Antisense oligomer formulations

Abstract

As used herein, the term "Na" refers to the amount of Na in cells of a subject in need thereof. V 1.1 Pharmaceutical formulations, kits, and methods of use thereof comprising antisense oligomers (ASOs) for treating a disease or condition by modulating protein expression are provided, wherein the ASOs modulate splicing of nonsense-mediated mRNA decay-inducing exons from pre-mRNA in cells of the subject, thereby treating a disease or condition in the subject. V 1.1 Regulating protein expression.

Description

[Technical Field]

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

[0002] Disorders of the nervous system are often associated with channelopathies, characterized by disturbances in the function of ion channels that mediate neuronal excitability, neuronal interactions, and overall brain function. Mutations in the SCN1A gene, part of the SCN1A-SCN2A-SCN3A gene cluster that encodes the alpha pore-forming subunit of neuronal voltage-gated sodium channels, result in wild-type Na+ channels. V 1.1 Protein (Na V 1.1) V 1.1 Expressing proteins or Na V Mutations in the SCN1A gene are associated with the development of many diseases and conditions, such as Dravet syndrome (DS) (Miller, et al., 1993-2015, Gene Reviews, Eds. Pagon RA, et al., Seattle (WA): University of Washington, Seattle, Bookshelf ID: NBK1318, and Mulley, et al., 2005, Hum. Mutat. 25:535-542). Summary of the Invention

[0003] Alternative splicing events in the SCN1A gene can produce non-productive mRNA transcripts, which can then cause abnormal protein expression.Therapeutic agents that can target the alternative splicing events in the SCN1A gene can regulate the expression level of functional protein and / or inhibit abnormal protein expression in Dravet syndrome patients.Such therapeutic agents can be used to treat the condition caused by the deficiency of SCN1A protein, SCN8A protein, or SCN5A protein.

[0004] Selecting the appropriate drug formulation, dosage, dosing regimen, and patient population is a crucial step in pharmaceutical development. For example, without adequate information on dosage, a physician cannot prescribe a drug to a patient. For example, if a dose or dosage range that allows safe and predictable administration cannot be identified, the drug will not be medically useful or commercially viable. Therefore, determining the correct drug dosage is a key challenge that must be addressed in clinical practice. Finding a therapeutically effective dose and dosing regimen for a drug requires balancing patient compliance, the drug's therapeutic efficacy, and side effects, which requires considerable skill. For example, the appropriate dose and dosing regimen may be found through clinical trials. Clinical trials are part of an approved process, require the investment of significant intellectual property and financial resources from various parties, and are not within the scope of a physician's daily work. For example, patient compliance can be crucial for optimal treatment of various conditions. The higher the required dosage, the more difficult the treatment plan and the less likely patients are to comply. Pharmaceuticals can improve patients' quality of life (QOL), but only if used correctly. Therefore, selecting appropriate drug dosages, formulations, dosing regimens, and patient populations is complex and unpredictable. Structurally similar compounds vary significantly in solubility, toxicity, activity, stability, and pharmacological properties. Furthermore, animal models and human subjects differ significantly in physiology. Therefore, translating preclinical information into clinically effective treatments is an unpredictable and challenging task.

[0005] As used herein, in a human subject in need thereof, Na V 1.1 Appropriate pharmaceutical formulations, doses, dosing regimens and patient populations are provided for treating or reducing the likelihood of developing diseases or conditions characterized by under-expression or under-function of a protein.

[0006] Provided herein are pharmaceutical formulations, 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 unbuffered, and (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.

[0007] Also provided herein is 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 storage of the pharmaceutical formulation at −20° C. or a certain temperature and relative humidity for a certain period of time; (b) the pharmaceutical formulation has a shelf life of a certain period when stored at −20° C. or a certain temperature and relative humidity; (c) the percentage of an impurity in the pharmaceutical formulation with an HPLC relative retention time of 0.92 is 2.5% or less after storage of the pharmaceutical formulation at −20° C. or a certain temperature and relative humidity for a certain period of time; and (d) the percentage of an impurity in the pharmaceutical formulation with an HPLC relative retention time of 0.98 is 2.5% or less after storage of the pharmaceutical formulation at −20° C. or a certain temperature and relative humidity for a certain period of time. (e) the percentage of any unspecified impurity in the pharmaceutical formulation by HPLC is 1.8% or less after storage of the pharmaceutical formulation at -20°C or a certain temperature and relative humidity for a period of time, (f) the percentage of total impurities in the pharmaceutical formulation by HPLC is 10% or less after storage of the pharmaceutical formulation at -20°C or a certain temperature and relative humidity for a period of time, (g) after storage of the pharmaceutical formulation at -20°C or a certain temperature and relative humidity for a 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 period of time, the osmolality of the pharmaceutical composition is 310 to 360 mOsm / kg, and / or (i) no observable particle formation is observed after storage of the pharmaceutical formulation at -20°C or a certain temperature and relative humidity for a 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 period is 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, 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 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.

[0009] Also provided herein is 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 lacks NaHPO and / or NaHPO, and (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.

[0010] In some embodiments, the liquid composition lacks phosphate ions.

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

[0012] Also provided herein is 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) MgCl or MgCl 6H 0, and d) CaCl or CaCl 2H 0.

[0013] In some embodiments, the liquid composition comprises 0.1-50 mM CaCl2 or CaCl22H2O.

[0014] In some embodiments, the liquid composition comprises 1-2 mM CaCl2 or CaCl22H2O.

[0015] In some embodiments, the liquid composition comprises about 1.4 mM CaCl or CaClH0.

[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 MgCl or MgCl 6H O.

[0019] In some embodiments, the liquid composition comprises 5-250 mM NaCl, 0.1-20 mM KCl, 0.1-50 mM CaCl or CaCl 2H 2 O, and 0.1-50 mM MgCl or MgCl 2 6H 2 O.

[0020] Also provided herein are pharmaceutical formulations, wherein the pharmaceutical formulation is a liquid composition comprising i) an antisense oligomer (ASO), and ii) a pharmaceutically acceptable diluent, wherein the liquid composition lacks calcium ions and / or magnesium ions, and (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 intracerebral space of a human subject; and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

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

[0022] In some embodiments, the buffer has a pKa at 25°C 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.

[0023] In some embodiments, the buffering agent is effective in 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 buffering agent 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 administration into the intrathecal space, cerebrospinal fluid, or brain of a human subject.

[0026] In some embodiments, the liquid composition is formulated for administration to the cerebrospinal fluid of 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 comprises a modified sugar moiety.

[0029] Also provided herein are kits 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 of the ASO with the pharmaceutically acceptable diluent produces a liquid composition comprising the ASO, the liquid composition is not buffered, 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.

[0030] In some embodiments, the kit includes (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 a liquid composition comprising the ASO is produced by mixing the ASO with the pharmaceutically acceptable diluent, and wherein (a) the ASO is stable in the pharmaceutical formulation after storage of the pharmaceutical formulation at −20° C. or a certain temperature and relative humidity for a certain period of time, (b) the pharmaceutical formulation has a shelf life of a certain period when stored at −20° C. or a certain temperature and relative humidity, (c) the percentage of an impurity in the pharmaceutical formulation with an HPLC relative retention time of 0.92 is 2.5% or less after storage of the pharmaceutical formulation at −20° C. or a certain temperature and relative humidity for a certain period of time, and (d) the percentage of an impurity in the pharmaceutical formulation with an HPLC relative retention time of 0.98 is 2.5% or less after storage of the pharmaceutical formulation at −20° C. or a certain temperature and relative humidity for a certain period of time. (e) the percentage of any unspecified impurity in the pharmaceutical formulation by HPLC is 1.8% or less after storage of the pharmaceutical formulation at -20°C or a certain temperature and relative humidity for a certain period of time; (f) the percentage of total impurities in the pharmaceutical formulation by HPLC is 10% or less after storage of the pharmaceutical formulation at -20°C or a certain temperature and relative humidity for a certain period of time; (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 osmolality of the pharmaceutical composition is 310 to 360 mOsm / kg; and / or (i) after storage of the pharmaceutical formulation at -20°C or a certain temperature and relative humidity for a certain period of time, no observable particle formation is observed. 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 period is 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, 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 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.

[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, the liquid composition lacking NaHPO and / or NaHPO, 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.

[0033] In some embodiments, the liquid composition lacks phosphate ions.

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

[0035] In some embodiments, the kit includes (i) a concentrate containing an antisense oligomer (ASO) and (ii) a pharmaceutically acceptable diluent consisting of a) NaCl, b) KCl, c) MgCl or MgCl 6H 0, and d) CaCl or CaCl 2H 0, wherein the concentrate is miscible with the pharmaceutically acceptable diluent, and mixing the ASO with the pharmaceutically acceptable diluent produces a liquid composition containing the ASO.

[0036] In some embodiments, the liquid composition comprises 0.1-50 mM CaCl2 or CaCl22H2O.

[0037] In some embodiments, the liquid composition comprises 1-2 mM CaCl2 or CaCl22H2O.

[0038] In some embodiments, the liquid composition comprises about 1.4 mM CaCl or CaClH0.

[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 MgCl or MgCl 6H O.

[0042] In some embodiments, the liquid composition comprises 5-250 mM NaCl, 0.1-20 mM KCl, 0.1-50 mM CaCl or CaCl 2H 2 O, and 0.1-50 mM MgCl or MgCl 2 6H 2 O.

[0043] Also provided herein are kits 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, the liquid composition lacking calcium ions 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 comprises a buffer.

[0045] In some embodiments, the buffer has a pKa at 25°C 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.

[0046] In some embodiments, the buffering agent is effective in 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 buffering agent 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 administration into the intrathecal space, cerebrospinal fluid, or brain of a human subject.

[0049] In some embodiments, the liquid composition is formulated for administration to the cerebrospinal fluid of 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 comprises a modified sugar moiety.

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

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

[0054] In some embodiments, the liquid composition comprises 0.1 to 20 mM KCl.

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

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

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

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

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

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

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

[0062] In some embodiments, the liquid composition comprises 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 solubilized 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 polydisperse.

[0067] In some embodiments, the liquid composition has an osmolality of less than 150 mM.

[0068] In some embodiments, the liquid composition has an osmolality of about 130 mM.

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

[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 t-butylhydroxyquinoline (TBHQ), butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E, or any combination thereof.

[0074] In some embodiments, the liquid composition is preservative-free.

[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 suitable for administration: (i) as a 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 a T-2'-methoxyethyl sugar moiety.

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

[0080] In some embodiments, the ASO comprises a thymidine containing 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 between 8 and 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 between 8 and 20 nucleobases.

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

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

[0089] In some embodiments, the ASO comprises phosphorothioate linkages.

[0090] In some embodiments, each internucleoside linkage of the ASO is a phosphorothioate linkage.

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

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

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

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

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

[0096] In some embodiments, the liquid composition comprises 0.1, 0.5, 1, 2.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22.5, 25, 27.5, 30, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, 52.5, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 5, 57.5, 60, 62.5, 65, 67.5, 70, 72.5, 75, 77.5, 80, 82.5, 85, 87.5, 90, 92.5, 95, 97.5, 100, 102.5, 105, 107.5, 110, 112.5, 115, 117.5, 120, 122.5, 125, 127. 5, 130, 132.5, 135, 137.5, 140, 142.5, 145, 147.5, 150, 152.5, 155, 157.5, 160, 162.5, 165, 167.5, 170, 172.5, 175, 177.5, 180, 182.5, 185, 187.5, 190, 192 Contains 0.5, 195, 197.5, 200, 202.5, 205, 207.5, 210, 212.5, 215, 217.5, 220, 222.5, 225, 227.5, 230, 232.5, 235, 237.5, 240, 242.5, 245, 247.5, or 250 mg of ASO.

[0097] In some embodiments, the ASO is present in the liquid composition at a concentration of 0.1 to 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 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, 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 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.

[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 80% sequence identity to any one of SEQ ID NOs: 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 to any one of SEQ ID NOs: 21-67, 210-256, or 304-1099.

[0105] In some embodiments, the ASO provided herein consists of a sequence having at least 83%, 88%, 94%, or 100% sequence identity to any one of SEQ ID NOs: 21-67, 210-256, or 304-1099.

[0106] In some embodiments, the ASO has the following chemical structure: [ka] or a salt thereof.

[0107] In some embodiments, the ASO has the following chemical structure: [ka] It is a compound according to the following:

[0108] In some aspects, the present disclosure essentially provides (a) an antisense oligomer (ASO) at a concentration of about 0.1 mg / mL to about 500 mg / mL, wherein the ASO has the following chemical structure: [ka] or a salt thereof; (b) calcium chloride dihydrate (CaCl22H2O) at a concentration of about 0.1 mM to about 50 mM; (c) magnesium chloride hexahydrate (MgCl26H2O) 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.

[0109] In some embodiments, the pharmaceutical formulation further comprises sodium hydroxide (NaOH) and / or hydrochloric acid (HCl) in an amount that provides the pharmaceutical formulation with a pH of 6.6 to 7.6. In some embodiments, 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 embodiments, the pharmaceutical formulation essentially comprises: (a) an antisense oligomer (ASO) at a concentration of about 0.1 mg / mL to about 500 mg / mL, wherein the ASO has the following chemical structure: [ka] or a salt thereof, (b) calcium chloride dihydrate (CaCl22H2O) at a concentration of about 0.1 mM to about 50 mM, (c) magnesium chloride hexahydrate (MgCl26H2O) 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) 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.

[0110] In some embodiments, the concentration of the ASO is about 0.1 mg / mL to about 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. In some embodiments, 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 embodiments, 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 embodiments, 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 L, 50mg / mL, 52.5mg / mL, 55mg / mL, 57.5mg / mL, 60mg / mL, 62.5mg / mL, 65mg / mL, 67.5mg / mL, 70mg / mL, 72.5mg / mL, 75mg / mL, 77.5mg / mL, 80mg / mL, 82.5mg / mL , 85mg / mL, 87.5mg / mL, 90mg / mL, 92.5mg / mL, 95mg / mL, 97.5mg / mL, 100mg / mL, 102.5mg / mL, 105mg / mL, 107.5mg / mL, 110mg / mL, 112.5mg / mL, 115mg / mL, 117.5mg / mL、120mg / mL、122.5mg / mL、125mg / mL、127.5mg / mL、130mg / mL、132.5mg / mL、135mg / mL、137.5mg / mL、140mg / mL、142.5mg / mL、147.5mg / mL、150mg / mL 、152.5mg / mL、155mg / mL、157.5mg / mL、160mg / mL、162.5mg / mL、165mg / mL、167.5mg / mL、170mg / mL、172.5mg / mL、175mg / mL、177.5mg / mL、180mg / mL、182.5mg / mL、185mg / mL g / mL、187.5mg / mL、190mg / mL、192.5mg / mL、195mg / mL、197.5mg / mL、200mg / mL、202.5mg / mL、205mg / mL、207.5mg / mL、210mg / mL、212.5mg / mL、215mg / mL、217.5mg / mL、 220mg / mL、222.5mg / mL、225mg / mL、227.5mg / mL、230mg / mL、232.5mg / mL、235mg / mL、237.5mg / mL、240mg / mL、242.5mg / mL、245mg / mL、247.5mg / mL、or 250mg / mL。

[0111] In some embodiments, 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 embodiments, the concentration of calcium chloride dihydrate is about 1 mM to about 2 mM. In some embodiments, the concentration of calcium chloride dihydrate is about 1.4 mM. In some embodiments, 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 embodiments, the concentration of magnesium chloride hexahydrate is about 0.6 mM to about 1 mM. In some embodiments, the concentration of magnesium chloride hexahydrate is about 0.79 mM. In some embodiments, the potassium chloride concentration is 0.5 mM to 10 mM, 1 mM to 7.5 mM, or 2 mM to 5 mM. In some embodiments, the potassium chloride concentration is about 2 mM to about 5 mM. In some embodiments, the potassium chloride concentration is about 3 mM. In some embodiments, the sodium chloride concentration is 25 mM to 250 mM, 100 mM to 160 mM, 110 mM to 140 mM, or 130 mM to 160 mM. In some embodiments, the sodium chloride concentration is about 125 mM to 145 mM. In some embodiments, the sodium chloride concentration is about 130 mM. In some embodiments, the sodium chloride concentration is about 140 mM to 160 mM. In some embodiments, the sodium chloride concentration is about 150 mM. In some embodiments, the calcium chloride dihydrate concentration is about 0.5 mM to about 5 mM, the magnesium chloride hexahydrate concentration is about 0.3 mM to about 1.25 mM, the potassium chloride concentration is about 1 mM to about 10 mM, and the sodium chloride concentration is about 100 mM to 180 mM. In some embodiments, the calcium chloride dihydrate concentration is about 1 mM to about 2 mM, the magnesium chloride hexahydrate concentration is about 0.6 mM to about 1 mM, the potassium chloride concentration is about 2 mM to about 5 mM, and the sodium chloride concentration is about 120 mM to 160 mM.In some embodiments, 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 embodiments, the pH of the pharmaceutical composition is about 6.6 to about 7.6. In some embodiments, the pH of the pharmaceutical composition is about 6.8 to about 7.2. In some embodiments, the pH of the pharmaceutical composition is about 6.9 to about 7.1. In some embodiments, 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 embodiments, the volume of the pharmaceutical composition is about 10 mL.

[0112] In some aspects, the present disclosure essentially provides (a) an antisense oligomer (ASO) at a concentration of about 0.1 mg / mL to about 500 mg / mL, wherein the ASO has the following chemical structure: [ka] or a salt thereof, (b) a compound according to the formula (I) or a salt thereof, 2+ ), (c) magnesium ions (Mg 2+ ), (d) potassium ions (K + ), (e) sodium ions (Na ) at a concentration of about 25 mM to about 250 mM + ), (f) chloride ions (Cl) at a concentration of about 25 mM to about 250 mM + ), and (g) water.

[0113] In some aspects, the present disclosure essentially provides (a) an antisense oligomer (ASO) at a concentration of about 0.1 mg / mL to about 500 mg / mL, wherein the ASO has the following chemical structure: [ka] or a salt thereof, (b) a compound according to the formula (I) or a salt thereof, 2+ ), (c) magnesium ions (Mg 2+ ), (d) potassium ions (K + ), (e) sodium ions (Na + ), (f) chloride ions (Cl) at a concentration of approximately 160 mM + ), and (g) water.

[0114] In some aspects, provided herein are pharmaceutical formulations, 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.

[0115] In some aspects, also provided herein are pharmaceutical formulations, 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 lacks NaHPO and / or NaHPO, and (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 to the intrathecal space, cerebrospinal fluid, or brain of a human subject. In some embodiments, the liquid composition lacks phosphate ions. In some embodiments, the liquid composition comprises calcium ions, magnesium ions, and / or potassium ions.

[0116] In some aspects, also provided herein are pharmaceutical formulations, wherein the pharmaceutical formulations are liquid compositions comprising (i) an active pharmaceutical ingredient (API) and (ii) a pharmaceutically acceptable diluent consisting of a) NaCl, b) KCl, c) MgCl or MgCl 6H 0, and d) CaCl or CaCl 2H 0. In some embodiments, the liquid composition lacks phosphate ions. In some embodiments, the liquid composition comprises calcium ions, magnesium ions, and / or potassium ions.

[0117] 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 may be formulated using the pharmaceutically acceptable diluents provided herein. The active pharmaceutical ingredient may be a small molecule or a biologic, such as an organic compound, an antisense oligonucleotide, DNA, an antibody, or any other protein or polypeptide, a living organism such as a bacterium or fungus, a viral vector or virus-like particle, or any combination thereof.

[0118] Also provided herein are methods of treating a disease or condition or reducing the likelihood of developing a disease or condition in a subject in need thereof, the methods comprising administering to the subject a pharmaceutical composition disclosed herein.

[0119] In some embodiments, the subject is a human subject.

[0120] In some embodiments, the human subject is at most 18 years of age at the time of the first administration of the pharmaceutical composition.

[0121] In some embodiments, the method includes administering the ASO in a first dose of about 0.5 milligrams to about 500 milligrams.

[0122] In some embodiments, the method comprises administering multiple doses of the ASO.

[0123] In some embodiments, the disease or condition is a Na V 1.1 Characterized by a decrease in protein expression or function.

[0124] In some embodiments, the disease or condition is Dravet syndrome.

[0125] In some embodiments, the subject is characterized as having: a. Seizures begin before 12 months of age and involve recurrent focal motor, unilateral convulsive, or generalized tonic-clonic seizures, often prolonged, and precipitated by hyperthermia; b. No previous causative magnetic resonance imaging lesions; c. The absence of any other known etiology of any disease or condition other than Dravet syndrome; d. Normal development at the time of seizure onset; e. Having a pathogenic variant or a variant of uncertain significance in the SCN1A gene; f. Having received at least two previous epilepsy treatments that did not adequately control seizures; g. Four or more convulsive seizures in the 28 days prior to administration, with the convulsive seizures being any one of the following: hemiclonic, focal with motor signs, focal to bilateral tonic-clonic convulsions, generalized tonic-clonic convulsions, tonic, tonic or atonic (falling-down seizures), and clonic. h. Currently receiving an intervention for epilepsy or at least one antiepileptic medication at a stable dose for at least 4 weeks, where the intervention for epilepsy is a ketogenic diet, vagus nerve stimulation, or a cannabinoid or cannabis-derived product; or i. Any combination thereof.

[0126] In some embodiments, the subject is characterized by the absence of one or more of the following: a. One of the following mutations in the SCN1A gene: Thr226Met, Leu263Val, Val422Leu, Thr1174Ser, Trp1204Arg, Pro1345Ser, Gln1489Lys, Phe1499Leu, Arg1575Cys, Val1611Phe, Leu1624Pro, Arg1648Cys, Leu1649Gln, Leu1670Trp, Gly1674Arg, and Asp1866Tyr; b. A known pathogenic variant in another gene that causes epilepsy and is homozygous for a known recessive disorder; c. Currently being treated with a sodium channel blocker and an anticoagulant as maintenance therapy, where the sodium channel blocker is phenytoin, carbamazepine, oxcarbazepine, lamotrigine, lacosamide, or rufinamide, and the anticoagulant is not aspirin; d. A clinically significant unstable medical condition other than epilepsy; e. Clinically relevant symptoms or clinically significant illnesses other than epilepsy within the 4 weeks prior to treatment; f. History of epilepsy, brain or spinal cord disease other than Dravet syndrome, or history of bacterial meningitis or congenital brain abnormalities; g. Spinal cord malformations or other conditions that alter the free flow of cerebrospinal fluid (CSF), or implantation of a CSF drainage shunt; h. Clinically significant abnormal laboratory values ​​prior to administration; i. aspartate aminotransferase or alanine aminotransferase more than 2.5 times the upper limit of normal, serum creatinine higher than the upper limit of normal, or platelet count lower than the lower limit of normal; j. Clinically relevant abnormalities in a 12-lead electrocardiogram (ECG) taken before administration; k. Mental or behavioral disorders; l. Currently or in the past 4 weeks, taking an anticoagulant medication, and the anticoagulant is not aspirin; or m. Any combination thereof.

[0127] In some embodiments, the subject is 1-18 years old, 2-18 years old, 3-18 years old, 4-18 years old, 5-18 years old, 6-18 years old, 7-18 years old, 8-18 years old, 9-18 years old, 10-18 years old, 11-18 years old, 12-18 years old, 13-18 years old, 14-18 years old, 15-18 years old, 16-18 years old, or 17-18 years old.

[0128] In some embodiments, the subject is a human between the ages of 1 and 17 years old, 1 and 16 years old, 1 and 15 years old, 1 and 14 years old, 1 and 13 years old, 1 and 12 years old, 1 and 11 years old, 1 and 10 years old, 1 and 9 years old, 1 and 8 years old, 1 and 7 years old, 1 and 6 years old, 1 and 5 years old, 1 and 4 years old, 1 and 3 years old, or 1 and 2 years old.

[0129] In some embodiments, the subject is under 1 year old, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 years old.

[0130] In some embodiments, the pharmaceutical composition is administered to the intrathecal space of the subject.

[0131] In some embodiments, the pharmaceutical composition is administered into the cerebrospinal fluid of the subject.

[0132] In some embodiments, the pharmaceutical composition is administered intracerebrally to the subject.

[0133] In some embodiments, the pharmaceutical composition is administered into the cerebrospinal fluid in the brain of the subject.

[0134] In some embodiments, the pharmaceutical composition is administered as a bolus injection.

[0135] In some embodiments, the method comprises administering the pharmaceutical composition as a bolus injection over 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.

[0136] In some embodiments, the pharmaceutical composition is administered by infusion with a delivery pump.

[0137] In some embodiments, the pharmaceutical composition is administered by intraventricular injection.

[0138] In some embodiments, the pharmaceutical composition is administered by intrathecal injection.

[0139] In some embodiments, the method reduces or ameliorates at least one symptom of Dravet syndrome in a human subject.

[0140] In some embodiments, the symptom of Dravet syndrome is seizures.

[0141] In some embodiments, administration reduces or ameliorates seizure frequency, seizure intensity, or seizure duration.

[0142] In some embodiments, the method further comprises assessing the tolerability or efficacy of the pharmaceutical composition.

[0143] In some embodiments, the method further comprises administering to the subject a subsequent dose of about 0.5 milligrams to about 500 milligrams of a pharmaceutical composition comprising the ASO.

[0144] In some embodiments, the subsequent doses are 0.1, 0.5, 1, 2.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22.5, 25, 27.5, 30, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, 52.5, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80 5, 57.5, 60, 62.5, 65, 67.5, 70, 72.5, 75, 77.5, 80, 82.5, 85, 87.5, 90, 92.5, 95, 97.5, 100, 102.5, 105, 107.5, 110, 112.5, 115, 117.5, 120, 122.5, 125, 127 .5, 130, 132.5, 135, 137.5, 140, 142.5, 145, 147.5, 150, 152.5, 155, 157.5, 160, 162.5, 165, 167.5, 170, 172.5, 175, 177.5, 180, 182.5, 185, 187.5, 190, 192.5, 195, 197.5, 200, 202.5, 205, 207.5, 210, 212.5, 215, 217.5, 220, 222.5, 225, 227.5, 230, 232.5, 235, 237.5, 240, 242.5, 245, 247.5, or 250 mg.

[0145] In some embodiments, a subsequent dose is less than the previous dose following an indication that administration of the previous dose was not tolerated.

[0146] In some embodiments, a subsequent dose is the same as the previous dose, following indications that administration of the previous dose is tolerated.

[0147] In some embodiments, a subsequent dose is greater than the previous dose, provided that administration of the previous dose is tolerated.

[0148] In some embodiments, a subsequent dose is the same as the previous dose, following an indication that administration of the previous dose is effective.

[0149] In some embodiments, subsequent doses are less than the previous dose, following an indication that administration of the previous dose is effective.

[0150] In some embodiments, a subsequent dose is greater than the previous dose following an indication that administration of the previous dose was ineffective.

[0151] In some embodiments, a subsequent dose is administered at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months after administration of the previous dose.

[0152] In some embodiments, the frequency of administration is maintained or reduced as indicated by the effectiveness of the previous dose.

[0153] In some embodiments, the frequency of administration is increased following indication that the previous dose was ineffective.

[0154] In some embodiments, the method further comprises administering at least one additional therapeutic agent or therapy.

[0155] In some embodiments, at least one additional therapeutic agent or therapy is administered simultaneously with the dose.

[0156] In some embodiments, at least one additional therapeutic agent or therapy is administered prior to administration of the dose.

[0157] In some embodiments, at least one additional therapeutic agent or therapy is administered after administration of the dose.

[0158] In some embodiments, Na V 1.1 Decreased expression or function of proteins containing NMD exons and Na V 1.1 It is associated with altered splicing of nonsense-mediated RNA decay-induced exons from protein-coding pre-mRNA.

[0159] In some embodiments, the ASO contains an NMD exon and V 1.1 Facilitate the exclusion of NMD exons from protein-coding pre-mRNAs.

[0160] In some embodiments, the ASO contains an NMD exon and V 1.1 Binding to a target portion of the pre-mRNA encoding the protein.

[0161] In some embodiments, the ASO contains an NMD exon and V 1.1 Facilitate the exclusion of NMD exons from protein-coding pre-mRNAs.

[0162] In some embodiments, the ASO inhibits Na when the ASO is introduced into a cell. V 1.1 Increase the levels of processed mRNA that encodes the protein.

[0163] In some embodiments, the ASO inhibits Na when the ASO is introduced into a cell. V 1.1 Increase protein levels.

[0164] In some embodiments, the target portion is within an intron sequence adjacent to the NMD exon.

[0165] In some embodiments, the target portion comprises at least one nucleotide of an NMD exon.

[0166] In some embodiments, the target portion is within an NMD exon.

[0167] Also provided herein is a method of making the pharmaceutical compositions described herein, the method comprising diluting an antisense oligomer (ASO) in a pharmaceutically acceptable diluent, thereby making a liquid composition.

[0168] In some embodiments, ASO is 3mg / mL、4mg / mL、4.5mg / mL、5mg / mL、6mg / mL、7mg / mL、9mg / mL、10mg / mL、11mg / mL、12mg / mL、13mg / mL、14mg / mL、15mg / mL、16mg / mL、17mg / mL mg / mL、18mg / mL、19mg / mL、20mg / mL、22mg / mL、25mg / mL、28mg / mL、30mg / mL、44mg / mL、55mg / mL、66mg / mL、77mg / mL、88mg / mL、99mg / mL、100mg / mL、22.5mg / mL, 25mg / mL, 27.5mg / mL, 30mg / mL, 32.5mg / mL, 35mg / mL, 37.5mg / mL, 40mg / mL, 42.5mg / mL, 45mg / mL, 47.5mg / mL, 50mg / mL, 52.5mg / mL, 55mg / mL, 57.5mg / mL, 60mg / mL, 62.5mg / mL, 65mg / mL, 67.5mg / mL, 70mg / mL, 72.5mg / mL, 75mg / mL, 77.5mg / mL, 80mg / mL, 82.5mg / mL, 85mg / mL, 87.5mg / mL, 90mg / mL, 92. 5mg / mL、95mg / mL、97.5mg / mL、100mg / mL、102.5mg / mL、105mg / mL、107.5mg / mL、110mg / mL、112.5mg / mL、115mg / mL、117.5mg / mL、120mg / mL、122.5mg / mL 、125mg / mL、127.5mg / mL、130mg / mL、132.5mg / mL、135mg / mL、137.5mg / mL、140mg / mL、142.5mg / mL、145mg / mL、147.5mg / mL、150mg / mL、152.5mg / mL、155mg / mL g / mL、157.5mg / mL、160mg / mL、162.5mg / mL、165mg / mL、167.5mg / mL、170mg / mL、172.5mg / mL、175mg / mL、177.5mg / mL、180mg / mL、182.5mg / mL、185mg / mL 、187.5mg / mL、190mg / mL、192.5mg / mL、195mg / mL、197.5mg / mL、200mg / mL、202.5mg / mL、205mg / mL、207.5mg / mL、210mg / mL、212.5mg / mL、215mg / mL、217.It is present in liquid compositions at concentrations of 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.

[0169] In some embodiments, the method further comprises diluting the liquid composition with an additional amount of a pharmaceutically acceptable diluent, thereby creating a liquid composition.

[0170] In some embodiments, the ASO is present in the liquid composition at a concentration, wherein the ASO is present in a concentration of 0.1 to 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 ... The compound is present in the liquid composition at a concentration of 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, 30 mg / mL, or 33 mg / mL.

[0171] In some embodiments, the method further comprises filtering the liquid composition.

[0172] In some embodiments, filtering comprises filtering the liquid composition at least twice or filtering through at least two membranes.

[0173] In some embodiments, filtering comprises filtering the liquid composition through a 0.45 μm membrane and a 0.2 μm membrane.

[0174] In some embodiments, at least two of the 0.45 μm membrane and / or the 0.2 μm membrane comprise polyethersulfone membranes.

[0175] In some embodiments, the method further comprises filling a vial with the liquid composition.

[0176] In some embodiments, the vial is sterilized and / or pyrogen-free.

[0177] In some embodiments, the method further comprises attaching a stopper to the vial.

[0178] In some embodiments, the stopper is sterilized and / or pyrogen-free.

[0179] In some embodiments, the method further comprises capping the vial with a seal.

[0180] In some embodiments, the seal is sterilized and / or pyrogen-free.

[0181] In some embodiments, the method is performed aseptically.

[0182] In some embodiments, the method further comprises storing the vial at a temperature for a period of time.

[0183] In some embodiments, the temperature is -20±5°C.

[0184] In some embodiments, the period is 36 months or less.

[0185] In some embodiments, the period is 24 months or less.

[0186] In some embodiments, the method further comprises administering the liquid composition to a human subject after storage.

[0187] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. [Brief explanation of the drawings]

[0188] The features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings.

[0189] [Figure 1A] 1A-1B show a schematic diagram of a target pre-mRNA containing a nonsense-mediated mRNA decay-inducing exon (NMD exon mRNA) and the therapeutic-mediated elimination of the nonsense-mediated mRNA decay-inducing exon from the pre-mRNA to increase expression of a full-length target protein or functional RNA. FIG. 1A shows a cell divided into nuclear and cytoplasmic compartments. In the nucleus, the pre-mRNA transcript of a target gene undergoes splicing to generate processed mRNA. This processed mRNA is transported to the cytoplasm and translated into the target protein. For this target gene, a portion of the processed mRNA contains the nonsense-mediated mRNA decay-inducing exon (NMD exon mRNA). This exon is degraded in the cytoplasm, and the target protein is not produced. [Figure 1B]Figures 1A-1B show a schematic diagram of a target pre-mRNA containing a nonsense-mediated mRNA decay-inducing exon (NMD exon mRNA) and the therapeutic-mediated elimination of the NMD exon from the pre-mRNA to increase expression of a full-length target protein or functional RNA. Figure 1B shows an example of the same cell separated into nuclear and cytoplasmic compartments. Treatment with a therapeutic agent, such as an antisense oligomer (ASO), promotes the elimination of the NMD exon from the pre-mRNA, resulting in increased processed mRNA. The processed mRNA is then translated into high levels of the target protein. [Figure 1C] Figure 1C is a schematic diagram of therapeutic ASO-mediated elimination of nonsense-mediated mRNA decay-inducing exons from pre-mRNA, which reduces non-productive processed mRNAs (e.g., containing NMD exons) and increases productive mRNAs (e.g., not containing NMD exons), resulting in increased expression of full-length target proteins from the productive mRNAs. [Figure 1D] Figure ID shows the identification of an exemplary sequence in the SCN1A gene that encodes a nonsense-mediated mRNA decay (NMD)-inducing exon. The identification of a sequence in the SCN1A gene encoding an NMD-inducing exon using comparative genomics is shown and visualized in the UCSC genome browser. The top panel shows a scaled representation of the SCN1A gene. The level of conservation across 100 vertebrate species is shown as peaks. The highest peak corresponds to the exon (black box), while no peaks were observed in the majority of introns (arrowheaded lines). A conserved peak was identified in intron 20 (NM_006920), shown in the middle panel. Examination of the conserved sequence identified a 64-bp exon-like sequence (lower panel, sequence highlighted in gray) flanked by 3' and 5' splice sites (underlined sequences). Inclusion of this exon results in a frameshift, introducing a premature stop codon in exon 21, targeting the transcript for NMD. [Figure 2]FIG. 2 shows the timeline of the study design for monitoring wild-type (WT) and Dravet syndrome (DS) mice, as well as Kaplan-Meier curves showing survival of DS and WT littermate mice monitored for up to 14 weeks. [Figure 3] Figure 3 shows the experimental design of the EEG seizure monitoring study in DS mice and their WT littermates. [Figure 4A] Figures 4A-4E show the results of seizure monitoring in mice administered ASO-22 or phosphate-buffered saline (PBS). Figure 4A shows an example of EEG recording in a DS mouse. [Figure 4B] Figures 4A-4E show the results of seizure monitoring in mice administered ASO-22 or phosphate-buffered saline (PBS). Figure 4B shows the number of seizures occurring in various brain regions in the two mouse groups. * indicates p<0.05. [Figure 4C] Figures 4A-4E show the results of seizure monitoring in mice administered ASO-22 or phosphate-buffered saline (PBS). Figure 4C summarizes 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). * indicates p < 0.05. [Figure 4D] Figures 4A-4E show the results of seizure monitoring in mice administered ASO-22 or phosphate-buffered saline (PBS), and Figure 4D shows the number of mice in each group that experienced multiple seizures. [Figure 4E] Figures 4A-4E show the results of seizure monitoring in mice administered ASO-22 or phosphate-buffered saline (PBS). Figure 4E shows the effect of ASO-22 on the latency to the first recorded seizure between P22 and P46 in DS mice administered PBS (n = 21) or ASO-22 (n = 21). [Figure 5A]Figures 5A-5G show that a single ICV injection of 20 μg of ASO-22 at P2 reduced the incidence of sudden unexpected death in epilepsy (SUDEP) and increased NaV1.1 protein expression in DS mice. Figure 5A is a schematic representation of the experimental design. [Figure 5B] Figures 5A-5G show that a single ICV injection of 20 μg of ASO-22 at P2 reduced the incidence of sudden unexpected death in epilepsy (SUDEP) and increased NaV1.1 protein expression in DS mice. Figures 5B, 5C, 5D, 5E, 5F, and 5G show the ASO-22 concentration, fold change in Scn1a gene expression, and NaV1.1 expression in brain tissue at 7 and 14 weeks after a single ICV injection of ASO-22 (20 μg) or PBS at P2, respectively. [Figure 5C] Figures 5A-5G show that a single ICV injection of 20 μg of ASO-22 at P2 reduced the incidence of sudden unexpected death in epilepsy (SUDEP) and increased NaV1.1 protein expression in DS mice. Figures 5B, 5C, 5D, 5E, 5F, and 5G show the ASO-22 concentration, fold change in Scn1a gene expression, and NaV1.1 expression in brain tissue at 7 and 14 weeks after a single ICV injection of ASO-22 (20 μg) or PBS at P2, respectively. [Figure 5D]Figures 5A-5G show that a single ICV injection of 20 μg of ASO-22 at P2 reduced the incidence of sudden unexpected death in epilepsy (SUDEP) and increased NaV1.1 protein expression in DS mice. Figures 5B, 5C, 5D, 5E, 5F, and 5G show the ASO-22 concentration, fold change in Scn1a gene expression, and NaV1.1 expression in brain tissue at 7 and 14 weeks after a single ICV injection of ASO-22 (20 μg) or PBS at P2, respectively. [Figure 5E] Figures 5A-5G show that a single ICV injection of 20 μg of ASO-22 at P2 reduced the incidence of sudden unexpected death in epilepsy (SUDEP) and increased NaV1.1 protein expression in DS mice. Figures 5B, 5C, 5D, 5E, 5F, and 5G show the ASO-22 concentration, fold change in Scn1a gene expression, and NaV1.1 expression in brain tissue at 7 and 14 weeks after a single ICV injection of ASO-22 (20 μg) or PBS at P2, respectively. [Figure 5F] Figures 5A-5G show that a single ICV injection of 20 μg of ASO-22 at P2 reduced the incidence of sudden unexpected death in epilepsy (SUDEP) and increased NaV1.1 protein expression in DS mice. Figures 5B, 5C, 5D, 5E, 5F, and 5G show the ASO-22 concentration, fold change in Scn1a gene expression, and NaV1.1 expression in brain tissue at 7 and 14 weeks after a single ICV injection of ASO-22 (20 μg) or PBS at P2, respectively. [Figure 5G]Figures 5A-5G show that a single ICV injection of 20 μg of ASO-22 at P2 reduced the incidence of sudden unexpected death in epilepsy (SUDEP) and increased NaV1.1 protein expression in DS mice. Figures 5B, 5C, 5D, 5E, 5F, and 5G show the ASO-22 concentration, fold change in Scn1a gene expression, and NaV1.1 expression in brain tissue at 7 and 14 weeks after a single ICV injection of ASO-22 (20 μg) or PBS at P2, respectively. [Figure 6A] Figures 6A-6B show the survival rates of DS and WT mice after a single ICV injection of ASO-22 (60 μg) or PBS at P14. [Figure 6B] Figures 6A-6B show the survival rates of DS and WT mice after a single ICV injection of ASO-22 (60 μg) or PBS at P14. [Figure 7A] Figures 7A-7F show ASO-22 exposure, Scn1a expression, and NaV1.1 expression in brain tissue at P35 and P90, respectively, after a single ICV injection of ASO-22 (60 μg) or PBS at P14. [Figure 7B] Figures 7A-7F show ASO-22 exposure, Scn1a expression, and NaV1.1 expression in brain tissue at P35 and P90, respectively, after a single ICV injection of ASO-22 (60 μg) or PBS at P14. [Figure 7C] Figures 7A-7F show ASO-22 exposure, Scn1a expression, and NaV1.1 expression in brain tissue at P35 and P90, respectively, after a single ICV injection of ASO-22 (60 μg) or PBS at P14. [Figure 7D] Figures 7A-7F show ASO-22 exposure, Scn1a expression, and NaV1.1 expression in brain tissue at P35 and P90, respectively, after a single ICV injection of ASO-22 (60 μg) or PBS at P14. [Figure 7E]Figures 7A-7F show ASO-22 exposure, Scn1a expression, and NaV1.1 expression in brain tissue at P35 and P90, respectively, after a single ICV injection of ASO-22 (60 μg) or PBS at P14. [Figure 7F] Figures 7A-7F show ASO-22 exposure, Scn1a expression, and NaV1.1 expression in brain tissue at P35 and P90, respectively, after a single ICV injection of ASO-22 (60 μg) or PBS at P14. [Figure 8] FIG. 8 shows the experimental conditions and the number of monkeys used per group. [Figure 9A] 9A-9B show the levels of ASO-22 in various regions of the brain of cynomolgus monkeys on days 3 and 29 of the study, respectively. [Figure 9B] 9A-9B show the levels of ASO-22 in various regions of the brain of cynomolgus monkeys on days 3 and 29 of the study, respectively. [Figure 10A] 10A-10B show the levels of NaV1.1 protein in various regions of the brain of cynomolgus monkeys on days 3 and 29, respectively. [Figure 10B] 10A-10B show the levels of NaV1.1 protein in various regions of the brain of cynomolgus monkeys on days 3 and 29, respectively. [Figure 11A] 11A-11B show the ratio of productive SCN1A genes to total SCN1A genes as an assessment of target engagement in cynomolgus monkeys at days 3 and 29. [Figure 11B] 11A-11B show the ratio of productive SCN1A genes to total SCN1A genes as an assessment of target engagement in cynomolgus monkeys at days 3 and 29. [Figure 12A] FIG. 12A shows the plasma pharmacokinetics of ASO-22 in cynomolgus monkeys at various time points after intrathecal administration. [Figure 12B] FIG. 12B shows the levels of ASO-22 in the cerebrospinal fluid (CSF) of cynomolgus monkeys on days 3 and 29 of the study. [Figure 13A] Figures 13A-13D show the identification of alternative splicing events in SCN1A that result in NMD. Figure 13A shows SCN1A splicing isoforms with or without alternative exons in ReN cells, as demonstrated by RT-PCR. [Figure 13B] Figures 13A-13D show the identification of alternative splicing events in SCN1A that result in NMD. Figure 13B shows the assessment of alternative splicing events in the SCN1A gene in cerebral cortex from four species. [Figure 13C] Figures 13A-13D show the identification of alternative splicing events in SCN1A that result in NMD. Figure 13C shows an image of a TBE PAGE gel of RT-PCR products corresponding to the productive transcript (lower band, 498 bp) and non-productive transcript (upper band, 562 bp) of Scn1a amplified from total RNA extracted from the brains of WT C57BL / 6J mice at P0-P20 and 10 months of age. Mouse Gapdh was used as a loading control. [Figure 13D] Figures 13A-13D show the identification of alternative splicing events in SCN1A that result in NMD. Figure 13D summarizes the expression of productive and non-productive transcripts of Scn1a in postnatal mouse brain, calculated using the optical density of the PCR products shown in Figure 13C. [Figure 14A] Figures 14A-14E show that selected ASOs suppressed NMD splicing events and increased productive SCN1A mRNA expression in ReN cells. [Figure 14B] Figures 14A-14E show that selected ASOs suppressed NMD splicing events and increased productive SCN1A mRNA expression in ReN cells. [Figure 14C] Figures 14A-14E show that selected ASOs suppressed NMD splicing events and increased productive SCN1A mRNA expression in ReN cells. [Figure 14D]Figures 14A-14E show that selected ASOs suppressed NMD splicing events and increased productive SCN1A mRNA expression in ReN cells. [Figure 14E] Figures 14A-14E show that selected ASOs suppressed NMD splicing events and increased productive SCN1A mRNA expression in ReN cells. [Figure 15A] Figures 15A-15C show the dose-dependent effect of ASO-22 on the splicing and expression of SCN1A mRNA in ReN cells. [Figure 15B] Figures 15A-15C show the dose-dependent effect of ASO-22 on the splicing and expression of SCN1A mRNA in ReN cells. [Figure 15C] Figures 15A-15C show the dose-dependent effect of ASO-22 on the splicing and expression of SCN1A mRNA in ReN cells. [Figure 16A] Figures 16A-16H show that ASO-22 ICV injection caused a dose-dependent and sustained increase in productive Scn1a mRNA and NaV1.1 protein expression in the mouse brain. [Figure 16B] Figures 16A-16H show that ASO-22 ICV injection caused a dose-dependent and sustained increase in productive Scn1a mRNA and NaV1.1 protein expression in the mouse brain. [Figure 16C] Figures 16A-16H show that ASO-22 ICV injection caused a dose-dependent and sustained increase in productive Scn1a mRNA and NaV1.1 protein expression in the mouse brain. [Figure 16D] Figures 16A-16H show that ASO-22 ICV injection caused a dose-dependent and sustained increase in productive Scn1a mRNA and NaV1.1 protein expression in the mouse brain. [Figure 16E]Figures 16A-16H show that ASO-22 ICV injection caused a dose-dependent and sustained increase in productive Scn1a mRNA and NaV1.1 protein expression in the mouse brain. [Figure 16F] Figures 16A-16H show that ASO-22 ICV injection caused a dose-dependent and sustained increase in productive Scn1a mRNA and NaV1.1 protein expression in the mouse brain. [Figure 16G] Figures 16A-16H show that ASO-22 ICV injection caused a dose-dependent and sustained increase in productive Scn1a mRNA and NaV1.1 protein expression in the mouse brain. [Figure 16H] Figures 16A-16H show that ASO-22 ICV injection caused a dose-dependent and sustained increase in productive Scn1a mRNA and NaV1.1 protein expression in the mouse brain. [Figure 17] FIG. 17 shows the dose-dependent effect of ASO-22 on Scn1a mRNA expression in the brains of ICV-injected neonatal mice (§=non-productive, *=productive). [Figure 18] FIG. 18 shows the dose-dependent effect of ASO-22 on NaV1.1 expression in the brains of ICV-injected neonatal mice. [Figure 19] FIG. 19 shows the expression of Scn1a mRNA in the brain of mice at various days after injection (§=non-productive, *=productive). [Figure 20] FIG. 20 shows the expression of NaV1.1 in the brain of mice at various days after injection. [Figure 21] Figure 21 shows the validation of the two anti-NaV1.1 antibodies used in the Examples. The specificity of the two anti-NaV1.1 antibodies, Alomone ASC-001 and NeuroMab 75-023, was tested using total protein prepared from the brain of an Scn1a- / - mouse (center lane) and the brains of two WT littermates (left and right lanes). [Figure 22] Figure 22 shows a schematic diagram of the clinical manifestations of Dravet syndrome and their relative incidence by age. AA: atypical seizures; AE: acute encephalopathy; CG: crouching gait; CPS: complex partial seizures; DD: developmental delay; DS: Dravet syndrome; EEG: electroencephalogram; FSz: complex febrile seizures; GMS: generalized motor seizures; HS: thermal sensitivity; m: month; MSz: myoclonic seizures; OS: confusion; SE: status epilepticus; SUDEP: sudden death in epilepsy; y: year; *60% have moderate fever, most have chronic generalized unilateral motor seizures; **The exact incidence of AA and CPS is unknown because it is difficult to distinguish them without ictal EEG recordings. See, e.g., Gataullina and Dulac, 2017, the entire contents of which are incorporated herein by reference. [Figure 23] FIG. 23 shows TANGO (Targeted Augmentation of Nuclear Gene Output) that can be used to treat Dravet Syndrome. [Figure 24] FIG. 24 shows the transforming potential of the TANGO method in Dravet syndrome. [Figure 25] The study design is shown in Figure 25. The Phase 1 / 2a, open-label, two-part study was conducted at approximately 20 sites in the United States. [Figure 26] Figure 26 shows a schematic diagram of the study design. [Figure 27] Figure 27 shows the patient inclusion and exclusion criteria. [Figure 28] Figure 28 shows the test evaluation. [Figure 29] FIG. 29 shows the effect of phosphate on the pH of ASO-1 formulations. [Figure 30] Figure 30 shows a comparison of the self-buffering capacity of oligonucleotides and pH for dose settings of 33 mg / mL and 5 mg / mL of ASO-1. [Figure 31] FIG. 31 shows the Fourier transform infrared spectroscopy (FTIR) readings. [Figure 32] FIG. 32 shows scanning electron microscopy-energy dispersive X-ray spectroscopy (SEM-EDS). [Figure 33] Figure 33 shows representative photographs of fiber-like particles present in an ASO formulation at 1 and 3 months when stored 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 7.0-7.5. [Figure 34] Figure 34 shows representative photographs of large waxy fragments observed during stability testing of a formulation containing 4.58 mM ASO-1, 1.4 mM CaCl, 0.79 mM MgCl, 3 mM KCl, 0.70 mM NaHPO·2H2O, and 0.3 mM NaHPO·2H2O without pH adjustment, or a formulation containing 4.58 mM ASO-1, 1.4 mM CaCl, 0.79 mM MgCl, 3 mM KCl, 150 mM NaCl, 0.70 mM NaHPO·2H2O, and 0.3 mM NaHPO·2H2O. These large waxy fragments were present at all stability conditions (2–8°C, 25°C / 60% RH, and 40°C / 75% RH). DETAILED DESCRIPTION OF THE INVENTION

[0190] Certain specific details are described herein to provide a thorough understanding of various embodiments. However, those skilled in the art will understand that the present disclosure may 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.

[0191] 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 belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below.

[0192] definition As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0193] It should be noted that the term "or" is typically used in its sense to include "and / or" unless the context clearly dictates otherwise. As used herein, the terms "and / or" and "any combination thereof," as well as their grammatical equivalents, may be used interchangeably. These terms may convey that any combination is specifically contemplated. For illustrative purposes only, the following phrases "A, B and / or C" or "A, B, C, or any combination thereof" may mean "A alone, B alone, C alone, A and B, B and C, A and C, and A, B and C." The term "or" may be used conjunctively or disjunctively unless the context clearly dictates disjunctive use.

[0194] The term "about" or "approximately" means within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, e.g., the limitations of the measurement system. For example, "about" can mean within one or more standard deviations, as is customary in the art. Alternatively, "about" can mean within 20%, 10%, 5%, or 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, within 5-fold, or more preferably within 2-fold of a value. When a particular value is described in this application and claims, unless otherwise specified, "about" should be assumed to mean within an acceptable error range for the particular value.

[0195] As used in the specification and claims, the terms "comprising" (and any form of including, e.g., "comprise" and "comprises"), "having" (and any form of having, e.g., "have" and "has"), "including" (and any form of including, e.g., "includes" and "include"), or "containing" (and any form of containing, e.g., "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. It is contemplated that any embodiment discussed herein can be implemented with respect to any method or composition of the disclosure, and vice versa. Furthermore, the compositions of the disclosure can be used to practice the methods of the disclosure.

[0196] References herein to "embodiments," "some embodiments," "an embodiment," "one embodiment," "particular embodiments," or "other embodiments" mean that the particular feature, structure, or characteristic described in association with the embodiment is included in at least some, but not necessarily all, embodiments of the present disclosure. To facilitate understanding of this disclosure, a number of terms and phrases are defined below.

[0197] The terms "oligonucleotide sequence," "nucleic acid sequence," "polynucleic acid sequence," "nucleotide sequence," and "nucleotide acid sequence" are used interchangeably herein in their broadest sense, have the same meaning herein, and preferably refer to DNA or RNA. A nucleic acid sequence is a polymer comprising or consisting of nucleotide monomers covalently linked to each other by sugar / phosphate-backbone phosphodiester bonds. The term "nucleic acid sequence" also encompasses modified nucleic acid sequences, such as DNA or RNA with, for example, base modifications, sugar modifications, or backbone modifications.

[0198] The terms "fragment" or "fragment of a sequence," which have the same meaning herein, are shorter portions of the full-length sequence of a nucleic acid molecule, such as DNA or RNA, or a protein. Thus, a fragment typically consists of a sequence that is identical to a corresponding stretch within the full-length sequence. In the context of the present invention, a preferred sequence fragment consists of a contiguous subsequence of an entity, such as nucleotides or amino acids, that corresponds to a contiguous subsequence of an entity in the molecule from which the fragment is derived, and corresponds to 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 molecule from which the fragment is derived (i.e., the full-length molecule). For example, a "fragment" or "functional fragment" of a polynucleotide or polypeptide is a fragment of a polynucleotide or polypeptide, be it an immature or mature polynucleotide or polypeptide, that is less than full length and has 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 the full-length mature reference polynucleotide or polypeptide. The subject fragments can be produced by recombinant, synthetic, or digestive enzymatic methods.

[0199] For example, the term "recombinant" when used with reference to a cell, nucleic acid, protein, or vector indicates that the cell, nucleic acid, protein, or vector has been modified by or is the result of experimental methods. Thus, for example, the term "recombinant polynucleotide" can refer to a polynucleotide that is not naturally occurring but is synthesized or manipulated in vitro, e.g., a polynucleotide produced by experimental methods. Recombinant polynucleotides can be synthesized in the laboratory and / or prepared by recombinant DNA methods, e.g., by using enzymatic modification of DNA, such as restriction enzyme 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 appropriate conditions, recombinant polynucleic acids or RNAs can be introduced into cells, and recombinant polypeptides can be expressed within the cells. Recombinant proteins can contain amino acid residues not present in the naturally occurring (non-recombinant) form of the protein, or can contain modified, e.g., labeled, amino acid residues.

[0200] The term "isolated" means that a polynucleotide, polypeptide, protein, or fragment thereof is separated from cells or other components with which it is normally associated in nature. For example, with respect to a polynucleotide, an isolated polynucleotide is one that is separated from the 5' and 3' ends with which it is normally associated in its native sequence. As will be apparent to those of skill in the art, a non-naturally occurring polynucleotide, polypeptide, protein, or fragment thereof does not require "isolation" to be distinguished from its native counterpart. Furthermore, an "enriched," "isolated," or "diluted" polynucleotide, polypeptide, protein, or fragment thereof is distinguishable from its native counterpart in that the concentration or number of molecules per volume is more "enriched," or less "isolated," or "diluted," than its native counterpart.

[0201] As used herein, "nucleotide" refers to a nucleoside that further comprises a phosphate linking group. As used herein, "linked nucleosides" may or may not be linked by a phosphate bond, and thus include, but are not limited to, "linked nucleotides." As used herein, "linked nucleosides" are nucleosides that are linked in a contiguous sequence (i.e., there are no additional nucleosides between the linked nucleosides).

[0202] As used herein, "nucleobase" means a group of atoms that can be linked to a sugar moiety to produce a nucleoside that can be incorporated into an oligonucleotide, where the group of atoms can bind to a complementary natural nucleobase of another oligonucleotide or another nucleic acid. The nucleobase can be natural or modified.

[0203] As used herein, "nucleoside" refers to a compound comprising a nucleobase moiety and a sugar moiety. Nucleosides include, but are not limited to, natural nucleosides (found in DNA and RNA) and modified nucleosides. Nucleosides may be linked to a phosphate moiety.

[0204] As used herein, "natural sugar moiety" means a ribofuranosyl found in naturally occurring RNA or a deoxyribofuranosyl found in naturally occurring DNA.

[0205] As used herein, "sugar moiety" means a naturally occurring or modified sugar moiety of a nucleoside.

[0206] As used herein, "modified sugar moiety" means a substituted sugar moiety, a bicyclic or tricyclic sugar moiety, or a sugar surrogate.

[0207] As used herein, the term "antisense oligonucleotide" refers to a synthetic antisense oligonucleotide (ASO) or antisense oligonucleotide analog, typically 12–30 nucleotides in length, designed to hybridize to RNA via Watson-Crick base pairing. ASOs can be designed to bind to protein-coding RNA (mRNA) as well as non-coding RNAs, such as microRNAs or large non-coding RNAs. After binding to a target RNA, ASOs can modulate the function of the target RNA through several different mechanisms. These mechanisms include degradation of pre-mRNA in the nucleus by RNase H1 or mature RNA in the cytoplasm, and degradation of the RNA in the cytoplasm by the RISC complex (Ago2) or ribozymes or DNAzymes. ASOs can also modulate RNA function through non-degradative mechanisms, such as modulating splicing or polyadenylation in the nucleus, and protein translation in the cytoplasm.

[0208] The term "hybridize" refers to the formation of hydrogen bonds, which may be via Watson-Crick, Hoogsteen, or reversed Hoogsteen hydrogen bonds, between complementary nucleoside or nucleotide bases. As used herein, "complementary" refers to precise pairing between two nucleotides. Oligonucleotides, and DNA or RNA, are complementary to each other when a sufficient number of corresponding positions in each molecule are occupied by nucleotides that can hydrogen bond with each other.

[0209] The term "identical" or percentage "identity," in the context of two or more nucleic acid or polypeptide sequences, refers to two or more sequences or subsequences that are the same, or that have a specified percentage of the same nucleotides or amino acid residues (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, across an entire polypeptide sequence of the invention or across a specific region of an individual domain of a polypeptide of the invention) when compared and aligned for maximum correspondence across a comparison window or designated region, as measured using a sequence comparison algorithm or by manual alignment and visual inspection. Sequences that are at least about 80% identical are said to be "substantially identical." In some embodiments, two sequences are 100% identical. In some embodiments, the two sequences are 100% identical over the entire length of one of the sequences (e.g., the shorter of the two sequences if the sequences are of different lengths). In various embodiments, identity can refer to the complement of the subject sequence.

[0210] In some embodiments, identity exists over a region that is at least about 2 to about 400 amino acids or nucleotides in length. In some embodiments, identity exists over a region that is 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 length. In some embodiments, the identity exists over a region that is 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 in length.

[0211] In some embodiments, the identity is 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 to about 400, about 20 to about 400, about 21 to about 400, about 22 to about 400, about 23 to about 400, about 24 to about 400, about 25 to about 400, about 26 to about 400, about 27 to about 400, about 28 to about 400, about 29 to about 400, about 30 to about 400, about 31 to about 400, about 32 to about 400, about 33 to about 400, about 34 to about 400, or about 35 to about 400 amino acids or nucleotides in length. In some embodiments, the identity is 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 to about 400, about 71 to about 400, about 72 to about 400, about 73 to about 400, about 74 to about 400, about 75 to about 400, about 76 to about 400, about 77 to about 400, about 78 to about 400, about 79 to about 400, about 80 to about 400, about 81 to about 400, about 82 to about 400, about 83 to about 400, about 84 to about 400, about 85 to about 400, about 86 to about 400, about 87 to about 400, about 88 to about 400, about 89 to about 400, about 90 to about 400, about 91 to about 400, about 92 to about 400, about 93 to about 400, about 94 to about 400, about 95 to about 400, about 96 to about 400, about 97 to about 400, about 98 to about 400, about 99 to about 500, about 99 to about 500, about 99 to about It is present over a region that is about 400, about 72 to about 400, about 73 to about 400, about 74 to about 400, about 75 to about 400, about 80 to about 400, about 85 to about 400, about 90 to about 400, about 100 to about 400, about 150 to about 400, about 200 to about 400, about 250 to about 400, about 300 to about 400, or about 350 to about 400 amino acids or nucleotides in length.

[0212] In some embodiments, the identity is 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 317, about 62 to about 343 317, 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, or about 25 to about 62 amino acids or nucleotides in length.

[0213] The term "genetically modified" refers to containing and / or expressing a foreign gene or nucleic acid sequence that subsequently modifies the genotype or phenotype of the cell or its progeny cells. In other words, it refers to any addition, deletion, or disruption to the cell's endogenous nucleotides.

[0214] The term "operably linked" can refer to a functional relationship between two or more nucleic acid sequences, such as the functional relationship between a transcribed sequence and a transcriptional control sequence or signal sequence. For example, a target motif or a nucleic acid encoding a target motif is operably linked to a coding sequence if it is expressed as a preprotein involved in targeting the polypeptide encoded by the coding sequence to the cell membrane, an intracellular compartment, or an extracellular compartment. For example, a signal peptide or a nucleic acid encoding a signal peptide is operably linked to a coding sequence if it is expressed as a preprotein involved in the secretion of the polypeptide encoded by the coding sequence. For example, a promoter is operably linked if it stimulates or regulates the transcription of a coding sequence.

[0215] The term "subject" or "patient" includes vertebrates or mammals. Examples of mammals include, but are not limited to, any species of the following mammalian classes: humans, non-human primates, such as chimpanzees, and other ape and monkey species; farm animals, such as cows, horses, sheep, goats, and pigs; domestic animals, such as rabbits, dogs, and cats; and laboratory animals, including rodents, such as rats, mice, and guinea pigs. In one aspect, a mammal is a human. As used herein, the term "animal" includes humans and non-human animals. In one embodiment, a "non-human animal" is a mammal, e.g., a rodent, such as a rat or a mouse. In one embodiment, the non-human animal is a mouse.

[0216] A "control" is a substitute subject or sample used in an experiment for comparison purposes. A control can be a "positive" control or a "negative" control.

[0217] Pharmaceutical Composition In one embodiment, provided herein is 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 unbuffered, and (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.

[0218] 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 at 4°C for at least 1 or 2 years.

[0219] 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 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.

[0220] In another aspect, provided herein is 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 lacks NaHPO and / or NaHPO, 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 intracerebral brain of a human subject; and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

[0221] In some embodiments, the liquid composition lacks phosphate ions.

[0222] In some embodiments, the liquid composition comprises calcium ions, magnesium ions, and / or potassium ions.

[0223] In another aspect, provided herein is 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) MgCl or MgCl 6H 0, and d) CaCl or CaCl 2H 0.

[0224] In some embodiments, the liquid composition comprises 0.1-50 mM CaCl2 or CaCl22H2O.

[0225] In some embodiments, the liquid composition comprises 1-2 mM CaCl2 or CaCl22H2O.

[0226] In some embodiments, the liquid composition comprises about 1.4 mM CaCl or CaClH0.

[0227] In some embodiments, the liquid composition comprises 0.1-50 mM MgCl2 or MgCl2 6H2O.

[0228] In some embodiments, the liquid composition comprises 0.5-1.5 mM MgCl2 or MgCl2 6H2O.

[0229] In some embodiments, the liquid composition comprises about 0.79 mM MgCl or MgCl 6H O.

[0230] In some embodiments, the liquid composition comprises 5-250 mM NaCl, 0.1-20 mM KCl, 0.1-50 mM CaCl or CaCl 2H 2 O, and 0.1-50 mM MgCl or MgCl 2 6H 2 O.

[0231] In another aspect, provided herein is 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 lacks calcium ions and / or magnesium ions, and (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 intracerebral brain of a human subject; and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

[0232] In some embodiments, the liquid composition is formulated for administration into the intrathecal space, cerebrospinal fluid, or brain of a human subject.

[0233] In some embodiments, the liquid composition is formulated for administration to the cerebrospinal fluid of the brain of a human subject.

[0234] In some embodiments, the ASO comprises at least one modified sugar moiety.

[0235] In some embodiments, each nucleotide of the antisense oligomer comprises a modified sugar moiety.

[0236] In another aspect, provided herein is 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 of the ASO with the pharmaceutically acceptable diluent produces a liquid composition comprising the ASO, the liquid composition is not buffered; and (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.

[0237] In some embodiments, a kit includes (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 mixing the ASO with the pharmaceutically acceptable diluent produces a liquid composition comprising the ASO, wherein the ASO is stable in the liquid composition at 4°C for at least 1 or 2 years.

[0238] 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 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.

[0239] In some embodiments, a kit includes: (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, the liquid composition lacking NaHPO and / or NaHPO; and (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.

[0240] In some embodiments, the liquid composition lacks phosphate ions.

[0241] In some embodiments, the liquid composition comprises calcium ions, magnesium ions, and / or potassium ions.

[0242] In some embodiments, a kit includes (i) a concentrate containing an antisense oligomer (ASO) and (ii) a pharmaceutically acceptable diluent consisting of a) NaCl, b) KCl, c) MgCl or MgCl 6H 0, and d) CaCl or CaCl 2H 0, wherein the concentrate is miscible with the pharmaceutically acceptable diluent, and mixing the ASO with the pharmaceutically acceptable diluent produces a liquid composition containing the ASO.

[0243] In some embodiments, a kit includes: (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, the liquid composition lacking calcium ions 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.

[0244] In some embodiments, the liquid composition is formulated for administration into the intrathecal space, cerebrospinal fluid, or brain of a human subject.

[0245] In some embodiments, the liquid composition is formulated for administration to the cerebrospinal fluid of the brain of a human subject.

[0246] In some embodiments, the ASO comprises at least one modified sugar moiety.

[0247] In some embodiments, each nucleotide of the antisense oligomer comprises a modified sugar moiety.

[0248] In some embodiments, the kit further comprises (iii) instructions for diluting or solubilizing the ASO in a pharmaceutically acceptable diluent.

[0249] In some embodiments, the liquid composition comprises 25-250 mM NaCl.

[0250] In some embodiments, the liquid composition comprises 0.1 to 20 mM KCl.

[0251] In some embodiments, the liquid composition comprises 2-4 mM KCl.

[0252] In some embodiments, the liquid composition comprises about 3 mM KCl.

[0253] In some embodiments, the liquid composition comprises 100-160 mM NaCl.

[0254] In some embodiments, the liquid composition comprises 125-145 mM NaCl.

[0255] In some embodiments, the liquid composition comprises about 130 mM NaCl.

[0256] In some embodiments, the liquid composition comprises a buffered (pH 6.6-7.6) solution.

[0257] In some embodiments, the liquid composition comprises 0.1-50 mM Na2HPO4.

[0258] In some embodiments, the liquid composition comprises 0.1-50 mM NaH2PO4.

[0259] 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.

[0260] In some embodiments, the ASO is solubilized in a pharmaceutically acceptable diluent.

[0261] In some embodiments, the pharmaceutically acceptable diluent is an isotonic solution.

[0262] In some embodiments, the ASO is not substantially polydisperse.

[0263] In some embodiments, the liquid composition has an osmolality of less than 150 mM.

[0264] In some embodiments, the liquid composition has an osmolality of about 130 mM.

[0265] In some embodiments, the liquid composition further comprises a carbohydrate.

[0266] In some embodiments, the carbohydrate comprises D-glucose.

[0267] In some embodiments, the liquid composition further comprises 1-100 mM D-glucose.

[0268] In some embodiments, the liquid composition further comprises an antioxidant.

[0269] In some embodiments, the antioxidant is t-butylhydroxyquinoline (TBHQ), butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E, or any combination thereof.

[0270] In some embodiments, the ASOs described herein are solubilized or diluted in an artificial cerebrospinal fluid (aCSF) solution. In some embodiments, the ASOs described herein are solubilized or diluted in an isotonic solution.

[0271] As used herein, the term "artificial cerebrospinal fluid (aCSF)" refers to a biological buffer solution commonly used as a vehicle solution for drug administration to the central nervous system (CNS). CSF closely matches the electrolyte concentration and physiological compatibility of endogenous CSF, for example, and provides an essential environment for neuronal tissue by maintaining homeostasis, osmolality, and pH at physiological levels.

[0272] As used herein, the term "isotonic solution" refers to a solution that contains an electrolyte balance similar to that of plasma in the bloodstream. Administration of an isotonic solution to a subject or patient can increase the subject's or patient's fluid volume without fluid shifts. Examples of isotonic solutions include, but are not limited to, 0.9% saline, lactated Ringer's solution, Ringer's solution, plasma-lyte, and 5% dextrose in water (D5W).

[0273] As used herein, the term "hypotonic solution" refers to a solution having a lower electrolyte concentration than plasma. For example, administration of a hypotonic solution via an intravenous route can result in fluid shifting out of the bloodstream and into areas of higher concentration in the interstitial and intracellular spaces. Examples of hypotonic solutions include, but are not limited to, 0.45% saline (half-saline), 0.33% NaCl solution, 0.225% NaCl solution, and 2.5% dextrose in water (D 2.5 W) is one example.

[0274] As used herein, the term "hypertonic solution" refers to a solution having a higher electrolyte concentration than plasma. For example, administration of a hypertonic solution via an intravenous route can result in fluid shifts from interstitial and intracellular spaces into the bloodstream, resulting in electrolyte dilution. Examples of hypertonic solutions include, but are not limited to, 3% NaCl solution, 5% dextrose in 0.45% NaCl (D5 1 / 2 NS), 5% dextrose in 0.9% saline (D5NS), 5% dextrose in lactated Ringer's solution (D5LR), 10% dextrose in water (D 10 W), 20% dextrose aqueous solution (D 20 W), and 50% dextrose solution (D 50 W) is one example.

[0275] In some embodiments, the ASOs described herein are solubilized or diluted in a phosphate buffer solution (pH 6.6-7.6). In some embodiments, the ASOs described herein are solubilized or diluted in a phosphate buffer solution (pH 6.0-8.0). In some embodiments, the ASOs described herein are solubilized or diluted in a phosphate buffer solution (pH 5.0-8.0). In some embodiments, the ASOs described herein may be administered 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 It is solubilized or diluted in phosphate buffer solution of pH 6.5-8.5, pH 6.6-8.5, pH 6.7-8.5, pH 6.8-8.5, pH 6.9-8.5, pH 7.0-8.5, pH 7.1-8.5, pH 7.2-8.5, pH 7.3-8.5, pH 7.4-8.5, pH 7.5-8.5, pH 7.6-8.5, pH 7.7-8.5, pH 7.8-8.5, pH 7.9-8.5, pH 8.0-8.5, pH 8.1-8.5, pH 8.2-8.5, pH 8.3-8.5, or pH 8.4-8.5.In some embodiments, the ASOs described herein may be administered at pH 4.5 to 8.3, pH 4.5 to 8.2, pH 4.5 to 8.1, pH 4.5 to 8.0, pH 4.5 to 7.9, pH 4.5 to 7.8, pH 4.5 to 7.7, pH 4.5 to 7.6, pH 4.5 to 7.5, pH 4.5 to 7.4, pH 4.5 to 7.3, pH 4.5 to 7.2, pH 4.5 to 7.1, pH 4.5 to 7.0, pH 4.5 to 6.9, pH 4.5 to 6.8, pH 4.5 to 6.7, pH 4.5 to 6.6, pH 4.5 to 6.5, pH Solubilized or diluted in phosphate buffer solution of pH 4.5-6.4, pH 4.5-6.3, pH 4.5-6.2, pH 4.5-6.1, pH 4.5-6.0, pH 4.5-5.9, pH 4.5-5.8, pH 4.5-5.7, pH 4.5-5.6, pH 4.5-5.5, pH 4.5-5.4, pH 4.5-5.3, pH 4.5-5.2, pH 4.5-5.1, pH 4.5-5.0, pH 4.5-4.9, pH 4.5-4.8, pH 4.5-4.7, or pH 4.5-4.6. In some embodiments, the ASOs described herein are solubilized or diluted in a phosphate buffer solution 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, the ASOs described herein are solubilized or diluted in a phosphate buffer solution of 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, the ASOs described herein are solubilized or diluted in a phosphate buffer solution of 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, the ASOs described herein are solubilized or diluted in a phosphate buffer solution of 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, the ASOs described herein are solubilized or diluted in a phosphate buffer solution having a pH of 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, the ASOs described herein are solubilized or diluted in a phosphate buffer solution having a pH of 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, the ASOs described herein are solubilized 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.

[0276] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 25-250 mM NaCl.

[0277] In some embodiments, the ASOs described herein may be 25-250, 30-250, 35-250, 40-250, 45-250, 50-250, 55-250, 60-250, 65-250, 70-250, 75-250, 80-250, 85-250, 90-250, 95-250, 100-250, 105-250, 110-250, 115-250, 120-250, 125-250, 130-250, 135-250, 140-250 , 145-250, 150-250, 155-250, 160-250, 165-250, 170-250, 175-250, 180-250, 185-250, 190-250, 195-250, 200-250, 205-250, 210-250, 215-250, 220-250, 225-250, 230-250, 235-250, 240-250, or 245-250 mM NaCl. In some embodiments, the ASOs described herein may be 25 to 245, 25 to 240, 25 to 235, 25 to 230, 25 to 225, 25 to 220, 25 to 215, 25 to 210, 25 to 205, 25 to 200, 25 to 195, 25 to 190, 25 to 185, 25 to 180, 25 to 175, 25 to 170, 25 to 165, 25 to 160, 25 to 155, 25 to 150, 25 to 145, 25 to 140, 25 to Solubilized or diluted in a buffer containing 135, 25-130, 25-125, 25-120, 25-115, 25-110, 25-105, 25-110, 25-105, 25-100, 25-95, 25-90, 25-85, 25-80, 25-75, 25-70, 25-65, 25-60, 25-55, 25-50, 25-45, 25-40, 25-35, or 25-30 mM NaCl. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 30-245, 35-240, 40-235, 45-230, 50-225, 55-220, 60-215, 65-210, 70-205, 75-200, 80-195, 85-190, 90-185, 95-180, 100-175, 105-170, 110-165, 115-160, 120-155, 125-150, 130-145, or 135-140 mM NaCl.In some embodiments, the ASOs described herein are 100-140, 101-140, 102-140, 103-140, 104-140, 105-140, 106-140, 107-140, 108-140, 109-140, 110-140, 111-140, 112-140, 113-140, 114-140, 115-140, 116-140, 117-140, 118-140, 119-140, 120 140, 121, 140, 122, 140, 123, 140, 124, 140, 125, 140, 126, 140, 127, 140, 128, 140, 129, 140, 130, 140, 131, 140, 132, 140, 133, 140, 134, 140, 135, 140, 136, 140, 137, 140, 138, 140, or 139, 140 mM NaCl. In some embodiments, the ASOs described herein are 100-139, 100-138, 100-137, 100-136, 100-135, 100-134, 100-133, 100-132, 100-131, 100-130, 100-129, 100-128, 100-127, 100-126, 100-125, 100-124, 100-123, 100-122, 100-121, 100-120 , 100-119, 100-118, 100-117, 100-116, 100-115, 100-114, 100-113, 100-112, 100-111, 100-110, 100-109, 100-108, 100-107, 100-106, 100-105, 100-104, 100-103, 100-102, or 100-101 mM NaCl. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, or 140 mM NaCl.In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing up to 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, or 140 mM NaCl. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, or 140 mM NaCl.

[0278] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 0.1 to 20 mM KCl.

[0279] In some embodiments, the ASOs described herein may be 0.1-40, 0.1-39, 0.1-38, 0.1-37, 0.1-36, 0.1-35, 0.1-34, 0.1-33, 0.1-32, 0.1-31, 0.1-30, 0.1-29, 0.1-28, 0.1-27, 0.1-26, 0.1-25, 0.1-24, 0.1-23, 0.1-22, 0. Solubilized or diluted in a buffer containing 1-21, 0.1-20, 0.1-19, 0.1-18, 0.1-17, 0.1-16, 0.1-15, 0.1-14, 0.1-13, 0.1-12, 0.1-10, 0.1-9, 0.1-8, 0.1-7, 0.1-6, 0.1-5, 0.1-4, 0.1-3, 0.1-2, or 0.1-1 mM KCl. In some embodiments, the ASOs described herein may be 0.2 to 40, 0.3 to 40, 0.4 to 40, 0.5 to 40, 0.6 to 40, 0.7 to 40, 0.8 to 40, 0.9 to 40, 1 to 40, 2 to 40, 3 to 40, 4 to 40, 5 to 40, 6 to 40, 7 to 40, 8 to 40, 9 to 40, 10 to 40, 11 to 40, 12 to 40, 13 to 40, 14 to 40, 15 to 40, 16 to 40, Solubilized or diluted in a buffer containing 17-40, 18-40, 19-40, 20-40, 21-40, 22-40, 23-40, 24-40, 25-40, 26-40, 27-40, 28-40, 29-40, 30-40, 31-40, 32-40, 33-40, 34-40, 35-40, 36-40, 37-40, 38-40, or 39-40 mM KCl. In some embodiments, the ASOs described herein may be 0.1 to 3.5, 0.2 to 3.5, 0.3 to 3.5, 0.4 to 3.5, 0.5 to 3.5, 0.6 to 3.5, 0.7 to 3.5, 0.8 to 3.5, 0.9 to 3.5, 1.0 to 3.5, 1.1 to 3.5, 1.2 to 3.5, 1.3 to 3.5, 1.4 to 3.5, 1.5 to 3.5, 1.6 to 3.5, 1.7 to 3.5, 1.8 Solubilized or diluted in buffer containing 1.0-3.5, 1.9-3.5, 2.0-3.5, 2.1-3.5, 2.2-3.5, 2.3-3.5, 2.4-3.5, 2.5-3.5, 2.6-3.5, 2.7-3.5, 2.8-3.5, 2.9-3.5, 3.0-3.5, 3.1-3.5, 3.2-3.5, 3.3-3.5, or 3.4-3.5 mM KCl.In some embodiments, the ASOs described herein may be 0.1 to 3.4, 0.1 to 3.3, 0.1 to 3.2, 0.1 to 3.1, 0.1 to 3.0, 0.1 to 2.9, 0.1 to 2.8, 0.1 to 2.7, 0.1 to 2.6, 0.1 to 2.5, 0.1 to 2.4, 0.1 to 2.3, 0.1 to 2.2, 0.1 to 2.1, 0.1 to 2.0, 0.1 to 1.9, 0.1 to 1.8 , 0.1-1.7, 0.1-1.6, 0.1-1.5, 0.1-1.4, 0.1-1.3, 0.1-1.2, 0.1-1.1, 0.1-1.0, 0.1-0.9, 0.1-0.8, 0.1-0.7, 0.1-0.6, 0.1-0.5, 0.1-0.4, 0.1-0.3, or 0.1-0.2 mM KCl. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, or 3.5 mM KCl. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing up to 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, or 3.5 mM KCl. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, or 3.5 mM KCl.

[0280] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 0.1-50 mM Na2HPO4.

[0281] In some embodiments, the ASOs described herein may be 0.01 to 100, 0.02 to 100, 0.03 to 100, 0.04 to 100, 0.05 to 100, 0.06 to 100, 0.07 to 100, 0.08 to 100, 0.09 to 100, 0.1 to 100, 0.2 to 100, 0.3 to 100, 0.4 to 100, 0.5 to 100, 0.6 to 100, 0.7 to 100, 0.8 to 100, 0.9 to 100, 1 to 100, 2 to 100, 3 to 100, Solubilized or diluted in a buffer containing 4-100, 5-100, 6-100, 7-100, 8-100, 9-100, 10-100, 15-100, 20-100, 25-100, 30-100, 35-100, 40-100, 45-100, 50-100, 55-100, 60-100, 65-100, 70-100, 75-100, 80-100, 85-100, 90-100, or 95-100 mM NaHPO. In some embodiments, the ASOs described herein may be 0.01 to 95, 0.01 to 90, 0.01 to 85, 0.01 to 80, 0.01 to 75, 0.01 to 70, 0.01 to 65, 0.01 to 60, 0.01 to 55, 0.01 to 50, 0.01 to 45, 0.01 to 40, 0.01 to 35, 0.01 to 30, 0.01 to 25, 0.01 to 20, 0.01 to 15, 0.01 to 10, 0.01 to 9, 0.01 to 8, 0.01 to 7, 0.01 to 6, 0.01 to 5, 0.01 to 4, 0.01 to 5, 0.01 to 6, 0.01 to 7, 0.01 to 8, 0.01 to 9, 0.01 to 10, 0.01 to 15, 0.01 to 10 ... Solubilized or diluted in a buffer containing 1-3, 0.01-2, 0.01-1, 0.01-0.9, 0.01-0.8, 0.01-0.7, 0.01-0.6, 0.01-0.5, 0.01-0.4, 0.01-0.3, 0.01-0.2, 0.01-0.1, 0.01-0.09, 0.01-0.08, 0.01-0.07, 0.01-0.06, 0.01-0.05, 0.01-0.04, 0.01-0.03, or 0.01-0.02 mM NaHPO.In some embodiments, the ASOs described herein may be 0.1 to 3.0, 0.1 to 2.9, 0.1 to 2.8, 0.1 to 2.7, 0.1 to 2.6, 0.1 to 2.5, 0.1 to 2.4, 0.1 to 2.3, 0.1 to 2.2, 0.1 to 2.1, 0.1 to 2.0, 0.1 to 1.9, 0.1 to 1.8, 0.1 to 1.7, 0.1 to 1.6, 0.1 to 2.8 ...8, 0.1 to 2.8, 0.1 to 2.9, 0.1 to 2.8 The sample is solubilized or diluted in a buffer containing 0.1-1.5, 0.1-1.4, 0.1-1.3, 0.1-1.2, 0.1-1.1, 0.1-1.0, 0.1-0.9, 0.1-0.8, 0.1-0.7, 0.1-0.6, 0.1-0.5, 0.1-0.4, 0.1-0.3, or 0.1-0.2 mM Na2HPO4. In some embodiments, the ASOs described herein may be 0.1 to 3.0, 0.2 to 3.0, 0.3 to 3.0, 0.4 to 3.0, 0.5 to 3.0, 0.6 to 3.0, 0.7 to 3.0, 0.8 to 3.0, 0.9 to 3.0, 1.0 to 3.0, 1.2 to 3.0, 1.3 to 3.0, 1.4 to 3.0, 1.5 to 3.0, 1.6 to 3.0, 1.7 to 3.0, 1.8 to 3.0, 1.9 to 3.0, 2.0 to 3.0, 2.1 to 3.0, 2.2 to 3.0, 2.3 to 3.0, 2.4 to 3.0, 2.5 to 3.0, 2.6 to 3.0, 2.7 to 3.0, 2.8 to 3.0, 2.9 to 3.0, 3.0 to 3.0, 3.1 to 3.0, 3.2 to 3.0, 3.3 to 3.0, 3.4 to 3.0, 3.5 to 3.0, 3.6 to 3.0, 3.7 to 3.0, 3.8 to 3.0, 3.9 to 3.0, 3.1 to 3.0, 3.1 to 3.0, 3.1 to 3.0, 3.1 to 3.0, 3.2 to 3.0, 3.3 to 3.0, 3.4 to 3.0, 3.5 to 3.0, 3.6 to 3.0, 3.7 to 3.0, 3.8 to 3.0, 3.9 to 3.0 Solubilized or diluted in buffer containing 0.0, 1.7-3.0, 1.8-3.0, 1.9-3.0, 2.0-3.0, 2.1-3.0, 2.2-3.0, 2.3-3.0, 2.4-3.0, 2.5-3.0, 2.6-3.0, 2.7-3.0, 2.8-3.0, or 2.9-3.0 mM NaHPO. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 mM Na2HPO4. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing up to 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 mM NaHPO.In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 mM NaHPO.

[0282] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 0.1 to 50 mM NaH2PO4.

[0283] In some embodiments, the ASOs described herein may be 0.01 to 100, 0.02 to 100, 0.03 to 100, 0.04 to 100, 0.05 to 100, 0.06 to 100, 0.07 to 100, 0.08 to 100, 0.09 to 100, 0.1 to 100, 0.2 to 100, 0.3 to 100, 0.4 to 100, 0.5 to 100, 0.6 to 100, 0.7 to 100, 0.8 to 100, 0.9 to 100, 1 to 100, 2 to 100, 3 to 100, The solution is solubilized or diluted in a buffer containing 4-100, 5-100, 6-100, 7-100, 8-100, 9-100, 10-100, 15-100, 20-100, 25-100, 30-100, 35-100, 40-100, 45-100, 50-100, 55-100, 60-100, 65-100, 70-100, 75-100, 80-100, 85-100, 90-100, or 95-100 mM NaH2PO4. In some embodiments, the ASOs described herein may be 0.01 to 95, 0.01 to 90, 0.01 to 85, 0.01 to 80, 0.01 to 75, 0.01 to 70, 0.01 to 65, 0.01 to 60, 0.01 to 55, 0.01 to 50, 0.01 to 45, 0.01 to 40, 0.01 to 35, 0.01 to 30, 0.01 to 25, 0.01 to 20, 0.01 to 15, 0.01 to 10, 0.01 to 9, 0.01 to 8, 0.01 to 7, 0.01 to 6, 0.01 to 5, 0.01 to 4, 0.01 to 5, 0.01 to 6, 0.01 to 7, 0.01 to 8, 0.01 to 9, 0.01 to 10, 0.01 to 15, 0.01 to 10 ... Solubilized or diluted in a buffer containing 1-3, 0.01-2, 0.01-1, 0.01-0.9, 0.01-0.8, 0.01-0.7, 0.01-0.6, 0.01-0.5, 0.01-0.4, 0.01-0.3, 0.01-0.2, 0.01-0.1, 0.01-0.09, 0.01-0.08, 0.01-0.07, 0.01-0.06, 0.01-0.05, 0.01-0.04, 0.01-0.03, or 0.01-0.02 mM NaH2PO4.In some embodiments, the ASOs described herein may be 0.1 to 3.0, 0.1 to 2.9, 0.1 to 2.8, 0.1 to 2.7, 0.1 to 2.6, 0.1 to 2.5, 0.1 to 2.4, 0.1 to 2.3, 0.1 to 2.2, 0.1 to 2.1, 0.1 to 2.0, 0.1 to 1.9, 0.1 to 1.8, 0.1 to 1.7, 0.1 to 1.6, 0.1 to 2.8 ...8, 0.1 to 2.8, 0.1 to 2.9, 0.1 to 2.8 The sample is solubilized or diluted in a buffer containing 0.1-1.5, 0.1-1.4, 0.1-1.3, 0.1-1.2, 0.1-1.1, 0.1-1.0, 0.1-0.9, 0.1-0.8, 0.1-0.7, 0.1-0.6, 0.1-0.5, 0.1-0.4, 0.1-0.3, or 0.1-0.2 mM NaH2PO4. In some embodiments, the ASOs described herein may be 0.1 to 3.0, 0.2 to 3.0, 0.3 to 3.0, 0.4 to 3.0, 0.5 to 3.0, 0.6 to 3.0, 0.7 to 3.0, 0.8 to 3.0, 0.9 to 3.0, 1.0 to 3.0, 1.2 to 3.0, 1.3 to 3.0, 1.4 to 3.0, 1.5 to 3.0, 1.6 to 3.0, 1.7 to 3.0, 1.8 to 3.0, 1.9 to 3.0, 2.0 to 3.0, 2.1 to 3.0, 2.2 to 3.0, 2.3 to 3.0, 2.4 to 3.0, 2.5 to 3.0, 2.6 to 3.0, 2.7 to 3.0, 2.8 to 3.0, 2.9 to 3.0, 3.0 to 3.0, 3.1 to 3.0, 3.2 to 3.0, 3.3 to 3.0, 3.4 to 3.0, 3.5 to 3.0, 3.6 to 3.0, 3.7 to 3.0, 3.8 to 3.0, 3.9 to 3.0, 3.1 to 3.0, 3.1 to 3.0, 3.1 to 3.0, 3.1 to 3.0, 3.2 to 3.0, 3.3 to 3.0, 3.4 to 3.0, 3.5 to 3.0, 3.6 to 3.0, 3.7 to 3.0, 3.8 to 3.0, 3.9 to 3.0 Solubilized or diluted in a buffer containing 0.0, 1.7-3.0, 1.8-3.0, 1.9-3.0, 2.0-3.0, 2.1-3.0, 2.2-3.0, 2.3-3.0, 2.4-3.0, 2.5-3.0, 2.6-3.0, 2.7-3.0, 2.8-3.0, or 2.9-3.0 mM NaH2PO4. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 mM NaH2PO4. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing up to 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 mM NaH2PO4.In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 mM NaH2PO4.

[0284] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 0.1-50 mM CaCl2.

[0285] In some embodiments, the ASOs described herein may be 0.1 to 50, 0.2 to 50, 0.3 to 50, 0.4 to 50, 0.5 to 50, 0.6 to 50, 0.7 to 50, 0.8 to 50, 0.9 to 50, 1.0 to 50, 1.1 to 50, 1.2 to 50, 1.3 to 50, 1.4 to 50, 1.5 to 50, 1.6 to 50, 1.7 to 50, 1.8 to 50, 1.9 to 50, 2.0 to 50, 2.1 to 50, 2.2 to 50, 2.3 to 50, 2.4 to 50, 2.5 to 50, 2.6 to 50, 2.7 to 50, 2.8 to 50, 2.9 to 50, 3.0 to 50, 3.1 to 50, 3.2 to 50, 3.3 to 50, 3.4 to 50, 3.5 to 50, 3.6 to 50, 3.7 to 50, 3.8 to 50, 3.9 to 50, 4.0 to 50, 4.1 to 50, 4.2 to 50, 4.3 to 50, 4.4 to 50, 4.5 to 50, 4.6 to 50, 4.7 to 50, 4.8 to 50, 4.9 to 50, 5.0 to 50, 5.10 to 50, 5.11 to 50, 5.12 to 50, 5.13 to 50, 5.14 to 50 50, 2.7-50, 2.8-50, 2.9-50, 3.0-50, 3.1-50, 3.2-50, 3.3-50, 3.4-50, 3.5-50, 3.6-50, 3.7-50, 3.8-50, 3.9-50, 4-50, 5-50, 6-50, 7-50, 8-50, 9-50, 10-50, 15-50, 20-50, 25-50, 30-50, 35-50, 40-50, or 45-50 mM CaCl2. In some embodiments, the ASOs described herein may be 0.1 to 45, 0.1 to 40, 0.1 to 35, 0.1 to 30, 0.1 to 25, 0.1 to 20, 0.1 to 15, 0.1 to 10, 0.1 to 5, 0.1 to 4, 0.1 to 4.9, 0.1 to 4.8, 0.1 to 4.7, 0.1 to 4.6, 0.1 to 4.5, 0.1 to 4.4, 0.1 to 4.3, 0.1 to 4.2, 0.1 to 4.1, 0.1 to 4.0, 0.1 to 3.9, 0.1 to 3.8, 0.1 to 3.7, 0.1 to 3.6, 0.1 to 3.5, 0.1 to 3.4, 0.1 to 3.3, 0.1 to 3.2, 0.1 to 3.1, 0.1 to 3.0, 0. Solubilized or diluted in buffer containing 1-2.9, 0.1-2.8, 0.1-2.7, 0.1-2.6, 0.1-2.5, 0.1-2.4, 0.1-2.3, 0.1-2.2, 0.1-2.1, 0.1-2.0, 0.1-1.9, 0.1-1.8, 0.1-1.7, 0.1-1.6, 0.1-1.5, 0.1-1.4, 0.1-1.3, 0.1-1.2, 0.1-1.1, 0.1-1.0, 0.1-0.9, 0.1-0.8, 0.1-0.7, 0.1-0.6, 0.1-0.5, 0.1-0.4, 0.1-0.3, or 0.1-0.2 mM CaCl.In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing at least 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0 mM CaCl2. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing up to 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0 mM CaCl2. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0 mM CaCl2.

[0286] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 0.1-50 mM MgCl2.

[0287] In some embodiments, the ASOs described herein may be 0.1-50, 0.2-50, 0.3-50, 0.4-50, 0.5-50, 0.6-50, 0.7-50, 0.8-50, 0.9-50, 1.0-50, -50, 1.1-50, 1.2-50, 1.3-50, 1.4-50, 1.5-50, 1.6-50, 1.7-50, 1.8-50, 1.9-50, 2.0-50, 2.1-50, 2.2-50, 2.3-50, 2.4-50, 2.5-50, 2.6-50, 2.7-50, 2.8-50, 2.9-50, 3.0-50, 3.10-50, 3.11-50, 3.12-50, 3.13-50, 3.14-50, 3.15-50, 3.16-50, 3.17-50, 3.18-50, 3.19-50, 3.20-50, 3.21-50, 3.22-50, 3.23-50, 3.24-50, 3.25-50, 3.26-50, 3.27-50, 3.28-50, 3.29-50, 3.30-50, 3.31-50, 3.32-50, 3.33-50, 3.34-50, 3.35-50, 3.36-50, 3.37-50, 3. Solubilized or diluted in buffer containing 6-50, 2.7-50, 2.8-50, 2.9-50, 3.0-50, 3.1-50, 3.2-50, 3.3-50, 3.4-50, 3.5-50, 3.6-50, 3.7-50, 3.8-50, 3.9-50, 4-50, 5-50, 6-50, 7-50, 8-50, 9-50, 10-50, 15-50, 20-50, 25-50, 30-50, 35-50, 40-50, or 45-50 mM MgCl2. In some embodiments, the ASOs described herein may be 0.1 to 45, 0.1 to 40, 0.1 to 35, 0.1 to 30, 0.1 to 25, 0.1 to 20, 0.1 to 15, 0.1 to 10, 0.1 to 5, 0.1 to 4, 0.1 to 4.9, 0.1 to 4.8, 0.1 to 4.7, 0.1 to 4.6, 0.1 to 4.5, 0.1 to 4.4, 0.1 to 4.3, 0.1 to 4.2, 0.1 to 4.1, 0.1 to 4.0, 0.1 to 3.9, 0.1 to 3.8, 0.1 to 3.7, 0.1 to 3.6, 0.1 to 3.5, 0.1 to 3.4, 0.1 to 3.3, 0.1 to 3.2, 0.1 to 3.1, 0.1 to 3.0, 0. Solubilized or diluted in buffer containing 1-2.9, 0.1-2.8, 0.1-2.7, 0.1-2.6, 0.1-2.5, 0.1-2.4, 0.1-2.3, 0.1-2.2, 0.1-2.1, 0.1-2.0, 0.1-1.9, 0.1-1.8, 0.1-1.7, 0.1-1.6, 0.1-1.5, 0.1-1.4, 0.1-1.3, 0.1-1.2, 0.1-1.1, 0.1-1.0, 0.1-0.9, 0.1-0.8, 0.1-0.7, 0.1-0.6, 0.1-0.5, 0.1-0.4, 0.1-0.3, or 0.1-0.2 mM MgCl.In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0 mM MgCl2. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing up to 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0 mM MgCl2. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0 mM MgCl2.

[0288] In some embodiments, the ASO is solubilized or diluted in a buffer further containing 1-100 mM NaHCO3, 1-100 mM KHCO3, or a combination thereof.

[0289] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 1-100 mM NaHCO3.

[0290] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 1-99, 1-95, 1-90, 1-85, 1-80, 1-75, 1-70, 1-65, 1-60, 1-55, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 mM NaHCO3. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 2-100, 3-100, 4-100, 5-100, 6-100, 7-100, 8-100, 9-100, 10-100, 15-100, 20-100, 25-100, 30-100, 35-100, 40-100, 45-100, 50-100, 55-100, 60-100, 65-100, 70-100, 75-100, 80-100, 85-100, 90-100, or 95-100 mM NaHCO3. In some embodiments, the ASOs described herein are selected from the group consisting of: 24.0 to 28.0, 24.0 to 27.9, 24.0 to 27.8, 24.0 to 27.7, 24.0 to 27.6, 24.0 to 27.5, 24.0 to 27.4, 24.0 to 27.3, 24.0 to 27.2, 24.0 to 27.1, 24.0 to 27.0, 24.0 to 26.9, 24.0 to 26.8, 24.0 to 26.7, 24.0 to 26.6, 24.0 to 26.5, 24.0 to 26.4, 24.0 to 26.3, 24.0 to 26.2, 24.0 to 26.1, 24.0 24.0-24.9, 24.0-24.8, 24.0-24.7, 24.0-24.6, 24.0-24.5, 24.0-24.4, 24.0-24.3, 24.0-24.2, or 24.0-24.1 mM NaHCO3.In some embodiments, the ASOs described herein are 24.1 to 28.0, 24.2 to 28.0, 24.3 to 28.0, 24.4 to 28.0, 24.5 to 28.0, 24.6 to 28.0, 24.7 to 28.0, 24.8 to 28.0, 24.9 to 28.0, 25.0 to 28.0, 25.1 to 28.0, 25.2 to 28.0, 25.3 to 28.0, 25.4 to 28.0, 25.5 to 28.0, 25.6 to 28.0, 25.7 to 28.0, 25.8 to 28.0, 25.9 to 28.0, 26.0 to 28.0 , 26.1-28.0, 26.2-28.0, 26.3-28.0, 26.4-28.0, 26.5-28.0, 26.6-28.0, 26.7-28.0, 26.8-28.0, 26.9-28.0, 27.0-28.0, 27.1-28.0, 27.2-28.0, 27.3-28.0, 27.4-28.0, 27.5-28.0, 27.6-28.0, 27.7-28.0, 27.8-28.0, or 27.9-28.0 mM NaHCO3. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing at least 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, or 28.0 mM NaHCO3. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing up to 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, or 28.0 mM NaHCO3.In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, or 28.0 mM NaHCO3.

[0291] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 1-100 mM KHCO3.

[0292] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 1-99, 1-95, 1-90, 1-85, 1-80, 1-75, 1-70, 1-65, 1-60, 1-55, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 mM KHCO3. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 2-100, 3-100, 4-100, 5-100, 6-100, 7-100, 8-100, 9-100, 10-100, 15-100, 20-100, 25-100, 30-100, 35-100, 40-100, 45-100, 50-100, 55-100, 60-100, 65-100, 70-100, 75-100, 80-100, 85-100, 90-100, or 95-100 mM KHCO3. In some embodiments, the ASOs described herein are selected from the group consisting of: 24.0-28.0, 24.0-27.9, 24.0-27.8, 24.0-27.7, 24.0-27.6, 24.0-27.5, 24.0-27.4, 24.0-27.3, 24.0-27.2, 24.0-27.1, 24.0-27.0, 24.0-26.9, 24.0-26.8, 24.0-26.7, 24.0-26.6, 24.0-26.5, 24.0-26.4, 24.0-26.3, 24.0-26.2, 24.0-26.1, 24.0-26.2, 24.0-26.3, 24.0-26.4, 24.0-26.5, 24.0-26.6, 24.0-26.7, 24.0-26.8, 24.0-26.9, 24.0-26.9, 24.0-26.1, 24.0-26.2, 24.0-26.3, 24.0-26.4, 24.0-26.5, 24.0-26.6, 24.0-26.7, 24.0-26.8, 24.0-26.9, 24.0-26.1, 24.0-26.2, 24.0-26.3, 24.0-26.4, 24.0-26.5, 24.0-26.6, 24.0-26. Solubilized or diluted in a buffer containing 0-26.0, 24.0-25.9, 4.0-25.8, 24.0-25.7, 24.0-25.6, 24.0-25.5, 24.0-25.4, 24.0-25.3, 24.0-25.2, 24.0-25.1, 24.0-25.0, 24.0-24.9, 24.0-24.8, 24.0-24.7, 24.0-24.6, 24.0-24.5, 24.0-24.4, 24.0-24.3, 24.0-24.2, or 24.0-24.1 mM KHCO3.In some embodiments, the ASOs described herein are 24.1 to 28.0, 24.2 to 28.0, 24.3 to 28.0, 24.4 to 28.0, 24.5 to 28.0, 24.6 to 28.0, 24.7 to 28.0, 24.8 to 28.0, 24.9 to 28.0, 25.0 to 28.0, 25.1 to 28.0, 25.2 to 28.0, 25.3 to 28.0, 25.4 to 28.0, 25.5 to 28.0, 25.6 to 28.0, 25.7 to 28.0, 25.8 to 28.0, 25.9 to 28.0, 26.0 to 28.0 , 26.1-28.0, 26.2-28.0, 26.3-28.0, 26.4-28.0, 26.5-28.0, 26.6-28.0, 26.7-28.0, 26.8-28.0, 26.9-28.0, 27.0-28.0, 27.1-28.0, 27.2-28.0, 27.3-28.0, 27.4-28.0, 27.5-28.0, 27.6-28.0, 27.7-28.0, 27.8-28.0, or 27.9-28.0 mM KHCO3. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing at least 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, or 28.0 mM KHCO3. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing up to 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, or 28.0 mM KHCO3.In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, or 28.0 mM KHCO3.

[0293] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 0-50 mM KH2PO4.

[0294] In some embodiments, the ASOs described herein may be 0-100, 0.01-100, 0.02-100, 0.03-100, 0.04-100, 0.05-100, 0.06-100, 0.07-100, 0.08-100, 0.09-100, 0.1-100, 0.2-100, 0.3-100, 0.4-100, 0.5-100, 0.6-100, 0.7-100, 0.8-100, 0.9-100, 1-100, 2-100, 3-100, 4-100, 5-100, 6-100, 7-100, 8-100, 9-100, 10-100, 11-100, 12-100, 13-100, 14-100, 15-100, 16-100, 17-100, 18-100, 19-100, 21-100, 22-100, 23-100, 24-100, 25-100, 26-100, 27-100, 28-100, 29-100, 31-100, 32-100, 33-100, 34-100, 35-100, 36-100, 37-100, 38-100, 39-100, 41-100, 42-100, 43-100, 44-100, 4 The sample is solubilized or diluted in a buffer containing 00, 4-100, 5-100, 6-100, 7-100, 8-100, 9-100, 10-100, 15-100, 20-100, 25-100, 30-100, 35-100, 40-100, 45-100, 50-100, 55-100, 60-100, 65-100, 70-100, 75-100, 80-100, 85-100, 90-100, or 95-100 mM KH2PO4. In some embodiments, the ASOs described herein may be selected from the group consisting of: 0 to 95, 0 to 90, 0 to 85, 0 to 80, 0 to 75, 0 to 70, 0 to 65, 0 to 60, 0 to 55, 0 to 50, 0 to 45, 0 to 40, 0 to 35, 0 to 30, 0 to 25, 0 to 20, 0 to 15, 0 to 10, 0 to 9, 0 to 8, 0 to 7, 0 to 6, 0 to 5, 0 to 4, 0 to 3, 0 to 2, Solubilized or diluted in a buffer containing 0-1, 0-0.9, 0-0.8, 0-0.7, 0-0.6, 0-0.5, 0-0.4, 0-0.3, 0-0.2, 0-0.1, 0-0.09, 0-0.08, 0-0.07, 0-0.06, 0-0.05, 0-0.04, 0-0.03, or 0-0.02 mM KH2PO4.In some embodiments, the ASOs described herein may be 0.01-95, 0.01-90, 0.01-85, 0.01-80, 0.01-75, 0.01-70, 0.01-65, 0.01-60, 0.01-55, 0.01-50, 0.01-45, 0.01-40, 0.01-35, 0.01-30, 0.01-25, 0.01-20, 0.01-15, 0.01-10, 0.01-9, 0.01-8, 0.01-7, 0.01-6, 0.01-5, 0.01-4, 0.01-5, 0.01-6, 0.01-7, 0.01-8, 0.01-9, 0.01-10, 0.01-15, 0.01-10 ... The sample is solubilized or diluted in a buffer containing 0.01-3, 0.01-2, 0.01-1, 0.01-0.9, 0.01-0.8, 0.01-0.7, 0.01-0.6, 0.01-0.5, 0.01-0.4, 0.01-0.3, 0.01-0.2, 0.01-0.1, 0.01-0.09, 0.01-0.08, 0.01-0.07, 0.01-0.06, 0.01-0.05, 0.01-0.04, 0.01-0.03, or 0.01-0.02 mM KH2PO4. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 0-3.0, 0-2.9, 0-2.8, 0-2.7, 0-2.6, 0-2.5, 0-2.4, 0-2.3, 0-2.2, 0-2.1, 0-2.0, 0-1.9, 0-1.8, 0-1.7, 0-1.6, 0-1.5, 0-1.4, 0-1.3, 0-1.2, 0-1.1, 0-1.0, 0-0.9, 0-0.8, 0-0.7, 0-0.6, 0-0.5, 0-0.4, 0-0.3, or 0-0.2 mM KH2PO4. In some embodiments, the ASOs described herein may be 0.1 to 3.0, 0.1 to 2.9, 0.1 to 2.8, 0.1 to 2.7, 0.1 to 2.6, 0.1 to 2.5, 0.1 to 2.4, 0.1 to 2.3, 0.1 to 2.2, 0.1 to 2.1, 0.1 to 2.0, 0.1 to 1.9, 0.1 to 1.8, 0.1 to 1.7, 0.1 to 1.6, Solubilized or diluted in a buffer containing 0.1-1.5, 0.1-1.4, 0.1-1.3, 0.1-1.2, 0.1-1.1, 0.1-1.0, 0.1-0.9, 0.1-0.8, 0.1-0.7, 0.1-0.6, 0.1-0.5, 0.1-0.4, 0.1-0.3, or 0.1-0.2 mM KH2PO4.In some embodiments, the ASOs described herein may be 0-3.0, 0.1-3.0, 0.2-3.0, 0.3-3.0, 0.4-3.0, 0.5-3.0, 0.6-3.0, 0.7-3.0, 0.8-3.0, 0.9-3.0, 1.0-3.0, 1.2-3.0, 1.3-3.0, 1.4-3.0, 1.5-3.0, 1.6-3.0, 1.7-3.0, 1.8-3.0, 1.9-3.0, 2.0-3.0, 2.10-3.0, 2.11-3.0, 2.12-3.0, 2.13-3.0, 2.14-3.0, 2.15-3.0, 2.16-3.0, 2.17-3.0, 2.18-3.0, 2.19-3.0, 2.20-3.0, 2.21-3.0, 2.22-3.0, 2.23-3.0, 2.24-3.0, 2.25-3.0, 2.26-3.0, 2.27-3.0, 2.28-3.0, 2.29-3.0, 2.30-3.0, 2.31-3.0, 2.32-3.0, 2.33-3.0, 2.34-3.0, 2.35-3.0, 2.36-3.0, 2.37-3.0, 2.38-3.0, 2.39-3.0, 2.40-3.0, 2.41-3.0, Solubilized or diluted in buffer containing 0.6-3.0, 1.7-3.0, 1.8-3.0, 1.9-3.0, 2.0-3.0, 2.1-3.0, 2.2-3.0, 2.3-3.0, 2.4-3.0, 2.5-3.0, 2.6-3.0, 2.7-3.0, 2.8-3.0, or 2.9-3.0 mM KH2PO4. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing at least 0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 mM KH2PO4. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing up to 0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 mM KH2PO4. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 mM KH2PO4.

[0295] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 0-50 mM NaH2PO4.

[0296] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 0-50, 0-45, 0-40, 0-35, 0-30, 0-25, 0-20, 0-19, 0-18, 0-17, 0-16, 0-15, 0-14, 0-13, 0-12, 0-11, 0-10, 0-9, 0-8, 0-7, 0-6, 0-5, 0-4, 0-3, 0-2, 0-1, 0-0.9, 0-0.8, 0-0.7, 0-0.6, 0-0.5, 0-0.4, 0-0.3, or 0-0.2 mM NaH2PO4. In some embodiments, the ASOs described herein may be 0.1 to 50, 0.1 to 45, 0.1 to 40, 0.1 to 35, 0.1 to 30, 0.1 to 25, 0.1 to 20, 0.1 to 19, 0.1 to 18, 0.1 to 17, 0.1 to 16, 0.1 to 15, 0.1 to 14, 0.1 to 13, 0.1 to 12, 0.1 to 11, 0.1 to 10, 0.1 to 9, 0.1-8, 0.1-7, 0.1-6, 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1, 0.1-0.9, 0.1-0.8, 0.1-0.7, 0.1-0.6, 0.1-0.5, 0.1-0.4, 0.1-0.3, or 0.1-0.2 mM NaH2PO4. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 0-50, 0.1-50, 0.2-50, 0.3-50, 0.4-50, 0.5-50, 0.6-50, 0.7-50, 0.8-50, 0.9-50, 1-50, 2-50, 3-50, 4-50, 5-50, 6-50, 7-50, 8-50, 9-50, 1-50, 11-50, 12-50, 13-50, 14-50, 15-50, 16-50, 17-50, 18-50, 19-50, 20-50, 25-50, 30-50, 35-50, 40-50, or 45-50 mM NaH2PO4.In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 0-20, 0.1-20, 0.2-20, 0.3-20, 0.4-20, 0.5-20, 0.6-20, 0.7-20, 0.8-20, 0.9-20, 1-20, 2-20, 3-20, 4-20, 5-20, 6-20, 7-20, 8-20, 9-20, 10-20, 11-20, 12-20, 13-20, 14-20, 15-20, 16-20, 17-20, 18-20, or 19-20 mM NaH2PO4. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing at least 0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mM NaH2PO4. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing at most 0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mM NaH2PO4. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mM NaH2PO4.

[0297] In some embodiments, the ASO is solubilized in a liquid composition that is not buffered by a buffering agent. A buffering agent in the liquid formulations described herein is an agent other than an active pharmaceutical ingredient (e.g., an ASO described herein) in the formulation that buffers the pH of the formulation.

[0298] In some embodiments, the ASO is solubilized in a liquid composition containing a buffer. In some embodiments, the buffer has a pKa at 25°C 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. In some embodiments, the buffer is effective in a pH range of about 3.6-5.6, about 5.5-6.5, about 5.5-7.4, about 3.0-6.2, or about 5.8-7.2. 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.

[0299] In some embodiments, the ASO is stable in a pharmaceutical formulation at -20°C for at least 1, 2, or 3 years. In some embodiments, the ASO is stable in a pharmaceutical formulation at -4°C for at least 1, 2, or 3 years. In some embodiments, the ASO is stable in a pharmaceutical formulation at 25°C for at least 1, 2, or 3 years. In some embodiments, the ASO is stable in the pharmaceutical formulation after storage of the pharmaceutical formulation 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, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the ASO is stable in the pharmaceutical formulation after storage of the pharmaceutical formulation at −20° C. for at least 12 months. In some embodiments, the ASO is stable in the pharmaceutical formulation after storage of the pharmaceutical formulation at −20° C. for at least 24 months. In some embodiments, the ASO is stable in the pharmaceutical formulation after storage of the pharmaceutical formulation at −20° C. for at least 36 months. In some embodiments, the ASO is stable in 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.In some embodiments, the ASO is stable in the pharmaceutical formulation at 25° 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the ASO is stable in the pharmaceutical formulation at 30° 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the ASO is stable in the pharmaceutical formulation at 37°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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.In some embodiments, the ASO is stable in the pharmaceutical formulation at 40° 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the ASO is stable in the pharmaceutical formulation after storage of the pharmaceutical formulation at 4°C and 55%, 60%, 65%, 70%, or 75% relative humidity 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the ASO is stable in the pharmaceutical formulation after storage of the pharmaceutical formulation at 25° C. and 55%, 60%, 65%, 70%, or 75% relative humidity 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.In some embodiments, the ASO is stable in the pharmaceutical formulation after storage of the pharmaceutical formulation at 30° C. and 55%, 60%, 65%, 70%, or 75% relative humidity 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the ASO is stable in the pharmaceutical formulation after storage of the pharmaceutical formulation at 37° C. and 55%, 60%, 65%, 70%, or 75% relative humidity 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the ASO is stable in the pharmaceutical formulation after storage of the pharmaceutical formulation at 40° C. and 55%, 60%, 65%, 70%, or 75% relative humidity 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the ASO is stable in the pharmaceutical formulation, according to the identification of the molecule by LC / MS with a molecular weight of 7197.2 ± 4.0 Da.

[0300] In some embodiments, the pharmaceutical formulation has a shelf life of at least 1, 2, or 3 years when stored at −20° C. In some embodiments, the pharmaceutical formulation has a shelf life of at least 1, 2, or 3 years when stored at 4° C. In some embodiments, the pharmaceutical formulation has a shelf life of at least 1, 2, or 3 years when stored at 25° C. In some embodiments, the pharmaceutical formulation has a shelf life of 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years when stored at −20° C. In some embodiments, the ASO is stable in the pharmaceutical formulation after storage of the pharmaceutical formulation at −20° C. for at least 12 months. In some embodiments, the pharmaceutical formulation has a shelf life of 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years when stored at 4°C. In some embodiments, the pharmaceutical formulation has a shelf life of 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years when stored at 25°C.In some embodiments, the pharmaceutical formulation has a shelf life of 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years when stored at 30°C. In some embodiments, the pharmaceutical formulation has a shelf life of 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years when stored at 37°C. In some embodiments, the pharmaceutical formulation has a shelf life of 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years when stored at 40°C.In some embodiments, the pharmaceutical formulation has a shelf life of 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years when stored at 4°C and 55%, 60%, 65%, 70%, or 75% relative humidity. In some embodiments, the pharmaceutical formulation has a shelf life of 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years when stored at 25° C. and 55%, 60%, 65%, 70%, or 75% relative humidity. In some embodiments, the pharmaceutical formulation has a shelf life of 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years when stored at 30° C. and 55%, 60%, 65%, 70%, or 75% relative humidity.In some embodiments, the pharmaceutical formulation has a shelf life of 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years when stored at 37° C. and 55%, 60%, 65%, 70%, or 75% relative humidity. In some embodiments, the pharmaceutical formulation has a shelf life of 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years when stored at 40° C. and 55%, 60%, 65%, 70%, or 75% relative humidity.

[0301] In some embodiments, the percent impurity in the pharmaceutical formulation with an HPLC relative retention time of 0.92 is 2.5% or less after storing the pharmaceutical formulation 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, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of an impurity in a pharmaceutical formulation with an HPLC relative retention time of 0.92 is 2.5% or less after storage of the pharmaceutical formulation for at least 12 months at −20° C. In some embodiments, the percent of an impurity in a pharmaceutical formulation with an HPLC relative retention time of 0.92 is 2.5% or less after storage of the pharmaceutical formulation for at least 24 months at −20° C. In some embodiments, the percent of an impurity in a pharmaceutical formulation with an HPLC relative retention time of 0.92 is 2.5% or less after storage of the pharmaceutical formulation for at least 36 months at −20° C. In some embodiments, the percent impurity in the pharmaceutical formulation with an HPLC relative retention time of 0.92 is 2.5% or less 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.In some embodiments, the percent impurity in the pharmaceutical formulation with an HPLC relative retention time of 0.92 is 2.5% or less after storing the pharmaceutical formulation at 25° 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent impurity in the pharmaceutical formulation with an HPLC relative retention time of 0.92 is 2.5% or less after storing the pharmaceutical formulation at 30° 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent impurity in the pharmaceutical formulation with an HPLC relative retention time of 0.92 is 2.5% or less after storing the pharmaceutical formulation at 37° 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.In some embodiments, the percent impurity in the pharmaceutical formulation with an HPLC relative retention time of 0.92 is 2.5% or less after storing the pharmaceutical formulation at 40° 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of an impurity in the pharmaceutical formulation with an HPLC relative retention time of 0.92 is 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 11 is 2.5% or less after storing the pharmaceutical formulation for 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of an impurity in the pharmaceutical formulation with an HPLC relative retention time of 0.92 is 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 11 is 2.5% or less after storing the pharmaceutical formulation for 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.In some embodiments, the percent of an impurity in the pharmaceutical formulation with an HPLC relative retention time of 0.92 is 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, is 2.5% or less after storing the pharmaceutical formulation for 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of an impurity in the pharmaceutical formulation with an HPLC relative retention time of 0.92 is 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, is 2.5% or less after storing the pharmaceutical formulation for 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of an impurity in the pharmaceutical formulation with an HPLC relative retention time of 0.92 is 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, is 2.5% or less after storing the pharmaceutical formulation for 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.

[0302] In some embodiments, the percent impurity in the pharmaceutical formulation with an HPLC relative retention time of 0.98 is 3.5% or less after storing the pharmaceutical formulation 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, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of an impurity in a pharmaceutical formulation with an HPLC relative retention time of 0.98 is 3.5% or less after storage of the pharmaceutical formulation for at least 12 months at −20° C. In some embodiments, the percent of an impurity in a pharmaceutical formulation with an HPLC relative retention time of 0.98 is 3.5% or less after storage of the pharmaceutical formulation for at least 24 months at −20° C. In some embodiments, the percent of an impurity in a pharmaceutical formulation with an HPLC relative retention time of 0.98 is 3.5% or less after storage of the pharmaceutical formulation for at least 36 months at −20° C. In some embodiments, the percent impurity in the pharmaceutical formulation with an HPLC relative retention time of 0.98 is 3.5% or less 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.In some embodiments, the percent impurity in the pharmaceutical formulation with an HPLC relative retention time of 0.98 is 3.5% or less after storing the pharmaceutical formulation at 25° 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent impurity in the pharmaceutical formulation with an HPLC relative retention time of 0.98 is 3.5% or less after storing the pharmaceutical formulation at 30° 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent impurity in the pharmaceutical formulation with an HPLC relative retention time of 0.98 is 3.5% or less after storing the pharmaceutical formulation at 37° 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.In some embodiments, the percent impurity in the pharmaceutical formulation with an HPLC relative retention time of 0.98 is 3.5% or less after storing the pharmaceutical formulation at 40° 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of an impurity in the pharmaceutical formulation with an HPLC relative retention time of 0.98 is 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 11 is 3.5% or less after storing the pharmaceutical formulation for 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of an impurity in the pharmaceutical formulation with an HPLC relative retention time of 0.98 is 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 11 is 3.5% or less after storing the pharmaceutical formulation for 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.In some embodiments, the percent of an impurity in the pharmaceutical formulation with an HPLC relative retention time of 0.98 is 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, is 3.5% or less after storing the pharmaceutical formulation for 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of an impurity in the pharmaceutical formulation with an HPLC relative retention time of 0.98 is 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, is 3.5% or less after storing the pharmaceutical formulation for 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of an impurity in the pharmaceutical formulation with an HPLC relative retention time of 0.98 is 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, is 3.5% or less after storing the pharmaceutical formulation for 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.

[0303] In some embodiments, the percent of any unspecified impurity in the pharmaceutical formulation by HPLC is 1.8% or less after storing the pharmaceutical formulation 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, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of any unspecified impurity in the pharmaceutical formulation by HPLC is 1.8% or less after storing the pharmaceutical formulation for at least 12 months at −20° C. In some embodiments, the percent of any unspecified impurity in the pharmaceutical formulation by HPLC is 1.8% or less after storing the pharmaceutical formulation for at least 24 months at −20° C. In some embodiments, the percent of any unspecified impurity in the pharmaceutical formulation by HPLC is 1.8% or less after storing the pharmaceutical formulation for at least 36 months at −20° C. In some embodiments, the percent of any unspecified impurity in the pharmaceutical formulation by HPLC is 1.8% or less 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.In some embodiments, the percent of any unspecified impurity in the pharmaceutical formulation by HPLC is 1.8% or less after storing the pharmaceutical formulation at 25° 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of any unspecified impurity in the pharmaceutical formulation by HPLC is 1.8% or less after storing the pharmaceutical formulation at 30° 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of any unspecified impurity in the pharmaceutical formulation by HPLC is 1.8% or less after storing the pharmaceutical formulation at 37° 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.In some embodiments, the percent of any unspecified impurity in the pharmaceutical formulation by HPLC is 1.8% or less after storing the pharmaceutical formulation at 40° 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of any unspecified impurity in the pharmaceutical formulation by HPLC is 1.8% or less after storing the pharmaceutical formulation at 4° C. and 55%, 60%, 65%, 70%, or 75% relative humidity 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of any unspecified impurity in the pharmaceutical formulation by HPLC is 1.8% or less after storing the pharmaceutical formulation at 25° C. and 55%, 60%, 65%, 70%, or 75% relative humidity 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.In some embodiments, the percent of any unspecified impurity in the pharmaceutical formulation by HPLC is 1.8% or less after storing the pharmaceutical formulation at 30° C. and 55%, 60%, 65%, 70%, or 75% relative humidity for at least 1, 23, 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of any unspecified impurity in the pharmaceutical formulation by HPLC is 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, is 1.8% or less after storing the pharmaceutical formulation for 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of any unspecified impurity in the pharmaceutical formulation by HPLC is 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, is 1.8% or less after storing the pharmaceutical formulation for 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.

[0304] In some embodiments, the percent of total impurities in the pharmaceutical formulation by HPLC is 10% or less after storing the pharmaceutical formulation 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, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of total impurities in the pharmaceutical formulation by HPLC is 10% or less after storing the pharmaceutical formulation for at least 12 months at −20° C. In some embodiments, the percent of total impurities in the pharmaceutical formulation by HPLC is 10% or less after storing the pharmaceutical formulation for at least 24 months at −20° C. In some embodiments, the percent of total impurities in the pharmaceutical formulation by HPLC is 10% or less after storing the pharmaceutical formulation for at least 36 months at −20° C. In some embodiments, the percent of total impurities in the pharmaceutical formulation by HPLC is 10% or less 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.In some embodiments, the percent of total impurities in the pharmaceutical formulation by HPLC is 10% or less after storing the pharmaceutical formulation at 25° 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of total impurities in the pharmaceutical formulation by HPLC is 10% or less after storing the pharmaceutical formulation at 30° 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of total impurities in the pharmaceutical formulation by HPLC is 10% or less after storing the pharmaceutical formulation at 37° 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.In some embodiments, the percent of total impurities in the pharmaceutical formulation by HPLC is 10% or less after storing the pharmaceutical formulation at 40° 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of total impurities in the pharmaceutical formulation by HPLC is 10% or less after storing the pharmaceutical formulation at 4° C. and 55%, 60%, 65%, 70%, or 75% relative humidity 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of total impurities in the pharmaceutical formulation by HPLC is 10% or less after storing the pharmaceutical formulation at 25° C. and 55%, 60%, 65%, 70%, or 75% relative humidity 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.In some embodiments, the percent of total impurities in the pharmaceutical formulation by HPLC is 10% or less after storing the pharmaceutical formulation at 30° C. and 55%, 60%, 65%, 70%, or 75% relative humidity 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of total impurities in the pharmaceutical formulation by HPLC is 10% or less after storing the pharmaceutical formulation at 37° C. and 55%, 60%, 65%, 70%, or 75% relative humidity 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of total impurities in the pharmaceutical formulation by HPLC is 10% or less after storing the pharmaceutical formulation at 40° C. and 55%, 60%, 65%, 70%, or 75% relative humidity 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.

[0305] 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 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, 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 pH of the pharmaceutical composition is 6.6 to 7.6 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the pH of the pharmaceutical composition is 6.6 to 7.6 after storing the pharmaceutical formulation at 25° 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.In some embodiments, the pH of the pharmaceutical composition is 6.6 to 7.6 after storing the pharmaceutical formulation at 30° 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the pH of the pharmaceutical composition is 6.6 to 7.6 after storing the pharmaceutical formulation at 37° 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the pH of the pharmaceutical composition is 6.6 to 7.6 after storing the pharmaceutical formulation at 40° 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.In some embodiments, the pH of the pharmaceutical composition is 6.6 to 7.6 after storing the pharmaceutical formulation at 4° C. and 55%, 60%, 65%, 70%, or 75% relative humidity 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the pH of the pharmaceutical composition is 6.6 to 7.6 after storing the pharmaceutical formulation at 25° C. and 55%, 60%, 65%, 70%, or 75% relative humidity 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the pH of the pharmaceutical composition is 6.6 to 7.6 after storing the pharmaceutical formulation at 30° C. and 55%, 60%, 65%, 70%, or 75% relative humidity 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.In some embodiments, the pH of the pharmaceutical composition is 6.6 to 7.6 after storing the pharmaceutical formulation at 37° C. and 55%, 60%, 65%, 70%, or 75% relative humidity 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the pH of the pharmaceutical composition is 6.6 to 7.6 after storing the pharmaceutical formulation at 40° C. and 55%, 60%, 65%, 70%, or 75% relative humidity 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.

[0306] In some embodiments, the osmolality of the pharmaceutical composition is 310-360 mOsm / kg after storing the pharmaceutical formulation 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, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the osmolality of the pharmaceutical composition is 310-360 mOsm / kg after storing the pharmaceutical formulation for at least 12 months at -20° C. In some embodiments, the osmolality of the pharmaceutical composition is 310-360 mOsm / kg after storing the pharmaceutical formulation for at least 24 months at -20° C. In some embodiments, the osmolality of the pharmaceutical composition is 310-360 mOsm / kg after storing the pharmaceutical formulation for at least 36 months at -20° C. In some embodiments, the osmolality of the pharmaceutical composition is 310-360 mOsm / kg 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.In some embodiments, the osmolality of the pharmaceutical composition is 310-360 mOsm / kg at 25° C. after storing the pharmaceutical formulation 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the osmolality of the pharmaceutical composition is 310-360 mOsm / kg after storing the pharmaceutical formulation at 30° 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the osmolality of the pharmaceutical composition is 310-360 mOsm / kg after storing the pharmaceutical formulation at 37° 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.In some embodiments, the osmolality of the pharmaceutical composition is 310-360 mOsm / kg after storing the pharmaceutical formulation at 40° 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the osmolality of the pharmaceutical composition is 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 310 to 360 mOsm / kg after storing the pharmaceutical preparation for 3, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the osmolality of the pharmaceutical composition is 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 310 to 360 mOsm / kg after storing the pharmaceutical preparation for 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.In some embodiments, the osmolality of the pharmaceutical composition is 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 310 to 360 mOsm / kg after storing the pharmaceutical preparation for 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the osmolality of the pharmaceutical composition is 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 310 to 360 mOsm / kg after storing the pharmaceutical preparation for 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the osmolality of the pharmaceutical composition is 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 310 to 360 mOsm / kg after storing the pharmaceutical preparation for 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.

[0307] In some embodiments, formation of particles greater than 50 μm in diameter is not observed or does not occur after storing the pharmaceutical formulation 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, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the formation of particles greater than 50 μm in diameter is not observed or does not occur after storage of the pharmaceutical formulation for at least 12 months at −20° C. In some embodiments, the formation of particles greater than 50 μm in diameter is not observed or does not occur after storage of the pharmaceutical formulation for at least 24 months at −20° C. In some embodiments, the formation of particles greater than 50 μm in diameter is not observed or does not occur after storage of the pharmaceutical formulation for at least 36 months at −20° C. In some embodiments, formation of particles greater than 50 μm in diameter is not observed or does not occur 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.In some embodiments, formation of particles greater than 50 μm in diameter is not observed or no such particles are formed after storage of the pharmaceutical formulation at 25° 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, formation of particles greater than 50 μm in diameter is not observed or no such particles are formed after storage of the pharmaceutical formulation at 30° 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, formation of particles greater than 50 μm in diameter is not observed or no such particles are formed after storing the pharmaceutical formulation at 37° 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.In some embodiments, formation of particles greater than 50 μm in diameter is not observed or no such particles are formed after storing the pharmaceutical formulation at 40° 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the saturation temperature may be 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, After storing the pharmaceutical formulation for 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years, no particles are observed to form or no such particles are formed with a diameter greater than 50 μm. In some embodiments, the saturation temperature is 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, After storing the pharmaceutical formulation for 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years, no particles are observed to form or no such particles are formed with a diameter greater than 50 μm.In some embodiments, the saturation temperature is 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, After storing the pharmaceutical formulation for 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years, no particles are observed to form or no such particles are formed with a diameter greater than 50 μm. In some embodiments, the serotonin concentration is 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, After storing the pharmaceutical formulation for 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years, no particles are observed to form or no such particles are formed with a diameter greater than 50 μm. In some embodiments, the solubility of 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 1 After storing the pharmaceutical formulation for 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years, no particles are observed to form or no such particles are formed with a diameter greater than 50 μm.

[0308] In some embodiments, no observable particle formation is observed after storage of the pharmaceutical formulation 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, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, no observable particle formation is observed after storage of the pharmaceutical formulation at −20° C. for at least 12 months. In some embodiments, no observable particle formation is observed after storing the pharmaceutical formulation for at least 24 months at −20° C. In some embodiments, no observable particle formation is observed after storing the pharmaceutical formulation for at least 36 months at −20° C. In some embodiments, no observable particle formation is observed 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, no observable particle formation is observed after storing the pharmaceutical formulation at 25° 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.In some embodiments, no observable particle formation is observed after storing the pharmaceutical formulation at 30° 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, no observable particle formation is observed after storing the pharmaceutical formulation at 37° 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, no observable particle formation is observed after storing the pharmaceutical formulation at 40° 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.In some embodiments, no observable particle formation is observed after storing the pharmaceutical formulation at 4° C. and 55%, 60%, 65%, 70%, or 75% relative humidity 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, no observable particle formation is observed after storing the pharmaceutical formulation at 25° C. and 55%, 60%, 65%, 70%, or 75% relative humidity 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, no observable particle formation is observed after storing the pharmaceutical formulation at 30° C. and 55%, 60%, 65%, 70%, or 75% relative humidity 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.In some embodiments, no observable particle formation is observed after storing the pharmaceutical formulation at 37° C. and 55%, 60%, 65%, 70%, or 75% relative humidity 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, no observable particle formation is observed after storing the pharmaceutical formulation at 40° C. and 55%, 60%, 65%, 70%, or 75% relative humidity 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.

[0309] In some embodiments, the ASO is solubilized in a buffer that does not contain Na2HPO4 and / or NaH2PO4.

[0310] In some embodiments, the ASO is solubilized or diluted in a buffer solution further comprising a carbohydrate. In some embodiments, the carbohydrate comprises D-glucose. In some embodiments, the ASO is solubilized or diluted in a buffer solution further comprising 1 to 100 mM D-glucose.

[0311] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 1-100 mM D-glucose.

[0312] In some embodiments, the ASO described herein is solubilized or diluted in a buffer containing 1-100, 1-95, 1-90, 1-85, 1-80, 1-75, 1-70, 1-65, 1-60, 1-55, 1-50, 1-45, 1-40, 1-35, 1-30, 1-29, 1-28, 1-27, 1-26, 1-25, 1-24, 1-23, 1-22, 1-21, 1-20, 1-19, 1-18, 1-17, 1-16, 1-15, 1-14, 1-13, 1-12, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 mM D-glucose. In some embodiments, the ASOs described herein may be 2-100, 3-100, 4-100, 5-100, 6-100, 7-100, 8-100, 9-100, 10-100, 11-100, 12-100, 13-100, 14-100, 15-100, 16-100, 17-100, 18-100, 19-100, 20-100, 21-100, 22-100, 23-100, 24 The sample is solubilized or diluted in a buffer containing ∼100, 25–100, 26–100, 29–100, 28–100, 29–100, 30–100, 35–100, 40–100, 45–100, 50–100, 55–100, 60–100, 65–100, 70–100, 75–100, 80–100, 85–100, 90–100, or 95–100 mM D-glucose. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 2-30, 3-30, 4-30, 5-30, 6-30, 7-30, 8-30, 9-30, 10-30, 11-30, 12-30, 13-30, 14-30, 15-30, 16-30, 17-30, 18-30, 19-30, 20-30, 21-30, 22-30, 23-30, 24-30, 25-30, 26-30, 27-30, 28-30, or 29-30 mM D-glucose. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 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, or 30 mM D-glucose.In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing at most 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, or 30 mM D-glucose. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing at most 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, or 30 mM D-glucose.

[0313] In some embodiments, the ASO described herein is solubilized or diluted in a buffer containing 1-100, 1-95, 1-90, 1-85, 1-80, 1-75, 1-70, 1-65, 1-60, 1-55, 1-50, 1-45, 1-40, 1-35, 1-30, 1-29, 1-28, 1-27, 1-26, 1-25, 1-24, 1-23, 1-22, 1-21, 1-20, 1-19, 1-18, 1-17, 1-16, 1-15, 1-14, 1-13, 1-12, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 mM glucose. In some embodiments, the ASOs described herein may be 2 to 100, 3 to 100, 4 to 100, 5 to 100, 6 to 100, 7 to 100, 8 to 100, 9 to 100, 10 to 100, 11 to 100, 12 to 100, 13 to 100, 14 to 100, 15 to 100, 16 to 100, 17 to 100, 18 to 100, 19 to 100, 20 to 100, 21 to 100, 22 to 100, 23 to 100, 24 to 100, 25 to 100, 26 to 100, 27 to 100, 28 to 100, 29 to 100, 30 to 100, 31 to 100, 32 to 100, 33 to 100, 34 to 100, 35 to 100, 36 to 100, 37 to 100, 38 to 100, 39 to 100, 40 to 100, 41 to 100, 42 to 100, 43 to 100, 44 to 100, 45 to 100, 46 to 100, 47 to 100, 48 to 100, 49 to 100, 50 to 100, 51 to 100, 52 to 100, 53 to 100, 54 to 100, 55 to 100, 56 to 100, 57 to 100, 58 Solubilized or diluted in a buffer containing 4-100, 25-100, 26-100, 29-100, 28-100, 29-100, 30-100, 35-100, 40-100, 45-100, 50-100, 55-100, 60-100, 65-100, 70-100, 75-100, 80-100, 85-100, 90-100, or 95-100 mM glucose. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 2-30, 3-30, 4-30, 5-30, 6-30, 7-30, 8-30, 9-30, 10-30, 11-30, 12-30, 13-30, 14-30, 15-30, 16-30, 17-30, 18-30, 19-30, 20-30, 21-30, 22-30, 23-30, 24-30, 25-30, 26-30, 27-30, 28-30, or 29-30 mM glucose. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 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, or 30 mM glucose.In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing at most 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, or 30 mM glucose. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing at most 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, or 30 mM glucose.

[0314] In some embodiments, the ASO is solubilized or diluted in a buffer containing 25-250 mM NaCl, 0.1-20 mM KCl, 0.1-50 mM NaHPO, 0.1-50 mM NaHPO, 0.1-50 mM CaCl, and 0.1-50 mM MgCl.

[0315] In some embodiments, the ASO is solubilized or diluted in a buffer containing 150 mM NaCl, 3.0 mM KCl, 0.7 mM NaHPO, 0.3 mM NaHPO, 0.79 mM MgCl, and 1.4 mM CaCl.

[0316] In some embodiments, the ASO is solubilized or diluted in a buffer solution further comprising an antioxidant. In some embodiments, the antioxidant is t-butylhydroxyquinoline (TBHQ), butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E, or any combination thereof. In some embodiments, the ASO is solubilized or diluted in a buffer solution further comprising an antioxidant, wherein the antioxidant is ascorbic acid (vitamin C), glutathione, lipoic acid, uric acid, carotene, α-tocopherol (vitamin E), ubiquinol (coenzyme Q), or any combination thereof.

[0317] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer 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.

[0318] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer 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.

[0319] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer 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.

[0320] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer 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.

[0321] In some embodiments, the pharmaceutical composition does not contain a preservative. In some embodiments, the pharmaceutical composition contains a preservative.

[0322] In some embodiments, the ASO described herein is present in the pharmaceutical composition at a concentration of 5 to 250 mg / mL.

[0323] In some embodiments, the ASOs described herein may be from 5 to 250, 5 to 247.5, 5 to 245, 5 to 242.5, 5 to 240, 5 to 237.5, 5 to 235, 5 to 232.5, 5 to 230, 5 to 227.5, 5 to 225, 5 to 225.5, 5 to 220, 5 to 217.5, 5 to 215, 5 to 212.5, 5 to 210, 5 to 205.5, 5 to 205, 5 to 202.5, 5 to 200, 5 ~197.5, 5~195, 5~192.5, 5~190, 5~187.5, 5~185, 5~182.5, 5~180, 5~177.5, 5~175, 5~172.5, 5~170, 5~167.5, 5~165, 5~162.5, 5~160, 5~157.5, 5~155, 5~152.5, 5~150, 5~147.5, 5~145, 5~142.5, 5~140, 5~137. 5, 5~135, 5~132.5, 5~130, 5~127.5, 5~125, 5~122.5, 5~120, 5~117.5, 5~115, 5~112.5, 5~110, 5~107.5, 5~105, 5~102.5, 5~100, 5~97.5, 5~95, 5~92.5, 5~90, 5~87.5, 5~85, 5~82.5, 5~80, 5~77.5, 5~75, 5~72.5 , 5 to 70, 5 to 67.5, 5 to 65, 5 to 62.5, 5 to 60, 5 to 57.5, 5 to 55, 5 to 52.5, 5 to 50, 5 to 47.5, 5 to 45, 5 to 42.5, 5 to 40, 5 to 37.5, 5 to 35, 5 to 32.5, 5 to 30, 5 to 27.5, 5 to 25, 5 to 22.5, 5 to 20, 5 to 17.5, 5 to 15, 5 to 12.5, or 5 to 10 mg / mL.In some embodiments, the ASOs described herein may be 10 to 250, 15 to 250, 20 to 250, 25 to 250, 30 to 250, 35 to 250, 40 to 250, 45 to 250, 50 to 250, 55 to 250, 60 to 250, 65 to 250, 70 to 250, 75 to 250, 80 to 250, 85 to 250, 90 to 250, 95 to 250, 100 to 250, 105 to 250, 110 to 250, 115 to 250, 120 to 250, 125 to 250, 130 to 250, 140 to 250, 150 to 250, 160 to 250, 170 to 250, 180 to 250, 190 to 250, 200 to 250, 210 to 250, 220 to 250, 230 to 250, 240 to 250, 250 to 260, 260 to 270, 270 to 280, 280 to 290, 290 to 300, 300 to 310, 310 to 320, 320 to 330, 330 to 340, 340 to 350, 350 to 360, 360 to 370, 370 to 380, 380 to 390, 390 to 400, 400 to 4 The compound is present in the pharmaceutical composition at a concentration of 35-250, 140-250, 145-250, 150-250, 155-250, 160-250, 165-250, 170-250, 175-250, 180-250, 185-250, 190-250, or 195-250, 200-250, 205-250, 210-250, 215-250, 220-250, 225-250, 230-250, 235-250, 240-250, or 245-250 mg / mL.In some embodiments, the ASOs described herein comprise 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69 , 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190 , 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250 mg / mL.In some embodiments, the ASOs described herein comprise at most 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 34, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, or 250 mg / mL.In some embodiments, the ASOs described herein are 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134 , 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250 mg / mL.

[0324] In some embodiments, the ASO described herein is present in the pharmaceutical composition at a concentration of 0.1 to 250 mg / mL. In some embodiments, the ASO described herein is present in the pharmaceutical 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, 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 described herein is present in the pharmaceutical composition at a concentration 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 described herein is present in the pharmaceutical composition at a concentration 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 the diluent.

[0325] In some embodiments, the ASO described in this specification is 0.1mg / mL~250mg / mL、0.2mg / mL~250mg / mL、0.3mg / mL~250mg / mL、0.4mg / mL~250mg / mL、0.5mg / mL~250mg / mL、0.6mg / mL~250mg / mL、0.7mg / mL~250mg / mL、0.8mg / mL~250mg / mL、0.9mg / mL~250mg / mL、1.0mg / mL~250mg / mL 、1.1mg / mL~250mg / mL、1.2mg / mL~250mg / mL、1.3mg / mL~250mg / mL、1.4mg / mL~250mg / mL、1.5mg / mL~250mg / mL、1.6mg / mL~25 0mg / mL、1.7mg / mL~250mg / mL、1.8mg / mL~250mg / mL、1.9mg / mL~250mg / mL、2.0mg / mL~250mg / mL、2.1mg / mL~250mg / mL、2.2mg / mL mL~250mg / mL、2.3mg / mL~250mg / mL、2.4mg / mL~250mg / mL、2.5mg / mL~250mg / mL、2.6mg / mL~250mg / mL、2.7mg / mL~250mg / mL、 2.8mg / mL~250mg / mL、2.9mg / mL~250mg / mL、3.0mg / mL~250mg / mL、3.1mg / mL~250mg / mL、3.2mg / mL~250mg / mL、3.3mg / mL~250mg / mL g / mL、3.4mg / mL~250mg / mL、3.5mg / mL~250mg / mL、3.6mg / mL~250mg / mL、3.7mg / mL~250mg / mL、3.8mg / mL~250mg / mL、3.9mg / mL L~250mg / mL、4.0mg / mL~250mg / mL、5.0mg / mL~250mg / mL、6.0mg / mL~250mg / mL、7.0mg / mL~250mg / mL、8.0mg / mL~250mg / mL、9.Present in the pharmaceutical composition at a concentration of 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, 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 mg / mL to 250 mg / mL, 190 mg / mL to 250 mg / mL, l95 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.

[0326] In some embodiments, the ASO described herein is 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, 0.1 mg / mL to 170 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 135 mg / 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.Present in the pharmaceutical composition at a concentration of 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 mg / mL, 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.

[0327] ​In some embodiments, the ASO described herein is present in a diluent at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.10, 5.11, 5.12, 5.13, 5.14, 5.15, 5.16, 5.17, 5.18, 5.19, 5.20, 5.21, 5.22, 5.23, 5.24, 5.25, 5.26, 5.27, 5.28, 5.29, 5.30, 5.31, 5.32, 5.33, 5.34, 5.35, 5.36, 5.37, 5.38, 5.39, 5.40, 5.41, 5.42, 5.43, 5.44, 5.45, 5.46, 5.47, 5.48, 5.49, 5.9, 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78 , 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 8, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, or 250 mg / mL. In some embodiments, the ASO described herein is present in a diluent at a concentration of at most 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.10, 3.11, 3.12, 3.13, 3.14, 3.15, 3.16, 3.17, 3.18, 3.19, 3.20, 3.21, 3.22, 3.23, 3.24, 3.25, 3.26, 3.27, 3.28, 3.29, 3.30, 3.31, 3.32, 3.33, 3.34, 3.35, 3.36, 3.37, 3.38, 3.39, 3.40, 3.41, 3.42, 3.43, 3.44, 3.45, 3.46, 3.47, 3.48, 3.49, 3.50, 3.51, 3.52, 3.53, 3.54, 3.55, 3.56, 3.57, 3.58, 3.59, 3.60, 3.61, 3.62, 3.63, 3.64, 3.65, 3.4、2.5、2.6、2.7、2.8、2.9、3.0、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4.0、4.1、4.2、4.3、4.4、4.5、4.6、4.7、4.8、4.9, 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78 , 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 8, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, or 250 mg / mL. In some embodiments, the ASO described herein is present in a diluent at 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.10, 3.11, 3.12, 3.13, 3.14, 3.15, 3.16, 3.17, 3.18, 3.19, 3.20, 3.21, 3.22, 3.23, 3.25, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54 , 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126 6, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, and the compound is present in the pharmaceutical composition at a concentration of 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250 mg / mL.

[0328] For example, pharmaceutical compositions containing agents such as antisense oligonucleotides or antisense oligomers for use in any of the described compositions and methods can be prepared according to standard techniques known in the pharmaceutical industry and described in the published literature.In some embodiments, the pharmaceutical composition for treating a subject comprises an effective amount of any antisense oligomer described herein, or its pharmaceutically acceptable salt, solvate, hydrate or ester.In some embodiments, the pharmaceutical composition described herein further comprises a pharmaceutically acceptable excipient, carrier, or diluent.

[0329] Pharmaceutical compositions can be formulated in a standard manner using one or more pharmaceutically acceptable inactive ingredients that facilitate the processing of active agents into pharmaceutically usable preparations.Suitable formulations depend on the selected route of administration, and general descriptions of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Edition (Lippincott Williams & Wilkins 1999).These documents are incorporated herein by reference.In some embodiments, pharmaceutical compositions facilitate the administration of compounds to living organisms.

[0330] Such compositions may include a buffer such as, for example, neutral buffered saline, phosphate buffered saline, etc.; a carbohydrate such as, for example, glucose, mannose, sucrose, or dextran, mannitol, etc.; a protein; a polypeptide, or an amino acid such as, for example, glycine; an antioxidant; a chelating agent such as, for example, EDTA or glutathione; an adjuvant (e.g., aluminum hydroxide); and a preservative.

[0331] The terms "pharmaceutical composition" and "pharmaceutical formulation" (or "formulation") are used interchangeably and refer to a mixture or solution containing one or more pharmaceutically acceptable excipients together with a therapeutically effective amount of an active pharmaceutical ingredient to be administered to a subject.

[0332] The term "pharmaceutically acceptable" refers to the properties of a material that is generally safe, non-toxic, and not biologically or otherwise undesirable, and that is useful in preparing pharmaceutical compositions acceptable for veterinary use as well as human pharmaceutical use. "Pharmaceutically acceptable" can also refer to a material, such as a carrier or diluent, that does not interfere with the biological activity or properties of a compound and is relatively non-toxic. That is, the material may be administered to an individual without producing undesired biological effects or deleteriously interacting with any of the components of the composition in which it is contained.

[0333] The terms "pharmaceutically acceptable excipient," "pharmaceutically acceptable carrier," and "therapeutically inactive excipient" are used interchangeably and refer to any pharmaceutically acceptable ingredient in a pharmaceutical composition that has no therapeutic activity and is non-toxic to a subject to which it is administered, such as a disintegrant, binder, filler, solvent, buffer, isotonicity agent, stabilizer, antioxidant, surfactant, carrier, diluent, excipient, preservative, or lubricant used in formulating a pharmaceutical product.

[0334] In some embodiments, the compositions are prepared with carriers that protect the components of the composition from rapid elimination from the body, such as sustained-release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparing such formulations will be apparent to those skilled in the art. Materials are also commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells using monoclonal antibodies against viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811, the entire contents of which are incorporated herein by reference.

[0335] For example, pharmaceutical compositions or pharmaceutical preparations containing agents such as antisense oligonucleotides for use in any of the described compositions and methods can be prepared according to standard techniques known in the pharmaceutical industry and described in published literature.In embodiments, pharmaceutical compositions or preparations for treating subjects comprise an effective amount of any of the antisense oligomers described herein, or their pharmaceutically acceptable salts, solvates, hydrates or esters.Pharmaceutical preparations containing antisense oligomers can further comprise pharmaceutically acceptable excipients, diluents or carriers.

[0336] Pharmaceutically acceptable salts are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., and are commensurate with a reasonable benefit / risk ratio (see, e.g., S.M. Berge, et al., J. Pharmaceutical See 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 compounds, or can be prepared separately by reacting the free base function with a suitable organic acid. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or salts of amino groups formed with organic acids such as, for example, acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or salts formed by other documented methods, such as, for example, ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, etc. salts, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc.Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as, for example, halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0337] In some embodiments, provided herein are methods of making the pharmaceutical compositions described herein.

[0338] Pharmaceutical preparations In some aspects, provided herein is a pharmaceutical formulation comprising an antisense oligomer (ASO described herein), and a pharmaceutically acceptable diluent, wherein the ASO described herein comprises a sequence having at least 80% sequence identity to any one of SEQ ID NOs: 21-67, 210-256, or 304-1099, and is at least about 0.1, 0.5, 1, 2.5, 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 1 , 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22.5, 25, 27.5, 30, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, 52.5, 55, 57.5, 60, 62.5, 65, 67.5, 70, 72.5, 75, 77.5, 80, 82.5, 85, 87.5, 90, 92.5, 95, 97.5, 100, 102. 5, 105, 107.5, 110, 112.5, 115, 117.5, 120, 122.5, 125, 127.5, 130, 132.5, 135, 137.5, 140, 142.5, 145, 147.5, 150, 152.5, 155, 157.5, 160, 162.5, 165, 167.5, 170, 172.5, 175, 177.5, 180, 182.5, 185, 187.5, 190 , 192.5, 195, 197.5, 200, 202.5, 205, 207.5, 210, 212.5, 215, 217.5, 220, 222.5, 225, 227.5, 230, 232.5, 235, 237.5, 240, 242.5, 245, 247.5, or 250 mg of an ASO described herein is dissolved or suspended in solution at a concentration of 0.1 to 250 mg / mL. In some embodiments, the ASO described herein comprises a sequence having at least 80% sequence identity to any one of the sequences listed in Tables 4A, 4B, 5A, 5B, 6A, 6B, 7, 8A, and 8B.

[0339] In some embodiments, the ASO 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%, 88%, 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 to any one of SEQ ID NOs: 21-67, 210-256, or 304-1099. In some embodiments, the ASO 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%, 88%, 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 to any one of SEQ ID NOs: 21-67, 210-256, or 304-1099. In some embodiments, the ASOs described herein consist 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%, 88%, 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 to any one of the sequences listed in Tables 4A, 4B, 5A, 5B, 6A, 6B, 7, 8A and 8B.

[0340] In some embodiments, the ASO described herein is a compound of the structure set forth in formula (I) (free acid) or a salt thereof. [ka]

[0341] In some embodiments, the ASO described herein is a compound of the structure set forth in formula (II) (sodium salt). [ka]

[0342] In any of the structural formulas (representations of compounds) presented herein, two curved lines and a line between them are used to connect the phosphorus (P) and oxygen (O) atoms. The two curved lines and the line between them should be viewed as a single, integrated segment and represent the covalent bond between the phosphorus and oxygen atoms, which is part of the backbone linkage (e.g., phosphodiester or phosphorothioate bond) between two adjacent nucleotides. In any of the structural formulas, neither vertex (corner) where the curved line joins the line represents a carbon atom or the presence of a -CH2- at the relevant position in the compound represented by the structural formula.

[0343] In some examples, the ASO described herein is all-P-ambo-2'-O-(2-methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioguanylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl. -(3'→5')-2'-O-(2-methoxyethyl)-P-thioguanylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioguanylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioguanylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thio Ocytidylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioguanylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methylcytidine or a salt thereof.

[0344] In some examples, the sodium salt described herein is all-P-ambo-2'-O-(2-methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioguanylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiouri Dilyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioguanylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioguanylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioguanylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P -Thiocytidylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioguanylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)-5- The sodium salt of methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methylcytidine.

[0345] In some embodiments, the range is about 1 to 500, 2 to 500, 3 to 500, 4 to 500, 5 to 500, 6 to 500, 7 to 500, 8 to 500, 9 to 500, 10 to 500, 15 to 500, 20 to 500, 25 to 500, 30 to 500, 35 to 500, 40 to 500, 45 to 500, 50 to 500, 55 to 500, 60 to 500, 65 to 500, 70 to 500, 75 to 500, 80 to 500, 85 to 500, 90 to 500, 95 to 500, 100 to 500, 105 to 500, 110 to 500, 115 ~500, 120~500, 125~500, 130~500, 135~500, 140~500, 145~500, 150~500, 155~500, 160~500, 165~500, 170~500, 175~500, 180~500, 185~500, 190~500, 195~500, 205~500, 210~500, 215~500, 220~500, 225~500, 230~500, 235~500, 240~500, 245~500, 250~500, 255~50 0, 260~500, 265~500, 270~500, 275~500, 280~500, 285~500, 290~500, 295~500, 300~500, 305~500, 310~500, 315~500, 320~500, 325~500, 330~500, 335~500, 340~500, 345~500, 350~500, 355~500, 360~500, 365~500, 370~500, 375~500, 380~500, 385~500, 390~500, 3 95-500, 400-500, 405-500, 410-500, 415-500, 420-500, 425-500, 430-500, 435-500, 440-500, 445-500, 450-500, 455-500, 460-500, 465-500, 470-500, 475-500, 480-500, 485-500, 490-500, or 495-500 mg of an ASO described herein is dissolved or suspended in a solution at a concentration of 5-200 mg / mL.In some embodiments, the range is from about 1 to 495, 1 to 490, 1 to 485, 1 to 480, 1 to 475, 1 to 470, 1 to 465, 1 to 460, 1 to 455, 1 to 450, 1 to 445, 1 to 440, 1 to 435, 1 to 430, 1 to 425, 1 to 420, 1 to 415, 1 to 410, 1 to 405, 1 to 400, 1 to 395, 1 to 390, 1 to 385, 1 to 380, 1 to 375, 1 to 370 , 1-365, 1-360, 1-355, 1-350, 1-345, 1-340, 1-335, 1-330, 1-325, 1-320, 1-315, 1-310, 1-305, 1-300, 1-295, 1-290, 1-285, 1-280, 1-275, 1-270, 1-265, 1-260, 1-255, 1-250, 1-245, 1-240, 1-235, 1-2 30, 1-225, 1-220, 1-215, 1-210, 1-205, 1-200, 1-195, 1-190, 1-185, 1-180, 1-175, 1-170, 1-165, 1-160, 1-155, 1-150, 1-145, 1-140, 1-135, 1-130, 1-125, 1-120, 1-115, 1-110, 1-105, 1-100, 1-95, 1- 90, 1-85, 1-80, 1-75, 1-70, 1-65, 1-60, 1-55, 1-0, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 mg of an ASO described herein is dissolved or suspended in a solution at a concentration of 5-200 mg / mL.

[0346] In some embodiments, at least about 0.1, 0.5, 1, 2.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22.5, 25, 27.5, 30, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, 52.5, 55, 57.5, 60, 62 .5, 65, 67.5, 70, 72.5, 75, 77.5, 80, 82.5, 85, 87.5, 90, 92.5, 95, 97.5, 100, 102.5, 105, 107.5, 110, 112.5, 115, 117.5, 120, 122.5, 125, 127.5, 130, 132.5, 135, 137.5, 140, 142.5, 145, 147.5, 150, 152.5, 155, 157.5, 160, 162.5, 165, 167.5, 170, 172.5, 175, 177.5, 180, 182.5, 185, 187.5, 190, 192.5, 195, 197.5, 200, 202.5, 205, 207.5 , 210, 212.5, 215, 217.5, 220, 222.5, 225, 227.5, 230, 232.5, 235, 237.5, 240, 242.5, 245, 247.5, or 250 mg of an ASO described herein is dissolved or suspended in a solution at a concentration of 0.1 to 250 mg / mL.In some embodiments, the concentration is at most about 0.1, 0.5, 1, 2.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22.5, 25, 27.5, 30, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, 52.5, 55, 57.5, 60, 62. 5, 65, 67.5, 70, 72.5, 75, 77.5, 80, 82.5, 85, 87.5, 90, 92.5, 95, 97.5, 100, 102.5, 105, 107.5, 110, 112.5, 115, 117.5, 120, 122.5, 125, 127.5, 130, 132.5, 135, 137.5, 1 40, 142.5, 145, 147.5, 150, 152.5, 155, 157.5, 160, 162.5, 165, 167.5, 170, 172.5, 175, 177.5, 180, 182.5, 185, 187.5, 190, 192.5, 195, 197.5, 200, 202.5, 205, 207.5 , 210, 212.5, 215, 217.5, 220, 222.5, 225, 227.5, 230, 232.5, 235, 237.5, 240, 242.5, 245, 247.5, or 250 mg of an ASO described herein is dissolved or suspended in a solution at a concentration of 0.1 to 250 mg / mL.In some embodiments, the amount of acetaminophen is about 0.1, 0.5, 1, 2.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22.5, 25, 27.5, 30, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, 52.5, 55, 57.5, 60, 62.5, 65, 67.5, 70, 72.5, 75, 77.5, 80, 82.5, 85, 87.5, 90, 92.5, 95, 97.5, 100, 102.5, 105, 107.5, 110, 112.5, 115, 117.5, 120, 122.5, 125, 127.5, 130, 132.5, 135, 137.5, 14 0, 142.5, 145, 147.5, 150, 152.5, 155, 157.5, 160, 162.5, 165, 167.5, 170, 172.5, 175, 177.5, 180, 182.5, 185, 187.5, 190, 192.5, 195, 197.5, 200, 202.5, 205, 207.5, 210, 212.5, 215, 217.5, 220, 222.5, 225, 227.5, 230, 232.5, 235, 237.5, 240, 242.5, 245, 247.5, or 250 mg of an ASO described herein is dissolved or suspended in a solution at a concentration of 0.1 to 250 mg / mL.

[0347] In some embodiments, the ASOs described herein may be from 5 to 250, 5 to 247.5, 5 to 245, 5 to 242.5, 5 to 240, 5 to 237.5, 5 to 235, 5 to 232.5, 5 to 230, 5 to 227.5, 5 to 225, 5 to 225.5, 5 to 220, 5 to 217.5, 5 to 215, 5 to 212.5, 5 to 210, 5 to 205.5, 5 to 205, 5 to 202.5, 5 to 200, 5 to 1 97.5, 5~195, 5~192.5, 5~190, 5~187.5, 5~185, 5~182.5, 5~180, 5~177.5, 5~175, 5~172.5, 5~170, 5~167.5, 5~165, 5~162.5, 5~160, 5~157.5, 5~155, 5~152.5, 5~150, 5~147.5, 5~145, 5~142.5, 5~140, 5~137.5, 5 ~135, 5~132.5, 5~130, 5~127.5, 5~125, 5~122.5, 5~120, 5~117.5, 5~115, 5~112.5, 5~110, 5~107.5, 5~105, 5~102.5, 5~100, 5~97.5, 5~95, 5~92.5, 5~90, 5~87.5, 5~85, 5~82.5, 5~80, 5~77.5, 5~75, 5~72.5, 5~70 , 5-67.5, 5-65, 5-62.5, 5-60, 5-57.5, 5-55, 5-52.5, 5-50, 5-47.5, 5-45, 5-42.5, 5-40, 5-37.5, 5-35, 5-32.5, 5-30, 5-27.5, 5-25, 5-22.5, 5-20, 5-17.5, 5-15, 5-12.5, or 5-10 mg / mL.In some embodiments, the ASOs described herein may be 10 to 250, 15 to 250, 20 to 250, 25 to 250, 30 to 250, 35 to 250, 40 to 250, 45 to 250, 50 to 250, 55 to 250, 60 to 250, 65 to 250, 70 to 250, 75 to 250, 80 to 250, 85 to 250, 90 to 250, 95 to 250, 100 to 250, 105 to 250, 110 to 250, 115 to 250, 120 to 250, 125 to 250, 130 to 250, 135 to 250, 140 to 250, 145 to 250, 150 to 250, 160 to 250, 170 to 250, 180 to 250, 190 to 250, 200 to 250, 210 to 250, 220 to 250, 230 to 250, 240 to 250, 250 to 260, 260 to 270, 270 to 280, 280 to 300, 310 to 320, 330 to 340, 350 to 360, 370 to 380, 380 to 390, 390 to 400, 410 to 420, 420 to 430, 430 to 440, 440 to 4 and / or dissolved or suspended in solution at a concentration of 250, 140-250, 145-250, 150-250, 155-250, 160-250, 165-250, 170-250, 175-250, 180-250, 185-250, 190-250, or 195-250, 200-250, 205-250, 210-250, 215-250, 220-250, 225-250, 230-250, 235-250, 240-250, or 245-250 mg / mL.In some embodiments, the ASOs described herein comprise 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134 , 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191 , 192, 193, 194, 195, 196, 197, 198, 199, 200, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250 mg / mL.In some embodiments, the ASOs described herein comprise at most 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70 , 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250 mg / mL.In some embodiments, the ASO described herein is 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 20, 21, 1, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 5, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 23 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250 mg / mL.

[0348] 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, the ASO described herein is solubilized or diluted in an isotonic solution.

[0349] In some embodiments, the ASOs described herein are solubilized or diluted in a phosphate buffer solution (pH 6.6-7.6). In some embodiments, the ASOs described herein are solubilized or diluted in a phosphate buffer solution (pH 6.0-8.0). In some embodiments, the ASOs described herein are solubilized or diluted in a phosphate buffer solution (pH 5.0-8.0). In some embodiments, the ASOs described herein may be administered at pH 4.5 to 8.5, pH 4.6 to 8.5, pH 4.7 to 8.5, pH 4.8 to 8.5, pH 4.9 to 8.5, pH 5.0 to 8.5, pH 5.1 to 8.5, pH 5.2 to 8.5, pH 5.3 to 8.5, pH 5.4 to 8.5, pH 5.5 to 8.5, pH 5.6 to 8.5, pH 5.7 to 8.5, pH 5.8 to 8.5, pH 5.9 to 8.5, pH 6.0 to 8.5, pH 6.1 to 8.5, pH 6.2 to 8.5, pH 6.3 to 8.5, pH 6.4 to 8.5, pH It is solubilized or diluted in phosphate buffer solution of pH 6.5-8.5, pH 6.6-8.5, pH 6.7-8.5, pH 6.8-8.5, pH 6.9-8.5, pH 7.0-8.5, pH 7.1-8.5, pH 7.2-8.5, pH 7.3-8.5, pH 7.4-8.5, pH 7.5-8.5, pH 7.6-8.5, pH 7.7-8.5, pH 7.8-8.5, pH 7.9-8.5, pH 8.0-8.5, pH 8.1-8.5, pH 8.2-8.5, pH 8.3-8.5, or pH 8.4-8.5.In some embodiments, the ASOs described herein may be administered at pH 4.5 to 8.3, pH 4.5 to 8.2, pH 4.5 to 8.1, pH 4.5 to 8.0, pH 4.5 to 7.9, pH 4.5 to 7.8, pH 4.5 to 7.7, pH 4.5 to 7.6, pH 4.5 to 7.5, pH 4.5 to 7.4, pH 4.5 to 7.3, pH 4.5 to 7.2, pH 4.5 to 7.1, pH 4.5 to 7.0, pH 4.5 to 6.9, pH 4.5 to 6.8, pH 4.5 to 6.7, pH 4.5 to 6.6, pH 4.5 to 6.5, pH Solubilized or diluted in phosphate buffer solution of pH 4.5-6.4, pH 4.5-6.3, pH 4.5-6.2, pH 4.5-6.1, pH 4.5-6.0, pH 4.5-5.9, pH 4.5-5.8, pH 4.5-5.7, pH 4.5-5.6, pH 4.5-5.5, pH 4.5-5.4, pH 4.5-5.3, pH 4.5-5.2, pH 4.5-5.1, pH 4.5-5.0, pH 4.5-4.9, pH 4.5-4.8, pH 4.5-4.7, or pH 4.5-4.6. In some embodiments, the ASOs described herein are solubilized or diluted in a phosphate buffer solution 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, the ASOs described herein are solubilized or diluted in a phosphate buffer solution of 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, the ASOs described herein are solubilized or diluted in a phosphate buffer solution of 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, the ASOs described herein are solubilized or diluted in a phosphate buffer solution of 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, the ASOs described herein are solubilized or diluted in a phosphate buffer solution having a pH of 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, the ASOs described herein are solubilized or diluted in a phosphate buffer solution having a pH of 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, the ASOs described herein are solubilized 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.

[0350] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 25-250 mM NaCl.

[0351] In some embodiments, the ASOs described herein may be 25-250, 30-250, 35-250, 40-250, 45-250, 50-250, 55-250, 60-250, 65-250, 70-250, 75-250, 80-250, 85-250, 90-250, 95-250, 100-250, 105-250, 110-250, 115-250, 120-250, 125-250, 130-250, 135-250, 140-250 , 145-250, 150-250, 155-250, 160-250, 165-250, 170-250, 175-250, 180-250, 185-250, 190-250, 195-250, 200-250, 205-250, 210-250, 215-250, 220-250, 225-250, 230-250, 235-250, 240-250, or 245-250 mM NaCl. In some embodiments, the ASOs described herein may be 25 to 245, 25 to 240, 25 to 235, 25 to 230, 25 to 225, 25 to 220, 25 to 215, 25 to 210, 25 to 205, 25 to 200, 25 to 195, 25 to 190, 25 to 185, 25 to 180, 25 to 175, 25 to 170, 25 to 165, 25 to 160, 25 to 155, 25 to 150, 25 to 145, 25 to 140, 25 to Solubilized or diluted in a buffer containing 135, 25-130, 25-125, 25-120, 25-115, 25-110, 25-105, 25-110, 25-105, 25-100, 25-95, 25-90, 25-85, 25-80, 25-75, 25-70, 25-65, 25-60, 25-55, 25-50, 25-45, 25-40, 25-35, or 25-30 mM NaCl. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 30-245, 35-240, 40-235, 45-230, 50-225, 55-220, 60-215, 65-210, 70-205, 75-200, 80-195, 85-190, 90-185, 95-180, 100-175, 105-170, 110-165, 115-160, 120-155, 125-150, 130-145, or 135-140 mM NaCl.In some embodiments, the ASOs described herein are 100-140, 101-140, 102-140, 103-140, 104-140, 105-140, 106-140, 107-140, 108-140, 109-140, 110-140, 111-140, 112-140, 113-140, 114-140, 115-140, 116-140, 117-140, 118-140, 119-140, 120 140, 121, 140, 122, 140, 123, 140, 124, 140, 125, 140, 126, 140, 127, 140, 128, 140, 129, 140, 130, 140, 131, 140, 132, 140, 133, 140, 134, 140, 135, 140, 136, 140, 137, 140, 138, 140, or 139, 140 mM NaCl. In some embodiments, the ASOs described herein are 100-139, 100-138, 100-137, 100-136, 100-135, 100-134, 100-133, 100-132, 100-131, 100-130, 100-129, 100-128, 100-127, 100-126, 100-125, 100-124, 100-123, 100-122, 100-121, 100-120 , 100-119, 100-118, 100-117, 100-116, 100-115, 100-114, 100-113, 100-112, 100-111, 100-110, 100-109, 100-108, 100-107, 100-106, 100-105, 100-104, 100-103, 100-102, or 100-101 mM NaCl. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, or 140 mM NaCl.In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing up to 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, or 140 mM NaCl. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, or 140 mM NaCl.

[0352] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 0.1 to 20 mM KCl.

[0353] In some embodiments, the ASOs described herein may be 0.1-40, 0.1-39, 0.1-38, 0.1-37, 0.1-36, 0.1-35, 0.1-34, 0.1-33, 0.1-32, 0.1-31, 0.1-30, 0.1-29, 0.1-28, 0.1-27, 0.1-26, 0.1-25, 0.1-24, 0.1-23, 0.1-22, 0. Solubilized or diluted in a buffer containing 1-21, 0.1-20, 0.1-19, 0.1-18, 0.1-17, 0.1-16, 0.1-15, 0.1-14, 0.1-13, 0.1-12, 0.1-10, 0.1-9, 0.1-8, 0.1-7, 0.1-6, 0.1-5, 0.1-4, 0.1-3, 0.1-2, or 0.1-1 mM KCl. In some embodiments, the ASOs described herein may be 0.2 to 40, 0.3 to 40, 0.4 to 40, 0.5 to 40, 0.6 to 40, 0.7 to 40, 0.8 to 40, 0.9 to 40, 1 to 40, 2 to 40, 3 to 40, 4 to 40, 5 to 40, 6 to 40, 7 to 40, 8 to 40, 9 to 40, 10 to 40, 11 to 40, 12 to 40, 13 to 40, 14 to 40, 15 to 40, 16 to 40, Solubilized or diluted in a buffer containing 17-40, 18-40, 19-40, 20-40, 21-40, 22-40, 23-40, 24-40, 25-40, 26-40, 27-40, 28-40, 29-40, 30-40, 31-40, 32-40, 33-40, 34-40, 35-40, 36-40, 37-40, 38-40, or 39-40 mM KCl. In some embodiments, the ASOs described herein may be 0.1 to 3.5, 0.2 to 3.5, 0.3 to 3.5, 0.4 to 3.5, 0.5 to 3.5, 0.6 to 3.5, 0.7 to 3.5, 0.8 to 3.5, 0.9 to 3.5, 1.0 to 3.5, 1.1 to 3.5, 1.2 to 3.5, 1.3 to 3.5, 1.4 to 3.5, 1.5 to 3.5, 1.6 to 3.5, 1.7 to 3.5, 1.8 Solubilized or diluted in buffer containing 1.0-3.5, 1.9-3.5, 2.0-3.5, 2.1-3.5, 2.2-3.5, 2.3-3.5, 2.4-3.5, 2.5-3.5, 2.6-3.5, 2.7-3.5, 2.8-3.5, 2.9-3.5, 3.0-3.5, 3.1-3.5, 3.2-3.5, 3.3-3.5, or 3.4-3.5 mM KCl.In some embodiments, the ASOs described herein may be 0.1 to 3.4, 0.1 to 3.3, 0.1 to 3.2, 0.1 to 3.1, 0.1 to 3.0, 0.1 to 2.9, 0.1 to 2.8, 0.1 to 2.7, 0.1 to 2.6, 0.1 to 2.5, 0.1 to 2.4, 0.1 to 2.3, 0.1 to 2.2, 0.1 to 2.1, 0.1 to 2.0, 0.1 to 1.9, 0.1 to 1.8 , 0.1-1.7, 0.1-1.6, 0.1-1.5, 0.1-1.4, 0.1-1.3, 0.1-1.2, 0.1-1.1, 0.1-1.0, 0.1-0.9, 0.1-0.8, 0.1-0.7, 0.1-0.6, 0.1-0.5, 0.1-0.4, 0.1-0.3, or 0.1-0.2 mM KCl. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, or 3.5 mM KCl. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing up to 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, or 3.5 mM KCl. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, or 3.5 mM KCl.

[0354] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 0.1-50 mM Na2HPO4.

[0355] In some embodiments, the ASOs described herein may be 0.01 to 100, 0.02 to 100, 0.03 to 100, 0.04 to 100, 0.05 to 100, 0.06 to 100, 0.07 to 100, 0.08 to 100, 0.09 to 100, 0.1 to 100, 0.2 to 100, 0.3 to 100, 0.4 to 100, 0.5 to 100, 0.6 to 100, 0.7 to 100, 0.8 to 100, 0.9 to 100, 1 to 100, 2 to 100, 3 to 100, Solubilized or diluted in a buffer containing 4-100, 5-100, 6-100, 7-100, 8-100, 9-100, 10-100, 15-100, 20-100, 25-100, 30-100, 35-100, 40-100, 45-100, 50-100, 55-100, 60-100, 65-100, 70-100, 75-100, 80-100, 85-100, 90-100, or 95-100 mM NaHPO. In some embodiments, the ASOs described herein may be 0.01 to 95, 0.01 to 90, 0.01 to 85, 0.01 to 80, 0.01 to 75, 0.01 to 70, 0.01 to 65, 0.01 to 60, 0.01 to 55, 0.01 to 50, 0.01 to 45, 0.01 to 40, 0.01 to 35, 0.01 to 30, 0.01 to 25, 0.01 to 20, 0.01 to 15, 0.01 to 10, 0.01 to 9, 0.01 to 8, 0.01 to 7, 0.01 to 6, 0.01 to 5, 0.01 to 4, 0.01 to 5, 0.01 to 6, 0.01 to 7, 0.01 to 8, 0.01 to 9, 0.01 to 10, 0.01 to 15, 0.01 to 10 ... Solubilized or diluted in a buffer containing 1-3, 0.01-2, 0.01-1, 0.01-0.9, 0.01-0.8, 0.01-0.7, 0.01-0.6, 0.01-0.5, 0.01-0.4, 0.01-0.3, 0.01-0.2, 0.01-0.1, 0.01-0.09, 0.01-0.08, 0.01-0.07, 0.01-0.06, 0.01-0.05, 0.01-0.04, 0.01-0.03, or 0.01-0.02 mM NaHPO.In some embodiments, the ASOs described herein may be 0.1 to 3.0, 0.1 to 2.9, 0.1 to 2.8, 0.1 to 2.7, 0.1 to 2.6, 0.1 to 2.5, 0.1 to 2.4, 0.1 to 2.3, 0.1 to 2.2, 0.1 to 2.1, 0.1 to 2.0, 0.1 to 1.9, 0.1 to 1.8, 0.1 to 1.7, 0.1 to 1.6, 0.1 to 2.8 ...8, 0.1 to 2.8, 0.1 to 2.9, 0.1 to 2.8 The sample is solubilized or diluted in a buffer containing 0.1-1.5, 0.1-1.4, 0.1-1.3, 0.1-1.2, 0.1-1.1, 0.1-1.0, 0.1-0.9, 0.1-0.8, 0.1-0.7, 0.1-0.6, 0.1-0.5, 0.1-0.4, 0.1-0.3, or 0.1-0.2 mM Na2HPO4. In some embodiments, the ASOs described herein may be 0.1 to 3.0, 0.2 to 3.0, 0.3 to 3.0, 0.4 to 3.0, 0.5 to 3.0, 0.6 to 3.0, 0.7 to 3.0, 0.8 to 3.0, 0.9 to 3.0, 1.0 to 3.0, 1.2 to 3.0, 1.3 to 3.0, 1.4 to 3.0, 1.5 to 3.0, 1.6 to 3.0, 1.7 to 3.0, 1.8 to 3.0, 1.9 to 3.0, 2.0 to 3.0, 2.1 to 3.0, 2.2 to 3.0, 2.3 to 3.0, 2.4 to 3.0, 2.5 to 3.0, 2.6 to 3.0, 2.7 to 3.0, 2.8 to 3.0, 2.9 to 3.0, 3.0 to 3.0, 3.1 to 3.0, 3.2 to 3.0, 3.3 to 3.0, 3.4 to 3.0, 3.5 to 3.0, 3.6 to 3.0, 3.7 to 3.0, 3.8 to 3.0, 3.9 to 3.0, 3.1 to 3.0, 3.1 to 3.0, 3.1 to 3.0, 3.1 to 3.0, 3.2 to 3.0, 3.3 to 3.0, 3.4 to 3.0, 3.5 to 3.0, 3.6 to 3.0, 3.7 to 3.0, 3.8 to 3.0, 3.9 to 3.0 Solubilized or diluted in buffer containing 0.0, 1.7-3.0, 1.8-3.0, 1.9-3.0, 2.0-3.0, 2.1-3.0, 2.2-3.0, 2.3-3.0, 2.4-3.0, 2.5-3.0, 2.6-3.0, 2.7-3.0, 2.8-3.0, or 2.9-3.0 mM NaHPO. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 mM NaHPO. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing up to 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 mM NaHPO.In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 mM NaHPO.

[0356] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 0.1-50 mM NaH2PO4.

[0357] In some embodiments, the ASOs described herein may be 0.01 to 100, 0.02 to 100, 0.03 to 100, 0.04 to 100, 0.05 to 100, 0.06 to 100, 0.07 to 100, 0.08 to 100, 0.09 to 100, 0.1 to 100, 0.2 to 100, 0.3 to 100, 0.4 to 100, 0.5 to 100, 0.6 to 100, 0.7 to 100, 0.8 to 100, 0.9 to 100, 1 to 100, 2 to 100, 3 to 100, The solution is solubilized or diluted in a buffer containing 4-100, 5-100, 6-100, 7-100, 8-100, 9-100, 10-100, 15-100, 20-100, 25-100, 30-100, 35-100, 40-100, 45-100, 50-100, 55-100, 60-100, 65-100, 70-100, 75-100, 80-100, 85-100, 90-100, or 95-100 mM NaH2PO4. In some embodiments, the ASOs described herein may be 0.01 to 95, 0.01 to 90, 0.01 to 85, 0.01 to 80, 0.01 to 75, 0.01 to 70, 0.01 to 65, 0.01 to 60, 0.01 to 55, 0.01 to 50, 0.01 to 45, 0.01 to 40, 0.01 to 35, 0.01 to 30, 0.01 to 25, 0.01 to 20, 0.01 to 15, 0.01 to 10, 0.01 to 9, 0.01 to 8, 0.01 to 7, 0.01 to 6, 0.01 to 8, 0.01 to 9, 0.01 to 10, 0.01 to 15, 0.01 to 10 ... Solubilized or diluted in buffer containing 0.01-5, 0.01-4, 0.01-3, 0.01-2, 0.01-1, 0.01-0.9, 0.01-0.8, 0.01-0.7, 0.01-0.6, 0.01-0.5, 0.01-0.4, 0.01-0.3, 0.01-0.2, 0.01-0.1, 0.01-0.09, 0.01-0.08, 0.01-0.07, 0.01-0.06, 0.01-0.05, 0.01-0.04, 0.01-0.03, or 0.01-0.02 mM NaH2PO4.In some embodiments, the ASOs described herein may be 0.1 to 3.0, 0.1 to 2.9, 0.1 to 2.8, 0.1 to 2.7, 0.1 to 2.6, 0.1 to 2.5, 0.1 to 2.4, 0.1 to 2.3, 0.1 to 2.2, 0.1 to 2.1, 0.1 to 2.0, 0.1 to 1.9, 0.1 to 1.8, 0.1 to 1.7, 0.1 to 1.6, 0.1 to 2.8 ...8, 0.1 to 2.8, 0.1 to 2.9, 0.1 to 2.8 The sample is solubilized or diluted in a buffer containing 0.1-1.5, 0.1-1.4, 0.1-1.3, 0.1-1.2, 0.1-1.1, 0.1-1.0, 0.1-0.9, 0.1-0.8, 0.1-0.7, 0.1-0.6, 0.1-0.5, 0.1-0.4, 0.1-0.3, or 0.1-0.2 mM NaH2PO4. In some embodiments, the ASOs described herein may be 0.1 to 3.0, 0.2 to 3.0, 0.3 to 3.0, 0.4 to 3.0, 0.5 to 3.0, 0.6 to 3.0, 0.7 to 3.0, 0.8 to 3.0, 0.9 to 3.0, 1.0 to 3.0, 1.2 to 3.0, 1.3 to 3.0, 1.4 to 3.0, 1.5 to 3.0, 1.6 to 3.0, 1.7 to 3.0, 1.8 to 3.0, 1.9 to 3.0, 2.0 to 3.0, 2.1 to 3.0, 2.2 to 3.0, 2.3 to 3.0, 2.4 to 3.0, 2.5 to 3.0, 2.6 to 3.0, 2.7 to 3.0, 2.8 to 3.0, 2.9 to 3.0, 3.0 to 3.0, 3.1 to 3.0, 3.2 to 3.0, 3.3 to 3.0, 3.4 to 3.0, 3.5 to 3.0, 3.6 to 3.0, 3.7 to 3.0, 3.8 to 3.0, 3.9 to 3.0, 3.1 to 3.0, 3.1 to 3.0, 3.1 to 3.0, 3.1 to 3.0, 3.2 to 3.0, 3.3 to 3.0, 3.4 to 3.0, 3.5 to 3.0, 3.6 to 3.0, 3.7 to 3.0, 3.8 to 3.0, 3.9 to 3.0 Solubilized or diluted in a buffer containing 0.0, 1.7-3.0, 1.8-3.0, 1.9-3.0, 2.0-3.0, 2.1-3.0, 2.2-3.0, 2.3-3.0, 2.4-3.0, 2.5-3.0, 2.6-3.0, 2.7-3.0, 2.8-3.0, or 2.9-3.0 mM NaH2PO4. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 mM NaH2PO4. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing up to 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 mM NaH2PO4.In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 mM NaH2PO4.

[0358] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 0.1-50 mM CaCl2.

[0359] In some embodiments, the ASOs described herein may be 0.1-50, 0.2-50, 0.3-50, 0.4-50, 0.5-50, 0.6-50, 0.7-50, 0.8-50, 0.9-50, 1.0-50, -50, 1.1-50, 1.2-50, 1.3-50, 1.4-50, 1.5-50, 1.6-50, 1.7-50, 1.8-50, 1.9-50, 2.0-50, 2.1-50, 2.2-50, 2.3-50, 2.4-50, 2.5-50, 2.6-50, 2.7-50, 2.8-50, 2.9-50, 2.10-50, 2.11-50, 2.12-50, 2.13-50, 2.14-50, 2.15-50, 2.16-50, 2.17-50, 2.18-50, 2.19-50, 2.20-50, 2.21-50, 2.22-50, 2.23-50, 2.24-50, 2.25-50, 2.26-50, 2.27-50, 2.28-50, 2.29-50, 2.30-50, 2.31-50, 2.32-50, 2.33-50, 2.34-50, 2.35-50, 2.36-50, 2.37-50, 2.38-50, 2 Solubilized or diluted in a buffer containing 2-50, 2.3-50, 2.4-50, 2.5-50, 2.6-50, 2.7-50, 2.8-50, 2.9-50, 3.0-50, 3.1-50, 3.2-50, 3.3-50, 3.4-50, 3.5-50, 3.6-50, 3.7-50, 3.8-50, 3.9-50, 4-50, 5-50, 6-50, 7-50, 8-50, 9-50, 10-50, 15-50, 20-50, 25-50, 30-50, 35-50, 40-50, or 45-50 mM CaCl2. In some embodiments, the ASOs described herein may be 0.1 to 45, 0.1 to 40, 0.1 to 35, 0.1 to 30, 0.1 to 25, 0.1 to 20, 0.1 to 15, 0.1 to 10, 0.1 to 5, 0.1 to 4, 0.1 to 4.9, 0.1 to 4.8, 0.1 to 4.7, 0.1 to 4.6, 0.1 to 4.5, 0.1 to 4.4, 0.1 to 4.3, 0.1 to 4.2, 0.1 to 4.1, 0.1 to 4.0, 0.1 to 3.9, 0.1 to 3.8, 0.1 to 3.7, 0.1 to 3.6, 0.1 to 3.5, 0.1 to 3.4, 0.1 to 3.3, 0.1 to 3.2, 0.1 to 3.1, 0.1 to 3.0, 0. Solubilized or diluted in buffer containing 1-2.9, 0.1-2.8, 0.1-2.7, 0.1-2.6, 0.1-2.5, 0.1-2.4, 0.1-2.3, 0.1-2.2, 0.1-2.1, 0.1-2.0, 0.1-1.9, 0.1-1.8, 0.1-1.7, 0.1-1.6, 0.1-1.5, 0.1-1.4, 0.1-1.3, 0.1-1.2, 0.1-1.1, 0.1-1.0, 0.1-0.9, 0.1-0.8, 0.1-0.7, 0.1-0.6, 0.1-0.5, 0.1-0.4, 0.1-0.3, or 0.1-0.2 mM CaCl.In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing at least 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0 mM CaCl2. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing up to 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0 mM CaCl2. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0 mM CaCl2.

[0360] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 0.1-50 mM MgCl2.

[0361] In some embodiments, the ASOs described herein may be 0.1-50, 0.2-50, 0.3-50, 0.4-50, 0.5-50, 0.6-50, 0.7-50, 0.8-50, 0.9-50, 1.0-50, -50, 1.1-50, 1.2-50, 1.3-50, 1.4-50, 1.5-50, 1.6-50, 1.7-50, 1.8-50, 1.9-50, 2.0-50, 2.1-50, 2.2-50, 2.3-50, 2.4-50, 2.5-50, 2.6-50, 2.7-50, 2.8-50, 2.9-50, 3.0-50, 3.10-50, 3.11-50, 3.12-50, 3.13-50, 3.14-50, 3.15-50, 3.16-50, 3.17-50, 3.18-50, 3.19-50, 3.20-50, 3.21-50, 3.22-50, 3.23-50, 3.24-50, 3.25-50, 3.26-50, 3.27-50, 3.28-50, 3.29-50, 3.30-50, 3.31-50, 3.32-50, 3.33-50, 3.34-50, 3.35-50, 3.36-50, 3.37-50, 3. Solubilized or diluted in buffer containing 6-50, 2.7-50, 2.8-50, 2.9-50, 3.0-50, 3.1-50, 3.2-50, 3.3-50, 3.4-50, 3.5-50, 3.6-50, 3.7-50, 3.8-50, 3.9-50, 4-50, 5-50, 6-50, 7-50, 8-50, 9-50, 10-50, 15-50, 20-50, 25-50, 30-50, 35-50, 40-50, or 45-50 mM MgCl2. In some embodiments, the ASOs described herein may be 0.1 to 45, 0.1 to 40, 0.1 to 35, 0.1 to 30, 0.1 to 25, 0.1 to 20, 0.1 to 15, 0.1 to 10, 0.1 to 5, 0.1 to 4, 0.1 to 4.9, 0.1 to 4.8, 0.1 to 4.7, 0.1 to 4.6, 0.1 to 4.5, 0.1 to 4.4, 0.1 to 4.3, 0.1 to 4.2, 0.1 to 4.1, 0.1 to 4.0, 0.1 to 3.9, 0.1 to 3.8, 0.1 to 3.7, 0.1 to 3.6, 0.1 to 3.5, 0.1 to 3.4, 0.1 to 3.3, 0.1 to 3.2, 0.1 to 3.1, 0.1 to 3.0, 0. Solubilized or diluted in buffer containing 1-2.9, 0.1-2.8, 0.1-2.7, 0.1-2.6, 0.1-2.5, 0.1-2.4, 0.1-2.3, 0.1-2.2, 0.1-2.1, 0.1-2.0, 0.1-1.9, 0.1-1.8, 0.1-1.7, 0.1-1.6, 0.1-1.5, 0.1-1.4, 0.1-1.3, 0.1-1.2, 0.1-1.1, 0.1-1.0, 0.1-0.9, 0.1-0.8, 0.1-0.7, 0.1-0.6, 0.1-0.5, 0.1-0.4, 0.1-0.3, or 0.1-0.2 mM MgCl.In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0 mM MgCl2. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing up to 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0 mM MgCl2. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0 mM MgCl2.

[0362] In some embodiments, the ASO is solubilized or diluted in a buffer further containing 1-100 mM NaHCO3, 1-100 mM KHCO3, or a combination thereof.

[0363] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 1-100 mM NaHCO3.

[0364] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 1-99, 1-95, 1-90, 1-85, 1-80, 1-75, 1-70, 1-65, 1-60, 1-55, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 mM NaHCO3. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 2-100, 3-100, 4-100, 5-100, 6-100, 7-100, 8-100, 9-100, 10-100, 15-100, 20-100, 25-100, 30-100, 35-100, 40-100, 45-100, 50-100, 55-100, 60-100, 65-100, 70-100, 75-100, 80-100, 85-100, 90-100, or 95-100 mM NaHCO3. In some embodiments, the ASOs described herein are selected from the group consisting of: 24.0 to 28.0, 24.0 to 27.9, 24.0 to 27.8, 24.0 to 27.7, 24.0 to 27.6, 24.0 to 27.5, 24.0 to 27.4, 24.0 to 27.3, 24.0 to 27.2, 24.0 to 27.1, 24.0 to 27.0, 24.0 to 26.9, 24.0 to 26.8, 24.0 to 26.7, 24.0 to 26.6, 24.0 to 26.5, 24.0 to 26.4, 24.0 to 26.3, 24.0 to 26.2, 24.0 to 26.1, 24.0 24.0-24.9, 24.0-24.8, 24.0-24.7, 24.0-24.6, 24.0-24.5, 24.0-24.4, 24.0-24.3, 24.0-24.2, or 24.0-24.1 mM NaHCO3.In some embodiments, the ASOs described herein are 24.1 to 28.0, 24.2 to 28.0, 24.3 to 28.0, 24.4 to 28.0, 24.5 to 28.0, 24.6 to 28.0, 24.7 to 28.0, 24.8 to 28.0, 24.9 to 28.0, 25.0 to 28.0, 25.1 to 28.0, 25.2 to 28.0, 25.3 to 28.0, 25.4 to 28.0, 25.5 to 28.0, 25.6 to 28.0, 25.7 to 28.0, 25.8 to 28.0, 25.9 to 28.0, 26.0 to 28.0 , 26.1-28.0, 26.2-28.0, 26.3-28.0, 26.4-28.0, 26.5-28.0, 26.6-28.0, 26.7-28.0, 26.8-28.0, 26.9-28.0, 27.0-28.0, 27.1-28.0, 27.2-28.0, 27.3-28.0, 27.4-28.0, 27.5-28.0, 27.6-28.0, 27.7-28.0, 27.8-28.0, or 27.9-28.0 mM NaHCO3. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing at least 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, or 28.0 mM NaHCO3. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing up to 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, or 28.0 mM NaHCO3.In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, or 28.0 mM NaHCO3.

[0365] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 1-100 mM KHCO3.

[0366] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 1-99, 1-95, 1-90, 1-85, 1-80, 1-75, 1-70, 1-65, 1-60, 1-55, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 mM KHCO3. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 2-100, 3-100, 4-100, 5-100, 6-100, 7-100, 8-100, 9-100, 10-100, 15-100, 20-100, 25-100, 30-100, 35-100, 40-100, 45-100, 50-100, 55-100, 60-100, 65-100, 70-100, 75-100, 80-100, 85-100, 90-100, or 95-100 mM KHCO3. In some embodiments, the ASOs described herein are selected from the group consisting of: 24.0-28.0, 24.0-27.9, 24.0-27.8, 24.0-27.7, 24.0-27.6, 24.0-27.5, 24.0-27.4, 24.0-27.3, 24.0-27.2, 24.0-27.1, 24.0-27.0, 24.0-26.9, 24.0-26.8, 24.0-26.7, 24.0-26.6, 24.0-26.5, 24.0-26.4, 24.0-26.3, 24.0-26.2, 24.0-26.1, 24.0-26.2, 24.0-26.3, 24.0-26.4, 24.0-26.5, 24.0-26.6, 24.0-26.7, 24.0-26.8, 24.0-26.9, 24.0-26.9, 24.0-26.1, 24.0-26.2, 24.0-26.3, 24.0-26.4, 24.0-26.5, 24.0-26.6, 24.0-26.7, 24.0-26.8, 24.0-26.9, 24.0-26.1, 24.0-26.2, 24.0-26.3, 24.0-26.4, 24.0-26.5, 24.0-26.6, 24.0-26. Solubilized or diluted in a buffer containing 0-26.0, 24.0-25.9, 4.0-25.8, 24.0-25.7, 24.0-25.6, 24.0-25.5, 24.0-25.4, 24.0-25.3, 24.0-25.2, 24.0-25.1, 24.0-25.0, 24.0-24.9, 24.0-24.8, 24.0-24.7, 24.0-24.6, 24.0-24.5, 24.0-24.4, 24.0-24.3, 24.0-24.2, or 24.0-24.1 mM KHCO3.In some embodiments, the ASOs described herein are 24.1 to 28.0, 24.2 to 28.0, 24.3 to 28.0, 24.4 to 28.0, 24.5 to 28.0, 24.6 to 28.0, 24.7 to 28.0, 24.8 to 28.0, 24.9 to 28.0, 25.0 to 28.0, 25.1 to 28.0, 25.2 to 28.0, 25.3 to 28.0, 25.4 to 28.0, 25.5 to 28.0, 25.6 to 28.0, 25.7 to 28.0, 25.8 to 28.0, 25.9 to 28.0, 26.0 to 28.0 , 26.1-28.0, 26.2-28.0, 26.3-28.0, 26.4-28.0, 26.5-28.0, 26.6-28.0, 26.7-28.0, 26.8-28.0, 26.9-28.0, 27.0-28.0, 27.1-28.0, 27.2-28.0, 27.3-28.0, 27.4-28.0, 27.5-28.0, 27.6-28.0, 27.7-28.0, 27.8-28.0, or 27.9-28.0 mM KHCO3. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing at least 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, or 28.0 mM KHCO3. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing up to 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, or 28.0 mM KHCO3.In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, or 28.0 mM KHCO3.

[0367] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 0-50 mM KH2PO4.

[0368] In some embodiments, the ASOs described herein may be 0-100, 0.01-100, 0.02-100, 0.03-100, 0.04-100, 0.05-100, 0.06-100, 0.07-100, 0.08-100, 0.09-100, 0.1-100, 0.2-100, 0.3-100, 0.4-100, 0.5-100, 0.6-100, 0.7-100, 0.8-100, 0.9-100, 1-100, 2-100, 3-100, 4-100, 5-100, 6-100, 7-100, 8-100, 9-100, 10-100, 11-100, 12-100, 13-100, 14-100, 15-100, 16-100, 17-100, 18-100, 19-100, 21-100, 22-100, 23-100, 24-100, 25-100, 26-100, 27-100, 28-100, 29-100, 31-100, 32-100, 33-100, 34-100, 35-100, 36-100, 37-100, 38-100, 39-100, 41-100, 42-100, 43-100, 44-100, 4 The sample is solubilized or diluted in a buffer containing 00, 4-100, 5-100, 6-100, 7-100, 8-100, 9-100, 10-100, 15-100, 20-100, 25-100, 30-100, 35-100, 40-100, 45-100, 50-100, 55-100, 60-100, 65-100, 70-100, 75-100, 80-100, 85-100, 90-100, or 95-100 mM KH2PO4. In some embodiments, the ASOs described herein may be selected from the group consisting of: 0 to 95, 0 to 90, 0 to 85, 0 to 80, 0 to 75, 0 to 70, 0 to 65, 0 to 60, 0 to 55, 0 to 50, 0 to 45, 0 to 40, 0 to 35, 0 to 30, 0 to 25, 0 to 20, 0 to 15, 0 to 10, 0 to 9, 0 to 8, 0 to 7, 0 to 6, 0 to 5, 0 to 4, 0 to 3, 0 to 2, Solubilized or diluted in a buffer containing 0-1, 0-0.9, 0-0.8, 0-0.7, 0-0.6, 0-0.5, 0-0.4, 0-0.3, 0-0.2, 0-0.1, 0-0.09, 0-0.08, 0-0.07, 0-0.06, 0-0.05, 0-0.04, 0-0.03, or 0-0.02 mM KH2PO4.In some embodiments, the ASOs described herein may be 0.01-95, 0.01-90, 0.01-85, 0.01-80, 0.01-75, 0.01-70, 0.01-65, 0.01-60, 0.01-55, 0.01-50, 0.01-45, 0.01-40, 0.01-35, 0.01-30, 0.01-25, 0.01-20, 0.01-15, 0.01-10, 0.01-9, 0.01-8, 0.01-7, 0.01-6, 0.01-5, 0.01-4, 0.01-5, 0.01-6, 0.01-7, 0.01-8, 0.01-9, 0.01-10, 0.01-15, 0.01-10 ... The sample is solubilized or diluted in a buffer containing 0.01-3, 0.01-2, 0.01-1, 0.01-0.9, 0.01-0.8, 0.01-0.7, 0.01-0.6, 0.01-0.5, 0.01-0.4, 0.01-0.3, 0.01-0.2, 0.01-0.1, 0.01-0.09, 0.01-0.08, 0.01-0.07, 0.01-0.06, 0.01-0.05, 0.01-0.04, 0.01-0.03, or 0.01-0.02 mM KH2PO4. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 0-3.0, 0-2.9, 0-2.8, 0-2.7, 0-2.6, 0-2.5, 0-2.4, 0-2.3, 0-2.2, 0-2.1, 0-2.0, 0-1.9, 0-1.8, 0-1.7, 0-1.6, 0-1.5, 0-1.4, 0-1.3, 0-1.2, 0-1.1, 0-1.0, 0-0.9, 0-0.8, 0-0.7, 0-0.6, 0-0.5, 0-0.4, 0-0.3, or 0-0.2 mM KH2PO4. In some embodiments, the ASOs described herein may be 0.1 to 3.0, 0.1 to 2.9, 0.1 to 2.8, 0.1 to 2.7, 0.1 to 2.6, 0.1 to 2.5, 0.1 to 2.4, 0.1 to 2.3, 0.1 to 2.2, 0.1 to 2.1, 0.1 to 2.0, 0.1 to 1.9, 0.1 to 1.8, 0.1 to 1.7, 0.1 to 1.6, Solubilized or diluted in a buffer containing 0.1-1.5, 0.1-1.4, 0.1-1.3, 0.1-1.2, 0.1-1.1, 0.1-1.0, 0.1-0.9, 0.1-0.8, 0.1-0.7, 0.1-0.6, 0.1-0.5, 0.1-0.4, 0.1-0.3, or 0.1-0.2 mM KH2PO4.In some embodiments, the ASOs described herein may be 0-3.0, 0.1-3.0, 0.2-3.0, 0.3-3.0, 0.4-3.0, 0.5-3.0, 0.6-3.0, 0.7-3.0, 0.8-3.0, 0.9-3.0, 1.0-3.0, 1.2-3.0, 1.3-3.0, 1.4-3.0, 1.5-3.0, 1.6-3.0, 1.7-3.0, 1.8-3.0, 1.9-3.0, 2.0-3.0, 2.10-3.0, 2.11-3.0, 2.12-3.0, 2.13-3.0, 2.14-3.0, 2.15-3.0, 2.16-3.0, 2.17-3.0, 2.18-3.0, 2.19-3.0, 2.20-3.0, 2.21-3.0, 2.22-3.0, 2.23-3.0, 2.24-3.0, 2.25-3.0, 2.26-3.0, 2.27-3.0, 2.28-3.0, 2.29-3.0, 2.30-3.0, 2.31-3.0, 2.32-3.0, 2.33-3.0, 2.34-3.0, 2.35-3.0, 2.36-3.0, 2.37-3.0, 2.38-3.0, 2.39-3.0, 2.40-3.0, 2.41-3.0, Solubilized or diluted in buffer containing 0.6-3.0, 1.7-3.0, 1.8-3.0, 1.9-3.0, 2.0-3.0, 2.1-3.0, 2.2-3.0, 2.3-3.0, 2.4-3.0, 2.5-3.0, 2.6-3.0, 2.7-3.0, 2.8-3.0, or 2.9-3.0 mM KH2PO4. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing at least 0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 mM KH2PO4. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing up to 0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 mM KH2PO4. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 mM KH2PO4.

[0369] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 0-50 mM NaH2PO4.

[0370] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 0-50, 0-45, 0-40, 0-35, 0-30, 0-25, 0-20, 0-19, 0-18, 0-17, 0-16, 0-15, 0-14, 0-13, 0-12, 0-11, 0-10, 0-9, 0-8, 0-7, 0-6, 0-5, 0-4, 0-3, 0-2, 0-1, 0-0.9, 0-0.8, 0-0.7, 0-0.6, 0-0.5, 0-0.4, 0-0.3, or 0-0.2 mM NaH2PO4. In some embodiments, the ASOs described herein may be 0.1 to 50, 0.1 to 45, 0.1 to 40, 0.1 to 35, 0.1 to 30, 0.1 to 25, 0.1 to 20, 0.1 to 19, 0.1 to 18, 0.1 to 17, 0.1 to 16, 0.1 to 15, 0.1 to 14, 0.1 to 13, 0.1 to 12, 0.1 to 11, 0.1 to 10, 0.1 to 9, 0.1-8, 0.1-7, 0.1-6, 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1, 0.1-0.9, 0.1-0.8, 0.1-0.7, 0.1-0.6, 0.1-0.5, 0.1-0.4, 0.1-0.3, or 0.1-0.2 mM NaH2PO4. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 0-50, 0.1-50, 0.2-50, 0.3-50, 0.4-50, 0.5-50, 0.6-50, 0.7-50, 0.8-50, 0.9-50, 1-50, 2-50, 3-50, 4-50, 5-50, 6-50, 7-50, 8-50, 9-50, 1-50, 11-50, 12-50, 13-50, 14-50, 15-50, 16-50, 17-50, 18-50, 19-50, 20-50, 25-50, 30-50, 35-50, 40-50, or 45-50 mM NaH2PO4.In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 0-20, 0.1-20, 0.2-20, 0.3-20, 0.4-20, 0.5-20, 0.6-20, 0.7-20, 0.8-20, 0.9-20, 1-20, 2-20, 3-20, 4-20, 5-20, 6-20, 7-20, 8-20, 9-20, 10-20, 11-20, 12-20, 13-20, 14-20, 15-20, 16-20, 17-20, 18-20, or 19-20 mM NaH2PO4. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing at least 0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mM NaH2PO4. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing at most 0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mM NaH2PO4. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mM NaH2PO4.

[0371] In some embodiments, the ASO is solubilized or diluted in a buffer solution further comprising a carbohydrate. In some embodiments, the carbohydrate comprises D-glucose. In some embodiments, the ASO is solubilized or diluted in a buffer solution further comprising 1 to 100 mM D-glucose.

[0372] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 1-100 mM D-glucose.

[0373] In some embodiments, the ASO described herein is solubilized or diluted in a buffer containing 1-100, 1-95, 1-90, 1-85, 1-80, 1-75, 1-70, 1-65, 1-60, 1-55, 1-50, 1-45, 1-40, 1-35, 1-30, 1-29, 1-28, 1-27, 1-26, 1-25, 1-24, 1-23, 1-22, 1-21, 1-20, 1-19, 1-18, 1-17, 1-16, 1-15, 1-14, 1-13, 1-12, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 mM D-glucose. In some embodiments, the ASOs described herein may be 2-100, 3-100, 4-100, 5-100, 6-100, 7-100, 8-100, 9-100, 10-100, 11-100, 12-100, 13-100, 14-100, 15-100, 16-100, 17-100, 18-100, 19-100, 20-100, 21-100, 22-100, 23-100, 24 Solubilized or diluted in a buffer containing ∼100, 25–100, 26–100, 29–100, 28–100, 29–100, 30–100, 35–100, 40–100, 45–100, 50–100, 55–100, 60–100, 65–100, 70–100, 75–100, 80–100, 85–100, 90–100, or 95–100 mM D-glucose. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 2-30, 3-30, 4-30, 5-30, 6-30, 7-30, 8-30, 9-30, 10-30, 11-30, 12-30, 13-30, 14-30, 15-30, 16-30, 17-30, 18-30, 19-30, 20-30, 21-30, 22-30, 23-30, 24-30, 25-30, 26-30, 27-30, 28-30, or 29-30 mM D-glucose. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing 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, or 30 mM D-glucose.In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing at most 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, or 30 mM D-glucose. In some embodiments, the ASOs described herein are solubilized or diluted in a buffer containing at most 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, or 30 mM D-glucose.

[0374] In some embodiments, the ASO is solubilized or diluted in a buffer containing 25-250 mM NaCl, 0.1-20 mM KCl, 0.1-50 mM NaHPO, 0.1-50 mM NaHPO, 0.1-50 mM CaCl, and 0.1-50 mM MgCl.

[0375] In some embodiments, the ASO is solubilized or diluted in a buffer containing 150 mM NaCl, 3.0 mM KCl, 0.7 mM NaHPO, 0.3 mM NaHPO, 0.79 mM MgCl, and 1.4 mM CaCl.

[0376] In some embodiments, the ASO is solubilized or diluted in a buffer solution further comprising an antioxidant. In some embodiments, the antioxidant is t-butylhydroxyquinoline (TBHQ), butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E, or any combination thereof. In some embodiments, the ASO is solubilized or diluted in a buffer solution further comprising an antioxidant, wherein the antioxidant is ascorbic acid (vitamin C), glutathione, lipoic acid, uric acid, carotene, α-tocopherol (vitamin E), ubiquinol (coenzyme Q), or any combination thereof.

[0377] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer 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.

[0378] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer 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.

[0379] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer 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.

[0380] In some embodiments, the ASOs described herein are solubilized or diluted in a buffer 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.

[0381] In some embodiments, the pharmaceutical formulation does not contain a preservative. In some embodiments, the pharmaceutical formulation contains a preservative.

[0382] In some embodiments, the ASO described herein is solubilized or diluted in a diluent to a concentration of 5 to 250 mg / mL.

[0383] In some embodiments, the ASO described herein is present in a diluent at a concentration of 5 to 250, 5 to 247.5, 5 to 245, 5 to 242.5, 5 to 240, 5 to 237.5, 5 to 235, 5 to 232.5, 5 to 230, 5 to 227.5, 5 to 225, 5 to 225.5, 5 to 220, 5 to 217.5, 5 to 215, 5 to 212.5, 5 to 210, 5 to 205.5, 5 to 205, 5 to 202.5, 5 to 20 0, 5~197.5, 5~195, 5~192.5, 5~190, 5~187.5, 5~185, 5~182.5, 5~180, 5~177.5, 5~175, 5~172.5, 5~170, 5~167.5, 5~165, 5~162.5, 5~160, 5~157.5, 5~155, 5~152.5, 5~150, 5~147.5, 5~145, 5~142.5, 5~140, 5~137 .5, 5~135, 5~132.5, 5~130, 5~127.5, 5~125, 5~122.5, 5~120, 5~117.5, 5~115, 5~112.5, 5~110, 5~107.5, 5~105, 5~102.5, 5~100, 5~97.5, 5~95, 5~92.5, 5~90, 5~87.5, 5~85, 5~82.5, 5~80, 5~77.5, 5~75, 5~72.5, Solubilized or diluted to a concentration of 5-70, 5-67.5, 5-65, 5-62.5, 5-60, 5-57.5, 5-55, 5-52.5, 5-50, 5-47.5, 5-45, 5-42.5, 5-40, 5-37.5, 5-35, 5-32.5, 5-30, 5-27.5, 5-25, 5-22.5, 5-20, 5-17.5, 5-15, 5-12.5, or 5-10 mg / mL.In some embodiments, the ASO described herein is present in a diluent at a concentration of 10-250, 15-250, 20-250, 25-250, 30-250, 35-250, 40-250, 45-250, 50-250, 55-250, 60-250, 65-250, 70-250, 75-250, 80-250, 85-250, 90-250, 95-250, 100-250, 105-250, 110-250, 115-250, 120-250, 125-250, 130-250, Solubilized or diluted to a concentration of 135-250, 140-250, 145-250, 150-250, 155-250, 160-250, 165-250, 170-250, 175-250, 180-250, 185-250, 190-250, or 195-250, 200-250, 205-250, 210-250, 215-250, 220-250, 225-250, 230-250, 235-250, 240-250, or 245-250 mg / mL.In some embodiments, the ASO described herein is 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68 , 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133 , 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250 mg / mL.In some embodiments, the ASO described herein is present in a diluent at a concentration of at most 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250 mg / mL.In some embodiments, the ASO described herein is 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122 0, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250 mg / mL.

[0384] In some embodiments, the ASO described herein is present in the pharmaceutical composition at a concentration of 0.1 mg / mL to 250 mg / mL. In some embodiments, the ASO described herein is present in the pharmaceutical 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, 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 described herein is present in the pharmaceutical composition at a concentration 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 is present in the pharmaceutical 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.In some embodiments, the ASO described herein is solubilized or diluted in a diluent to 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.

[0385] In some embodiments, the ASO described in this specification is 0.1mg / mL~250mg / mL、0.2mg / mL~250mg / mL、0.3mg / mL~250mg / mL、0.4mg / mL~250mg / mL、0.5mg / mL~250mg / mL、0.6mg / mL~250mg / mL、0.7mg / mL~250mg / mL、0.8mg / mL~250mg / mL、0.9mg / mL~250mg / mL、1.0mg / mL~250mg / mL 、1.1mg / mL~250mg / mL、1.2mg / mL~250mg / mL、1.3mg / mL~250mg / mL、1.4mg / mL~250mg / mL、1.5mg / mL~250mg / mL、1.6mg / mL~25 0mg / mL、1.7mg / mL~250mg / mL、1.8mg / mL~250mg / mL、1.9mg / mL~250mg / mL、2.0mg / mL~250mg / mL、2.1mg / mL~250mg / mL、2.2mg / mL mL~250mg / mL、2.3mg / mL~250mg / mL、2.4mg / mL~250mg / mL、2.5mg / mL~250mg / mL、2.6mg / mL~250mg / mL、2.7mg / mL~250mg / mL、 2.8mg / mL~250mg / mL、2.9mg / mL~250mg / mL、3.0mg / mL~250mg / mL、3.1mg / mL~250mg / mL、3.2mg / mL~250mg / mL、3.3mg / mL~250mg / mL g / mL、3.4mg / mL~250mg / mL、3.5mg / mL~250mg / mL、3.6mg / mL~250mg / mL、3.7mg / mL~250mg / mL、3.8mg / mL~250mg / mL、3.9mg / mL L~250mg / mL、4.0mg / mL~250mg / mL、5.0mg / mL~250mg / mL、6.0mg / mL~250mg / mL、7.0mg / mL~250mg / mL、8.0mg / mL~250mg / mL、9.0mg / mL~250mg / mL、10mg / mL~250mg / mL、15mg / mL~250mg / mL、20mg / mL~250mg / mL、25mg / mL~250mg / mL、30mg / mL~250mg / mL、35mg / mL~25mg / mL 50mg / mL、40mg / mL~250mg / mL、45mg / mL~250mg / mL、50mg / mL~250mg / mL、55mg / mL~250mg / mL、60mg / mL~250mg / mL、65mg / mL~250mg / mL、 70mg / mL~250mg / mL、75mg / mL~250mg / mL、80mg / mL~250mg / mL、85mg / mL~250mg / mL、90mg / mL~250mg / mL、95mg / mL~250mg / mL、100mg / mL ~250mg / mL、105mg / mL~250mg / mL、110mg / mL~250mg / mL、115mg / mL~250mg / mL、120mg / mL~250mg / mL、125mg / mL~250mg / mL、130mg / mL~2 50mg / mL、135mg / mL~250mg / mL、140mg / mL~250mg / mL、145mg / mL~250mg / mL、150mg / mL~250mg / mL、155mg / mL~250mg / mL、160mg / mL~250mg / mL mg / mL、165mg / mL~250mg / mL、170mg / mL~250mg / mL、175mg / mL~250mg / mL、180mg / mL~250mg / mL、185mg / mL~250mg / mL、190mg / mL~250mg / mL、195mg / mL~250mg / mL、200mg / mL~250mg / mL、205mg / mL~250mg / mL、210mg / mL~250mg / mL、215mg / mL~250mg / mL、220mg / mL~250mg / mL L、225mg / mL~250mg / mL、230mg / mL~250mg / mL、235mg / mL~250mg / mL、240mg / mL~250mg / mL、or 245mg / mL~250mg / mL are present in the concentration of the medicine.

[0386] In some embodiments, the ASO described herein is 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, 0.1 mg / mL to 170 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 135 mg / 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.It is present in the pharmaceutical composition at a concentration of 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 mg / mL, 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. <00​​In some embodiments, the ASO described herein is present in a diluent at a concentration of at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.10, 5.11, 5.12, 5.13, 5.14, 5.15, 5.16, 5.17, 5.18, 5.19, 5.20, 5.21, 5.22, 5.23, 5.24, 5.25, 5.26, 5.27, 5.28, 5.29, 5.30, 5.31, 5.32, 5.33, 5.34, 5.35, 5.36, 5.37, 5.38, 5.39, 5.40, 5.41, 5.42, 5.43, 5.44, 5.45, 5.46, 5.47, 5.48, 5.499, 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193 , 194, 195, 196, 197, 198, 199, 200, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250 mg / mL. In some embodiments, the ASO described herein is present in a diluent at a concentration of at most 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.10, 3.11, 3.12, 3.13, 3.14, 3.15, 3.16, 3.17, 3.18, 3.19, 3.20, 3.21, 3.22, 3.23, 3.24, 3.25, 3.26, 3.27, 3.28, 3.29, 3.30, 3.31, 3.32, 3.33, 3.34, 3.35, 3.36, 3.37, 3.38, 3.39, 3.40, 3.41, 3.42, 3.43, 3.44, 3.45, 3.46, 3.47, 3.48, 3.49, 3.50, 3.51, 3.52, 3.53, 3.54, 3.55, 3.56, 3.57, 3.58, 3.59, 3.60, 3.61, 3.62, 3.63, 3.64, 3.65, 3.3、2.4、2.5、2.6、2.7、2.8、2.9、3.0、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4.0、4.1、4.2、4.3、4.4、4.5、4.6、4.7、4.8、4.9, 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 1...

Claims

1. A pharmaceutical formulation, comprising: (i) antisense oligomers (ASOs), and (ii) a pharmaceutically acceptable diluent; the liquid composition is not buffered by a buffering agent; and (a) the liquid composition comprises calcium ions, magnesium ions, and / or potassium ions; (b) the pharmaceutical preparation is formulated for or suitable for administration to the intrathecal space, cerebrospinal fluid, or brain of a human subject; and / or (c) A pharmaceutical formulation wherein each nucleobase of said ASO comprises a modified sugar moiety.

2. A pharmaceutical formulation, comprising: (i) antisense oligomers (ASOs), and (ii) a pharmaceutically acceptable diluent; The liquid composition comprises Na ２ HPO ４ and / or NaH ２ P.O. ４ Lacking, and (a) the liquid composition comprises calcium ions, magnesium ions, and / or potassium ions; (b) the pharmaceutical preparation is formulated for or suitable for administration to the intrathecal space, cerebrospinal fluid, or brain of a human subject; and / or (c) A pharmaceutical formulation wherein each nucleobase of said ASO comprises a modified sugar moiety.

3. 3. The pharmaceutical formulation of claim 1 or 2, wherein the liquid composition lacks 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, comprising: (i) antisense oligomers (ASOs), and (ii) (a) NaCl, (b) KCl, (c) MgCl ２ or MgCl ２ 6H ２ O, and (d) CaCl ２ or CaCl ２ 2H ２ 1. A pharmaceutical formulation, which is a liquid composition comprising a pharmaceutically acceptable diluent consisting of: O.

6. The liquid composition contains 0.1 to 50 mM CaCl ２ or CaCl ２ 2H ２ The pharmaceutical formulation according to any one of claims 1 to 5, comprising O.

7. The liquid composition contains 1 to 2 mM CaCl ２ or CaCl ２ 2H ２ The pharmaceutical formulation according to any one of claims 1 to 6, comprising O.

8. The liquid composition contains about 1.4mM CaCl ２ or CaCl ２ 2H ２ The pharmaceutical formulation according to any one of claims 1 to 7, comprising O.

9. The liquid composition contains 0.1 to 50mM MgCl ２ or MgCl ２ 6H ２ The pharmaceutical formulation according to any one of claims 1 to 8, comprising O.

10. The liquid composition contains 0.5-1.5mM MgCl ２ or MgCl ２ 6H ２ The pharmaceutical formulation according to any one of claims 1 to 8, comprising O.

11. The liquid composition contains about 0.79 mM MgCl ２ or MgCl ２ 6H ２ The pharmaceutical formulation according to any one of claims 1 to 8, comprising O.

12. The liquid composition contains 5 to 250 mM NaCl, 0.1 to 20 mM KCl, and 0.1 to 50 mM CaCl. ２ or CaCl ２ 2H ２ O, and 0.1 to 50 mM MgCl ２ or MgCl ２ 6H ２ The pharmaceutical formulation according to any one of claims 1 to 11, comprising O.

13. A pharmaceutical formulation, comprising: (i) antisense oligomers (ASOs), and (ii) a pharmaceutically acceptable diluent; the liquid composition lacks calcium ions and / or magnesium ions, and (a) the liquid composition contains potassium ions; (b) the pharmaceutical preparation is formulated for or suitable for administration to the intrathecal space, cerebrospinal fluid, or brain of a human subject; and / or (c) A pharmaceutical formulation wherein each nucleobase of said ASO comprises a modified sugar moiety.

14. (a) the ASO is stable in the pharmaceutical formulation after storage of the pharmaceutical formulation at −20° C. or at a temperature and relative humidity for a period of time; (b) the pharmaceutical formulation has a shelf life of a certain period when stored at −20° C. or at a certain temperature and relative humidity; (c) the percentage of an impurity in the pharmaceutical formulation with an HPLC relative retention time of 0.92 is 2.5% or less after storing the pharmaceutical formulation at −20° C. or at a certain temperature and relative humidity for a certain period of time; (d) the percentage of an impurity in the pharmaceutical formulation with an HPLC relative retention time of 0.98 is 3.5% or less after storing the pharmaceutical formulation at −20° C. or at a certain temperature and relative humidity for a certain period of time; (e) the percentage of any unspecified impurity in said pharmaceutical formulation by HPLC is 1.8% or less after storage of said pharmaceutical formulation at −20° C. or at a certain temperature and relative humidity for a certain period of time; (f) the percentage of total impurities in the pharmaceutical formulation by HPLC is 10% or less after storage of the pharmaceutical formulation at −20° C. or at a certain temperature and relative humidity for a certain period of time; (g) the pH of the pharmaceutical composition is 6.6 to 7.6 after storing the pharmaceutical formulation at −20° C. or a period of time at a temperature and relative humidity; (h) the osmolality of the pharmaceutical composition is 310-360 mOsm / kg after storing the pharmaceutical formulation at −20° C. or a period of time at a temperature and relative humidity; and / or 14. The pharmaceutical composition of any one of claims 1 to 13, wherein (i) after storage of the pharmaceutical formulation for a period of time at -20°C or at a certain temperature and relative humidity, no observable particle formation is observed, or no particle formation greater than 50 μm in size is observed.

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

16. A pharmaceutical formulation, comprising: (i) antisense oligomers (ASOs), and (ii) a pharmaceutically acceptable diluent; (a) the ASO is stable in the pharmaceutical formulation after storage of the pharmaceutical formulation at −20° C. or at a temperature and relative humidity for a period of time; (b) the pharmaceutical formulation has a shelf life of a certain period when stored at −20° C. or at a certain temperature and relative humidity; (c) the percentage of an impurity in the pharmaceutical formulation with an HPLC relative retention time of 0.92 is 2.5% or less after storing the pharmaceutical formulation at −20° C. or at a certain temperature and relative humidity for a certain period of time; (d) the percentage of an impurity in the pharmaceutical formulation with an HPLC relative retention time of 0.98 is 3.5% or less after storing the pharmaceutical formulation at −20° C. or at a certain temperature and relative humidity for a certain period of time; (e) the percentage of any unspecified impurity in said pharmaceutical formulation by HPLC is 1.8% or less after storage of said pharmaceutical formulation at −20° C. or at a certain temperature and relative humidity for a certain period of time; (f) the percentage of total impurities in the pharmaceutical formulation by HPLC is 10% or less after storage of the pharmaceutical formulation at −20° C. or at a certain temperature and relative humidity for a certain period of time; (g) the pH of the pharmaceutical composition is 6.6 to 7.6 after storing the pharmaceutical formulation at −20° C. or a period of time at a temperature and relative humidity; (h) the osmolality of the pharmaceutical composition is 310-360 mOsm / kg after storing the pharmaceutical formulation at −20° C. or a period of time at a temperature and relative humidity; and / or (i) After storage of said pharmaceutical formulation at −20° C. or at a certain temperature and relative humidity for a certain period of time, no observable particle formation is observed, or no particle formation greater than 50 μm in size is observed.

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

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

19. 19. The pharmaceutical formulation of any one of claims 14 to 18, wherein the period is 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or 1, 2, 3, 4 or 5 years.

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

21. 21. The pharmaceutical formulation of claim 20, wherein the buffer has a pKa at 25°C 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.

22. 21. The pharmaceutical formulation of claim 20, wherein the buffering agent is effective in 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. 21. The pharmaceutical formulation of claim 20, wherein the buffering agent 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. 24. The pharmaceutical preparation of any one of claims 1 to 23, wherein the liquid composition is formulated for administration to the intrathecal space, cerebrospinal fluid, or brain of a human subject.

25. 24. The pharmaceutical preparation of any one of claims 1 to 23, wherein the liquid composition is formulated for administration to the cerebrospinal fluid in the brain of a human subject.

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

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

28. 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 mixing the ASO with the pharmaceutically acceptable diluent produces a liquid composition comprising the ASO; and the liquid composition is not buffered by a buffering agent; and (a) the liquid composition comprises calcium ions, magnesium ions, and / or potassium ions; (b) the pharmaceutical preparation is formulated for or suitable for administration to the intrathecal space, cerebrospinal fluid, or brain of a human subject; and / or (c) a kit wherein each nucleobase of said ASO comprises a modified sugar moiety.

29. 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 mixing the ASO with the pharmaceutically acceptable diluent produces a liquid composition comprising the ASO; The liquid composition comprises Na ２ HPO ４ and / or NaH ２ P.O. ４ Lacking, and (a) the liquid composition comprises calcium ions, magnesium ions, and / or potassium ions; (b) the pharmaceutical preparation is formulated for or suitable for administration to the intrathecal space, cerebrospinal fluid, or brain of a human subject; and / or (c) a kit wherein each nucleobase of said ASO comprises a modified sugar moiety.

30. 30. The kit of claim 28 or 29, wherein the liquid composition lacks 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 kit comprising: (i) a concentrate comprising an antisense oligomer (ASO), and (ii) (a) NaCl, (b) KCl, (c) MgCl ２ or MgCl ２ 6H ２ O, and (d) CaCl ２ or CaCl ２ 2H ２ O, and a pharmaceutically acceptable diluent consisting of the concentrate is miscible with the pharmaceutically acceptable diluent; and A kit wherein mixing the ASO with the pharmaceutically acceptable diluent produces a liquid composition comprising the ASO.

33. The liquid composition contains 0.1 to 50 mM CaCl ２ or CaCl ２ 2H ２ The kit of any one of claims 28 to 32, comprising O.

34. The liquid composition contains 1 to 2 mM CaCl ２ or CaCl ２ 2H ２ The kit of any one of claims 28 to 32, comprising O.

35. The liquid composition contains about 1.4mM CaCl ２ or CaCl ２ 2H ２ The kit of any one of claims 28 to 34, comprising O.

36. The liquid composition contains 0.1 to 50mM MgCl ２ or MgCl ２ 6H ２ The kit of any one of claims 28 to 35, comprising O.

37. The liquid composition contains 0.5-1.5mM MgCl ２ or MgCl ２ 6H ２ The kit of any one of claims 28 to 35, comprising O.

38. The liquid composition contains about 0.79 mM MgCl ２ or MgCl ２ 6H ２ The kit of any one of claims 28 to 35, comprising O.

39. The liquid composition contains 5 to 250 mM NaCl, 0.1 to 20 mM KCl, and 0.1 to 50 mM CaCl. ２ or CaCl ２ 2H ２ O, and 0.1 to 50 mM MgCl ２ or MgCl ２ 6H ２ The kit of any one of claims 28 to 38, comprising O.

40. 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; mixing the ASO with the pharmaceutically acceptable diluent produces a liquid composition comprising the ASO; the liquid composition lacks calcium ions and / or magnesium ions, and (a) the liquid composition contains potassium ions; (b) the pharmaceutical preparation is formulated for or suitable for administration to the intrathecal space, cerebrospinal fluid, or brain of a human subject; and / or (c) a kit wherein each nucleobase of said ASO comprises a modified sugar moiety.

41. (i) a concentrate comprising an antisense oligomer (ASO), and (ii) a pharmaceutically acceptable diluent, wherein the concentrate is miscible with the pharmaceutically acceptable diluent; mixing the ASO with the pharmaceutically acceptable diluent produces a liquid composition comprising the ASO; and (a) the ASO is stable in the pharmaceutical formulation after storage of the pharmaceutical formulation at −20° C. or at a temperature and relative humidity for a period of time; (b) the pharmaceutical formulation has a shelf life of a certain period when stored at −20° C. or at a certain temperature and relative humidity; (c) the percentage of an impurity in the pharmaceutical formulation with an HPLC relative retention time of 0.92 is 2.5% or less after storing the pharmaceutical formulation at −20° C. or at a certain temperature and relative humidity for a certain period of time; (d) the percentage of an impurity in the pharmaceutical formulation with an HPLC relative retention time of 0.98 is 3.5% or less after storing the pharmaceutical formulation at −20° C. or at a certain temperature and relative humidity for a certain period of time; (e) the percentage of any unspecified impurity in said pharmaceutical formulation by HPLC is 1.8% or less after storage of said pharmaceutical formulation at −20° C. or at a certain temperature and relative humidity for a certain period of time; (f) the percentage of total impurities in the pharmaceutical formulation by HPLC is 10% or less after storage of the pharmaceutical formulation at −20° C. or at a certain temperature and relative humidity for a certain period of time; (g) the pH of the pharmaceutical composition is 6.6 to 7.6 after storing the pharmaceutical formulation at −20° C. or a period of time at a temperature and relative humidity; (h) the osmolality of the pharmaceutical composition is 310-360 mOsm / kg after storing the pharmaceutical formulation at −20° C. or a period of time at a temperature and relative humidity; and / or 41. The kit of any one of claims 28 to 40, wherein (i) 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 is observed.

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

43. 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; mixing the ASO with the pharmaceutically acceptable diluent produces a liquid composition comprising the ASO; and (a) the ASO is stable in the pharmaceutical formulation after storage of the pharmaceutical formulation at −20° C. or at a temperature and relative humidity for a period of time; (b) the pharmaceutical formulation has a shelf life of a certain period when stored at −20° C. or at a certain temperature and relative humidity; (c) the percentage of an impurity in the pharmaceutical formulation with an HPLC relative retention time of 0.92 is 2.5% or less after storing the pharmaceutical formulation at −20° C. or at a certain temperature and relative humidity for a certain period of time; (d) the percentage of an impurity in the pharmaceutical formulation with an HPLC relative retention time of 0.98 is 3.5% or less after storing the pharmaceutical formulation at −20° C. or at a certain temperature and relative humidity for a certain period of time; (e) the percentage of any unspecified impurity in said pharmaceutical formulation by HPLC is 1.8% or less after storage of said pharmaceutical formulation at −20° C. or at a certain temperature and relative humidity for a certain period of time; (f) the percentage of total impurities in the pharmaceutical formulation by HPLC is 10% or less after storage of the pharmaceutical formulation at −20° C. or at a certain temperature and relative humidity for a certain period of time; (g) the pH of the pharmaceutical composition is 6.6 to 7.6 after storing the pharmaceutical formulation at −20° C. or a period of time at a temperature and relative humidity; (h) the osmolality of the pharmaceutical composition is 310-360 mOsm / kg after storing the pharmaceutical formulation at −20° C. or a period of time at a temperature and relative humidity; and / or (i) A kit, wherein no observable particle formation is observed after storing said pharmaceutical formulation at −20° C. or at a certain temperature and relative humidity for a certain period of time.

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

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

46. 46. ​​The kit of any one of claims 41 to 45, wherein the period of time is 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or 1, 2, 3, 4 or 5 years.

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

48. 48. The kit of claim 47, wherein the buffer has a pKa at 25°C of about 4.75, about 5.64, about 1.70, about 6.04, and about 9.09, about 3.1, about 4.7, about 6.4, or about 6.

50.

49. 48. The kit of claim 47, wherein the buffering agent is effective in 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. 48. The kit of claim 47, wherein the buffering agent 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. 51. The kit of any one of claims 28 to 50, wherein the liquid composition is formulated for administration to the intrathecal space, cerebrospinal fluid, or brain of a human subject.

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

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

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

55. (iii) the kit of any one of claims 28 to 54, further comprising instructions for diluting or solubilizing the ASO in the pharmaceutically acceptable diluent.

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

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

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

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

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

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

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

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

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

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

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

67. The liquid composition contains 0.1 to 50 mM Na ２ HPO ４ 67. The pharmaceutical formulation of any one of claims 13 to 27 or 56 to 66, or the kit of any one of claims 40 to 66, comprising:

68. The liquid composition contains 0.1 to 50 mM NaH ２ P.O. ４ 68. The pharmaceutical formulation of any one of claims 13 to 27 or 56 to 67, or the kit of any one of claims 40 to 67, comprising:

69. The liquid composition contains 5 to 250 mM NaCl, 0.1 to 20 mM KCl, 0.1 to 50 mM Na ２ HPO ４ , and 0.1 to 50 mM NaH ２ P.O. ４ 68. The pharmaceutical formulation of any one of claims 13 to 27 or 56 to 68, or the kit of any one of claims 40 to 68, comprising:

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

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

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

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

74. 74. The pharmaceutical formulation of any one of claims 1 to 27 or 56 to 73, or the kit of any one of claims 28 to 69 or 71 to 73, wherein the liquid composition has an osmolality of about 130 mM.

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

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

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

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

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

80. The pharmaceutical formulation of any one of claims 1 to 27 or 56 to 79, or the kit of any one of claims 28 to 69 or 71 to 79, wherein the liquid composition is preservative-free.

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

82. The liquid composition (i) administration as a bolus injection; (ii) administration by infusion with a delivery pump; (iii) administration by intracerebroventricular injection, and / or (iv) A pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 81, or a kit according to any one of claims 28 to 69 or 71 to 81, formulated for or suitable for administration by intrathecal injection.

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

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

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

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

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

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

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

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

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

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

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

94. The pharmaceutical formulation of any one of claims 1 to 27 or 56 to 93, or the kit of any one of claims 28 to 69 or 71 to 93, wherein each internucleoside linkage of the ASO is a phosphorothioate linkage.

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

96. 96. The pharmaceutical formulation of any one of claims 1 to 27 or 56 to 95, or the kit of 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. 97. The pharmaceutical formulation of any one of claims 1 to 27 or 56 to 96, or the kit of 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. 97. The pharmaceutical formulation of any one of claims 1 to 27 or 56 to 96, or the kit of any one of claims 28 to 69 or 71 to 96, wherein the liquid composition comprises 0.1, 0.5, 1, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50 mL of the pharmaceutically acceptable diluent.

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

100. The liquid composition is 0.1, 0.5, 1, 2.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22.5, 25, 27.5, 30, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, 52.5, 55, 57.5, 60, 62 .5, 65, 67.5, 70, 72.5, 75, 77.5, 80, 82.5, 85, 87.5, 90, 92.5, 95, 97.5, 100, 102.5, 105, 107.5, 110, 112.5, 115, 117.5, 120, 122.5, 125, 127.5, 130, 132.5, 135 , 137.5, 140, 142.5, 145, 147.5, 150, 152.5, 155, 157.5, 160, 162.5, 165, 167.5, 170, 172.5, 175, 177.5, 180, 182.5, 185, 187.5, 190, 192.5, 195, 197.5, 200, 2 100. The pharmaceutical formulation or kit of claim 99, comprising 02.5, 205, 207.5, 210, 212.5, 215, 217.5, 220, 222.5, 225, 227.5, 230, 232.5, 235, 237.5, 240, 242.5, 245, 247.5, or 250 mg of the ASO.

101. 100. The pharmaceutical formulation of any one of claims 1 to 27 or 56 to 100, or the kit of 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 to 500 mg / mL.

102. 102. The pharmaceutical formulation of any one of claims 1 to 27 or 56 to 101, or the kit of 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. 102. The pharmaceutical formulation of any one of claims 1 to 27 or 56 to 101, or the kit of 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. 100. The pharmaceutical formulation of any one of claims 1-27 or 56-100, or the kit of any one of claims 28-69 or 71-100, 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. 100. The pharmaceutical formulation of any one of claims 1 to 27 or 56 to 100, or the kit of 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. 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、52.5mg / mL、55mg / mL、57.5mg / mL、60mg / mL、62.5mg / mL、65mg / mL、67.5mg / mL、70mg / mL、72.5mg / mL、80mg / mL、 85mg / mL、87.5mg / mL、90mg / mL、92.5mg / mL、95mg / mL、97.5mg / mL、100mg / mL、102.5mg / mL、107.5mg / mL、110mg / mL、112.5mg / mL、115mg / mL 7.5mg / mL、120mg / mL、122.5mg / mL、125mg / mL、127.5mg / mL、130mg / mL、132.5mg / mL、135mg / mL、137.5mg / mL、140mg / mL、147.5mg / mL g / mL、150mg / mL、152.5mg / mL、155mg / mL、157.5mg / mL、160mg / mL、162.5mg / mL、167.5mg / mL、170mg / mL、172.5mg / mL、177.5mg / mL、 180mg / mL、182.5mg / mL、185mg / mL、187.5mg / mL、190mg / mL、192.5mg / mL、195mg / mL、197.5mg / mL、200mg / mL g / mL、212.5mg / mL、215mg / mL、217.5mg / mL、220mg / mL、222.5mg / mL、225mg / mL、227.5mg / mL、230mg / mL、237.5mg / mL、240mg / mL、The pharmaceutical formulation of any one of claims 1 to 27 or 56 to 100, or the kit of any one of claims 28 to 69 or 71 to 100, wherein the pharmaceutical formulation is present in the liquid composition at a concentration of 242.5 mg / mL, 245 mg / mL, 247.5 mg / mL, or 250 mg / mL.

107. 106. The pharmaceutical formulation of any one of claims 1 to 27 or 56 to 106, or the kit of any one of claims 28 to 69 or 71 to 106, wherein the ASO comprises a sequence having at least 80% sequence identity to any one of SEQ ID NOs: 21 to 67, 210 to 256, or 304 to 1099.

108. 106. The pharmaceutical formulation of any one of claims 1 to 27 or 56 to 106, or the kit of 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 to any one of SEQ ID NOs: 21 to 67, 210 to 256, or 304 to 1099.

109. 106. The pharmaceutical formulation of any one of claims 1 to 27 or 56 to 106, or the kit of any one of claims 28 to 69 or 71 to 106, wherein the ASO consists of a sequence having at least 83%, 88%, 94%, or 100% sequence identity to any one of SEQ ID NOs: 21 to 67, 210 to 256, or 304 to 1099.

110. The ASO has the following chemical structure: 【Chemistry 1】 or a salt thereof.

111. The ASO has the following chemical structure: 【Chemistry 2】 A pharmaceutical formulation according to any one of claims 1 to 27 or 56 to 106, or a kit according to any one of claims 28 to 69 or 71 to 106, wherein the compound is according to

112. (a) an antisense oligomer (ASO) at a concentration of about 0.1 mg / mL to about 500 mg / mL, said ASO having the following chemical structure: 【Transformation 3】 ASO, which is a compound according to the formula (I) or a salt thereof; (b) calcium chloride dihydrate (CaCl) at a concentration of about 0.1 mM to about 50 mM ２ 2H ２ O), (c) magnesium chloride hexahydrate (MgCl) at a concentration of about 0.1 mM to about 50 mM ２ 6H ２ O), (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.

113. 113. The pharmaceutical composition of claim 112, wherein the pharmaceutical formulation further comprises sodium hydroxide (NaOH) and / or hydrochloric acid (HCl) in an amount to provide the pharmaceutical formulation with a pH of 6.6 to 7.

6.

114. 113. 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) an antisense oligomer (ASO) at a concentration of about 0.1 mg / mL to about 500 mg / mL, said ASO having the following chemical structure: 【Chemistry 4】 ASO, which is a compound according to the formula (I) or a salt thereof; (b) calcium chloride dihydrate (CaCl) at a concentration of about 0.1 mM to about 50 mM ２ 2H ２ O), (c) magnesium chloride hexahydrate (MgCl) at a concentration of about 0.1 mM to about 50 mM ２ 6H ２ O), (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.

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

117. 116. The pharmaceutical composition of any one of claims 112-115, wherein the concentration of the ASO is 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.

118. 116. The pharmaceutical composition of any one of claims 112-115, wherein the ASO has 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.

119. 116. The pharmaceutical composition of any one of claims 112 to 115, wherein 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.

120. The concentration of 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 、50mg / mL、52.5mg / mL、55mg / mL、57.5mg / mL、60mg / mL、62.5mg / mL、65mg / mL、67.5mg / mL、70mg / mL、72.5mg / mL、77.5mg / mL、80mg / mL L、85mg / mL、87.5mg / mL、90mg / mL、92.5mg / mL、95mg / mL、97.5mg / mL、100mg / mL、102.5mg / mL、105mg / mL、107.5mg / mL、110mg / mL、112.5mg / mL、112.5mg / mL 117.5mg / mL、120mg / mL、122.5mg / mL、125mg / mL、127.5mg / mL、130mg / mL、132.5mg / mL、137.5mg / mL、140mg / mL、142.5mg / mL、147.5mg / mL mg / mL、150mg / mL、152.5mg / mL、155mg / mL、157.5mg / mL、160mg / mL、162.5mg / mL、165mg / mL、167.5mg / mL、170mg / mL、172.5mg / mL、177.5mg / mL 、180mg / mL、182.5mg / mL、185mg / mL、187.5mg / mL、190mg / mL、192.5mg / mL、195mg / mL、197.5mg / mL、200mg / mL、202.5mg / mL、207.5mg / mL、210mg / mL g / mL、212.5mg / mL、215mg / mL、217.5mg / mL、220mg / mL、222.5mg / mL、225mg / mL、227.5mg / mL、230mg / mL、237.5mg / mL、240mg / mL、The pharmaceutical composition according to any one of claims 112 to 115, wherein the concentration is 242.5 mg / mL, 245 mg / mL, 247.5 mg / mL, or 250 mg / mL.

121. 121. The pharmaceutical composition of any one of claims 112-120, wherein the calcium chloride dihydrate has a concentration of 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. 121. The pharmaceutical composition of any one of claims 112-120, wherein the concentration of calcium chloride dihydrate is from about 1 mM to about 2 mM.

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

124. 124. The pharmaceutical composition of any one of claims 112-123, wherein the magnesium chloride hexahydrate has a concentration of 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. 124. The pharmaceutical composition of any one of claims 112-123, wherein the concentration of the magnesium chloride hexahydrate is from about 0.6 mM to about 1 mM.

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

127. 127. The pharmaceutical composition of 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. 127. The pharmaceutical composition of any one of claims 112 to 126, wherein the concentration of potassium chloride is from about 2 mM to about 5 mM.

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

130. 130. The pharmaceutical composition of any one of claims 112-129, 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. 130. The pharmaceutical composition of any one of claims 112 to 129, wherein the concentration of sodium chloride is about 125 mM to 145 mM.

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

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

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

135. (i) the concentration of calcium chloride dihydrate is from about 0.5 mM to about 5 mM; (ii) the concentration of the 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 pharmaceutical composition of any one of claims 112 to 134, wherein the concentration of sodium chloride is about 100 mM to 180 mM.

136. (i) the concentration of calcium chloride dihydrate is from about 1 mM to about 2 mM; (ii) the concentration of the magnesium chloride hexahydrate is from 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 pharmaceutical composition of any one of claims 112 to 134, wherein the concentration of sodium chloride is about 120 mM to 160 mM.

137. (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 about 1.4 mM; (iii) the concentration of the magnesium chloride hexahydrate is about 0.79 mM; (iv) the concentration of potassium chloride is about 3 mM; and (v) the concentration of the sodium chloride is about 150 mM.

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

6.

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

2.

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

1.

141. 141. The pharmaceutical composition of 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. 141. The pharmaceutical composition of any one of claims 112 to 140, wherein the volume of the pharmaceutical composition is about 10 mL.

143. (a) an antisense oligomer (ASO) at a concentration of about 0.1 mg / mL to about 500 mg / mL, said ASO having the following chemical structure: 【Transformation 5】 ASO, which is a compound according to the formula (I) or a salt thereof; (b) calcium ions (Ca) at a concentration of about 0.1 mM to about 50 mM ２＋ ), (c) magnesium ions (Mg) at a concentration of about 0.1 mM to about 50 mM ２＋ ), (d) potassium ions (K) at a concentration of about 0.1 mM to about 20 mM ＋ ), (e) sodium ions (Na ) at a concentration of about 25 mM to about 250 mM ＋ ), (f) chloride ions (Cl) at a concentration of about 25 mM to about 250 mM － ), and (g) water.

144. (a) an antisense oligomer (ASO) at a concentration of about 0.1 mg / mL to about 500 mg / mL, said ASO having the following chemical structure: 【Transformation 6】 ASO, which is a compound according to the formula (I) or a salt thereof; (b) calcium ions (Ca) at a concentration of about 1.4 mM ２＋ ), (c) magnesium ions (Mg ２＋ ), (d) potassium ions (K) at a concentration of about 3 mM ＋ ), (e) sodium ions (Na) at a concentration of about 160 mM ＋ ), (f) chloride ions (Cl) at a concentration of about 160 mM － ), and (g) water.

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

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

147. 146. The method of claim 145, wherein the human subject is at most 18 years of age at the time of first administration of the pharmaceutical composition.

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

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

150. The disease or condition is characterized by the presence of Na Ｖ 150. The method of any one of claims 145 to 149, characterized by a decrease in the expression or function of 1.1 protein.

151. The method of any one of claims 145 to 149, wherein the disease or condition is Dravet syndrome.

152. The object is (i) Seizures occur before 12 months of age and involve recurrent focal motor, hemiconvulsive, or generalized tonic-clonic seizures, which are often prolonged and precipitated by hyperthermia; (ii) no previous causative magnetic resonance imaging lesion; (iii) the absence of any other known etiology of any disease or condition other than Dravet syndrome; (iv) normal development at the time of seizure onset; (v) the presence of a pathogenic variant or a variant of uncertain significance in the SCN1A gene; (vi) having received at least two previous epilepsy treatments that did not adequately control seizures; (vii) 4 or more convulsive seizures in the 28 days prior to administration, and the convulsive seizures are unilaterally clonic, focal with motor signs, focal to bilateral tonic-clonic convulsions, generalized tonic-clonic convulsions, tonic, tonic or atonic (fall seizures), or clonic; (viii) currently receiving an intervention for epilepsy or at least one antiepileptic medication at a dose that has been stable for at least four weeks, wherein the intervention for epilepsy is a ketogenic diet, vagus nerve stimulation, or a cannabinoid or cannabis-derived product; or (ix) any combination of (i) to (viii).

153. The object is (a) one of the following mutations in the SCN1A gene: Thr226Met, Leu263Val, Val422Leu, Thr1174Ser, Trp1204Arg, Pro1345Ser, Gln1489Lys, Phe1499Leu, Arg1575Cys, Val1611Phe, Leu1624Pro, Arg1648Cys, Leu1649Gln, Leu1670Trp, Gly1674Arg, and Asp1866Tyr; (b) a known pathogenic variant in another gene that causes epilepsy and is homozygous in the case of a known recessive disorder; (c) currently being treated with a sodium channel blocker and an anticoagulant as maintenance therapy, wherein the sodium channel blocker is phenytoin, carbamazepine, oxcarbazepine, lamotrigine, lacosamide, or rufinamide, and the anticoagulant is not aspirin; (d) a clinically significant unstable medical condition other than epilepsy; (e) clinically relevant symptoms or clinically significant illnesses other than epilepsy in the 4 weeks prior to dosing; (f) a history of epilepsy, a brain or spinal cord disease other than Dravet syndrome, or a history of bacterial meningitis or a congenital brain abnormality; (g) spinal cord malformations or other conditions that alter the free flow of cerebrospinal fluid (CSF), or implantation of a CSF drainage shunt; (h) clinically significant abnormal laboratory values ​​prior to administration; (i) aspartate aminotransferase or alanine aminotransferase more than 2.5 times the upper limit of normal, serum creatinine higher than the upper limit of normal, or platelet count lower than the lower limit of normal; (j) clinically relevant abnormalities in the 12-lead electrocardiogram (ECG) measured before administration; (k) mental or behavioral disorders; (l) currently or in the past four weeks, taking an anticoagulant medication, and said anticoagulant is not aspirin; or 153. The method of any one of claims 145 to 152, characterized in that it does not have one or more of: (m) any combination of (a) to (l).

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

155. 154. The method of any one of claims 145-153, wherein the subject is a human between 1 and 17 years old, 1 and 16 years old, 1 and 15 years old, 1 and 14 years old, 1 and 13 years old, 1 and 12 years old, 1 and 11 years old, 1 and 10 years old, 1 and 9 years old, 1 and 8 years old, 1 and 7 years old, 1 and 6 years old, 1 and 5 years old, 1 and 4 years old, 1 and 3 years old, or 1 and 2 years old.

156. 154. The method of any one of claims 145-153, wherein the subject is less than 1 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. 157. The method of any one of claims 145 to 156, wherein the pharmaceutical composition is administered to the intrathecal space of the subject.

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

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

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

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

162. 162. The method of claim 161, wherein the method comprises administering the pharmaceutical composition as a bolus injection over 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. 161. The method of any one of claims 145 to 160, wherein the pharmaceutical composition is administered by infusion with a delivery pump.

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

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

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

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

168. 168. The method of any one of claims 145-167, wherein said administering reduces or ameliorates seizure frequency, seizure intensity, or seizure duration.

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

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

171. The subsequent doses are 0.1, 0.5, 1, 2.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22.5, 25, 27.5, 30, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, 52.5, 55, 57.5, 60 , 62.5, 65, 67.5, 70, 72.5, 75, 77.5, 80, 82.5, 85, 87.5, 90, 92.5, 95, 97.5, 100, 102.5, 105, 107.5, 110, 112.5, 115, 117.5, 120, 122.5, 125, 127.5, 130, 132 .5, 135, 137.5, 140, 142.5, 145, 147.5, 150, 152.5, 155, 157.5, 160, 162.5, 165, 167.5, 170, 172.5, 175, 177.5, 180, 182.5, 185, 187.5, 190, 192.5, 195, 19 171. The method of claim 170, wherein the dose is 7.5, 200, 202.5, 205, 207.5, 210, 212.5, 215, 217.5, 220, 222.5, 225, 227.5, 230, 232.5, 235, 237.5, 240, 242.5, 245, 247.5, or 250 mg.

172. 172. The method of claim 170 or 171, wherein the subsequent dose is less than the previous dose following an indication that administration of the previous dose is not tolerated.

173. 172. The method of claim 170 or 171, wherein the subsequent dose is the same as the previous dose, following indications that administration of the previous dose is tolerated.

174. 172. The method of claim 170 or 171, wherein the subsequent dose is greater than the previous dose, following indications that administration of the previous dose is tolerated.

175. 172. The method of claim 170 or 171, wherein the subsequent dose is the same as the previous dose, following an indication that administration of the previous dose is effective.

176. 172. The method of claim 170 or 171, wherein the subsequent dose is less than the previous dose following an indication that administration of the previous dose is efficacious.

177. 172. The method of claim 170 or 171, wherein the subsequent dose is greater than the previous dose following an indication that administration of the previous dose was ineffective.

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

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

180. 180. The method of any one of claims 145 to 179, wherein the frequency of administration is increased following indication that the previous dose was ineffective.

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

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

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

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

185. Na Ｖ 1.1 The decrease in protein expression or function includes nonsense-mediated RNA decay-induced exon splicing, Ｖ 1.1 The method of any one of claims 150 to 184, wherein the method is associated with alteration of the NMD exon from the pre-mRNA encoding the protein.

186. The ASO contains the NMD exon, Ｖ 186. The method of any one of claims 150 to 185, which promotes the exclusion of the NMD exon from the pre-mRNA encoding a 1.1 protein.

187. The ASO contains the NMD exon, Ｖ 1.1 The method of any one of claims 150 to 186, wherein the method binds to a target portion of a pre-mRNA encoding a protein.

188. The ASO contains the NMD exon, Ｖ 188. The method of claim 187, which promotes the exclusion of the NMD exon from the pre-mRNA encoding a 1.1 protein.

189. When the ASO is introduced into a cell, the ASO acts as a Ｖ 189. The method of any one of claims 185 to 188, wherein the level of processed mRNA encoding a 1.1 protein is increased.

190. When the ASO is introduced into a cell, the ASO acts as a Ｖ 190. The method of any one of claims 185 to 189, wherein the level of 1.1 protein is increased.

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

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

193. 191. The method of any one of claims 185 to 190, wherein the target portion is within the NMD exon.

194. 145. A method of making the pharmaceutical composition of any one of claims 1-27 or 56-144, comprising diluting the antisense oligomer (ASO) in the pharmaceutically acceptable diluent, thereby making the liquid composition.

195. The above-mentioned アクが、3mg / mL、4mg / mL、4.5mg / mL、5mg / mL、6mg / mL、7mg / mL、9mg / mL、10mg / mL、11mg / mL、12mg / mL、13mg / mL、14mg / mL、15mg / mL、16mg / mL、17mg / mL、18 mg / mL、19mg / mL、20mg / mL、22mg / mL、25mg / mL、28mg / mL、30mg / mL、33mg / mL、44mg / mL、55mg / mL、66mg / mL、77mg / mL、88mg / mL、99mg / mL、100mg / mL、22.5m g / mL、25mg / mL、27.5mg / mL、30mg / mL、32.5mg / mL、35mg / mL、37.5mg / mL、40mg / mL、42.5mg / mL、45mg / mL、47.5mg / mL、50mg / mL、52.5mg / mL、57. 5mg / mL、60mg / mL、62.5mg / mL、65mg / mL、67.5mg / mL、70mg / mL、72.5mg / mL、75mg / mL、77.5mg / mL、80mg / mL、87.5mg / mL、90mg / mL 2.5mg / mL、95mg / mL、97.5mg / mL、100mg / mL、102.5mg / mL、105mg / mL、107.5mg / mL、110mg / mL、112.5mg / mL、117.5mg / mL、122.5mg / mL mL、125mg / mL、127.5mg / mL、130mg / mL、132.5mg / mL、135mg / mL、137.5mg / mL、140mg / mL、142.5mg / mL、147.5mg / mL、150mg / mL、152.5mg / mL 55mg / mL、157.5mg / mL、160mg / mL、162.5mg / mL、165mg / mL、167.5mg / mL、170mg / mL、172.5mg / mL、175mg / mL、182.5mg / mL、182.5mg / mL / mL、187.5mg / mL、190mg / mL、192.5mg / mL、195mg / mL、197.5mg / mL、200mg / mL、202.5mg / mL、205mg / mL、212.5mg / mL、212.5mg / mL195. The method of claim 194, wherein the hydroxybenzoate is present in the liquid composition at a concentration of 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. 196. The method of claim 195, wherein the method further comprises diluting the liquid composition with an additional amount of the pharmaceutically acceptable diluent, thereby creating the liquid composition.

197. The ASO is present in the liquid composition at a concentration of 0.1 to 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 197. The method of claim 196, wherein the hydroxybenzoate is present in the liquid composition at a concentration of 1000 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, 30 mg / mL, or 33 mg / mL.

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

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

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

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

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

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

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

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

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

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

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

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

211. 211. The method of claim 209 or 210, wherein the period is 36 months or less.

212. 212. The method of claim 211, wherein the period is 24 months or less.

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

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