-(3'→5')-2'- O-( 2-Methoxyethyl)- P- Thioadenosyl-(3'→5')-2'- O-( 2-Methoxyethyl)- P- Thioadenosyl-(3'→5')-2'- O- ( 2-Methoxyethyl)- P- Thioguanosine-(3'→5')-2'-O-( 2-Methoxyethyl)- P- Thioadenosyl-(3'→5')-2'- O-( 2-Methoxyethyl)-5-methyl- P- Thiouridine-(3'→5')-2'- O-( 2-Methoxyethyl)-5-methyl- P- Thiouridine-(3'→5')-2'- O-( 2-Methoxyethyl)- P- Thioadenosyl-(3'→5')-2'- O-( 2-Methoxyethyl)-5-methyl- P- Thiouridine-(3'→5')-2'- O-( Sodium salt of 2-methoxyethyl)-5-methylcytidine.

[0383] In some embodiments, about 1 - 500 mg, 2 - 500 mg, 3 - 500 mg, 4 - 500 mg, 5 - 500 mg, 6 - 500 mg, 7 - 500 mg, 8 - 500 mg, 9 - 500 mg, 10 - 500 mg, 15 - 500 mg, 20 - 500 mg, 25 - 500 mg, 30 - 500 mg, 35 - 500 mg, 40 - 500 mg, 45 - 500 mg, 50 - 500 mg, 55 - 500 mg, 60 - 500 mg, 65 - 500 mg, 70 - 500 mg, 75 - 500 mg, 80 - 500 mg, 85 - 500 mg, 90 - 500 mg, 95 - 500 mg, 100 - 500 mg, 105 - 500 mg, 110 - 500 mg, 115 - 500 mg, 120 - 500 mg, 125 - 500 mg, 130 - 500 mg, 135 - 500 mg, 140 - 500 mg, 145 - 500 mg, 150 - 500 mg, 155 - 500 mg, 160 - 500 mg, 165 - 500 mg, 170 - 500 mg, 175 - 500 mg, 180 - 500 mg, 185 - 500 mg, 190 - 500 mg, 195 - 500 mg, 205 - 500 mg, 210 - 500 mg, 215 - 500 mg, 220 - 500 mg, 225 - 500 mg, 230 - 500 mg, 235 - 500 mg, 240 - 500 mg, 245 - 500 mg, 250 - 500 mg, 255 - 500 mg, 260 - 500 mg, 265 - 500 mg, 270 - 500 mg, 275 - 500 mg, 280 - 500 mg, 285 - 500 mg, 290 - 500 mg, 295 - 500 mg, 300 - 500 mg, 305 - 500 mg, 310 - 500 mg, 315 - 500 mg, 320 - 500 mg, 325 - 500 mg, 330 - 500 mg, 335 - 500 mg, 340 - 500 mg, 345 - 500 mg, 350 - 500 mg, 355 - 500 mg, 360 - 500 mg, 365 - 500 mg, 370 - 500 mg, 375 - 500 mg, 380 - 500 mg, 385 - 500 mg, 390 - 500 mg, 395 - 500 mg, 400 - 500 mg, 405 - 500 mg, 410 - 500 mg, 415 - 500 mg, 420 - 500 mg, 425 - 500 mg, 430 - 500 mg, and 435 - __________________ASO, as described herein, is dissolved or suspended in solution at concentrations of 5–200 mg / mL. (The amounts of 440–500 mg, 445–500 mg, 450–500 mg, 455–500 mg, 460–500 mg, 465–500 mg, 470–500 mg, 475–500 mg, 480–500 mg, 485–500 mg, 490–500 mg, or 495–500 mg are also mentioned.) In some embodiments, approximately 1-495 mg, 1-490 mg, 1-485 mg, 1-480 mg, 1-475 mg, 1-470 mg, 1-465 mg, 1-460 mg, 1-455 mg, 1-450 mg, 1-445 mg, 1-440 mg, 1-435 mg, 1-430 mg, 1-425 mg, 1-420 mg, 1-415 mg, 1-410 mg, 1-405 mg, 1-400 mg, 1-395 mg, 1-390 mg, 1-385 mg, 1-380 mg, 1-375 mg, 1-370 mg, 1-365 mg, 1-360 mg, 1-355 mg, 1-350 mg, 1-345 mg, 1-340 mg, 1-335 mg, 1-330 mg, 1-325 mg, etc. mg, 1-320 mg, 1-315 mg, 1-310 mg, 1-305 mg, 1-300 mg, 1-295 mg, 1-290 mg, 1-285mg, 1-280 mg, 1-275 mg, 1-270 mg, 1-265 mg, 1-260 mg, 1-255 mg, 1-250 mg, 1-245 mg, 1-240 mg, 1-235 mg, 1-230 mg, 1-225 mg, 1-220 mg, 1-215 mg, 1-210 mg, 1-205 mg, 1-200mg, 1-195 mg, 1-190 mg, 1-185 mg, 1-180 mg, 1-175 mg, 1-170 mg, 1-165 mg, 1-160 mg, 1-155 mg, 1-150 mg, 1-145 mg, 1-140 mg, 1-135 mg, 1-130 mg, 1-125 mg, 1-120 mg, 1-115mg, 1-110 mg, 1-105 mg, 1-100 mg, 1-95 mg, 1-90 mg, 1-85 mg, 1-80 mg, 1-75 mg, 1-70mg, 1-65 mg, 1-60 mg, 1-55 mg, 1-0 mg, 1-45 mg, 1-40 mg, 1-35 mg, 1-30ASO, as described herein, is dissolved or suspended in solution at concentrations of 5-200 mg / mL.

[0384] In some embodiments, at least about 0.1 mg, 0.5 mg, 1 mg, 2.5 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg, 40 mg, 42.5 mg, 45 mg, 47.5 mg, 50 mg, 52.5 mg, 55 mg, 57.5 mg, 60 mg, 62.5 mg, 65 mg, 67.5 mg, 70 mg, 72.5 mg, 75 mg, 77.5mg, 80 mg, 82.5 mg, 85 mg, 87.5 mg, 90 mg, 92.5 mg, 95 mg, 97.5 mg, 100 102.5 mg mg, 150 mg, 152.5 mg, 155 mg, 157.5 mg, 160 mg, 162.5 mg, 165 mg, 167.5 mg, 170 mg, 172.5 mg, 175mg, 177.5 mg, 180 mg, 182.5 mg, 185 mg, 187.5 mg, 190 mg, 192.5 mg, 195 mg, 197.5 mg, 200 ASO as described herein is dissolved or suspended in solution at concentrations of 0.1–250 mg / mL. 202.5 mg, 205 mg, 207.5 mg, 210 mg, 212.5 mg, 215 mg, 217.5 mg, 220 mg, 222.5 mg, 225 mg, 227.5 mg, 230 mg, 232.5 mg, 235 mg, 237.5 mg, 240 mg, 242.5 mg, 245 mg, 247.5 mg, or 250 mg.In some embodiments, up to about 0.1 mg, 0.5 mg, 1 mg, 2.5 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg 37.5 mg mg, 95 mg, 97.5 mg, 100 102.5 mg mg, 150 mg, 152.5 mg, 155 mg, 157.5 mg, 160 mg, 162.5 mg, 165 mg, 167.5 mg, 170 mg, 172.5 mg, 175 mg, 177.5 mg, 180mg, 182.5 mg, 185 mg, 187.5 mg, 190 mg, 192.5 mg, 195 mg, 197.5 mg, 200 ASO as described herein is dissolved or suspended in solution at concentrations of 0.1–250 mg / mL. 202.5 mg, 205 mg, 207.5 mg, 210 mg, 212.5 mg, 215 mg, 217.5 mg, 220 mg, 222.5 mg, 225 mg, 227.5 mg, 230 mg, 232.5 mg, 235 mg, 237.5 mg, 240 mg, 242.5 mg, 245 mg, 247.5 mg, or 250 mg.In some embodiments, about 0.1 mg, 0.5 mg, 1 mg, 2.5 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35mg, 37.5 mg, 40 mg, 42.5 mg, 45 mg, 47.5 mg, 50 mg, 52.5 mg, 55 mg, 57.5 mg, 60 mg, 62.5mg, 65 mg, 67.5 mg, 70 mg, 72.5 mg, 75 mg, 77.5 mg, 80 mg, 82.5 mg, 85 mg, 87.5 mg, 90mg, 92.5 mg, 95 mg, 97.5 mg, 100 mg, 102.5 mg, 105 mg, 107.5 mg, 110 mg, 112.5 mg, 115 mg, 117.5 mg, 120 mg, 122.5 mg, 125 mg, 127.5 mg, 130 mg, 132.5 mg, 135 mg, 137.5 mg, 140 mg, 142.5 mg, 145 mg, 147.5 mg, 150 152.5 mg mg, 200 mg, 202.5 mg, 205 ASO as described herein is dissolved or suspended in solution at concentrations of 0.1–250 mg / mL. 207.5 mg, 210 mg, 212.5 mg, 215 mg, 217.5 mg, 220 mg, 222.5 mg, 225 mg, 227.5 mg, 230 mg, 232.5 mg, 235 mg, 237.5 mg, 240 mg, 242.5 mg, 245 mg, 247.5 mg, or 250 mg.

[0385] In some embodiments, the ASO as described herein is at 5 - 250 mg / mL, 5 - 247.5 mg / mL, 5 - 245 mg / mL, 5 - 242.5 mg / mL, 5 - 240 mg / mL, 5 - 237.5 mg / mL, 5 - 235 mg / mL, 5 - 232.5 mg / mL, 5 - 230 mg / mL, 5 - 227.5 mg / mL, 5 - 225 mg / mL, 5 - 225.5 mg / mL, 5 - 220 mg / mL, 5 - 217.5 mg / mL, 5 - 215 mg / mL, 5 - 212.5 mg / mL, 5 - 210 mg / mL, 5 - 205.5 mg / mL, 5 - 205 mg / mL, 5 - 202.5 mg / mL, 5 - 200 mg / mL, 5 - 197.5 mg / mL, 5 - 195 mg / mL, 5 - 192.5 mg / mL, 5 - 190 mg / mL, 5 - 187.5 mg / mL, 5 - 185 mg / mL, 5 - 182.5 mg / mL, 5 - 180 mg / mL, 5 - 177.5 mg / mL, 5 - 175 mg / mL, 5 - 172.5 mg / mL, 5 - 170 mg / mL, 5 - 167.5 mg / mL, 5 - 165 mg / mL, 5 - 162.5 mg / mL, 5 - 160 mg / mL, 5 - 157.5 mg / mL, 5 - 155 mg / mL, 5 - 152.5 mg / mL, 5 - 150 mg / mL, 5 - 147.5 mg / mL, 5 - 145 mg / mL, 5 - 142.5 mg / mL, 5 - 140 mg / mL, 5 - 137.5 mg / mL, 5 - 135 mg / mL, 5 - 132.5 mg / mL, 5 - 130 mg / mL, 5 - 127.5 mg / mL, 5 - 125 mg / mL, 5 - 122.5 mg / mL, 5 - 120 mg / mL, 5 - 117.5 mg / mL, 5 - 115 mg / mL, 5 - 112.5 mg / mL, 5 - 110 mg / mL, 5 - 107.5 mg / mL, 5 - 105 mg / mL, 5 - 102.5 mg / mL, 5 - 100 mg / mL, 5 - 97.5 mg / mL, 5 - 95 mg / mL, 5 - 92.5 mg / mL, 5 - 90 mg / mL, 5 - 87.5 mg / mL, 5 - 85 mg / mL, 5 - 82.5 mg / mL, 5 - 80 mg / mL, 5 - 77.5 mg / mL, 5 - 75 mg / mL, 5 - 72.5 mg / mL, 5 - 70 mg / mL, 5 - 67.5 mg / mL, 5 - 65 mg / mL, 5 - 62.5 mg / mL, 5 - 60 mg / mL, 5 - 57.5The concentrations of 5-55 mg / mL, 5-52.5 mg / mL, 5-50 mg / mL, 5-47.5 mg / mL, 5-45 mg / mL, 5-42.5 mg / mL, 5-40 mg / mL, 5-37.5 mg / mL, 5-35 mg / mL, 5-32.5 mg / mL, 5-30 mg / mL, 5-27.5 mg / mL, 5-25 mg / mL, 5-22.5 mg / mL, 5-20 mg / mL, 5-17.5 mg / mL, 5-15 mg / mL, 5-12.5 mg / mL, or 5-10 mg / mL are dissolved or suspended in solution. In some embodiments, as described herein, ASO is expressed in concentrations of 10-250 mg / mL, 15-250 mg / mL, 20-250 mg / mL, 25-250 mg / mL, 30-250 mg / mL, 35-250 mg / mL, 40-250 mg / mL, 45-250 mg / mL, 50-250 mg / mL, 55-250 mg / mL, 60-250 mg / mL, 65-250 mg / mL, 70-250 mg / mL, 75-250 mg / mL, 80-250 mg / mL, 85-250 mg / mL, 90-250 mg / mL, 95-250 mg / mL, 100-250 mg / mL, 105-250 mg / mL, 110-250 mg / mL, 115-250 mg / mL, 120-250 mg / mL. mg / mL, 125-250 mg / mL, 130-250 mg / mL, 135-250 mg / mL, 140-250 mg / mL, 145-250mg / mL, 150-250 mg / mL, 155-250 mg / mL, 160-250 mg / mL, 165-250 mg / mL, 170-250 mg / mL, 175-250 mg / mL, 180-250 mg / mL, 185-250 mg / mL, 190-250 mg / mL, or 195-250 mg / mL, 200-250 mg / mL, 205-250 mg / mL, 210-250 mg / mL, 215-250 mg / mL, 220-250 mg / mL, 225-250 mg / mL, 230-250 ASO is dissolved or suspended in solution at concentrations of 235-250 mg / mL, 240-250 mg / mL, or 245-250 mg / mL. In some embodiments, ASO as described herein is dissolved or suspended in solution at concentrations of at least 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, or 7 mg / mL.mg / mL、8 mg / mL、9 mg / mL、10 mg / mL、11 mg / mL、12 mg / mL、13 mg / mL、14 mg / mL、15 mg / mL、16 mg / mL、17 mg / mL、18 mg / mL、19 mg / mL、20 mg / mL、21 mg / mL、22mg / mL、23 mg / mL、24 mg / mL、25 mg / mL、26 mg / mL、27 mg / mL、28 mg / mL、29 mg / mL、30 mg / mL、31 mg / mL、32 mg / mL、33 mg / mL、34 mg / mL、35 mg / mL、36 mg / mL、37 mg / mL、38 mg / mL、39mg / mL、40 mg / mL、41 mg / mL、42 mg / mL、43 mg / mL、44 mg / mL、45 mg / mL、46 mg / mL、47 mg / mL、48 mg / mL、49 mg / mL、50 mg / mL、51 mg / mL、52 mg / mL、53 mg / mL、54 mg / mL、55 mg / mL、56mg / mL、57 mg / mL、58 mg / mL、59 mg / mL、60 mg / mL、61 mg / mL、62 mg / mL、63 mg / mL、64 mg / mL、65 mg / mL、66 mg / mL、67 mg / mL、68 mg / mL、69 mg / mL、70 mg / mL、71 mg / mL、72 mg / mL、73mg / mL、74 mg / mL、75 mg / mL、76 mg / mL、77 mg / mL、78 mg / mL、79 mg / mL、80 mg / mL、81 mg / mL、82 mg / mL、83 mg / mL、84 mg / mL、85 mg / mL、86 mg / mL、87 mg / mL、88 mg / mL、89 mg / mL、90mg / mL、91 mg / mL、92 mg / mL、93 mg / mL、94 mg / mL、95 mg / mL、96 mg / mL、97 mg / mL、98 mg / mL、99 mg / mL、100 mg / mL、101 mg / mL、102 mg / mL、103 mg / mL、104 mg / mL、105 mg / mL、106mg / mL、107 mg / mL、108 mg / mL、109 mg / mL、110 mg / mL、111 mg / mL、112 mg / mL、113 mg / mL、114 mg / mL、115 mg / mL、116 mg / mL、117mg / mL、118 mg / mL、119 mg / mL、120 mg / mL、121 mg / mL、122 mg / mL、123 mg / mL、124 mg / mL、125 mg / mL、126 mg / mL、127 mg / mL、128 mg / mL、129mg / mL、130 mg / mL、131 mg / mL、132 mg / mL、133 mg / mL、134 mg / mL、135 mg / mL、136 mg / mL、137 mg / mL、138 mg / mL、139 mg / mL、140 mg / mL、141 mg / mL、142 mg / mL、143 mg / mL、144 mg / mL、145 mg / mL、146 mg / mL、147 mg / mL、148 mg / mL、149 mg / mL、150 mg / mL、151 mg / mL、152mg / mL、153 mg / mL、154 mg / mL、155 mg / mL、156 mg / mL、157 mg / mL、158 mg / mL、159 mg / mL、160 mg / mL、161 mg / mL、162 mg / mL、163 mg / mL、164 mg / mL、165 mg / mL、166 mg / mL、167 mg / mL、168 mg / mL、169 mg / mL、170 mg / mL、171 mg / mL、172 mg / mL、173 mg / mL、174 mg / mL、175mg / mL、176 mg / mL、177 mg / mL、178 mg / mL、179 mg / mL、180 mg / mL、181 mg / mL、182 mg / mL、183 mg / mL、184 mg / mL、185 mg / mL、186 mg / mL、187 mg / mL、188 mg / mL、189 mg / mL、190 mg / mL、191 mg / mL、192 mg / mL、193 mg / mL、194 mg / mL、195 mg / mL、196 mg / mL、197 mg / mL、198mg / mL、199 mg / mL、200 mg / mL、210 mg / mL、211 mg / mL、212 mg / mL、213 mg / mL、214 mg / mL、215 mg / mL、216 mg / mL、217 mg / mL、218 mg / mL、219 mg / mL、220 mg / mL、221 mg / mL、222 mg / mL、223 mg / mL、224 mg / mL、225 mg / mL、226dissolved or suspended in solution at a concentration of mg / mL, 227 mg / mL, 228 mg / mL, 229 mg / mL, 230 mg / mL, 231 mg / mL, 232 mg / mL, 233 mg / mL, 234 mg / mL, 235 mg / mL, 236 mg / mL, 237 mg / mL, 238 mg / mL, 239 mg / mL, 240 mg / mL, 241 mg / mL, 242 mg / mL, 243 mg / mL, 244 mg / mL, 245 mg / mL, 246 mg / mL, 247 mg / mL, 248 mg / mL, 249 mg / mL or 250 mg / mL. In some embodiments, the ASO as described herein is at a concentration of up to 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 21 mg / mL, 22 mg / mL, 23 mg / mL, 24 mg / mL, 25 mg / mL, 26 mg / mL, 27 mg / mL, 28 mg / mL, 29 mg / mL, 30 mg / mL, 31 mg / mL, 32 mg / mL, 33 mg / mL, 34 mg / mL, 35 mg / mL, 36 mg / mL, 37 mg / mL, 38 mg / mL, 39 mg / mL, 40 mg / mL, 41 mg / mL, 42 mg / mL, 43 mg / mL, 44 mg / mL, 45 mg / mL, 46 mg / mL, 47 mg / mL, 48 mg / mL, 49 mg / mL, 50 mg / mL, 51 mg / mL, 52 mg / mL, 53 mg / mL, 54 mg / mL, 55 mg / mL, 56 mg / mL, 57 mg / mL, 58 mg / mL, 59 mg / mL, 60 mg / mL, 6l mg / mL, 62 mg / mL, 63 mg / mL, 64 mg / mL, 65 mg / mL, 66 mg / mL, 67 mg / mL, 68 mg / mL, 69 mg / mL, 70 mg / mL, 71 mg / mL, 72 mg / mL, 73 mg / mL, 74 mg / mL, 75 mg / mL, 76 mg / mL, 77 mg / mL, 78 mg / mL, 79 mg / mL, 80 mg / mL, 81mg / mL、82mg / mL、83 mg / mL、84 mg / mL、85 mg / mL、86 mg / mL、87 mg / mL、88 mg / mL、89 mg / mL、90 mg / mL、91 mg / mL、92 mg / mL、93 mg / mL、94 mg / mL、95 mg / mL、96 mg / mL、97 mg / mL、98 mg / mL、99mg / mL、100 mg / mL、101 mg / mL、102 mg / mL、103 mg / mL、104 mg / mL、105 mg / mL、106 mg / mL、107 mg / mL、108 mg / mL、109 mg / mL、110 mg / mL、111 mg / mL、112 mg / mL、113 mg / mL、114 mg / mL、115 mg / mL、116 mg / mL、117 mg / mL、118 mg / mL、119 mg / mL、120 mg / mL、121 mg / mL、122mg / mL、123 mg / mL、124 mg / mL、125 mg / mL、126 mg / mL、127 mg / mL、128 mg / mL、129 mg / mL、130 mg / mL、131 mg / mL、132 mg / mL、133 mg / mL、134 mg / mL、135 mg / mL、136 mg / mL、137 mg / mL、138 mg / mL、139 mg / mL、140 mg / mL、141 mg / mL、142 mg / mL、143 mg / mL、144 mg / mL、145mg / mL、146 mg / mL、147 mg / mL、148 mg / mL、149 mg / mL、150 mg / mL、151 mg / mL、152 mg / mL、153 mg / mL、154 mg / mL、155 mg / mL、156 mg / mL、157 mg / mL、158 mg / mL、159 mg / mL、160 mg / mL、161 mg / mL、162 mg / mL、163 mg / mL、164 mg / mL、165 mg / mL、166 mg / mL、167 mg / mL、168mg / mL、169 mg / mL、170 mg / mL、171 mg / mL、172 mg / mL、173 mg / mL、174 mg / mL、175 mg / mL、176 mg / mL、177 mg / mL、178 mg / mL、179 mg / mL、180 mg / mL、181 mg / mL、182 mg / mL、183dissolved or suspended in solution at a concentration of mg / mL, 184 mg / mL, 185 mg / mL, 186 mg / mL, 187 mg / mL, 188 mg / mL, 189 mg / mL, 190 mg / mL, 191 mg / mL, 192 mg / mL, 193 mg / mL, 194 mg / mL, 195 mg / mL, 196 mg / mL, 197 mg / mL, 198 mg / mL, 199 mg / mL, 200 mg / mL, 210 mg / mL, 211 mg / mL, 212 mg / mL, 213 mg / mL, 214 mg / mL, 215 mg / mL, 216 mg / mL, 217 mg / mL, 218 mg / mL, 219 mg / mL, 220 mg / mL, 221 mg / mL, 222 mg / mL, 223 mg / mL, 224 mg / mL, 225 mg / mL, 226 mg / mL, 227 mg / mL, 228 mg / mL, 229 mg / mL, 230 mg / mL, 231 mg / mL, 232 mg / mL, 233 mg / mL, 234 mg / mL, 235 mg / mL, 236 mg / mL, 237 mg / mL, 238 mg / mL, 239 mg / mL, 240 mg / mL, 241 mg / mL, 242 mg / mL, 243 mg / mL, 244 mg / mL, 245 mg / mL, 246 mg / mL, 247 mg / mL, 248 mg / mL, 249 mg / mL or 250 mg / mL. In some embodiments, the ASO as described herein is at 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 21 mg / mL, 22 mg / mL, 23 mg / mL, 24 mg / mL, 25 mg / mL, 26 mg / mL, 27 mg / mL, 28 mg / mL, 29 mg / mL, 30 mg / mL, 31 mg / mL, 32 mg / mL, 33 mg / mL, 34 mg / mL, 35 mg / mL, 36 mg / mL, 37 mg / mL, 38 mg / mL, 39 mg / mL, 40 mg / mL, 41 mg / mL, 42 mg / mL, 43 mg / mL, 44 mg / mL, 45mg / mL、46 mg / mL、47 mg / mL、48 mg / mL、49 mg / mL、50 mg / mL、51 mg / mL、52 mg / mL、53 mg / mL、54 mg / mL、55 mg / mL、56 mg / mL、57 mg / mL、58mg / mL、59 mg / mL、60 mg / mL、61 mg / mL、62 mg / mL、63 mg / mL、64 mg / mL、65 mg / mL、66 mg / mL、67 mg / mL、68 mg / mL、69 mg / mL、70 mg / mL、71 mg / mL、72 mg / mL、73 mg / mL、74 mg / mL、75mg / mL、76 mg / mL、77 mg / mL、78 mg / mL、79 mg / mL、80 mg / mL、81 mg / mL、82 mg / mL、83 mg / mL、84 mg / mL、85 mg / mL、86 mg / mL、87 mg / mL、88 mg / mL、89 mg / mL、90 mg / mL、91 mg / mL、92mg / mL、93 mg / mL、94 mg / mL、95 mg / mL、96 mg / mL、97 mg / mL、98 mg / mL、99 mg / mL、100 mg / mL、101 mg / mL、102 mg / mL、103 mg / mL、104 mg / mL、105 mg / mL、106 mg / mL、107 mg / mL、108mg / mL、109 mg / mL、110 mg / mL、111 mg / mL、112 mg / mL、113 mg / mL、114 mg / mL、115 mg / mL、116 mg / mL、117 mg / mL、118 mg / mL、119 mg / mL、120 mg / mL、121 mg / mL、122 mg / mL、123 mg / mL、124 mg / mL、125 mg / mL、126 mg / mL、127 mg / mL、128 mg / mL、129 mg / mL、130 mg / mL、131mg / mL、132 mg / mL、133 mg / mL、134 mg / mL、135 mg / mL、136 mg / mL、137 mg / mL、138 mg / mL、139 mg / mL、140 mg / mL、141 mg / mL、142 mg / mL、143 mg / mL、144 mg / mL、145 mg / mL、146 mg / mL、147 mg / mL、148 mg / mL、149 mg / mL、150 mg / mL、151dissolved or suspended in solution at a concentration of mg / mL, 152 mg / mL, 153 mg / mL, 154 mg / mL, 155 mg / mL, 156 mg / mL, 157 mg / mL, 158 mg / mL, 159 mg / mL, 160 mg / mL, 161 mg / mL, 162 mg / mL, 163 mg / mL, 164 mg / mL, 165 mg / mL, 166 mg / mL, 167 mg / mL, 168 mg / mL, 169 mg / mL, 170 mg / mL, 171 mg / mL, 172 mg / mL, 173 mg / mL, 174 mg / mL, 175 mg / mL, 176 mg / mL, 177 mg / mL, 178 mg / mL, 179 mg / mL, 180 mg / mL, 181 mg / mL, 182 mg / mL, 183 mg / mL, 184 mg / mL, 185 mg / mL, 186 mg / mL, 187 mg / mL, 188 mg / mL, 189 mg / mL, 190 mg / mL, 191 mg / mL, 192 mg / mL, 193 mg / mL, 194 mg / mL, 195 mg / mL, 196 mg / mL, 197 mg / mL, 198 mg / mL, 199 mg / mL, 200 mg / mL, 210 mg / mL, 211 mg / mL, 212 mg / mL, 213 mg / mL, 214 mg / mL, 215 mg / mL, 216 mg / mL, 217 mg / mL, 218 mg / mL, 219 mg / mL, 220 mg / mL, 221 mg / mL, 222 mg / mL, 223 mg / mL, 224 mg / mL, 225 mg / mL, 226 mg / mL, 227 mg / mL, 228 mg / mL, 229 mg / mL, 230 mg / mL, 231 mg / mL, 232 mg / mL, 233 mg / mL, 234 mg / mL, 235 mg / mL, 236 mg / mL, 237 mg / mL, 238 mg / mL, 239 mg / mL, 240 mg / mL, 241 mg / mL, 242 mg / mL, 243 mg / mL, 244 mg / mL, 245 mg / mL, 246 mg / mL, 247 mg / mL, 248 mg / mL, 249 mg / mL or 250 mg / mL.

[0386] In some embodiments, the pharmaceutically acceptable diluent comprises an artificial cerebrospinal fluid (aCSF) solution. In some embodiments, the solution comprises a cerebrospinal fluid (CSF) sample from a subject. In some embodiments, ASO as described herein is dissolved or diluted in an isotonic solution.

[0387] In some embodiments, ASO as described herein is dissolved or diluted in a phosphate buffer solution (pH 6.6–7.6). In some embodiments, ASO as described herein is dissolved or diluted in a phosphate buffer solution (pH 6.0–8.0). In some embodiments, ASO as described herein is dissolved or diluted in a phosphate buffer solution (pH 5.0–8.0). In some embodiments, as described herein, ASO is dissolved or diluted at pH 4.5–8.5, pH 4.6–8.5, pH 4.7–8.5, pH 4.8–8.5, pH 4.9–8.5, pH 5.0–8.5, pH 5.1–8.5, pH 5.2–8.5, pH 5.3–8.5, pH 5.4–8.5, pH 5.5–8.5, pH 5.6–8.5, pH 5.7–8.5, pH 5.8–8.5, pH 5.9–8.5, pH 6.0–8.5, pH 6.1–8.5, pH 6.2–8.5, pH 6.3–8.5, pH 6.4–8.5, pH 6.5–8.5, pH 6.6–8.5, pH 6.7–8.5, pH In phosphate buffer solutions with pH values ​​of 6.8-8.5, 6.9-8.5, 7.0-8.5, 7.1-8.5, 7.2-8.5, 7.3-8.5, 7.4-8.5, 7.5-8.5, 7.6-8.5, 7.7-8.5, 7.8-8.5, 7.9-8.5, 8.0-8.5, 8.1-8.5, 8.2-8.5, 8.3-8.5, or 8.4-8.5.In some embodiments, as described herein, ASO is dissolved or diluted at pH 4.5–8.3, pH 4.5–8.2, pH 4.5–8.1, pH 4.5–8.0, pH 4.5–7.9, pH 4.5–7.8, pH 4.5–7.7, pH 4.5–7.6, pH 4.5–7.5, pH 4.5–7.4, pH 4.5–7.3, pH 4.5–7.2, pH 4.5–7.1, pH 4.5–7.0, pH 4.5–6.9, pH 4.5–6.8, pH 4.5–6.7, pH 4.5–6.6, pH 4.5–6.5, pH 4.5–6.4, pH 4.5–6.3, pH 4.5–6.2, pH 4.5–6.1, pH In phosphate buffer solutions with pH values ​​of 4.5-6.0, 4.5-5.9, 4.5-5.8, 4.5-5.7, 4.5-5.6, 4.5-5.5, 4.5-5.4, 4.5-5.3, 4.5-5.2, 4.5-5.1, 4.5-5.0, 4.5-4.9, 4.5-4.8, 4.5-4.7, or 4.5-4.6. In some embodiments, as described herein, ASO is dissolved or diluted in phosphate buffer solutions at pH 6.0–7.6, pH 6.1–7.6, pH 6.2–7.6, pH 6.3–7.6, pH 6.4–7.6, pH 6.5–7.6, pH 6.6–7.6, pH 6.7–7.6, pH 6.8–7.6, pH 6.9–7.6, pH 7.0–7.6, pH 7.1–7.6, pH 7.2–7.6, pH 7.3–7.6, pH 7.4–7.6, or pH 7.5–7.6. In some embodiments, as described herein, ASO is dissolved or diluted in phosphate buffer solutions at pH 6.6–8.0, pH 6.6–7.9, pH 6.6–7.8, pH 6.6–7.7, pH 6.6–7.6, pH 6.6–7.5, pH 6.6–7.4, pH 6.6–7.3, pH 6.6–7.2, pH 6.6–7.1, pH 6.6–7.0, pH 6.6–6.9, pH 6.6–6.8, or pH 6.6–6.7.In some embodiments, as described herein, ASO is dissolved or diluted in phosphate buffer solutions at pH 6.0–8.0, pH 6.1–8.0, pH 6.2–8.0, pH 6.3–8.0, pH 6.4–8.0, pH 6.5–8.0, pH 6.6–8.0, pH 6.7–8.0, pH 6.8–8.0, pH 6.9–8.0, pH 7.0–8.0, pH 7.1–8.0, pH 7.2–8.0, pH 7.3–8.0, pH 7.4–8.0, pH 7.5–8.0, pH 7.6–8.0, pH 7.7–8.0, pH 7.8–8.0, or pH 7.9–8.0. In some embodiments, as described herein, ASO is dissolved or diluted in phosphate buffer solutions at pH 6.0–7.9, pH 6.0–7.8, pH 6.0–7.7, pH 6.0–7.6, pH 6.0–7.5, pH 6.0–7.4, pH 6.0–7.3, pH 6.0–7.2, pH 6.0–7.1, pH 6.0–7.0, pH 6.0–6.9, pH 6.0–6.8, pH 6.0–6.7, pH 6.0–6.6, pH 6.0–6.5, pH 6.0–6.4, pH 6.0–6.3, pH 6.0–6.2, or pH 6.0–6.1. In some embodiments, ASO as described herein is dissolved or diluted in a phosphate buffer solution with pH 5.7–8.5, 5.8–8.4, 5.9–8.3, 6.0–8.2, 6.1–8.1, 6.2–8.0, 6.3–7.9, 6.4–7.8, 6.5–7.7, or 6.6–7.6. In some embodiments, ASO as described herein is dissolved or diluted in a phosphate buffer solution with pH about 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or 8.0. In some embodiments, as described herein, ASO is dissolved or diluted in a phosphate buffer solution at pH 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or 8.0.

[0388] In some embodiments, ASO, as described herein, is dissolved or diluted in a buffer solution containing 25-250 mM NaCl.

[0389] In some embodiments, as described herein, ASO is dissolved or diluted in solutions containing 25-250 mM, 30-250 mM, 35-250 mM, 40-250 mM, 45-250 mM, 50-250 mM, 55-250 mM, 60-250 mM, 65-250 mM, 70-250 mM, 75-250 mM, 80-250 mM, 85-250 mM, 90-250 mM, 95-250 mM, 100-250 mM, 105-250 mM, 110-250 mM, 115-250 mM, 120-250 mM, 125-250 mM, 130-250 mM, 135-250 mM, 140-250 mM, 145 ... 210-250 mM 215-250mM, 220-250mM, 225-250mM, 230-250mM, 235-250mM, 240-250mM or 245-250mMNaCl. In some embodiments, as described herein, ASO is dissolved or diluted in solutions containing 25-245 mM, 25-240 mM, 25-235 mM, 25-230 mM, 25-225 mM, 25-220 mM, 25-215 mM, 25-210 mM, 25-205 mM, 25-200 mM, 25-195 mM, 25-190 mM, 25-185 mM, 25-180 mM, 25-175 mM, 25-170 mM, 25-165 mM, 25-160 mM, 25-155 mM, 25-150 mM, 25-145 mM, 25-140 mM, 25-135 mM, 25-130 mM, 25-125 mM, 25-120 ... mm, 25-115 mm, 25-110 mm, 25-105 mm, 25-110 mm, 25-105 mm, 25-100 mm, 25-95 mm, 25-90 mm, 25-85 mm, 25-80 mm, 25-75 mm, 25-70 mm, 25-65 mm, 25-60 25-55mM, 25-50mM, 25-45mM, 25-40mM, 25-35mM or 25-30mM NaCl.In some embodiments, as described herein, ASO is dissolved or ...

Claims

1. A pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition, the liquid composition comprising: (i) antisense oligomers (ASO), and (ii) Pharmaceutically acceptable diluents; The liquid composition is not buffered by a buffer; and in: (a) The liquid composition comprises calcium ions, magnesium ions, and / or potassium ions. (b) The drug formulation is formulated for or suitable for administration into the intrathecal space, cerebrospinal fluid, or brain of a human subject, and / or (c) Each nucleobase of the ASO contains a modified sugar moiety.

2. A pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition, the liquid composition comprising: (i) antisense oligomers (ASO), and (ii) Pharmaceutically acceptable diluents; The liquid composition is deficient in Na2HPO4 and / or NaH2PO4; and in: (a) The liquid composition comprises calcium ions, magnesium ions, and / or potassium ions. (b) The drug formulation is formulated for or suitable for administration into the intrathecal space, cerebrospinal fluid, or brain of a human subject, and / or (c) Each nucleobase of the ASO contains a modified sugar moiety.

3. The pharmaceutical formulation according to claim 1 or 2, wherein the liquid composition is deficient in phosphate ions.

4. The pharmaceutical formulation according to any one of claims 1 to 3, wherein the liquid composition comprises calcium ions, magnesium ions and / or potassium ions.

5. A pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition, the liquid composition comprising: (i) antisense oligomers (ASO), and (ii) A pharmaceutically acceptable diluent, wherein the pharmaceutically acceptable diluent comprises the following: (a) NaCl, (b) KCl, (c) MgCl2 or MgCl2 6H2O, and (d) CaCl2 or CaCl2 2H2O.

6. The pharmaceutical formulation according to any one of claims 1 to 5, wherein the liquid composition comprises 0.1-50 mM CaCl2 or CaCl2 2H2O.

7. The pharmaceutical formulation according to any one of claims 1 to 6, wherein the liquid composition comprises 1-2 mM CaCl2 or CaCl2 2H2O.

8. The pharmaceutical formulation according to any one of claims 1 to 7, wherein the liquid composition comprises about 1.4 mM CaCl2 or CaCl2 2H2O.

9. The pharmaceutical formulation according to any one of claims 1 to 8, wherein the liquid composition comprises 0.1-50 mM MgCl2 or MgCl2 6H2O.

10. The pharmaceutical formulation according to any one of claims 1 to 8, wherein the liquid composition comprises 0.5-1.5 mM MgCl2 or MgCl2 6H2O.

11. The pharmaceutical formulation according to any one of claims 1 to 8, wherein the liquid composition comprises about 0.79 mM MgCl2 or MgCl2 6H2O.

12. The pharmaceutical formulation according to any one of claims 1 to 11, wherein the liquid composition comprises 5-250 mM NaCl, 0.1-20 mM KCl, 0.1-50 mM CaCl2 or CaCl2 2H2O and 0.1-50 mM MgCl2 or MgCl2 6H2O.

13. A pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition, the liquid composition comprising: (i) antisense oligomers (ASO), and (ii) Pharmaceutically acceptable diluents; The liquid composition described above is deficient in calcium and / or magnesium ions; and in: (a) The liquid composition contains potassium ions, (b) The drug formulation is formulated for or suitable for administration into the intrathecal space, cerebrospinal fluid, or brain of a human subject, and / or (c) Each nucleobase of the ASO contains a modified sugar moiety.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein: (a) The ASO is stable in the pharmaceutical formulation after the formulation has been stored at -20°C or at a certain temperature and relative humidity for a certain period of time; (b) The pharmaceutical preparation has a shelf life of a certain period when stored at -20°C or at a certain temperature and relative humidity; (c) After storing the pharmaceutical formulation at -20°C or at a certain temperature and relative humidity for a certain period of time, the percentage of impurities in the pharmaceutical formulation does not exceed 2.5% based on an HPLC relative retention time of 0.92; (d) After storing the pharmaceutical formulation at -20°C or at a certain temperature and relative humidity for a certain period of time, the percentage of impurities in the pharmaceutical formulation does not exceed 3.5% based on an HPLC relative retention time of 0.98; (e) After storing the pharmaceutical formulation at -20°C or at a certain temperature and relative humidity for a certain period of time, the percentage of any unspecified impurities in the pharmaceutical formulation does not exceed 1.8% according to HPLC; (f) After storing the pharmaceutical formulation at -20°C or at a certain temperature and relative humidity for a certain period of time, the percentage of total impurities in the pharmaceutical formulation does not exceed 10% according to HPLC; (g) After storing the pharmaceutical formulation at -20°C or at a certain temperature and relative humidity for a certain period of time, the pH of the pharmaceutical composition is 6.6 to 7.6; (h) After storing the pharmaceutical formulation at -20°C or at a certain temperature and relative humidity for a certain period of time, the osmotic pressure of the pharmaceutical composition is 310 mOsm / kg to 360 mOsm / kg; and / or (i) No observable particle formation or particle formation with a size greater than 50 µm was observed after the drug formulation was stored at -20°C or at a certain temperature and relative humidity for a certain period of time.

15. The pharmaceutical composition according to any one of claims 1 to 13, wherein after storing the pharmaceutical formulation at -20°C or at a certain temperature and relative humidity for a certain period of time, no observable particle formation or particle formation with a size greater than 50 µm is observed.

16. A pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition, the liquid composition comprising: (i) antisense oligomers (ASO), and (ii) Pharmaceutically acceptable diluents, in: (a) The ASO is stable in the pharmaceutical formulation after the formulation has been stored at -20°C or at a certain temperature and relative humidity for a certain period of time; (b) The pharmaceutical preparation has a shelf life of a certain period when stored at -20°C or at a certain temperature and relative humidity; (c) After storing the pharmaceutical formulation at -20°C or at a certain temperature and relative humidity for a certain period of time, the percentage of impurities in the pharmaceutical formulation does not exceed 2.5% based on an HPLC relative retention time of 0.92; (d) After storing the pharmaceutical formulation at -20°C or at a certain temperature and relative humidity for a certain period of time, the percentage of impurities in the pharmaceutical formulation does not exceed 3.5% based on an HPLC relative retention time of 0.98; (e) After storing the pharmaceutical formulation at -20°C or at a certain temperature and relative humidity for a certain period of time, the percentage of any unspecified impurities in the pharmaceutical formulation does not exceed 1.8% according to HPLC; (f) After storing the pharmaceutical formulation at -20°C or at a certain temperature and relative humidity for a certain period of time, the percentage of total impurities in the pharmaceutical formulation does not exceed 10% according to HPLC; (g) After storing the pharmaceutical formulation at -20°C or at a certain temperature and relative humidity for a certain period of time, the pH of the pharmaceutical composition is 6.6 to 7.6; (h) After storing the pharmaceutical formulation at -20°C or at a certain temperature and relative humidity for a certain period of time, the osmotic pressure of the pharmaceutical composition is 310 mOsm / kg to 360 mOsm / kg; and / or (i) No observable particle formation or particle formation with a size greater than 50 µm was observed after the drug formulation was stored at -20°C or at a certain temperature and relative humidity for a certain period of time.

17. The pharmaceutical formulation according to any one of claims 14 to 16, wherein the temperature is 4°C, 25°C, 30°C, 37°C, or 40°C.

18. The pharmaceutical formulation according to any one of claims 14 to 17, wherein the relative humidity is about 55%, 60%, 65%, 70%, or 75%.

19. The pharmaceutical formulation according to any one of claims 14 to 18, wherein the time period is at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, or 31 weeks. 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years.

20. The pharmaceutical formulation according to any one of claims 2 to 19, wherein the liquid composition comprises a buffer.

21. The pharmaceutical formulation of claim 20, wherein the buffer has a pKa of about 4.75; about 5.64; about 1.70, about 6.04 and about 9.09; about 3.1, about 4.7 and about 6.4; or about 6.50 at 25°C.

22. The pharmaceutical formulation of claim 20, wherein the buffer is an effective buffer solution with a pH range of about 3.6 to 5.6, about 5.5 to 6.5, about 5.5 to 7.4, about 3.0 to 6.2, or about 5.8 to 7.

2.

23. The pharmaceutical formulation of claim 20, wherein the buffer is selected from the group consisting of: acetate, succinate, histidine, citrate, 2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3-diol (Bis-Tris), and any combination thereof.

24. The pharmaceutical formulation according to any one of claims 1 to 23, wherein the liquid composition is formulated for administration into the intrathecal space, cerebrospinal fluid, or brain of a human subject.

25. The pharmaceutical formulation according to any one of claims 1 to 23, wherein the liquid composition is formulated for administration into the cerebrospinal fluid of a human subject's brain.

26. The pharmaceutical formulation according to any one of claims 1 to 25, wherein the ASO comprises at least one modified sugar moiety.

27. The pharmaceutical formulation according to any one of claims 1 to 26, wherein each nucleotide of the antisense oligomer comprises a modified sugar moiety.

28. A reagent kit comprising: (i) a concentrate comprising an antisense oligomer (ASO); and (ii) a pharmaceutically acceptable diluent, wherein the concentrate is miscible with the pharmaceutically acceptable diluent; and The ASO is mixed with the pharmaceutically acceptable diluent to produce a liquid composition containing the ASO, and The liquid composition is not buffered by a buffer; and in: (a) The liquid composition comprises calcium ions, magnesium ions, and / or potassium ions. (b) The drug formulation is formulated for or suitable for administration into the intrathecal space, cerebrospinal fluid, or brain of a human subject, and / or (c) Each nucleobase of the ASO contains a modified sugar moiety.

29. A reagent kit comprising: (i) a concentrate comprising an antisense oligomer (ASO); and (ii) a pharmaceutically acceptable diluent, wherein the concentrate is miscible with the pharmaceutically acceptable diluent; and The ASO is mixed with the pharmaceutically acceptable diluent to produce a liquid composition containing the ASO. The liquid composition is deficient in Na2HPO4 and / or NaH2PO4; and in: (a) The liquid composition comprises calcium ions, magnesium ions, and / or potassium ions. (b) The drug formulation is formulated for or suitable for administration into the intrathecal space, cerebrospinal fluid, or brain of a human subject, and / or (c) Each nucleobase of the ASO contains a modified sugar moiety.

30. The kit according to claim 28 or 29, wherein the liquid composition is deficient in phosphate ions.

31. The kit according to any one of claims 28 to 30, wherein the liquid composition comprises calcium ions, magnesium ions and / or potassium ions.

32. A reagent kit comprising: (i) a concentrate comprising an antisense oligomer (ASO); and (ii) A pharmaceutically acceptable diluent, wherein the pharmaceutically acceptable diluent comprises the following: (a) NaCl, (b) KCl, (c) MgCl2 or MgCl2 6H2O, and (d) CaCl2 or CaCl2 2H2O, The concentrate is miscible with the pharmaceutically acceptable diluent; and The ASO is mixed with a pharmaceutically acceptable diluent to produce a liquid composition containing the ASO.

33. The kit according to any one of claims 28 to 32, wherein the liquid composition comprises 0.1-50 mM CaCl2 or CaCl2 2H2O.

34. The kit according to any one of claims 28 to 32, wherein the liquid composition comprises 1-2 mM CaCl2 or CaCl2 2H2O.

35. The kit according to any one of claims 28 to 34, wherein the liquid composition comprises about 1.4 mM CaCl2 or CaCl2 2H2O.

36. The kit according to any one of claims 28 to 35, wherein the liquid composition comprises 0.1-50 mmol / L MgCl2 or MgCl2·6H2O.

37. The kit according to any one of claims 28 to 35, wherein the liquid composition comprises 0.5-1.5 mM MgCl2 or MgCl26H2O.

38. The kit according to any one of claims 28 to 35, wherein the liquid composition comprises about 0.79 mM MgCl2 or MgCl2 6H2O.

39. The kit according to any one of claims 28 to 38, wherein the liquid composition comprises 5-250 mM NaCl, 0.1-20 mM KCl, 0.1-50 mM CaCl2 or CaCl2 2H2O and 0.1-50 mM MgCl2 or MgCl2 6H2O.

40. A reagent kit comprising: (i) a concentrate comprising an antisense oligomer (ASO); and (ii) A pharmaceutically acceptable diluent, wherein the concentrate is miscible with the pharmaceutically acceptable diluent; The ASO is mixed with the pharmaceutically acceptable diluent to produce a liquid composition containing the ASO. The liquid composition described above is deficient in calcium and / or magnesium ions; and in: (a) The liquid composition contains potassium ions, (b) The drug formulation is formulated for or suitable for administration into the intrathecal space, cerebrospinal fluid, or brain of a human subject, and / or (c) Each nucleobase of the ASO contains a modified sugar moiety.

41. The kit according to any one of claims 28 to 40, wherein: (i) a concentrate comprising an antisense oligomer (ASO); and (ii) A pharmaceutically acceptable diluent, wherein the concentrate is miscible with the pharmaceutically acceptable diluent; The ASO is mixed with the pharmaceutically acceptable diluent to produce a liquid composition containing the ASO, and in: (a) The ASO is stable in the pharmaceutical formulation after the formulation has been stored at -20°C or at a certain temperature and relative humidity for a certain period of time; (b) The pharmaceutical preparation has a shelf life of a certain period when stored at -20°C or at a certain temperature and relative humidity; (c) After storing the pharmaceutical formulation at -20°C or at a certain temperature and relative humidity for a certain period of time, the percentage of impurities in the pharmaceutical formulation does not exceed 2.5% based on an HPLC relative retention time of 0.92; (d) After storing the pharmaceutical formulation at -20°C or at a certain temperature and relative humidity for a certain period of time, the percentage of impurities in the pharmaceutical formulation does not exceed 3.5% based on an HPLC relative retention time of 0.98; (e) After storing the pharmaceutical formulation at -20°C or at a certain temperature and relative humidity for a certain period of time, the percentage of any unspecified impurities in the pharmaceutical formulation does not exceed 1.8% according to HPLC; (f) After storing the pharmaceutical formulation at -20°C or at a certain temperature and relative humidity for a certain period of time, the percentage of total impurities in the pharmaceutical formulation does not exceed 10% according to HPLC; (g) After storing the pharmaceutical formulation at -20°C or at a certain temperature and relative humidity for a certain period of time, the pH of the pharmaceutical composition is 6.6 to 7.6; (h) After storing the pharmaceutical formulation at -20°C or at a certain temperature and relative humidity for a certain period of time, the osmotic pressure of the pharmaceutical composition is 310 mOsm / kg to 360 mOsm / kg; and / or (i) No observable particulate formation was observed after the drug formulation was stored at -20°C or at a certain temperature and relative humidity for a certain period of time.

42. The kit according to any one of claims 28 to 40, wherein no observable particle formation is observed after the pharmaceutical formulation has been stored at -20°C or at a certain temperature and relative humidity for a certain period of time.

43. A reagent kit comprising: (i) a concentrate comprising an antisense oligomer (ASO); and (ii) A pharmaceutically acceptable diluent, wherein the concentrate is miscible with the pharmaceutically acceptable diluent; The ASO is mixed with the pharmaceutically acceptable diluent to produce a liquid composition containing the ASO, and in: (a) The ASO is stable in the pharmaceutical formulation after the formulation has been stored at -20°C or at a certain temperature and relative humidity for a certain period of time; (b) The pharmaceutical preparation has a shelf life of a certain period when stored at -20°C or at a certain temperature and relative humidity; (c) After storing the pharmaceutical formulation at -20°C or at a certain temperature and relative humidity for a certain period of time, the percentage of impurities in the pharmaceutical formulation does not exceed 2.5% based on an HPLC relative retention time of 0.92; (d) After storing the pharmaceutical formulation at -20°C or at a certain temperature and relative humidity for a certain period of time, the percentage of impurities in the pharmaceutical formulation does not exceed 3.5% based on an HPLC relative retention time of 0.98; (e) After storing the pharmaceutical formulation at -20°C or at a certain temperature and relative humidity for a certain period of time, the percentage of any unspecified impurities in the pharmaceutical formulation does not exceed 1.8% according to HPLC; (f) After storing the pharmaceutical formulation at -20°C or at a certain temperature and relative humidity for a certain period of time, the percentage of total impurities in the pharmaceutical formulation does not exceed 10% according to HPLC; (g) After storing the pharmaceutical formulation at -20°C or at a certain temperature and relative humidity for a certain period of time, the pH of the pharmaceutical composition is 6.6 to 7.6; (h) After storing the pharmaceutical formulation at -20°C or at a certain temperature and relative humidity for a certain period of time, the osmotic pressure of the pharmaceutical composition is 310 mOsm / kg to 360 mOsm / kg; and / or (i) No observable particulate formation was observed after the drug formulation was stored at -20°C or at a certain temperature and relative humidity for a certain period of time.

44. The kit according to any one of claims 41 to 43, wherein the temperature is 4°C, 25°C, 30°C, 37°C or 40°C.

45. The kit according to any one of claims 41 to 44, wherein the relative humidity is about 55%, 60%, 65%, 70%, or 75%.

46. ​​The kit according to any one of claims 41 to 45, wherein the time period is at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 3 2 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks or 52 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months, or 1 year, 2 years, 3 years, 4 years or 5 years.

47. The kit according to any one of claims 29 to 46, wherein the liquid composition comprises a buffer.

48. The kit according to claim 47, wherein the buffer has a pKa of about 4.75, about 5.64, about 1.70, about 6.04, about 9.09, about 3.1, about 4.7, about 6.4 or about 6.50 at 25°C.

49. The kit of claim 47, wherein the buffer is an effective buffer solution with a pH range of about 3.6 to 5.6, about 5.5 to 6.5, about 5.5 to 7.4, about 3.0 to 6.2, or about 5.8 to 7.

2.

50. The kit of claim 47, wherein the buffer is selected from the group consisting of: acetate, succinate, histidine, citrate, 2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3-diol (Bis-Tris), and any combination thereof.

51. The kit according to any one of claims 28 to 50, wherein the liquid composition is formulated for application to the intrathecal space, cerebrospinal fluid, or brain of a human subject.

52. The kit according to any one of claims 28 to 50, wherein the liquid composition is formulated for application to the cerebrospinal fluid in the brain of a human subject.

53. The kit according to any one of claims 28 to 52, wherein the ASO comprises at least one modified sugar moiety.

54. The kit according to any one of claims 28 to 53, wherein each nucleotide of the antisense oligomer comprises a modified sugar moiety.

55. The kit according to any one of claims 28 to 54, further comprising: (iii) Instructions for use in diluting or dissolving the ASO in a pharmaceutically acceptable diluent.

56. The pharmaceutical formulation according to any one of claims 1 to 27 or the kit according to any one of claims 28 to 55, wherein the liquid composition comprises 25-250 mM NaCl.

57. The pharmaceutical formulation according to any one of claims 1 to 27 or 56, or the kit according to any one of claims 28 to 56, wherein the liquid composition comprises 0.1-20 mM KCl.

58. The pharmaceutical formulation according to any one of claims 1 to 27, 56 or 57, or the kit according to any one of claims 28 to 57, wherein the liquid composition comprises 2-4 mM KCl.

59. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 58, or the kit according to any one of claims 28 to 58, wherein the liquid composition comprises about 3 mM KCl.

60. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 59, or the kit according to any one of claims 28 to 59, wherein the liquid composition comprises 100-160 mM NaCl.

61. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 59, or the kit according to any one of claims 28 to 59, wherein the liquid composition comprises about 150 mM NaCl.

62. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 60, or the kit according to any one of claims 28 to 60, wherein the liquid composition comprises 125-145 mM NaCl.

63. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 62, or the kit according to any one of claims 28 to 62, wherein the liquid composition comprises about 130 mM NaCl.

64. The pharmaceutical formulation according to any one of claims 13 to 27 or 56 to 63, or the kit according to any one of claims 40 to 63, wherein the liquid composition comprises a buffer solution (pH 6.6-7.6).

65. The pharmaceutical formulation according to any one of claims 13 to 27 or 56 to 63, or the kit according to any one of claims 40 to 63, wherein the liquid composition comprises a buffer solution (pH 6.8-7.2).

66. The pharmaceutical formulation according to any one of claims 13 to 27 or 56 to 63, or the kit according to any one of claims 40 to 63, wherein the liquid composition comprises a buffer solution (pH 6.9-7.1).

67. The pharmaceutical formulation according to any one of claims 13 to 27 or 56 to 66, or the kit according to any one of claims 40 to 66, wherein the liquid composition comprises 0.1-50 mM Na2HPO4.

68. The pharmaceutical formulation according to any one of claims 13 to 27 or 56 to 67, or the kit according to any one of claims 40 to 67, wherein the liquid composition comprises 0.1-50 mM NaH2PO4.

69. The pharmaceutical formulation according to any one of claims 13 to 27 or 56 to 68, or the kit according to any one of claims 40 to 68, wherein the liquid composition comprises 5-250 mM NaCl, 0.1-20 mM KCl, 0.1-50 mM Na2HPO4, and 0.1-50 mM NaH2PO4.

70. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 69, wherein the ASO is dissolved in the pharmaceutically acceptable diluent.

71. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 70, or the kit according to any one of claims 28 to 69, wherein the pharmaceutically acceptable diluent is an isotonic solution.

72. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 71, or the kit according to any one of claims 28 to 69 or 71, wherein the ASO is not substantially polydisperse.

73. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 72, or the kit according to any one of claims 28 to 69 or 71 to 72, wherein the osmotic pressure of the liquid composition is less than 150 mM.

74. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 73, or the kit according to any one of claims 28 to 69 or 71 to 73, wherein the osmotic pressure of the liquid composition is about 130 mM.

75. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 74, or the kit according to any one of claims 28 to 69 or 71 to 74, wherein the liquid composition further comprises carbohydrates.

76. The pharmaceutical formulation or kit according to claim 75, wherein the carbohydrate comprises D-glucose.

77. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 76, or the kit according to any one of claims 28 to 69 or 71 to 76, wherein the liquid composition further comprises 1-100 mM D-glucose.

78. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 77, or the kit according to any one of claims 28 to 69 or 71 to 77, wherein the liquid composition further comprises an antioxidant.

79. The pharmaceutical formulation or kit according to claim 78, wherein the antioxidant is tert-butylhydroxyquinoline (TBHQ), butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E, or any combination thereof.

80. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 79, or the kit according to any one of claims 28 to 69 or 71 to 79, wherein the liquid composition does not contain a preservative.

81. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 80, or the kit according to any one of claims 28 to 69 or 71 to 80, wherein the liquid composition is packaged in a disposable vial.

82. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 81, or the kit according to any one of claims 28 to 69 or 71 to 81, wherein the liquid composition is formulated for or adapted to (i) Administered via bolus injection; (ii) Administered by infusion using a delivery pump; (iii) Administered via intraventricular injection; and / or (iv) Administered via intrathecal injection.

83. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 82, or the kit according to any one of claims 28 to 69 or 71 to 82, wherein the ASO comprises a 2'-O-methoxyethyl moiety.

84. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 83, or the kit according to any one of claims 28 to 69 or 71 to 83, wherein the ASO comprises thymidine including a 2'-O-methoxyethyl moiety.

85. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 84, or the kit according to any one of claims 28 to 69 or 71 to 84, wherein each nucleobase of the ASO comprises a 2'-O-methoxyethyl moiety.

86. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 85, or the kit according to any one of claims 28 to 69 or 71 to 85, wherein the ASO consists of 8 to 50 nucleobases.

87. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 85, or the kit according to any one of claims 28 to 69 or 71 to 85, wherein the ASO consists of fewer than 35 nucleobases.

88. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 85, or the kit according to any one of claims 28 to 69 or 71 to 85, wherein the ASO consists of 16 to 20 nucleobases.

89. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 85, or the kit according to any one of claims 28 to 69 or 71 to 85, wherein the ASO consists of 12 to 20 nucleobases.

90. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 85, or the kit according to any one of claims 28 to 69 or 71 to 85, wherein the ASO consists of 8 to 20 nucleobases.

91. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 90, or the kit according to any one of claims 28 to 69 or 71 to 90, wherein the ASO comprises 5'-methylcytosine (5'-MeC).

92. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 91, or the kit according to any one of claims 28 to 69 or 71 to 91, wherein each cytosine of the ASO is 5'-methylcytosine (5'-MeC).

93. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 92, or the kit according to any one of claims 28 to 69 or 71 to 92, wherein the ASO comprises a thiophosphate bond.

94. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 93, or the kit according to any one of claims 28 to 69 or 71 to 93, wherein each nucleoside internucleotide bond of the ASO is a phosphate thioester bond.

95. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 94, or the kit according to any one of claims 28 to 69 or 71 to 94, wherein the ASO comprises locked nucleic acid (LNA).

96. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 95, or the kit according to any one of claims 28 to 69 or 71 to 95, wherein the liquid composition comprises 1 mL to 20 mL of the pharmaceutically acceptable diluent, 2 mL to 10 mL of the pharmaceutically acceptable diluent, or 1 mL to 5 mL of the pharmaceutically acceptable diluent.

97. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 96, or the kit according to any one of claims 28 to 69 or 71 to 96, wherein the liquid composition comprises 0.1 mL to 50 mL of the pharmaceutically acceptable diluent.

98. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 96, or the kit according to any one of claims 28 to 69 or 71 to 96, wherein the liquid composition comprises about 0.1 mL, 0.5 mL, 1 mL, 2 mL, 2.5 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, 10 mL, 11 mL, 12 mL, 13 mL, 14 mL, 15 mL, 16 mL, 17 mL, 18 mL, 19 mL, 20 mL, 25 mL, 30 mL, 35 mL, 40 mL, 45 mL, or 50 mL of the pharmaceutically acceptable diluent.

99. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 98, or the kit according to any one of claims 28 to 69 or 71 to 98, wherein the liquid composition comprises about 0.5 mg to about 500 mg of the ASO.

100. The pharmaceutical formulation or kit according to claim 99, wherein the liquid composition comprises 0.1 mg, 0.5 mg, 1 mg, 2.5 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg, 40 mg, 42.5 mg, 45 mg, 47.5 mg, 50 mg, 52.5 mg, 55 mg, 57.5 mg, 60 mg, 62.5 mg, 65 mg, 67.5 mg, 70 mg, 72.5 mg, 75 mg, 77.5 mg, 80 mg, 82.5 mg, 85 mg, 87.5 mg, 90 mg, 92.5 mg, 9 ... 97.5 mg mg, 145 mg, 147.5 mg, 150 mg, 152.5 mg, 155 mg, 157.5 mg, 160 mg, 162.5mg, 165 mg, 167.5 mg, 170 mg, 172.5 mg, 175 mg, 177.5 mg, 180 mg, 182.5 mg, 185 mg, 187.5 mg, 190 mg, 192.5 mg, 195 mg, 197.5 mg, 200 mg, 202.5 mg, 205 mg, 207.5 mg, 210mg, 212.5 mg, 215 mg, 217.5 mg, 220 mg, 222.5 mg, 225 mg, 227.5 mg, 230 mg, 232.5 mg, 235 mg, 237.5 mg, 240 mg, 242.5 mg, 245 mg, 247.5 mg or 250 mg of the ASO.

101. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 100, or the kit according to any one of claims 28 to 69 or 71 to 100, wherein the ASO is present in the liquid composition at a concentration of 0.1-500 mg / mL.

102. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 101, or the kit according to any one of claims 28 to 69 or 71 to 101, wherein the ASO is present in the liquid composition at a concentration of 0.1 mg / mL to 250 mg / mL.

103. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 101, or the kit according to any one of claims 28 to 69 or 71 to 101, wherein the ASO is present in the pharmaceutical formulation at a concentration of 6.7 mg / mL to 188 mg / mL, 6.8 mg / mL to 187 mg / mL, 3 mg / mL to 100 mg / mL, or 3 mg / mL to 33 mg / mL.

104. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 100, or the kit according to any one of claims 28 to 69 or 71 to 100, wherein the ASO is present in the liquid composition at a concentration of about 0.1 mg / mL, 0.5 mg / mL, 1 mg / mL, 2 mg / mL, 2.5 mg / mL, 3 mg / mL, 4 mg / mL, 4.5 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 22 mg / mL, 25 mg / mL, 28 mg / mL, or 33 mg / mL.

105. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 100, or the kit according to any one of claims 28 to 69 or 71 to 100, wherein the ASO is present in the liquid composition at a concentration of 11 mg / mL, 22 mg / mL, 33 mg / mL, 44 mg / mL, 55 mg / mL, 66 mg / mL, 77 mg / mL, 88 mg / mL, 99 mg / mL, or 100 mg / mL.

106. A pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 100, or a kit according to any one of claims 28 to 69 or 71 to 100, wherein the ASO is in the form of about 3 mg / mL, 4 mg / mL, 4.5 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 22.5 mg / mL, 25 mg / mL, 27.5 mg / mL, 30 mg / mL, 32.5 mg / mL, 35 mg / mL, 37.5 mg / mL, 40 mg / mL, 42.5 mg / mL, 45 mg / mL, 47.5 mg / mL, 50 mg / mL, 52.5 mg / mL, 55 mg / mL, etc. mg / mL, 57.5 mg / mL, 60 mg / mL, 62.5 mg / mL, 65 mg / mL, 67.5 mg / mL, 70 mg / mL, 72.5 mg / mL, 75 mg / mL, 77.5 mg / mL, 80 mg / mL, 82.5 mg / mL, 85mg / mL, 87.5 mg / mL, 90 mg / mL, 92.5 mg / mL, 95 mg / mL, 97.5 mg / mL, 100 mg / mL, 102.5 mg / mL, 105 mg / mL, 107.5 mg / mL, 110 mg / mL, 112.5 mg / mL, 115 mg / mL, 117.5 mg / mL, 120 mg / mL, 122.5 mg / mL, 125 mg / mL, 127.5 mg / mL, 130 mg / mL, 132.5 mg / mL, 135 mg / mL, 137.5mg / mL, 140 mg / mL, 142.5 mg / mL, 145 mg / mL, 147.5 mg / mL, 150 mg / mL, 152.5 mg / mL, 155mg / mL, 157.5 mg / mL, 160 mg / mL, 162.5 mg / mL, 165 mg / mL, 167.5 mg / mL, 170 mg / mL, 172.5mg / mL, 175 mg / mL, 177.5 mg / mL, 180 mg / mL, 182.5 mg / mL, 185 mg / mL, 187.5 mg / mL, 190mg / mL, 192.5 mg / mL, 195 mg / mL, 197.5 mg / mL, 200 mg / mL, 202.The liquid composition is present at concentrations of 5 mg / mL, 205 mg / mL, 207.5 mg / mL, 210 mg / mL, 212.5 mg / mL, 215 mg / mL, 217.5 mg / mL, 220 mg / mL, 222.5 mg / mL, 225 mg / mL, 227.5 mg / mL, 230 mg / mL, 232.5 mg / mL, 235 mg / mL, 237.5 mg / mL, 240 mg / mL, 242.5 mg / mL, 245 mg / mL, 247.5 mg / mL, or 250 mg / mL.

107. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 106, or the kit according to any one of claims 28 to 69 or 71 to 106, wherein the ASO comprises a sequence having at least 80% sequence identity with any one of SEQ ID NO: 21-67, 210-256 or 304-1099.

108. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 106, or the kit according to any one of claims 28 to 69 or 71 to 106, wherein the ASO comprises a sequence having at least 83%, 88%, 94%, or 100% sequence identity with any one of SEQ ID NO: 21-67, 210-256, or 304-1099.

109. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 106, or the kit according to any one of claims 28 to 69 or 71 to 106, wherein the ASO comprises a sequence having at least 83%, 88%, 94%, or 100% sequence identity with any one of SEQ ID NO: 21-67, 210-256, or 304-1099.

110. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 106, or the kit according to any one of claims 28 to 69 or 71 to 106, wherein the ASO is a compound according to the following chemical structure: 。 111. The pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 106, or the kit according to any one of claims 28 to 69 or 71 to 106, wherein the ASO is a compound according to the following chemical structure: 。 112. A liquid pharmaceutical preparation, which is essentially composed of the following: (a) an antisense oligomer (ASO) at a concentration of about 0.1 mg / mL to about 500 mg / mL, wherein the ASO is a compound with the following chemical structure: ； (b) Calcium chloride dihydrate (CaCl2 2H2O) with a concentration of about 0.1 mM to about 50 mM; (c) Magnesium chloride hexahydrate (MgCl2 6H2O) at a concentration of about 0.1 mM to about 50 mM; (d) Potassium chloride (KCl) with a concentration of about 0.1 mM to about 20 mM; (e) Sodium chloride (NaCl) at a concentration of about 25 mM to about 250 mM; and (f) Water.

113. The pharmaceutical composition of claim 112, wherein the pharmaceutical formulation further comprises an amount of sodium hydroxide (NaOH) and / or hydrochloric acid (HCl) providing a pH of 6.6 to 7.6 for the pharmaceutical formulation.

114. The pharmaceutical composition of claim 112, wherein the pharmaceutical formulation further comprises sodium hydroxide (NaOH) at a concentration of about 0.1 mM to about 20 mM and / or hydrochloric acid (HCl) at a concentration of about 0.1 mM to about 20 mM.

115. A liquid pharmaceutical preparation, which is essentially composed of the following: (a) an antisense oligomer (ASO) at a concentration of about 0.1 mg / mL to about 500 mg / mL, wherein the ASO is a compound with the following chemical structure: ； (b) Calcium chloride dihydrate (CaCl2 2H2O) with a concentration of about 0.1 mM to about 50 mM; (c) Magnesium chloride hexahydrate (MgCl2 6H2O) at a concentration of about 0.1 mM to about 50 mM; (d) Potassium chloride (KCl) with a concentration of about 0.1 mM to about 20 mM; (e) Sodium chloride (NaCl) with a concentration of about 25 mM to about 250 mM; (f) Sodium hydroxide (NaOH) with a concentration of about 0.1 mM to about 20 mM and / or hydrochloric acid (HCl) with a concentration of about 0.1 mM to about 20 mM; and (g) Water.

116. The pharmaceutical composition according to any one of claims 112 to 115, wherein the concentration of said ASO is from about 0.1 mg / mL to about 250 mg / mL.

117. The pharmaceutical composition according to any one of claims 112 to 115, wherein the concentration of said ASO is from 6.7 mg / mL to 188 mg / mL, from 6.8 mg / mL to 187 mg / mL, from 3 mg / mL to 100 mg / mL, or from 3 mg / mL to 33 mg / mL.

118. The pharmaceutical composition according to any one of claims 112 to 115, wherein the concentration of said ASO is about 0.1 mg / mL, 0.5 mg / mL, 1 mg / mL, 2 mg / mL, 2.5 mg / mL, 3 mg / mL, 4 mg / mL, 4.5 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 22 mg / mL, 25 mg / mL, 28 mg / mL, or 33 mg / mL.

119. The pharmaceutical composition according to any one of claims 112 to 115, wherein the concentration of ASO is 11 mg / mL, 22 mg / mL, 33 mg / mL, 44 mg / mL, 55 mg / mL, 66 mg / mL, 77 mg / mL, 88 mg / mL, 99 mg / mL or 100 mg / mL.

120. The pharmaceutical composition according to any one of claims 112 to 115, wherein the concentration of the ASO is about 3 mg / mL, 4 mg / mL, 4.5 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 22.5 mg / mL, 25 mg / mL, 27.5 mg / mL, 30 mg / mL, 32.5 mg / mL, 35 mg / mL, 37.5 mg / mL, 40 mg / mL, 42.5 mg / mL, 45 mg / mL, 47.5 mg / mL, 50 mg / mL, 52.5 mg / mL, 55 mg / mL, 57.5 mg / mL, 60 mg / mL, 62.5 mg / mL, 65 mg / mL, 67.5 mg / mL, 70 mg / mL, 72.5 mg / mL, 75 mg / mL, 77.5 mg / mL, 80 mg / mL, 82.5 mg / mL, 85 mg / mL, 87.5 mg / mL, 90 mg / mL, 92.5 mg / mL, 95 mg / mL, 97.5 mg / mL, 100 mg / mL, 102.5 mg / mL, 105 mg / mL, 107.5 mg / mL, 110 mg / mL, 112.5 mg / mL, 115 mg / mL, 117.5 mg / mL, 120 mg / mL, 122.5 mg / mL, 125 mg / mL, 127.5 mg / mL, 130 mg / mL, 132.5 mg / mL, 135 mg / mL, 137.5 mg / mL, 140 mg / mL, 142.5 mg / mL, 145 mg / mL, 147.5 mg / mL, 150 mg / mL, 152.5 mg / mL, 155 mg / mL, 157.5 mg / mL, 160 mg / mL, 162.5 mg / mL, 165 mg / mL, 167.5 mg / mL, 170 mg / mL, 172.5 mg / mL, 175 mg / mL, 177.5 mg / mL, 180 mg / mL, 182.5 mg / mL, 185 mg / mL, 187.5 mg / mL, 190 mg / mL, 192.5 mg / mL, 1 95 mg / mL, 197.5 mg / mL, 200 mg / mL, 202.5 mg / mL, 205 mg / mL, 207.5 mg / mL, 210 mg / mL, 212.5 mg / mL, 215 mg / mL, 217.5 mg / mL, 220 mg / mL, 222.5 mg / mL, 225 mg / mL, 227.5 mg / mL, 230 mg / mL, 232.5 mg / mL, 235 mg / mL, 237.5 mg / mL, 240 mg / mL, 242.5 mg / mL, 245 mg / mL, 247.5 mg / mL or 250 mg / mL.

121. The pharmaceutical composition according to any one of claims 112 to 120, wherein the concentration of calcium chloride dihydrate is 0.2 mM to 25 mM, 0.5 mM to 10 mM, 0.75 mM to 5 mM, or 1 mM to 2 mM.

122. The pharmaceutical composition according to any one of claims 112 to 120, wherein the concentration of calcium chloride dihydrate is from about 1 mM to about 2 mM.

123. The pharmaceutical composition according to any one of claims 112 to 120, wherein the concentration of calcium chloride dihydrate is about 1.4 mM.

124. The pharmaceutical composition according to any one of claims 112 to 123, wherein the concentration of magnesium chloride hexahydrate is 0.2 mM to 25 mM, 0.3 mM to 15 mM, 0.4 mM to 5 mM, 0.5 mM to 1.5 mM or 0.6 mM to 1 mM.

125. The pharmaceutical composition according to any one of claims 112 to 123, wherein the concentration of magnesium chloride hexahydrate is from about 0.6 mM to about 1 mM.

126. The pharmaceutical composition according to any one of claims 112 to 123, wherein the concentration of magnesium chloride hexahydrate is about 0.79 mM.

127. The pharmaceutical composition according to any one of claims 112 to 126, wherein the concentration of potassium chloride is 0.5 mM to 10 mM, 1 mM to 7.5 mM, or 2 mM to 5 mM.

128. The pharmaceutical composition according to any one of claims 112 to 126, wherein the concentration of potassium chloride is from about 2 mM to about 5 mM.

129. The pharmaceutical composition according to any one of claims 112 to 126, wherein the concentration of potassium chloride is about 3 mM.

130. The pharmaceutical composition according to any one of claims 112 to 129, wherein the concentration of sodium chloride is 25 mM to 250 mM, 100 mM to 160 mM, 110 mM to 140 mM, or 130 mM to 160 mM.

131. The pharmaceutical composition according to any one of claims 112 to 129, wherein the concentration of sodium chloride is about 125 mM to 145 mM.

132. The pharmaceutical composition according to any one of claims 112 to 129, wherein the concentration of sodium chloride is about 130 mM.

133. The pharmaceutical composition according to any one of claims 112 to 129, wherein the concentration of sodium chloride is about 140 mM to 160 mM.

134. The pharmaceutical composition according to any one of claims 112 to 129, wherein the concentration of sodium chloride is about 150 mM.

135. The pharmaceutical composition according to any one of claims 112 to 134, wherein: (i) The concentration of calcium chloride dihydrate is from about 0.5 mM to about 5 mM; (ii) The concentration of magnesium chloride hexahydrate is from about 0.3 mM to about 1.25 mM; (iii) The concentration of potassium chloride is from about 1 mM to about 10 mM; and (iv) The concentration of sodium chloride is approximately 100 mM to 180 mM.

136. The pharmaceutical composition according to any one of claims 112 to 134, wherein: (i) The concentration of calcium chloride dihydrate is about 1 mM to about 2 mM; (ii) The concentration of magnesium chloride hexahydrate is about 0.6 mM to about 1 mM; (iii) The concentration of potassium chloride is from about 2 mM to about 5 mM; and (iv) The concentration of sodium chloride is approximately 120 mM to 160 mM.

137. The pharmaceutical composition according to any one of claims 112 to 134, wherein: (i) The concentration of the ASO is about 3 mg / mL, about 4.5 mg / mL, about 7 mg / mL or about 33 mg / mL; (ii) The concentration of calcium chloride dihydrate is approximately 1.4 mM; (iii) The concentration of magnesium chloride hexahydrate is approximately 0.79 mM; (iv) The concentration of potassium chloride is approximately 3 mM; and (v) The concentration of sodium chloride is approximately 150 mM.

138. The pharmaceutical composition according to any one of claims 112 to 137, wherein the pH of the pharmaceutical composition is about 6.6 to about 7.

6.

139. The pharmaceutical composition according to any one of claims 112 to 137, wherein the pH of the pharmaceutical composition is about 6.8 to about 7.

2.

140. The pharmaceutical composition according to any one of claims 112 to 137, wherein the pH of the pharmaceutical composition is about 6.9 to about 7.

1.

141. The pharmaceutical composition according to any one of claims 112 to 140, wherein the volume of the pharmaceutical composition is about 5 mL, about 6 mL, about 7 mL, about 8 mL, about 9 mL, about 10 mL, about 12 mL, about 15 mL, about 20 mL, or about 25 mL.

142. The pharmaceutical composition according to any one of claims 112 to 140, wherein the volume of the pharmaceutical composition is about 10 mL.

143. A liquid pharmaceutical preparation, which is essentially composed of the following: (a) an antisense oligomer (ASO) at a concentration of about 0.1 mg / mL to about 500 mg / mL, wherein the ASO is a compound with the following chemical structure: ； (b) Calcium ions (Ca) at concentrations of approximately 0.1 mM to approximately 50 mM. 2+ ); (c) Magnesium ions (Mg) at concentrations of approximately 0.1 mM to approximately 50 mM 2+ ); (d) Potassium ions (K+) at concentrations of approximately 0.1 mM to approximately 20 mM + ); (e) Sodium ions (Na+) at a concentration of approximately 25 mM to approximately 250 mM + ); (f) Chloride ions (Cl) at concentrations of approximately 25 mM to approximately 250 mM - );as well as (g) Water.

144. A liquid pharmaceutical preparation, which is essentially composed of the following: (a) an antisense oligomer (ASO) at a concentration of about 0.1 mg / mL to about 500 mg / mL, wherein the ASO is a compound with the following chemical structure: ； (b) Calcium ions at a concentration of approximately 1.4 mM (Ca 2+ ); (c) Magnesium ions (Mg) at a concentration of approximately 0.79 mM 2+ ); (d) Potassium ions (K) at a concentration of approximately 3 mM + ); (e) Sodium ions at a concentration of approximately 160 mM (Na + ); (f) Chloride ions (Cl) at a concentration of approximately 160 mM - );as well as (g) Water.

145. A method for treating a disease or condition of a subject in need or reducing the likelihood of the subject having said disease or condition, the method comprising administering to the subject a pharmaceutical composition according to any one of claims 1 to 27 or 56 to 144.

146. The method of claim 145, wherein the subject is a human subject.

147. The method of claim 145, wherein the human subject is at most 18 years of age when the first dose of the pharmaceutical composition is administered.

148. The method of claim 145, wherein the method comprises administering the ASO at a first dose of about 0.5 mg to about 500 mg.

149. The method of claim 145, wherein the method comprises administering multiple doses of the ASO.

150. The method according to any one of claims 145 to 149, wherein the disease or symptom is characterized by the subject's Na V 1.1 Decreased protein expression or function.

151. The method according to any one of claims 145 to 149, wherein the disease or symptom is Dravet Syndrome.

152. The method according to any one of claims 145 to 151, wherein the subject is characterized by having the following: (i) Seizures occurring before 12 months of age, with recurrent focal motor or hemiconvulsive or generalized tonic-clonic seizures, which are usually prolonged and triggered by high fever. (ii) No history of causally related lesions on magnetic resonance imaging; (iii) Other known causes of disease or symptoms besides Delaware syndrome; (iv) Normal development during epileptic seizures; (v) SCN1A Pathogenic variants or variants with uncertain significance in genes; (vi) At least two prior epilepsy treatments, either of which failed to provide adequate seizure control; (vii) Four or more convulsive seizures during the 28 days prior to administration, wherein the convulsive seizures are hemiclonic, focal with motor signs, focal to bilateral tonic-clonic seizures, generalized tonic-clonic seizures, tonic, tonic or atonic (falling seizures) and clonic seizures. (viii) Current interventions for epilepsy or medications containing at least one antiepileptic drug at a stable dose for at least 4 weeks, wherein the epilepsy intervention is a ketogenic diet, vagus nerve stimulants, or cannabinoids or cannabis-derived products; or Any combination of (ix)(i)-(viii).

153. The method according to any one of claims 145 to 152, wherein the subject is characterized by not having one or more of the following: (a) The above SCN1A One of the following mutations in the gene: Thr226Met, Leu263Val, Val422Leu, Thr1174Ser, Trp1204Arg, Pro1345Ser, Gln1489Lys, Phe1499Leu, Arg1575Cys, Val1611Phe, Leu1624Pro, Arg1648Cys, Leu1649Gln, Leu1670Trp, Gly1674Arg, and Asp1866Tyr; (b) Another known pathogenic mutation in a gene that causes epilepsy, wherein the pathogenic mutation is homozygous in the case of a known recessive disease; (c) Sodium channel blockers are currently used for maintenance therapy and anticoagulation, wherein the sodium channel blocker is phenytoin, carbamazepine, oxcarbazepine, lamotrigine, lacosamide, or rufinamide, and wherein the anticoagulator is not aspirin. (d) Clinically significant and unstable medical conditions other than epilepsy; (e) Clinically relevant symptoms or clinically significant diseases other than epilepsy within 4 weeks prior to administration; (f) History of brain or spinal cord disease other than epilepsy, Dlaivé syndrome, or bacterial meningitis or brain malformation; (g) Spinal deformity or other conditions that alter the free flow of cerebrospinal fluid (CSF) or have an implanted CSF drainage shunt. (h) Clinically significant abnormal laboratory values ​​prior to administration; (i) Aspartate aminotransferase or alanine aminotransferase > 2.5 times the upper limit of normal, serum creatinine > the upper limit of normal, or platelet count < the lower limit of normal; (j) Clinically relevant abnormalities in the 12-lead electrocardiogram (ECG) measured prior to administration; (k) Mental or behavioral disorders; (l) Currently or within the past 4 weeks, taking an anticoagulant medication, wherein the anticoagulant is not aspirin; or Any combination of (m)(a)-(l).

154. The method according to any one of claims 145 to 153, wherein the subject is 1 to 18 years old, 2 to 18 years old, 3 to 18 years old, 4 to 18 years old, 5 to 18 years old, 6 to 18 years old, 7 to 18 years old, 8 to 18 years old, 9 to 18 years old, 10 to 18 years old, 11 to 18 years old, 12 to 18 years old, 13 to 18 years old, 14 to 18 years old, 15 to 18 years old, 16 to 18 years old, or 17 to 18 years old.

155. The method according to any one of claims 145 to 153, wherein the subject is a person aged 1 to 17 years, 1 to 16 years, 1 to 15 years, 1 to 14 years, 1 to 13 years, 1 to 12 years, 1 to 11 years, 1 to 10 years, 1 to 9 years, 1 to 8 years, 1 to 7 years, 1 to 6 years, 1 to 5 years, 1 to 4 years, 1 to 3 years, or 1 to 2 years.

156. The method according to any one of claims 145 to 153, wherein the subject is under one year old or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 years old.

157. The method according to any one of claims 145 to 156, wherein the pharmaceutical composition is administered into the intrathecal space of the subject.

158. The method according to any one of claims 145 to 156, wherein the pharmaceutical composition is administered to the cerebrospinal fluid of the subject.

159. The method according to any one of claims 145 to 156, wherein the pharmaceutical composition is administered to the brain of the subject.

160. The method according to any one of claims 145 to 156, wherein the pharmaceutical composition is administered to the cerebrospinal fluid in the brain of the subject.

161. The method according to any one of claims 145 to 160, wherein the pharmaceutical composition is administered by bolus injection.

162. The method of claim 161, wherein the method comprises administering the pharmaceutical composition by bolus injection within 1 to 60 minutes, 1 to 50 minutes, 1 to 40 minutes, 1 to 30 minutes, 1 to 20 minutes, 1 to 10 minutes, 1 to 5 minutes, or 1 to 3 minutes.

163. The method according to any one of claims 145 to 160, wherein the pharmaceutical composition is administered by infusion using a delivery pump.

164. The method according to any one of claims 145 to 163, wherein the pharmaceutical composition is administered by intraventricular injection.

165. The method according to any one of claims 145 to 163, wherein the pharmaceutical composition is administered by intrathecal injection.

166. The method according to any one of claims 145 to 165, wherein the method reduces or improves at least one symptom of Draway syndrome in the human subject.

167. The method of claim 166, wherein the symptom of Delaware syndrome is epileptic seizures.

168. The method according to any one of claims 145 to 167, wherein the application reduces or improves the frequency, intensity, or duration of seizures.

169. The method according to any one of claims 145 to 168, wherein the method further comprises evaluating the tolerability or efficacy of the pharmaceutical composition.

170. The method of any one of claims 145 to 169, wherein the method further comprises administering a pharmaceutical composition to the subject, the pharmaceutical composition comprising a subsequent dose of the ASO of about 0.5 mg to about 500 mg.

171. The method of claim 170, wherein the subsequent dose is 0.1 mg, 0.5 mg, 1 mg, 2.5 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg, 40 mg, 42.5 mg, 45 mg, 47.5 mg, 50 mg, 52.5 mg, 55 mg, 57.5 mg, 60 mg, 62.5 mg, 65 mg, 67.5 mg, 70 mg, 72.5 mg, 75 mg, 77.5 mg, 80 mg, 82.5 mg, 85 mg, 87.5 mg, 90 mg, 92.5 mg, 95 mg, 97.5 mg. mg, 100 mg, 102.5 mg, 105 mg, 107.5 mg, 110 mg, 112.5 mg, 115 mg, 117.5 mg, 120 mg, 122.5 mg, 125 mg, 127.5 mg, 130 mg, 132.5 mg, 135 mg, 137.5 mg, 140 mg, 142.5mg, 145 147.5 mg mg, 195 mg, 197.5 mg, 200 mg, 202.5 mg, 205 mg, 207.5 mg, 210 mg, 212.5 mg, 215 mg, 217.5 mg, 220 mg, 222.5 mg, 225 mg, 227.5 mg, 230 mg, 232.5 mg, 235 mg, 237.5mg, 240 mg, 242.5 mg, 245 mg, 247.5 mg or 250 mg.

172. The method of claim 170 or 171, wherein the subsequent dose is lower than the previous dose after administration intolerance to the indicated previous dose.

173. The method of claim 170 or 171, wherein after administration tolerance to the previous dose is indicated, the subsequent dose is the same as the previous dose.

174. The method of claim 170 or 171, wherein the subsequent dose is higher than the previous dose after administration tolerance to the indicated previous dose has been achieved.

175. The method of claim 170 or 171, wherein after the administration of the indicated previous dose has been effective, the subsequent dose is the same as the previous dose.

176. The method of claim 170 or 171, wherein the subsequent dose is lower than the previous dose after the administration of the indicated previous dose has been effective.

177. The method of claim 170 or 171, wherein the subsequent dose is higher than the previous dose after the administration of the indicated previous dose has been ineffective.

178. The method according to any one of claims 170 to 177, wherein the subsequent dose is administered at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months after the administration of the previous dose.

179. The method according to any one of claims 145 to 178, wherein the dose frequency is maintained or reduced after indicating that the previous dose is effective.

180. The method according to any one of claims 145 to 179, wherein the dose frequency is increased after indicating that the previous dose is ineffective.

181. The method according to any one of claims 145 to 180, wherein the method further comprises administering at least one additional therapeutic agent or therapy.

182. The method of claim 181, wherein the at least one additional therapeutic agent or therapy is administered simultaneously with the dose.

183. The method of claim 181, wherein the at least one additional therapeutic agent or therapy is administered prior to the administration of the dose.

184. The method of claim 181, wherein the at least one additional therapeutic agent or therapy is administered after the administration of the dose.

185. The method according to any one of claims 150 to 184, wherein Na V 1.1 Decreased protein expression or function is associated with exons containing nonsense-mediated RNA decay-induced exons encoding Na+. V 1.1 Splicing-related changes in the NMD exons of the protein's precursor mRNA.

186. The method according to any one of claims 150 to 185, wherein the ASO promotes the extraction of NMD exons and encoding the Na V The NMD exon is excluded from the precursor mRNA of the protein 1.

1.

187. The method according to any one of claims 150 to 186, wherein the ASO contains the NMD exon and encodes the Na V 1.1 Binding to the target portion of the protein's precursor mRNA.

188. The method of claim 187, wherein the ASO promotes the extraction of NMD exons and encoding the Na V The NMD exon is excluded from the precursor mRNA of the protein 1.

1.

189. The method according to any one of claims 185 to 188, wherein when the ASO is introduced into the cell, the ASO increases the encoding of the Na+. V 1.1 Levels of treated mRNA of the protein.

190. The method according to any one of claims 185 to 189, wherein when the ASO is introduced into the cell, the ASO increases the Na+. V 1.1 Protein levels.

191. The method according to any one of claims 185 to 190, wherein the targeting portion is located within an intron sequence adjacent to the NMD exon.

192. The method according to any one of claims 185 to 190, wherein the targeting portion comprises at least one nucleotide of the NMD exon.

193. The method according to any one of claims 185 to 190, wherein the targeting portion is located within the NMD exon.

194. A method for preparing a pharmaceutical composition according to any one of claims 1 to 27 or 56 to 144, wherein the method comprises diluting the antisense oligomer (ASO) in a pharmaceutically acceptable diluent, thereby preparing the liquid composition.

195. The method according to claim 194, wherein the ASO is at 3 mg / mL, 4 mg / mL, 4.5 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 22 mg / mL, 25 mg / mL, 28 mg / mL, 30 mg / mL, 33 mg / mL, 44 mg / mL, 55 mg / mL, 66 mg / mL, 77 mg / mL, 88 mg / mL, 99 mg / mL, 100 mg / mL, 22.5 mg / mL, 25 mg / mL, 27.5 mg / mL, 30 mg / mL, 32.5 mg / mL, 35 mg / mL, 37.5 mg / mL, 40 mg / mL, 42.5 mg / mL, 45 mg / mL, 47.5 mg / mL, 50 mg / mL, 52.5 mg / mL, 55 mg / mL, 57.5 mg / mL, 60 mg / mL, 62.5 mg / mL, 65 mg / mL, 67.5 mg / mL, 70 mg / mL, 72.5 mg / mL, 75 mg / mL, 77.5 mg / mL, 80 mg / mL, 82.5 mg / mL, 85 mg / mL, 87.5 mg / mL, 90 mg / mL, 92.5 mg / mL, 95 mg / mL, 97.5 mg / mL, 100 mg / mL, 102.5 mg / mL, 105 mg / mL, 107.5 mg / mL, 110 mg / mL, 112.5 mg / mL, 115 mg / mL, 117.5 mg / mL, 120 mg / mL, 122.5 mg / mL, 125 mg / mL, 127.5 mg / mL, 130 mg / mL, 132.5 mg / mL, 135 mg / mL, 137.5 mg / mL, 140 mg / mL, 142.5 mg / mL, 145 mg / mL, 147.The liquid composition is present at concentrations of 5 mg / mL, 190 mg / mL, 192.5 mg / mL, 195 mg / mL, 197.5 mg / mL, 200 mg / mL, 202.5 mg / mL, 205 mg / mL, 207.5 mg / mL, 210 mg / mL, 212.5 mg / mL, 215 mg / mL, 217.5 mg / mL, 220 mg / mL, 222.5 mg / mL, 225 mg / mL, 227.5 mg / mL, 230 mg / mL, 232.5 mg / mL, 235 mg / mL, 237.5 mg / mL, 240 mg / mL, 242.5 mg / mL, 245 mg / mL, 247.5 mg / mL, or 250 mg / mL.

196. The method of claim 195, wherein the method further comprises diluting the liquid composition with an additional volume of the pharmaceutically acceptable diluent, thereby preparing the liquid composition.

197. The method of claim 196, wherein the ASO is in the form of 0.1-500 mg / mL, 0.1 mg / mL to 250 mg / mL, 6.7 mg / mL to 188 mg / mL, 6.8 mg / mL to 187 mg / mL, 3 mg / mL to 100 mg / mL, or 3 mg / mL to 33 mg / mL, or about 0.1 mg / mL, 0.5 mg / mL, 1 mg / mL, 2 mg / mL, 2.5 mg / mL, 3 mg / mL, 4 mg / mL, 4.5 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 22 mg / mL, 25 mg / mL, or 25 mg / mL. The concentrations of mg / mL, 28 mg / mL, 30 mg / mL or 33 mg / mL present in the liquid composition are present in the liquid composition.

198. The method according to any one of claims 194 to 197, wherein the method further comprises filtering the liquid composition.

199. The method of claim 198, wherein filtration comprises filtering the liquid composition at least twice or filtering the liquid composition through at least two membranes.

200. The method of claim 198 or 199, wherein filtration comprises filtering the liquid composition through 0.45 μm membranes and 0.2 μm membranes.

201. The method of claim 199 or 200, wherein the at least two membranes, the 0.45 μm membrane and / or the 0.2 μm membrane comprise polyethersulfone membranes.

202. The method according to any one of claims 194 to 201, wherein the method further comprises filling a vial with the liquid composition.

203. The method of claim 202, wherein the vial is sterilized and / or depyrogenated.

204. The method of claim 202 or 203, wherein the method further comprises assembling the vial with a stopper.

205. The method of claim 204, wherein the stopper is sterilized and / or depyrogenated.

206. The method according to any one of claims 202 to 205, wherein the method further comprises capping the vial with a seal.

207. The method of claim 206, wherein the seal is sterilized and / or depyrogenated.

208. The method according to any one of claims 194 to 207, wherein the method is performed aseptically.

209. The method according to any one of claims 194 to 208, wherein the method further comprises storing the vial at a certain temperature for a certain period of time.

210. The method of claim 209, wherein the temperature is -20 ± 5°C.

211. The method according to claim 209 or 210, wherein the time period does not exceed 36 months.

212. The method of claim 211, wherein the time period does not exceed 24 months.

213. The method according to any one of claims 209 to 212, wherein the method further comprises administering the liquid composition to a human subject after the storage.

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