Pharmaceutical composition and its use

Abstract

This specification provides a pharmaceutical composition comprising Sequence ID No. 1, which is suitable for subcutaneous administration once a week, and Sequence ID No. 2 has a release half-life of more than approximately 100 hours.

Description

[Technical Field]

[0001] cross reference This application claims the interests of U.S. Provisional Patent Application No. 63 / 590,345, filed on 13 October 2023, and U.S. Provisional Patent Application No. 63 / 638,538, filed on 25 April 2024, the entire contents of each of these documents being incorporated herein by reference. [Background technology]

[0002] Through the secretion of parathyroid hormone (PTH), the parathyroid glands regulate blood calcium within a very narrow range (8-10 mg / dL in adults). Calcium stored in the bones is released in response to PTH, supporting central nervous system function, vasoconstriction and muscle contraction, enzyme and hormone secretion, and blood clotting. Mechanistically, PTH increases calcium concentration by stimulating the production of a biologically active form of vitamin D in the kidneys, while simultaneously mobilizing calcium and phosphates to be released from the bones, signaling the kidneys to eliminate excess phosphates, and maximizing tubular reabsorption of calcium in the kidneys.

[0003] Hypoparathyroidism (hypo PT) is a rare disorder characterized by insufficient production of parathyroid hormone (PTH). Individuals with hypo PT excrete excess calcium in their urine, have excess phosphate in their blood, and exhibit abnormally low bone turnover. Until the approval of NPS / Shire's Natpara® (rhPTH) by the U.S. Food and Drug Administration (FDA) in January 2015, hypoparathyroidism was one of the very few classic endocrine disorders that were not treated with hormone replacement. Natpara® offers only minimal efficacy compared to standard treatment consisting of high-dose calcium and vitamin D supplements. Nevertheless, the drug has been well-received since its commercial launch in 2015, demonstrating a significant, unmet need that exists in the treatment of hypo PT.

[0004] Because hypo PT is a rare disease, drugs developed for hypo PT benefit from Orphan Drug Designations by the FDA and the European Medicines Agency (EMA). Each emerging competitor is directed more toward the physiological restoration of PTH than Natpara®, primarily by normalizing serum calcium and mitigating the long-term effects of poorly controlled disease. The emerging competitors differ in their approaches to normalizing PTH and have considerable differences in their product profiles, including routes of administration, potency, frequency of administration, and therapeutic index. The compositions disclosed herein provide weekly treatment for subjects with hypo PT, which safely restores and maintains physiological levels of PTH throughout the week, providing subject-specific pharmacological benefits and significant convenience.

[0005] Hypo-parathyroid gland thromboplasty (hypo-PT) can be divided into primary and secondary types. Primary PT occurs when there are intrinsic defects within the parathyroid glands due to genetic causes. Hypo-PT due to genetic causes is particularly rare and is thought to account for less than 10% of all cases. Secondary or acquired PT occurs when previously functioning parathyroid glands are impaired, destroyed, or ablated. Secondary PT is far more common and accounts for approximately 90% of all cases.

[0006] At least 75% of acquired hypo thyroidectomy (hypo PT) cases are caused by anterior neck surgery (i.e., total thyroidectomy or radical neck dissection for head and neck malignancies) resulting from inadvertent or unavoidable removal or damage to the parathyroid gland and / or its blood supply. Transient hypo PT after thyroid surgery is relatively common, occurring in an estimated 7–46% of thyroid surgeries. Transient hypo PT resolves within weeks or months after surgery. Chronic hypo PT is rare, occurring in 0.9–1.6% of cases in surgical centers with experienced endocrine surgeons and high case volume. However, a high rate of 6.6% has been reported after thyroid surgery, highlighting the importance of expertise and experience in avoiding permanent damage resulting in hypo PT.

[0007] In adults following anterior neck surgery, the second most common acquired cause of hypo PT is thought to be autoimmune disease. This can affect one or more of the parathyroid glands. Autoimmune-mediated disease is estimated to cause less than 10% of acquired hypo PT. Other secondary causes include rare invasive lesions due to metastatic disease or iron / copper overload, exposure to ionizing radiation, or sometimes unknown origin (idiopathic).

[0008] Estimates of the prevalence of hypoPT in the United States range from 60,000 to 115,000 patients. Experts suggest that the best estimate based on a large health plan claims database is 77,000 patients, of which 58,793 are insured. Data in other regions is extremely limited, with documented estimates ranging from 70,000 to 267,000 in Europe, 20,000 in Japan, and 30,000 for the rest of the world.

[0009] Chronic hypothyroidism (hypo-PT) is a rapidly progressing disease caused by the development of thyroid diseases, including cancer, and their treatment, particularly surgery. For example, between 1996 and 2006, the total number of thyroidectomies performed in the United States increased by 39%, from 66,864 to 92,931. The number of thyroidectomies performed annually in the United States is now estimated to be 150,000. The number of people potentially affected by hypo-PT is increasing. Since thyroid diseases affect women more than men, over 70% of patients with hypo-PT are women.

[0010] Most people with calcium levels outside the normal physiological range experience discomfort. Due to the vital role of calcium in nerve and muscle function, patients with hypocalcemia may experience tingling or burning of the extremities (paresthesia), muscle twitching, muscle pain, involuntary muscle contractions (tetany), dry / rough skin, lack of concentration or attention, anxiety, and / or depression. Significantly low blood calcium levels can cause life-threatening laryngospasm, seizures, or cardiac arrhythmias requiring emergency treatment with IV calcium. Serious long-term consequences of hypo PT may include nephrocalcification, renal dysfunction / chronic kidney disease, calcium deposition in soft tissues, and overcalcified bones.

[0011] Hypo-PT is usually diagnosed through clinical history and laboratory tests. The diagnosis is typically characterized by low / undetectable levels of serum PTH and hypocalcemia, defined as total serum calcium below the lower limit of normal, as well as hyperphosphatemia. Levels of activated vitamin D and bone turnover markers are also usually in the lower portion to significantly lower range of normal, and calcium excretion is increased. Such laboratory results in the context of recent cervical surgery may lead to a simple diagnosis of hypo-PT. However, cases of hypo-PT can be very difficult to diagnose, especially when there is no known damage to the parathyroid gland.

[0012] There are no established guidelines for the management of hypo PT, so treatment is based on experience and clinical judgment. The main generally acceptable goals of chronic treatment are to maintain serum total calcium (low to low-normal range), serum phosphorus (high-normal range), 24-hour urinary calcium excretion (<7.5 mmol / d), and calcium phosphate product (<4.4 mmol / L2) within acceptable limits.

[0013] Standard treatment includes calcium, vitamin D metabolites, and sometimes thiazide diuretics. Recommended calcium supplements are calcium carbonate and calcium citrate, with the required amounts varying significantly (9-fold) among patients. 1,25(OH)2D3 (calcitriol), an active metabolite of vitamin D, helps maintain serum calcium levels by improving the efficiency of intestinal calcium absorption. Calcitriol is also administered over a wide (8-fold) dosage range. By enhancing distal tubular calcium reabsorption, thiazide diuretics (benzothiadiazines) may also be useful in treating hypo PT.

[0014] While it may seem easy to supplement deficiency calcium with calcium and vitamin D supplements, in reality, achieving good control is extremely difficult. Most patients experience a rollercoaster of alternating between dose levels that are too high and too low. Furthermore, calcium and vitamin D supplements do not correct the underlying PTH deficiency, which has therapeutic effects.

[0015] Patients with hypoparathyroidism experience a significant burden of illness, severely impacting their quality of life and the lives of their caregivers, family, and friends. NPS Pharmaceuticals conducted PARADOX, an epidemiological study of 374 patients, to assess the clinical, social, and economic impacts of hypoparathyroidism. Data was collected through a 30-minute web-based questionnaire developed with input from clinical experts, the Hypoparathyroidism Association, and patients. This questionnaire was primarily distributed via email to Hypoparathyroidism Association members, including adults who had lived in the United States for more than six months while having hypo PT. The results were published by Hadker et al. in Endocrine Practice, and the following are some key points: (i) 72% experienced more than 10 symptoms daily, and the most frequently reported were: (ii) Physical symptoms: fatigue (82%), muscle pain / tension (78%), paresthesia (76%), tetany (70%), joint pain or bone pain (67%), and limb pain or weakness (53%). (iii) Emotional symptoms: anxiety (59%) and depression (53%) (iv) Cognitive symptoms: brain fog / mental lethargy (72%), lack of concentration (65%), memory loss (61.5%), and sleep disturbances (57%). (v) 79% required hospitalization or emergency room visit, (vi) 45% reported that it was significantly disrupting their lives. (vii) 85% reported being unable to perform household activities. (viii) 20% experienced a disease-related (negative) change in employment status.

[0016] Other publications also confirm the disease burden of hypo PT. A cross-sectional study published by Arlt et al. in the European Journal of Endocrinology compared health and mood in 25 women with intact parathyroid function after thyroid surgery versus 25 women with postoperative hypo PT stably managed by calcium and vitamin D treatment after thyroid surgery, using validated questionnaires. Hypo PT patients had significantly higher global compliance scores on the Geissen complaint list, and the von Zersen symptom list and Symptom Checklist-90 were accompanied by increased subscale scores for anxiety, phobias, and their physical equivalents. Importantly, current conventional standards of treatment for hypo PT did not restore health in these patients. [Overview of the project]

[0017] In many cases, it is desirable to prolong the release time of an injected drug to extend its duration of action or reduce its toxic effects. Formulations that are readily soluble in the body are usually absorbed rapidly and provide a sudden burst of available drug, as opposed to the more desirable gradual release of the pharmacologically active product.

[0018] While various attempts have been made to provide controlled and extended-release pharmaceutical compounds, previously disclosed technologies have not succeeded in overcoming all the technical challenges, such as achieving optimal sustained-release time, maximizing stability and efficacy, reducing toxicity, maximizing reproducibility in preparation, and eliminating undesirable physical, biochemical, or toxicological effects introduced by undesirable matrix materials. Therefore, there is a need for formulations that safely and effectively extend the half-lives of existing drugs and improve their therapeutic index on a dose-by-dose and patient-by-patient basis. This is most important for drugs with a narrow therapeutic index that separates the dose for efficacy from the dose for toxicity. Insulin or PTH, which closely resembles thyroid hormones, is recognized as a drug in which a slightly excessive increase in calcium beyond the physiological range can have acute and chronic adverse consequences.

[0019] Mechanisms for providing extended release and enhanced therapeutic index include sequestering molecules at the injection site or using prodrug derivative forms of the drug, which are designed to delay the onset of action and extend the drug's half-life. Delayed onset of action is advantageous in that it allows for systemic distribution of the prodrug before activation. Therefore, administration of a prodrug can eliminate complications caused by peak activity at administration and increase the therapeutic index of the parent drug.

[0020] Furthermore, receptor recognition and subsequent processing by peptide and protein agonists are major pathways for the degradation of many peptide and protein-based drugs. Therefore, while the binding of a peptide drug to its receptor results in biological stimulation, it also initiates subsequent inactivation of peptide / protein-induced pharmacology through enzymatic degradation of the peptide or protein. Thus, the use of prodrugs can also delay the duration of action of the administered drug, allowing for even distribution throughout the body before activation. This disclosure provides compositions and methods for safely extending the biological effects of PTH while minimizing excessive effects immediately after administration.

[0021] In one embodiment, the present disclosure provides a pharmaceutical composition comprising SEQ ID NO: 1, which is suitable for subcutaneous administration once a week, and SEQ ID NO: 2 has a release half-life of more than approximately 100 hours.

[0022] In another embodiment, the Disclosure provides a method for treating a subject having hypoparathyroidism, osteoporosis, or osteopenia, the method comprising administering to the subject once a week a dose of at least about 30 μg, the dose comprising SEQ ID NO: 1.

[0023] In another aspect, the Disclosure provides a pharmaceutical composition comprising SEQ ID NO: 1, which is suitable for subcutaneous administration once a week, and after administration of SEQ ID NO: 1, the pharmacokinetic profile of SEQ ID NO: 2 exhibits a peak-to-trough ratio of less than approximately 2 in plasma.

[0024] In another aspect, the Disclosure provides a method for treating a subject having hypoparathyroidism, the method comprising (a) determining the level of the subject's C-terminal telopeptide (CTX) after administering SEQ ID NO: 1 once weekly to the subject, and (b) providing the subject with a continued once-weekly administration of SEQ ID NO: 1, wherein the level of CTX is less than 900 pg / mL.

[0025] In another aspect, the Disclosure provides a method for treating a subject having hypoparathyroidism, the method comprising: (a) determining the level of procollagen type I N-terminal propeptide (P1NP) in the subject after weekly administration of SEQ ID NO: 1; and (b) providing the subject with a continued weekly administration of SEQ ID NO: 1, wherein the level of P1NP in the subject is greater than approximately -50 μg / L.

[0026] Reference All publications, patents, and patent applications referenced herein are incorporated by reference to the same extent as each individual publication, patent, or patent application is specifically and individually referenced. To the extent that any publications and patents or patent applications referenced herein are in conflict with the disclosures contained herein, this Specification is intended to supersede and / or take precedence over any such conflicting material. [Brief explanation of the drawing]

[0027] Novel features of the present invention are described in detail in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by referring to the following detailed description, which describes exemplary embodiments in which the principles of the present invention are utilized, and to the appended drawings (hereinafter also "figure" and "FIG."). [Figure 1] This document outlines the design, objectives, and endpoints of the Phase 1 trial. [Figure 2] The plasma concentrations of compound 1 and 2 after weekly administration of compound 1 at various doses are shown. [Figure 3] This shows the mean change from baseline in CTX markers after weekly administration of compound 1 at various doses. [Figure 4] This shows the mean change from baseline in the P1NP marker after weekly administration of compound 1 at various doses. [Figure 5]The possible mechanism of action of compound 1 and its conversion to compound 2 are shown. [Figure 6A] The maximum serum calcium levels (Emax, adj) after weekly administration of compound 1 at various doses and time points are shown. [Figure 6B] The total serum calcium levels (AUEC0-τ, adj) after weekly administration of compound 1 at various doses and time points are shown. [Figure 7] This shows endogenous PTH in healthy patients after weekly administration of compound 1 at various doses and time points. Detailed description of the invention

[0028] The following description includes numerous exemplary configurations, methods, parameters, etc. However, it should be noted that such descriptions are not intended to limit the scope of this disclosure, but rather are provided as descriptions of exemplary embodiments.

[0029] The following description includes certain specific details in order to provide a complete understanding of the various embodiments of this disclosure. However, those skilled in the art will understand that this disclosure can be practiced without these details.

[0030] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art in which this invention pertains. All patents and publications referenced herein are invoked by reference.

[0031] As used herein, the “effective” amount or “therapeutic effective amount” of a drug refers to the amount of drug that is non-toxic but sufficient to provide the desired effect. The effective amount varies from subject to subject, or even within a subject over time, depending on the individual’s age and general condition, mode of administration, etc. Therefore, it is not always possible to determine the exact effective amount. However, the appropriate effective amount in any individual case can be determined by those skilled in the art using routine experiments.

[0032] When used in the specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly indicates otherwise.

[0033] The terms "salt" or "pharmaceutically acceptable salt" refer to salts derived from various organic and inorganic counterions known in the art. pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids that can derivate salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids that can derivate salts include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases that can derivate salts include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases that can induce salt formation include, for example, primary amines, secondary amines, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, specifically including isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0034] As used herein, the terms “parenteral administration” and “administered parenterally” mean modes of administration other than enteral and topical administration by injection, and include, but are not limited to, injections and infusions into veins, muscles, arteries, spinal canals, capsules, orbits, hearts, skin, peritoneal cavities, trachea, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, spinal cord, and sternal regions.

[0035] The term "pharmaceutically acceptable" is used herein to mean a compound, material, composition, and / or dosage form that is suitable for use in contact with human and animal tissues in proportion to a reasonable benefit-risk ratio, without excessive toxicity, irritation, allergic reactions, or other problems or complications, within the bounds of reasonable medical judgment.

[0036] As used herein, the terms “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” mean a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation and is not harmful to the subject. Some examples of substances that can function as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; and (9) peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil. This includes oils such as (10) glycols such as propylene glycol, (11) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol, (12) esters such as ethyl oleate and ethyl laurate, (13) agar, (14) buffers such as magnesium hydroxide and aluminum hydroxide, (15) alginic acid, (16) water free of pyrogens, (17) isotonic saline, (18) Ringer's solution, (19) ethyl alcohol, (20) phosphate buffer, and (21) other non-toxic, suitable substances used in pharmaceutical formulations.

[0037] In certain embodiments, the terms “prevent” or “preventing” in relation to a disease or disorder may refer to a compound that, in a statistical sample, reduces the incidence of the disorder or disease in a treated sample compared to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or disease compared to an untreated control sample.

[0038] As used herein, the terms “treat,” “treating,” or “treatment” include alleviating, abating, or ameliorating the symptoms of a disease or illness; preventing further symptoms; improving or preventing the underlying cause of symptoms; inhibiting a disease or illness, for example, preventing the onset of a disease or illness; relieving a disease or illness; causing regression of a disease or illness; alleviating a disease or illness caused by a disease or illness; or stopping the symptoms of a disease or illness, preventively and / or therapeutically.

[0039] As used herein, the term “peak-to-trough ratio” refers to the ratio between the highest and lowest plasma concentrations of a compound (e.g., compound 2) at steady state.

[0040] As used herein, the terms “phosphate-buffered saline” or “PBS” refer to an aqueous solution containing sodium chloride and sodium phosphate. While different formulations of PBS are known to those skilled in the art, for the purposes of this disclosure, the term “standard PBS” refers to a solution having a final concentration of 137 mM NaCl, 10 mM phosphate, and 2.7 mM KCl, and a pH of 7.2–7.4.

[0041] As used herein, the terms “native” or “natural” define a state that is found in nature. “Native amino acid” refers to an amino acid that is naturally occurring and produced by natural means.

[0042] As used herein, the term “amino acid” encompasses any molecule containing both an amino functional group and a carboxyl functional group, where the amino and carboxyl groups are bonded to the same carbon (α-carbon). The α-carbon may have one or two further organic substituents. Amino acids can be designated by their three-letter code, one-letter code, or, in some cases, by the name of their side chain. For example, a non-standard amino acid containing a cyclohexane group bonded to the α-carbon is called cyclohexane or cyclohexyl. For the purposes of this disclosure, designations of amino acids that do not specify their stereochemistry are intended to encompass either the L or D form or a racemic mixture of the amino acid. However, when an amino acid is designated by its three-letter code (e.g., Lys) or one-letter code (e.g., K), such designation is intended to specify the native L form of the amino acid, while the D form is specified by including a lowercase d before the three-letter code or single-letter code (i.e., dLys or dK). As used herein, the designation of a particular amino acid is intended to include natural amino acids, as well as any isotopically enriched derivatives thereof that have different molecular weights from natural amino acids but possess equivalent physical and biological properties.

[0043] As used herein, the term "hydroxyl acid" refers to an amino acid modified by substituting an alpha-carbon amino group with a hydroxyl group.

[0044] As used herein, the term “non-coded (non-canonical) amino acid” encompasses any amino acid that is not an L-isomer of any of the following 20 amino acids: Ala, Cys, Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val, Trp, Tyr.

[0045] A "dipeptide" is the result of linking an α-amino acid or α-hydroxyl acid with another amino acid via a peptide bond.

[0046] As used herein, the term "chemical cleavage" encompasses non-enzymatic reactions that result in the breakdown of covalent chemical bonds, for which no further names exist.

[0047] As used herein, an "acylated" amino acid is an amino acid that contains an acyl group that is unnatural to naturally occurring amino acids, regardless of the means by which it is produced. Exemplary methods for producing acylated amino acids and acylated peptides are known in the art and include steps of acyling the amino acid before inclusion in a peptide, or acyling the amino acid after peptide synthesis before inclusion, followed by chemically acyling the peptide. In some embodiments, the acyl group gives the peptide one or more of the following: (i) extension of half-life in circulation, (ii) delay of onset of action, (iii) extension of duration of action, (IV) improved resistance to proteases such as DPP-IV, and (v) altered potency at the PTH receptor.

[0048] A "bioactive peptide" refers to a peptide capable of exerting biological effects in vitro and / or in vivo. As used herein, general references to peptides are intended to include peptides having modified amino and carboxyl termini. For example, an amino acid sequence specifying standard amino acids is intended to include the standard N-terminal and C-terminal amino acids, as well as the corresponding C-terminal amino acids modified to include an amide group instead of the corresponding hydroxyl acid and / or terminal carboxylic acid at the N-terminus.

[0049] As used herein, an "acylated" amino acid is an amino acid that contains an acyl group that is unnatural to naturally occurring amino acids, regardless of the means by which it is produced. Exemplary methods for producing acylated amino acids and acylated peptides are known in the art and involve acyling an amino acid before incorporating it into a peptide or peptide synthesis, followed by chemical acyling of the peptide. In some embodiments, the acyl group gives the peptide one or more of the following: (i) extension of half-life in circulation, (ii) delay of onset of action, (iii) extension of duration of action, (IV) improved resistance to proteases such as DPP-IV, and (v) altered potency at the receptor for PTH.

[0050] As used herein, an alkylated amino acid is an amino acid that contains an alkyl group that is unnatural relative to a naturally occurring amino acid, regardless of the means by which it is produced. Exemplary methods for producing alkylated amino acids and alkylated peptides are known in the art and include alkylating the amino acids before they are incorporated into a peptide, or alkylating the amino acids and chemically alkylating the peptides before they are included in peptide synthesis.

[0051] As used herein, “receptor” is a molecule that recognizes and binds to a specific molecule in a high-affinity interaction, which results in several biological effects (direct or indirect) in a cell or in the cells and / or tissues of a host organism. “Cellular receptor” is a molecule on or inside a cell that recognizes and binds to a specific molecule, which results in several effects (direct or indirect) in the cell.

[0052] As used herein, the term “identity” refers to the similarity between two or more sequences. Identity is measured by dividing the number of identical amino acid residues by the total number of residues and multiplying the result by 100 to obtain a percentage. Thus, two copies of exactly the same sequence have 100% identity, while two sequences having amino acid deletions, additions, or substitutions to each other have a lower degree of identity. Those skilled in the art will recognize that several computer programs, such as those using algorithms like BLAST (Basic Local Alignment Search Tool, Altschul et al. (1993) J.Mol.Biol.215:403-410), are available for determining sequence identity.

[0053] As used herein, amino acid "substitution" refers to replacing one amino acid residue with a different amino acid residue.

[0054] As used herein, the term “conservative amino acid substitution” is defined herein as the substitution of one or fewer residues from the following five groups: I. Small aliphatic, nonpolar, or slightly polar residues: Ala, Ser, Thr, Pro, Gly; II. Polar, positively charged residues and their amides: Asp, Asn, Glu, Gln; III. Polar, positively charged residues: His, Arg, Lys, ornithine (Orn); IV. Large aliphatic, nonpolar residues: Met, Leu, Ile, Val, Cys, norleucine (Nle), homocysteine ​​(hCys); V. Large aromatic residues: Phe, Tyr, Trp, acetylphenylalanine, naphthylalanine (Nal).

[0055] As used herein, the general terms "polyethylene glycol chain" or "PEG chain" refer to a mixture of branched or linear condensation polymers of ethylene oxide and water, represented by the general formula H(OCH2CH2)kOH, where k is at least 2.

[0056] As used herein, the terms "miniPEG" or "OEG" refer to the following structure:

[0057] [ka] This defines functionalized polyethylene compounds that include the above.

[0058] As used herein, the term “pegylated” and similar terms refer to compounds modified from their native state by linking polyethylene glycol chains to them. A “pegylated polypeptide” is a polypeptide having a PEG chain covalently bonded to the polypeptide.

[0059] As used herein, “linker” or “spacer” is a bond, molecule, or group of molecules that connects two separate entities to one another. A linker may provide an optimal distance between two entities or may further supply a labile linkage that allows the two entities to separate from one another. Lackile linkages include photocleavable groups, acid-labile moieties, base-labile moieties, and enzyme-cleavable groups.

[0060] As used herein, “dimer” is a complex comprising two subunits covalently linked to each other via a linker. When used without any qualifying language, the term “dimer” encompasses both homodimers and heterodimers. A homodimer contains two identical subunits, while a heterodimer contains two distinct subunits that are substantially similar to each other.

[0061] "C1-C n Alkyl (C1-C n The term "alkyl)" (wherein n may be 1 to 6) as used herein refers to a branched or linear alkyl group having 1 to a specified number of carbon atoms. Typical C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0062] As used herein, the term C16-C20 fatty acids refers to those with the structure: -CO(CH2) 14 - 18 CH3 refers to the C16-C20 diacid, and the term C16-C20 diacid has the structure: -CO(CH2) 14-18COOH refers to the compound containing COOH, where the prefix "C16-C20" indicates the variable total number of carbons in the compound. For example, C18 diacid has the structure: -CO(CH2) 16 This represents COOH. As used herein, the generic reference for acylated amino acids includes both amino acids having a side chain acylated with a fatty acid and amino acids having a side chain acylated with a diacid.

[0063] The physiological conditions disclosed herein are intended to include a temperature of approximately 35–40°C and a pH of approximately 7.0–7.4, more typically including a pH of 7.2–7.4 and a temperature of 36–38°C. Physiological pH and temperature are precisely controlled in humans within highly defined ranges, and the conversion rate from dipeptide / drug conjugates (prodrugs) to drugs exhibits high intra-patient and inter-patient reproducibility.

[0064] As used herein, the term "about" means a value or range of values ​​that is 10 percent above or below the stated value or range of values, but is not intended to limit any value or range of values ​​to this broader definition alone.

[0065] Abbreviation Lowercase k = d-isomer of lysine

[0066] γE = 1-isomer of gamma, glutamic acid

[0067] (miniPEG)2=COCH2OCH2CH2OCH2CH2NH

[0068] COC16H32CO2H=(C18 diacid)

[0069] (N-Me)G = Sarcosine

[0070] Uppercase K = 1-isomer of lysine

[0071] compound In one embodiment, the present disclosure provides compound 1. In some cases, compound 1 is represented by k(γE-(miniPEG)2-γE-COC16H32CO2H)(N-Me)GSVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHK(γE)-miniPEG)2-γE-COC16H32CO2H)-OH (Sequence ID 1), where γE is the l-isomer of gamma-glutamic acid, (miniPEG)2 is COCH2OCH2CH2OCH2CH2NH, COC16H32CO2H is the C18 diacid, and (N-Me)G is sarcosine. In some cases, the compound is represented by PTH(1-33), dK-1(γE-2xOEG-γE-diacid C18(diacidC18)), N(Me)G0, K33(γE-2xOEG-γE-diacid C18). In some cases, compound 2 is represented by SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHK(γE-(miniPEG)2-γE-COC16H32CO2H)-OH(SEQ ID NO: 2). In some examples, SEQ ID NO: 2 is formed by cleavage of SEQ ID NO: 1. In some examples, SEQ ID NO: 2 is formed by in vivo cleavage of SEQ ID NO: 1.

[0072] This disclosure includes salts of the compounds described herein, in particular pharmaceutically acceptable salts. Compounds of the present invention having functional groups that are sufficiently acidic, sufficiently basic, or both, can react with several inorganic bases, as well as either inorganic or organic acids, to form salts. Alternatively, compounds that are inherently charged, such as compounds having quaternary nitrogen, can form salts with suitable counterions, such as halides, such as bromides, chlorides, or fluorides, in particular bromides.

[0073] Chemical substances having a carbon-carbon double bond or a carbon-nitrogen double bond may exist in the Z-form or E-form (or cis-form or trans-form). Furthermore, some chemical substances may exist in various tautomeric forms. Unless otherwise specified, the compounds described herein are intended to include all Z-, E- and tautomeric forms as well.

[0074] "Tautomer" refers to a molecule in which a proton shift from one atom of the molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In situations where tautomerization is possible, a chemical equilibrium of tautomers exists. The exact ratio of tautomers depends on several factors including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include

[0075] [Chemical Formula] are included.

[0076] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, for example, 2 H, 3 H, 11 C, 13 C, and / or 14 C content is used in an enriched form. In one particular embodiment, the compound is deuterated at at least one position. Such deuterated forms can be made by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve metabolic stability and / or efficacy, thus increasing the duration of action of the drug.

[0077] Unless otherwise specified, the compounds described herein are intended to contain different compounds only in the presence of one or more isotopically enriched atoms, for example, hydrogen replacement with deuterium or tritium, or 13 C or 14 Except for carbon substitution with carbon-enriched carbon, compounds having this structure are within the scope of this disclosure.

[0078] The compounds of this disclosure optionally contain unnatural proportions of atomic isotopes in one or more atoms constituting such compounds. For example, the compounds may be labeled with isotopes such as deuterium (2H), tritium (3H), iodine-125 (125I), or carbon-14 (14C). 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, and 125 All isotopic substitutions by I are intended. All isotopic changes of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0079] In certain embodiments, the compounds disclosed herein are 2 It has some or all of the 1H atoms replaced by H atoms. Methods for synthesizing deuterium-containing compounds are known in the art and include, but are not limited to, the following synthesis methods.

[0080] Deuterium-substituted compounds are synthesized using various methods, as described in Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32:

[0081] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Numerous deuterium-containing reagents and building blocks are commercially available from chemical vendors such as Aldrich Chemical Co.

[0082] The compounds of the present invention also include crystalline and amorphous forms of these compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same kind of activity, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrides), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0083] The compounds described herein may, in some cases, exist as diastereomers, enantiomers, or other stereoisomeric forms. Where absolute stereochemistry is not specified, the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms, as well as suitable mixtures thereof. Separation of stereoisomers may be performed by chromatography, or by forming diastereomers and separating them by recrystallization, or by chromatography, or by any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, incorporated herein by reference). Stereoiomers may also be obtained by stereoselective synthesis.

[0084] The methods and compositions described herein include the use of amorphous and crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. Similarly, in some embodiments, active metabolites of these compounds having the same type of activity are included within the scope of this disclosure. In addition, the compounds described herein may exist in non-solvated forms as well as in solvated forms with pharmaceutically acceptable solvents such as water and ethanol. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0085] As used herein, the term “prodrug” is defined as any compound that undergoes chemical modification before exhibiting its pharmacological effects.

[0086] Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. For example, they may be bioavailable by oral administration, whereas the parent drug is not. Prodrugs may help enhance the cellular permeability of a compound compared to the parent drug. Prodrugs may also have improved solubility in pharmaceutical compositions than the parent drug. Prodrugs may be designed as reversible drug derivatives to enhance drug transport to site-specific tissues or to be used as modifiers to increase intracellular drug residence.

[0087] In some embodiments, the design of the prodrug increases the lipophilicity of the pharmaceutical. In some embodiments, the design of the prodrug increases its effective water solubility. For example, Fedorak et al., Am.J.Physiol.,269:G210-218(1995), McLoed et al.,Gastroenterol,106:405-413(1994), Hochhaus et al.,Biomed.Chrom.,6:283-286(1992), J.Larsen and H.Bundgaard, Int.J.Pharmaceutics,37,87(1987), J.Larsen et al.,Int.J.Pharmaceutics,47,103(1988), Sinkula et al.,J.Pharm.Sci., 64:181-210(1975), T. Higuchi and V. Stela,Pro-drugs as Novel Delivery Systems,Vol.14 of the ACSSymposium Series, and Edward See B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987 (all of these documents are incorporated herein by reference). According to another embodiment, the present disclosure provides a method for producing the compounds defined above. The compounds can be synthesized using the prior art. Advantageously, these compounds can be conveniently synthesized from readily available starting materials.

[0088] Useful synthetic chemical transformations and methods for synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989), T.W. Greene and P.G. M. Wuts, Protective Groups in Organic Synthesis, 2nd ed. (1991), L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994), and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).

[0089] Pharmaceutical preparations In one embodiment, the disclosure provides a pharmaceutical composition comprising SEQ ID NO: 1. In some cases, the pharmaceutical composition comprises SEQ ID NO: 1 and is suitable for subcutaneous administration. In some cases, the pharmaceutical composition comprises SEQ ID NO: 1 and is suitable for subcutaneous administration once a week. In some embodiments, the pharmaceutical composition comprises SEQ ID NO: 1 and is suitable for subcutaneous administration once a week, and SEQ ID NO: 2 has a half-life of more than about 100 hours. In some cases, the pharmaceutical composition comprises SEQ ID NO: 1 and is suitable for subcutaneous administration once a week, and SEQ ID NO: 2 has a release half-life of more than about 100 hours. In some cases, the pharmaceutical composition comprises SEQ ID NO: 1 and is suitable for subcutaneous administration once a week, and SEQ ID NO: 2 has a release half-life of more than about 100 hours, and SEQ ID NO: 1 has a half-life of more than about 70 hours. In some cases, SEQ ID NO: 1 is converted to SEQ ID NO: 2. In some cases, SEQ ID NO: 1 is converted to SEQ ID NO: 2 after in vivo. In some cases, SEQ ID NO: 1 is converted to SEQ ID NO: 2 after in vivo cleavage. In some cases, SEQ ID NO: 1 is converted to SEQ ID NO: 2 via intramolecular self-cleavage. In some cases, SEQ ID NO: 1 is converted to SEQ ID NO: 2 after diketopiperazine cyclization. In some cases, SEQ ID NO: 1 is converted to SEQ ID NO: 2 after in vivo non-enzymatic cleavage. In some cases, the release half-life of SEQ ID NO: 2 is greater than approximately 130 hours. In some cases, the release half-life of SEQ ID NO: 2 is greater than approximately 140 hours. In some cases, the release half-life of SEQ ID NO: 2 is less than 250 hours. In some cases, the release half-life of SEQ ID NO: 2 is less than 200 hours. In some cases, the release half-life of SEQ ID NO: 2 is approximately 140 hours. In some cases, the release half-life of SEQ ID NO: 2 is less than 200 hours. In some cases, the release half-life of SEQ ID NO: 2 is approximately 150 hours. In some cases, the release half-life of SEQ ID NO: 2 is less than 200 hours. In some cases, the release half-life of SEQ ID NO: 2 is approximately 160 hours.In some cases, the emission half-life of SEQ ID NO: 2 is less than 180 hours. In some cases, the emission half-life of SEQ ID NO: 2 is less than 160 hours. In some cases, the emission half-life of SEQ ID NO: 2 is approximately 100 to 500 hours. In some cases, the emission half-life of SEQ ID NO: 2 is approximately 100 to 300 hours. In some cases, the emission half-life of SEQ ID NO: 2 is approximately 100 to 250 hours. In some cases, the emission half-life of SEQ ID NO: 2 is approximately 100 to 200 hours. In some cases, the emission half-life of SEQ ID NO: 2 is approximately 150 to 500 hours. In some cases, the emission half-life of SEQ ID NO: 2 is approximately 150 to 300 hours. In some cases, the emission half-life of SEQ ID NO: 2 is approximately 150 to 250 hours. In some cases, the release half-life of SEQ ID NO: 2 is approximately 150 to 200 hours. In some cases, the release half-life of SEQ ID NO: 2 is approximately 150 to 180 hours. In some cases, the release half-life of SEQ ID NO: 2 is approximately 150 to 160 hours. In some cases, the release half-life of SEQ ID NO: 2 is approximately 100 to 150 hours. In some cases, the release half-life of SEQ ID NO: 2 is approximately 120 to 150 hours. In some cases, the release half-life of SEQ ID NO: 2 is approximately 130 to 150 hours. In some cases, the release half-life of SEQ ID NO: 2 is approximately 140 to 150 hours. In some cases, the release half-life of SEQ ID NO: 2 is approximately 228 hours. In some cases, the release half-life of SEQ ID NO: 2 is approximately 194 hours. In some cases, the release half-life of SEQ ID NO: 2 is approximately 185 hours. In some cases, the half-life of SEQ ID NO: 2 is approximately 100 to 500 hours. In some cases, the half-life of SEQ ID NO: 2 is approximately 100 to 300 hours. In some cases, the half-life of SEQ ID NO: 2 is approximately 100 to 250 hours. In some cases, the half-life of SEQ ID NO: 2 is approximately 100 to 200 hours. In some cases, the half-life of SEQ ID NO: 2 is approximately 150 to 500 hours. In some cases, the half-life of SEQ ID NO: 2 is approximately 150 to 300 hours. In some cases, the half-life of SEQ ID NO: 2 is approximately 150 to 250 hours.In some cases, the half-life of SEQ ID NO: 2 is approximately 150 to 200 hours. In some cases, the half-life of SEQ ID NO: 2 is approximately 150 to 180 hours. In some cases, the half-life of SEQ ID NO: 2 is approximately 150 to 160 hours. In some cases, the half-life of SEQ ID NO: 2 is approximately 100 to 150 hours. In some cases, the half-life of SEQ ID NO: 2 is approximately 120 to 150 hours. In some cases, the half-life of SEQ ID NO: 2 is approximately 130 to 150 hours. In some cases, the half-life of SEQ ID NO: 2 is approximately 140 to 150 hours. In some cases, the half-life of SEQ ID NO: 2 is approximately 228 hours. In some cases, SEQ ID NO: 1 has a half-life of approximately 60 hours. In some cases, SEQ ID NO: 1 has a half-life of approximately 70 hours. In some cases, SEQ ID NO: 1 has a half-life of approximately 80 hours. In some cases, SEQ ID NO: 1 has a half-life of approximately 85 hours. In some cases, SEQ ID NO: 1 has a half-life of approximately 90 hours. In some cases, SEQ ID NO: 1 has a half-life of approximately 95 hours. In some cases, SEQ ID NO: 1 has a half-life of approximately 100 hours. In some cases, SEQ ID NO: 1 has a half-life of more than approximately 60 hours. In some cases, SEQ ID NO: 1 has a half-life of more than approximately 70 hours. In some cases, SEQ ID NO: 1 has a half-life of more than approximately 80 hours. In some cases, SEQ ID NO: 1 has a half-life of more than approximately 85 hours. In some cases, SEQ ID NO: 1 has a half-life of more than approximately 90 hours. In some cases, SEQ ID NO: 1 has a half-life of more than approximately 95 hours. In some cases, SEQ ID NO: 1 has a half-life of less than approximately 120 hours. In some cases, SEQ ID NO: 1 has a half-life of less than approximately 100 hours. In some cases, SEQ ID NO: 1 has a half-life shorter than the release half-life of SEQ ID NO: 2. In some cases, for the same dose, SEQ ID NO: 1 has a half-life shorter than that of SEQ ID NO: 2. In some cases, the release half-life of SEQ ID NO: 1 is approximately 60 to 100 hours. In some cases, the release half-life of SEQ ID NO: 1 is approximately 75 to 120 hours. In some cases, the dose includes the pharmaceutical composition, and the dose is approximately 200 μg to 900 μg.In some cases, the dose includes the pharmaceutical composition and is approximately 200 μg. In some cases, the dose includes the pharmaceutical composition and is approximately 400 μg. In some cases, the dose includes the pharmaceutical composition and is approximately 600 μg. In some cases, the dose includes the pharmaceutical composition and is approximately 900 μg. In some cases, SEQ ID NO: 1 provides the time to peak drug concentration (t) at least approximately 35 hours. max ) has. In some cases, Sequence ID 1 has at least about 40 hours of t max It has. In some cases, Sequence ID 1 has at least about 45 hours of t max It has. In some cases, Sequence ID 1 is less than 60 hours. max It has. In some cases, Sequence ID 1 is less than 55 hours. max It has. In some cases, Sequence ID 1 is less than 50 hours. max It has. In some cases, Sequence ID 2 has at least about 45 hours of t max It has. In some cases, Sequence ID 2 has at least about 50 hours of t max It has. In some cases, Sequence ID 2 has at least about 55 hours of t max It has. In some cases, Sequence ID 2 has at least about 60 hours of t max It has. In some cases, Sequence ID 2 has at least about 65 hours of t max It has. In some cases, Sequence ID 2 has at least about 67 hours of t max It has. In some cases, Sequence ID 2 is less than 75 hours. max It has. In some cases, Sequence ID 2 is less than 70 hours. max It has. In some cases, Sequence ID 2 is less than 65 hours. max It has. In some cases, Sequence ID 2 is less than 60 hours. max It has. In some cases, Sequence ID 2 is less than 55 hours. max It has. In some cases, Sequence ID 1 has at least about 35 hours of tmax Sequence ID 2 has at least about 45 hours of t max In some cases, SEQ ID NO: 2 has an AUC of at least about 100 hours for a dose containing about 200 μg of SEQ ID NO: 2. In some cases, SEQ ID NO: 2 has an AUC of at least about 180 hours for a dose containing about 400 μg of SEQ ID NO: 2. In some cases, SEQ ID NO: 2 has an AUC of at least about 320 hours for a dose containing about 600 μg of SEQ ID NO: 2. In some cases, SEQ ID NO: 2 has an AUC of at least about 420 hours for a dose containing about 900 μg of SEQ ID NO: 2. In some cases, the dose may be as described elsewhere in this specification. In some cases, the pharmaceutical composition further comprises pharmaceutically acceptable excipients. In some cases, the half-life is the circulation half-life. In some cases, the half-life is the circulation half-life in the subject. In some cases, the release half-life is the time it takes for the concentration or amount of the compound in the subject to be reduced by exactly half (50%).

[0090] In some embodiments, the emission half-life (t 1 / 2 ) is the time it takes for the concentration or amount of the drug (e.g., SEQ ID NO: 2) in the subject to be reduced by exactly half (50%).

[0091] In some embodiments, compound 1 is considered a prodrug. In some embodiments, compound 2 is considered an active drug. In some cases, compound 2 is the active drug formed from compound 1.

[0092] In some embodiments, the conjugate is represented by ABQ, where ABQ is k(γE-(miniPEG)2-γE-COC16H32CO2H)(N-Me)GSVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHK(γE-(miniPEG)2-γE-COC16H32CO2H)-OH. In some cases, AB is a self-cleaving dipeptide. In some cases, AB is represented by k(γE-(miniPEG)2-γE-COC16H32CO2H)(N-Me). In some cases, Q is represented by SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHK(γE-(miniPEG)2-γE-COC16H32CO2H)-OH. In some cases, ABQ is converted to AB and Q. In some cases, AB dissociates via a cyclization pathway, forming a cyclic compound and leaving Q behind (e.g., compound 2). In some cases, cyclization occurs at physiological pH. In some cases, cyclization occurs at approximately pH 7.4. In some cases, the chemical cleavage half-life (t) of AB from ABQ is... 1 / 2 The chemical cleavage half-life can be measured as described in WO2021242756A2 (PCT / US2021 / 034055) and US20230285578A1. In some cases, the chemical cleavage half-life is measured in standard PBS solution under physiological conditions.

[0093] In some embodiments, compound 1 is (SEQ ID NO: 1)

[0094] [ka] It is represented by [this].

[0095] In some embodiments, compound 2 (SEQ ID NO: 2)

[0096] [ka] It is represented by [this].

[0097] In certain embodiments, compositions comprising a therapeutically effective amount of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3, or a pharmaceutically acceptable salt thereof, are provided herein (also referred to herein as a "pharmaceutical agent").

[0098] The pharmaceutical composition may be formulated using one or more physiologically acceptable carriers, which include excipients and adjuvants that facilitate the processing of the pharmaceutical into pharmaceutically usable preparations. The appropriate formulation depends on the chosen route of administration. An overview of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa., Mack Publishing Company, 1995), Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975, Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980, and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, 1999).

[0099] The compositions and methods of this disclosure may be used to treat individuals requiring treatment. In certain embodiments, the individuals may be mammals such as humans or non-human mammals. When administered to animals such as humans, the compositions or pharmaceuticals are preferably administered as pharmaceutical compositions comprising, for example, a pharmaceutical and a pharmaceutically acceptable carrier or excipient. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline, or other solvents or vehicles such as glycols, glycerols, oils such as olive oil, or injectable organic esters. In preferred embodiments, if such a pharmaceutical composition is for administration to humans, particularly for invasive routes of administration, such as injection or implantation, which avoid transport or diffusion across the epithelial barrier, the aqueous solution is pyrogenic or substantially pyrogenic. Excipients may be selected, for example, to result in delayed release of the drug or to selectively target one or more cells, tissues, or organs. Pharmaceutical compositions may be in dosage unit forms such as tablets, capsules, granules, lyophilized reconstituted agents, powders, liquids, syrups, suppositories, and injections. Compositions may also be present in transdermal delivery systems, such as skin patches. Compositions may also be present in solutions suitable for topical administration, such as eye drops.

[0100] Pharmacoherent excipients may include, for example, physiologically acceptable agents that act to stabilize, increase the solubility of, or increase the absorption of compounds such as pharmaceuticals. Such physiologically acceptable agents include, for example, carbohydrates such as glucose, sucrose, or dextran; antioxidants such as ascorbic acid or glutathione; chelating agents; low molecular weight proteins; or other stabilizers or excipients. The selection of pharmaceutically acceptable excipients, including physiologically acceptable agents, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) may also be, for example, a liposome or other polymer matrix in which the compounds of the present invention can be incorporated. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, and metabolizable carriers, and are relatively simple to prepare and administer.

[0101] Pharmaceutical compositions can be administered to a target by any of a number of routes of administration, including, for example, orally, as drenches, tablets, sprinkle capsules and gelatin capsules, boluses, powders, granules, pastes for application to the tongue, absorption through the oral mucosa, for example, sublingual administration, for example, as pessaries, creams or foams, administration through the anus, rectum or vagina, for example, as sterile solutions or suspensions, parenteral administration including intramuscular, intravenous, subcutaneous or intrathecal administration, intranasal administration, intraperitoneal administration, subcutaneous administration, for example, as patches applied to the skin, transdermal administration, and topical administration, for example, as creams, ointments or sprays applied to the skin or as eye drops. Compounds can also be formulated for inhalation. In certain embodiments, compounds can be simply dissolved or suspended in sterile water.

[0102] The pharmaceutical composition may be a sterile aqueous solution or non-aqueous solution, a suspension or emulsion, such as a microemulsion. The excipients described herein are examples and are not limiting. An effective dose or therapeutically effective dose refers to the amount of one or more pharmaceuticals administered to a subject as a single dose or as part of a series of doses that is effective in producing the desired therapeutic effect.

[0103] Subjects may generally be monitored for therapeutic efficacy using assays and methods appropriate to the condition being treated, assays which are well known to those skilled in the art and are described herein. The pharmacokinetics of a drug or one or more metabolites administered to a subject may be monitored by determining the levels of the drug or metabolite in biological fluids, e.g., blood, blood fractions, e.g., serum, and / or urine, and / or other biological samples or tissues derived from the subject. Any method practiced in the art to detect drugs and described herein may be used to measure the levels of the drug or metabolite during a course of treatment.

[0104] The dosage of the medicinal products described herein for treating a disease or disorder may depend on the condition of the subject, i.e., the stage of the disease, the severity of the symptoms caused by the disease, the overall health status, as well as age, sex, and weight, and other factors apparent to those skilled in the art of medicine. The medicinal composition may be administered in a manner appropriate to the disease to be treated, as determined by those skilled in the art of medicine. In addition to the factors described herein and above regarding the use of medicinal products for treating a disease or disorder, the appropriate duration and frequency of administration of the medicinal product may also be determined or adjusted by factors such as the patient's disease, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. Optimal doses of the drug may generally be determined using experimental models and / or clinical trials. The optimal dose may depend on the subject's body mass, weight, or blood volume. The use of a minimum dose sufficient to provide effective treatment is usually preferred. The design and execution of preclinical and clinical trials of medicinal products, including when administered for prophylactic benefit, as described herein, is within the ordinary art of those skilled in the art. When two or more drugs are administered to treat a disease or disorder, the optimal dose of each drug may differ, for example, be less than when either drug is administered alone as monotherapy. In certain embodiments, the two drugs in combination may act synergistically or additively, and either drug may be used in a smaller amount than when administered alone. The amount of drug that can be administered per day may be, for example, about 0.01 mg / kg to 100 mg / kg, for example, about 0.1 to 1 mg / kg, about 1 to 10 mg / kg, about 10 to 50 mg / kg, or about 50 to 100 mg / kg body weight. In other embodiments, the amount of drug that can be administered per day may be about 0.01 mg / kg to 1000 mg / kg, about 100 to 500 mg / kg, or about 500 to 1000 mg / kg body weight. The optimal daily dose or per treatment course may vary depending on the disease or disorder being treated, as well as the route of administration and treatment regimen.

[0105] Pharmaceutical compositions, including medicinal products, can be formulated in a manner suitable for a delivery method by using techniques routinely practiced in the art. The composition may be in the form of a solid, e.g., tablet, capsule; a semi-solid, e.g., gel; a liquid; or a gas, e.g., aerosol. In other embodiments, the pharmaceutical composition is administered as a bolus injection.

[0106] Pharmaceutically acceptable excipients are well known in the pharmaceutical field and are described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th Ed., 2006, and Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed., Mack Pub. Co., Easton, PA (2005)). Exemplary pharmaceutically acceptable excipients include sterile saline and phosphate-buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, etc., may be provided in pharmaceutical compositions. Furthermore, antioxidants and suspending agents may also be used. Generally, the type of excipient is selected based on the mode of administration and the chemical composition of the active ingredient. Alternatively, the compositions described herein may be formulated as lyophilizates. The compositions described herein may be lyophilized or otherwise formulated as lyophilized products using one or more suitable excipient solutions to solubilize and / or dilute the pharmaceutical composition at the time of administration. In other embodiments, the pharmaceutical may be encapsulated in liposomes using techniques known and practiced in the art. In certain embodiments, the pharmaceutical is not formulated in liposomes for application to stents used to treat arteries that are not completely occluded but are highly occluded. The pharmaceutical compositions may be formulated for any suitable mode of administration described herein and in the art.

[0107] For example, pharmaceutical compositions for oral administration or injection, infusion, subcutaneous delivery, intramuscular delivery, intraperitoneal delivery, or other methods may be in liquid form. Liquid pharmaceutical compositions may include, for example, one or more of the following: sterile diluents, such as water, saline solution, preferably saline solution, Ringer's solution, isotonic sodium chloride, a fixing oil that can function as a solvent or suspension medium, polyethylene glycol, glycerin, propylene glycol, or other solvents, antimicrobial agents, antioxidants, chelating agents, buffers for adjusting isotonicity such as sodium chloride or dextrose, and pharmaceuticals. Parenteral compositions may be sealed in glass or plastic ampoules, disposable syringes, or multi-dose vials. The use of saline solution is preferred, and pharmaceutical compositions for injection are preferably sterile. In another embodiment, for the treatment of ophthalmic diseases or disorders, liquid pharmaceutical compositions may be applied to the eye in the form of eye drops. Liquid pharmaceutical compositions can be delivered orally.

[0108] For oral formulations, at least one of the pharmaceuticals described herein may be used alone or in combination with suitable additives for making tablets, powders, granules, or capsules, and optionally with diluents, buffers, wetting agents, preservatives, colorants, and flavoring agents. Pharmaceuticals may be formulated with buffers to protect the compound from the low pH environment in the stomach and / or from enteric coatings. Pharmaceuticals contained in pharmaceutical compositions may be formulated for oral delivery, for example, with flavoring agents in liquid, solid, or semi-solid formulations and / or with enteric coatings.

[0109] Pharmaceutical compositions comprising any one of the pharmaceuticals described herein may be formulated as sustained release or slow release, also known as timed release or controlled release. Such compositions are generally prepared using well-known techniques and may be administered, for example, by oral, rectal, intradermal, or subcutaneous implantation, or by implantation into a desired target site. Sustained-release formulations may contain the compound dispersed in a carrier matrix and / or contained in a reservoir surrounded by a rate-controlling membrane. Excipients for use in such formulations may be biocompatible and biodegradable, and preferably, the formulation provides a relatively constant level of release of the active ingredient. The amount of pharmaceutical contained in a sustained-release formulation depends on the implantation site, the rate of release and the expected duration, as well as the nature of the disease, disorder, or condition being treated or prevented.

[0110] In certain embodiments, pharmaceutical compositions containing a pharmaceutical product are formulated for transdermal, intradermal, or topical administration. The composition may be administered as a powder / talc or other solid, liquid, spray, aerosol, ointment, foam, cream, gel, or paste using a syringe, bandage, transdermal patch, insert, or syringe-like applicator. This is preferably in the form of a controlled-release or sustained-release formulation administered topically or directly injected into the skin adjacent to or within the area being treated, for example, intradermally or subcutaneously. The active composition may be delivered via iontophoresis. Antiseptics may be used to prevent the growth of fungi and other microorganisms. Suitable preservatives include, but are not limited to, benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, thimerosal, and combinations thereof.

[0111] Pharmaceutical compositions, including pharmaceuticals, may be formulated as emulsions for topical application. An emulsion contains one liquid dispersed in another. The emulsion may be an oil-in-water emulsion or a water-in-oil emulsion. Either or both of the oil and / or aqueous phases may contain one or more surfactants, emulsifiers, emulsifying stabilizers, buffers, and other excipients. The oil phase may contain other oily, pharmaceutically approved excipients. Suitable surfactants include, but are not limited to, anionic surfactants, non-ionic surfactants, cationic surfactants, and amphoteric surfactants. Compositions for topical application may also contain at least one suitable suspending agent, antioxidant, chelating agent, emollient, or wetting agent.

[0112] Ointments and creams can be formulated using, for example, an aqueous or oily base with appropriate thickeners and / or gelling agents added. Lotions can be formulated using an aqueous or oily base and generally also contain one or more emulsifiers, stabilizers, dispersants, suspenders, thickeners, or colorants. Liquid sprays can be delivered from a pressurized pack, for example, via a specially shaped closure. Oil-in-water emulsions can also be used in compositions, patches, bandages, and products. These systems are semi-solid emulsions, microemulsions, or foaming emulsion systems.

[0113] In some embodiments, the pharmaceuticals described herein may be formulated as inhaled agents. Inhaled methods allow for direct delivery of the drug to the airways. The pharmaceuticals may be formulated as aerosols, microspheres, liposomes, or nanoparticles. The pharmaceuticals may be formulated with solvents, gases, nitrates, or any combination thereof. The compositions described herein may optionally be formulated for delivery as liquid aerosols or inhalable dry powders. Liquid aerosol formulations may optionally be sprayed primarily into particle sizes that can be delivered to terminal and respiratory bronchioles and respiratory bronchioles. Liquid aerosols and inhalable dry powder formulations are preferably delivered through the endobronchial tree to the terminal bronchioles and ultimately to the parenchymal tissue.

[0114] The aerosolized formulations described herein are optionally delivered using an aerosol-forming device, such as a jet, a vibrating porous plate, or an ultrasonic nebulizer, which is preferably selected to enable the formation of aerosol particles having a mass medium average diameter mainly of 1 to 5 μm. Furthermore, the formulations preferably have a balanced osmolarity ionic strength and chloride concentration, as well as a minimum aerosolizable volume capable of delivering an effective dose of the drug. In addition, the aerosolized formulations preferably do not impair airway function and do not cause undesirable side effects.

[0115] Aerosolizing devices suitable for administering the aerosol formulations described herein include, for example, jet nebulizers, vibrating porous plate nebulizers, ultrasonic nebulizers, and energized dry powder inhalers, which can atomize formulations into aerosol particle sizes predominantly in the range of 1 to 5 μm. In this application, "predominantly" means that at least 70%, preferably more than 90%, of all generated aerosol particles are in the range of 1 to 5 grams. Jet nebulizers are pneumatically operated and decompose liquid solutions into aerosol droplets. Vibrating porous plate nebulizers work by using an ultrasonic vacuum generated by a rapidly vibrating porous plate to extrude solvent droplets through the plate. Ultrasonic nebulizers work by a piezoelectric crystal that shears liquids into small aerosol droplets. For example, a variety of suitable devices are available, including AeroNebox and AeroDose® vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, California), Sidestream® nebulizers (Medic-Aid Ltd., West Sussex, England), Pari LC® and Pari LC Star® jet nebulizers (Pari Respiratory Equipment, Inc., Richmond, Virginia), Aerosonics® (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Heiden, Germany), and UltraAire® (Omron Healthcare, Inc., Vernon Hills, Illinois) ultrasonic nebulizers.

[0116] In some embodiments, the pharmaceutical may be formulated with an oily base or ointment to form a semi-solid composition having a desired shape. In addition to the pharmaceutical, these semi-solid compositions may contain dissolved and / or suspended bactericides, preservatives, and / or buffer systems. Possible petrolatum components may be any paraffin ranging in viscosity from mineral oil incorporating isobutylene, colloidal silica, or stearate to paraffin wax. Absorbent bases may be used with oily systems. Additives may include cholesterol, lanolin (lanolin derivatives), beeswax, fatty alcohols, wool wax alcohols, low HLB (hydrophobellipophobe balance) emulsifiers, and classified ionic and nonionic surfactants, either alone or in combination.

[0117] Controlled-release or sustained-release transdermal or topical formulations can be achieved by adding time-delayed-release additives, such as polymer structures and matrices available in the art. For example, compositions may be administered using hot-melt extrusion articles, such as bioadhesive hot-melt extruded films. Formulations may include cross-linked polycarboxylic acid polymer formulations. A cross-linking agent may be present in an amount that provides adequate adhesion, allowing the system to remain attached to the target epithelial or endothelial cell surface for a sufficient time to enable the desired release of the compound.

[0118] Inserts, transdermal patches, bandages, or products may include a mixture or coating of polymers that provide a drug release at a constant rate over a long period of time. In some embodiments, the product, transdermal patch, or insert may include a water-soluble pore-forming agent, such as polyethylene glycol (PEG), which can be mixed with a water-insoluble polymer to increase the durability of the insert and extend the release of the active ingredient.

[0119] Transdermal devices (inserts, patches, bandages) may also contain water-insoluble polymers. Rate-controlling polymers may be useful for administration to sites where pH changes can be used to induce release. These rate-controlling polymers can be applied using a continuous coating film during the spraying and drying process of the active compound. In one embodiment, the coating formulation is used to coat a pellet containing the active ingredient, which is compressed to form a solid biodegradable insert.

[0120] Polymer formulations can also be used to provide controlled or sustained release. Bioadhesive polymers described in the Art may be used. For example, sustained-release gels and compounds can be incorporated into polymer matrices such as hydrophobic polymer matrices. Examples of polymer matrices include microparticles. Microparticles may be microspheres, and the core may be made of a different material from the polymer shell. Alternatively, the polymer may be cast as a thin slab or film, a powder produced by grinding or other standard techniques, or a gel such as a hydrogel. The polymer may also be in the form of a coating or portion of bandages, stents, catheters, vascular grafts, or other devices to facilitate the delivery of pharmaceuticals. Matrices can be formed by solvent evaporation, spray drying, solvent extraction, and other methods known to those skilled in the art.

[0121] A kit is provided having a unit dose of one or more of the drugs described herein, typically in oral or injectable doses. Such a kit may include a container containing the unit dose, an information package insert describing the use of the drug in the treatment of a disease and the attendant benefits, and optionally an instrument or device for the delivery of the composition.

[0122] In some embodiments, the kit provides a device for administering compound 1 (SEQ ID NO: 1) or a pharmaceutical composition containing compound 1 to a patient. The kit may further include various containers, such as vials, tubes, bottles, etc. Preferably, the kit will also include instructions for use. In some cases, the device in the kit is an aerosol dispensing device, and the composition is pre-packaged within the aerosol device. In some cases, the kit includes a syringe and a needle, and in some embodiments, compound 1 or a pharmaceutical composition containing compound 1 is pre-packaged within the syringe or injection pen using a low-gauge needle having, for example, sizes 29-31.

[0123] In some embodiments, the pharmaceutical composition containing SEQ ID NO: 1 is suitable for subcutaneous administration. In some cases, the pharmaceutical composition containing SEQ ID NO: 1 is suitable for subcutaneous administration once a week.

[0124] In some embodiments, the pharmaceutical composition comprises compound 1, is suitable for weekly subcutaneous administration, and after administration of compound 2, the pharmacokinetic profile of compound 2 exhibits a peak-to-trough ratio of less than approximately 2 in plasma. In some embodiments, the pharmaceutical composition comprises SEQ ID NO: 1, is suitable for weekly subcutaneous administration, and after administration of SEQ ID NO: 1, the pharmacokinetic profile of SEQ ID NO: 2 exhibits a peak-to-trough ratio of less than approximately 2 in plasma. In some cases, the peak-to-trough ratio is less than approximately 1.8 in plasma. In some cases, the peak-to-trough ratio is less than approximately 1.6 in plasma. In some cases, the peak-to-trough ratio is greater than approximately 1.1 in plasma. In some cases, the peak-to-trough ratio is greater than approximately 1.2 in plasma. In some cases, the peak-to-trough ratio is about 1.3 in plasma. In some cases, the peak-to-trough ratio is about 1.4 in plasma. In some cases, the peak-to-trough ratio is approximately 1.5 in plasma. In some cases, the peak-to-trough ratio is approximately 1.6 in plasma. In some cases, the peak-to-trough ratio is approximately 1.7 in plasma. In some cases, the peak-to-trough ratio is approximately 1.8 in plasma. In some cases, the peak-to-trough ratio is approximately 1.9 in plasma. In some cases, the peak-to-trough ratio is approximately 2 in plasma. In some cases, the peak-to-trough ratio is approximately 1.1 to 2 in plasma. In some cases, the peak-to-trough ratio is approximately 1.1 to 1.9 in plasma. In some cases, the peak-to-trough ratio is approximately 1.1 to 1.8 in plasma. In some cases, the peak-to-trough ratio is approximately 1.1 to 1.7 in plasma. In some cases, the peak-to-trough ratio is approximately 1.1 to 1.6 in plasma. In some cases, the peak-to-trough ratio is approximately 1.1 to 1.5 in plasma. In some cases, the peak-to-trough ratio is approximately 1.1 to 1.4 in plasma. In some cases, the peak-to-trough ratio is approximately 1.1 to 1.3 in plasma.In some cases, the peak-to-trough ratio in plasma is approximately 1.1 to 1.2. In some cases, the peak-to-trough ratio in plasma is approximately 1.2 to 2. In some cases, the peak-to-trough ratio in plasma is approximately 1.2 to 1.9. In some cases, the peak-to-trough ratio in plasma is approximately 1.2 to 1.8. In some cases, the peak-to-trough ratio in plasma is approximately 1.2 to 1.7. In some cases, the peak-to-trough ratio in plasma is approximately 1.2 to 1.6. In some cases, the peak-to-trough ratio in plasma is approximately 1.2 to 1.5. In some cases, the peak-to-trough ratio in plasma is approximately 1.2 to 1.4. In some cases, the peak-to-trough ratio in plasma is approximately 1.2 to 1.3. In some cases, the peak-to-trough ratio in plasma is approximately 1.3 to 2. In some cases, the peak-to-trough ratio in plasma is approximately 1.3 to 1.9. In some cases, the peak-to-trough ratio in plasma is approximately 1.3 to 1.8. In some cases, the peak-to-trough ratio in plasma is approximately 1.3 to 1.7. In some cases, the peak-to-trough ratio in plasma is approximately 1.3 to 1.6. In some cases, the peak-to-trough ratio in plasma is approximately 1.3 to 1.5. In some cases, the peak-to-trough ratio in plasma is approximately 1.3 to 1.4. In some cases, the peak-to-trough ratio in plasma is approximately 1.4 to 2. In some cases, the peak-to-trough ratio in plasma is approximately 1.4 to 1.9. In some cases, the peak-to-trough ratio in plasma is approximately 1.4 to 1.8. In some cases, the peak-to-trough ratio in plasma is approximately 1.4 to 1.7. In some cases, the peak-to-trough ratio in plasma is approximately 1.4 to 1.6. In some cases, the peak-to-trough ratio in plasma is approximately 1.4 to 1.5. In some cases, the peak-to-trough ratio in plasma is approximately 1.5 to 2. In some cases, the peak-to-trough ratio in plasma is approximately 1.5 to 1.9.In some cases, the peak-to-trough ratio in plasma is approximately 1.5 to 1.8. In some cases, the peak-to-trough ratio in plasma is approximately 1.5 to 1.7. In some cases, the peak-to-trough ratio in plasma is approximately 1.5 to 1.6. In some cases, the peak-to-trough ratio in plasma is approximately 1.6 to 2. In some cases, the peak-to-trough ratio in plasma is approximately 1.6 to 1.9. In some cases, the peak-to-trough ratio in plasma is approximately 1.6 to 1.8. In some cases, the peak-to-trough ratio in plasma is approximately 1.6 to 1.7. In some cases, the peak-to-trough ratio in plasma is approximately 1.7 to 2. In some cases, the peak-to-trough ratio in plasma is approximately 1.7 to 1.9. In some cases, the peak-to-trough ratio is approximately 1.7 to 1.8 in plasma. In some cases, the peak-to-trough ratio is measured at the steady state after subcutaneous administration of the pharmaceutical composition. In some cases, the steady state is defined as the point at which the input mass of compound 2 is equivalent to the mass cleared from the body by clearance during any given unit time. In some cases, the steady state is defined as the point at which the input mass of compound 2 is equivalent to the mass cleared from the body by clearance 300 hours prior.

[0125] In some cases, the peak-to-trough ratio is measured approximately 250 hours before subcutaneous administration of the pharmaceutical composition. In some cases, the peak-to-trough ratio is measured approximately 200 hours before subcutaneous administration of the pharmaceutical composition. In some cases, the peak-to-trough ratio is measured approximately 48 hours after subcutaneous administration of the pharmaceutical composition. In some cases, subcutaneous administration is performed by subcutaneous injection. In some cases, subcutaneous administration is performed using a pen device. In some cases, the administration is performed on non-human primates. In some cases, the administration is performed on monkeys. In some cases, the administration is performed on mice. In some cases, the administration is performed on humans.

[0126] In some embodiments, a pharmaceutical composition is provided in which disclosed compound 1 (SEQ ID NO: 1) is selected to provide an optimized level of compound 2 (SEQ ID NO: 2) in the patient's blood / serum / plasma. In some embodiments, a pharmaceutical composition is provided in which disclosed compound 1 (SEQ ID NO: 1) is selected to provide an optimized level of compound 2 (SEQ ID NO: 2) in the plasma of a subject. In some examples, the pharmaceutical composition comprises SEQ ID NO: 1, the pharmaceutical composition is suitable for once-weekly subcutaneous administration, and SEQ ID NO: 2 provides a maximum plasma concentration (C) of approximately 6 nmol / L when a dose containing SEQ ID NO: 1 is administered to the subject. max ) has a dose of 200 μg to 900 μg. The dose may be as described elsewhere in this specification. In some cases, Sequence ID No. 2 is formed by cleavage of Sequence ID No. 1.

[0127] In some embodiments, the pharmaceutical composition includes SEQ ID NO: 1, which is suitable for once-weekly subcutaneous administration, and SEQ ID NO: 2 is present at a maximum plasma concentration of at least about 0.4 (nmol / L) (C max ) has. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 max ) is at least about 0.6 (nmol / L). In some cases, the maximum plasma concentration (C) in SEQ ID NO: 2 max ) is at least about 0.8 (nmol / L). In some cases, the maximum plasma concentration (C) in SEQ ID NO: 2 max The maximum plasma concentration (C) in SEQ ID NO: 2 is at least about 1.0 (nmol / L). In some cases, the maximum plasma concentration (C) in SEQ ID NO: 2 is... max ) is at least about 1.2 (nmol / L). In some cases, the maximum plasma concentration (C) in SEQ ID NO: 2 max The maximum plasma concentration (C) is at least about 1.3 (nmol / L). In some cases, the maximum plasma concentration (C) in SEQ ID NO: 2 max The maximum plasma concentration (C) in SEQ ID NO: 2 is at least about 1.4 nmol / L. In some cases, the maximum plasma concentration (C) in SEQ ID NO: 2 is... max The maximum plasma concentration (C) is at least about 1.5 (nmol / L). In some cases, the maximum plasma concentration (C) shown in SEQ ID NO: 2 maxThe maximum plasma concentration (C) is at least about 1.6 (nmol / L). In some cases, the maximum plasma concentration (C) in SEQ ID NO: 2 max The maximum plasma concentration (C) is at least about 1.7 nmol / L. In some cases, the maximum plasma concentration (C) is max ) is at least about 1.8 (nmol / L). In some cases, the maximum plasma concentration (C) in SEQ ID NO: 2 max ) is at least about 1.9 (nmol / L). In some cases, the maximum plasma concentration (C) in SEQ ID NO: 2 max ) is at least about 2.0 (nmol / L). In some cases, the maximum plasma concentration (C) in SEQ ID NO: 2 max The maximum plasma concentration (C) in SEQ ID NO: 2 is at least about 2.1 nmol / L. In some cases, the maximum plasma concentration (C) in SEQ ID NO: 2 is... max The maximum plasma concentration (C) in SEQ ID NO: 2 is at least approximately 2.2 nmol / L. In some cases, the maximum plasma concentration (C) in SEQ ID NO: 2 is... max The maximum plasma concentration (C) in SEQ ID NO: 2 is at least approximately 2.3 nmol / L. In some cases, the maximum plasma concentration (C) in SEQ ID NO: 2 is... max The maximum plasma concentration (C) is at least about 2.4 nmol / L. In some cases, the maximum plasma concentration (C) in SEQ ID NO: 2 max The maximum plasma concentration (C) in SEQ ID NO: 2 is at least about 2.5 nmol / L. In some cases, the maximum plasma concentration (C) in SEQ ID NO: 2 is... max The maximum plasma concentration (C) in SEQ ID NO: 2 is at least about 2.6 nmol / L. In some cases, the maximum plasma concentration (C) in SEQ ID NO: 2 is... max The maximum plasma concentration (C) in SEQ ID NO: 2 is at least approximately 2.7 nmol / L. In some cases, the maximum plasma concentration (C) in SEQ ID NO: 2 is... max The maximum plasma concentration (C) in SEQ ID NO: 2 is at least approximately 2.8 nmol / L. In some cases, the maximum plasma concentration (C) in SEQ ID NO: 2 is... max ) is at least about 2.9 (nmol / L). In some cases, the maximum plasma concentration (C) in SEQ ID NO: 2 max The maximum plasma concentration (C) in SEQ ID NO: 2 is at least approximately 3.0 (nmol / L). In some cases, the maximum plasma concentration (C) in SEQ ID NO: 2 is... max ) is at least about 3.1 (nmol / L). In some cases, the maximum plasma concentration (C) in SEQ ID NO: 2 max) is at least about 3.2(nmol / L). In some cases, the maximum plasma concentration (C max ) is at most about 5.0(nmol / L). In some cases, the maximum plasma concentration (C max ) is at most about 4.0(nmol / L). In some cases, the maximum plasma concentration (C max ) is at most about 3.9(nmol / L). In some cases, the maximum plasma concentration (C max ) is at most about 3.8(nmol / L). In some cases, the maximum plasma concentration (C max ) is at most about 3.7(nmol / L). In some cases, the maximum plasma concentration (C max ) is at most about 3.6(nmol / L). In some cases, the maximum plasma concentration (C max ) is at most about 3.5(nmol / L). In some cases, the maximum plasma concentration (C max ) is at most about 3.4(nmol / L). In some cases, the maximum plasma concentration (C max ) is at most about 3.3(nmol / L). In some cases, the maximum plasma concentration (C max ) is at most about 3.2(nmol / L). In some cases, the maximum plasma concentration (C max ) is at most about 3.1(nmol / L). In some cases, the maximum plasma concentration (C max ) is at most about 3.0(nmol / L). In some cases, the maximum plasma concentration (C max ) is at most about 2.0(nmol / L). In some cases, the maximum plasma concentration (C max ) is about 0.6(nmol / L) to 4.0(nmol / L). In some cases, the maximum plasma concentration (C max ) is about 0.8(nmol / L) to 3.2(nmol / L). In some cases, the maximum plasma concentration (C maxThe ) is approximately 0.8 (nmol / L) to 2.4 (nmol / L). In some cases, the maximum plasma concentration (C) in SEQ ID NO: 2 max The ) is approximately 0.8 (nmol / L) to 1.3 (nmol / L). In some cases, the maximum plasma concentration (C) in SEQ ID NO: 2 max ) is approximately 0.8 (nmol / L). In some cases, the maximum plasma concentration (C) in SEQ ID NO: 2 max The concentration is approximately 1.3 nmol / L. In some cases, the maximum plasma concentration (C) in SEQ ID NO: 2 is... max The concentration is approximately 2.4 nmol / L. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 max The concentration is approximately 3.2 nmol / L.

[0128] In some embodiments, the pharmaceutical composition comprises SEQ ID NO: 1, which is suitable for once-weekly subcutaneous administration, and SEQ ID NO: 1 has a maximum plasma concentration of at least about 2.0 (nmol / L) (C max ) has. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1. max The maximum plasma concentration (C) of SEQ ID NO: 1 is at least approximately 3.0 nmol / L. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is at least approximately 3.0 nmol / L. max The maximum plasma concentration (C) is at least about 4.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 max The maximum plasma concentration (C) of SEQ ID NO: 1 is at least approximately 5.0 nmol / L. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The maximum plasma concentration (C) of SEQ ID NO: 1 is at least about 6.0 nmol / L. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The maximum plasma concentration (C) of SEQ ID NO: 1 is at least about 7.0 nmol / L. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max ) is at least about 8.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 max ) is at least about 9.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 max The maximum plasma concentration (C) is at least about 10.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 maxThe maximum plasma concentration (C) of SEQ ID NO: 1 is at least approximately 11.0 nmol / L. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The maximum plasma concentration (C) is at least about 12.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 max ) is at least about 13.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 max The maximum plasma concentration (C) is at least about 14.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 max The maximum plasma concentration (C) is at least about 15.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 max The maximum plasma concentration (C) of SEQ ID NO: 1 is at least approximately 16.0 nmol / L. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The maximum plasma concentration (C) is at least about 17.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 max The maximum plasma concentration (C) is approximately 20.0 nmol / L. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 max The maximum plasma concentration (C) of SEQ ID NO: 1 is at least approximately 19.0 nmol / L. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The maximum plasma concentration (C) of SEQ ID NO: 1 is at least approximately 19.0 nmol / L. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The maximum plasma concentration (C) of SEQ ID NO: 1 is at least approximately 18.0 nmol / L. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The maximum plasma concentration (C) is at least about 17.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 max The maximum plasma concentration (C) of SEQ ID NO: 1 is at least approximately 16.0 nmol / L. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The maximum plasma concentration (C) is at least about 15.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 max The maximum plasma concentration (C) is at least about 14.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 max ) is at least about 13.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 maxThe maximum plasma concentration (C) is at least about 12.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 max The maximum plasma concentration (C) of SEQ ID NO: 1 is at least approximately 11.0 nmol / L. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The maximum plasma concentration (C) is at least about 10.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 max ) is at least about 9.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 max ) is at least about 8.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 max The maximum plasma concentration (C) of SEQ ID NO: 1 is at least about 7.0 nmol / L. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The maximum plasma concentration (C) of SEQ ID NO: 1 is at least about 6.0 nmol / L. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The maximum plasma concentration (C) of SEQ ID NO: 1 is at least approximately 5.0 nmol / L. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The maximum plasma concentration (C) is at least about 4.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 max ) is at least about 3.0 (nmol / L). In some cases, C for SEQ ID NO: 1 is equal to SEQ ID NO: 2. max The ratio is at least about 4. In some cases, C for sequence number 1 relative to sequence number 2. max The ratio is at most about 6. In some cases, C for sequence number 1 relative to sequence number 2. max The ratio is approximately 4. In some cases, C for sequence number 1 relative to sequence number 2. max The ratio is approximately 4.2. In some cases, C for sequence number 1 relative to sequence number 2. max The ratio is approximately 5.4. In some cases, C for sequence number 1 relative to sequence number 2. max The ratio is approximately 5.5. In some cases, C for sequence number 1 relative to sequence number 2. max The ratio is approximately 4 to 6.

[0129] Treatment method In one embodiment, the present disclosure provides a method for treating a subject having hypoparathyroidism, osteoporosis, or osteopenia, the method comprising administering to the subject a dose of at least about 30 micrograms (μg) once a week, the dose comprising SEQ ID NO: 1. In some embodiments, a method is provided for treating a subject having hypoparathyroidism, osteoporosis, or osteopenia, the method comprising administering to the subject a dose of at least about 30 μg once a week, the dose comprising a pharmaceutical composition comprising SEQ ID NO: 1. In some embodiments, a method is provided for treating a subject having hypoparathyroidism, the method comprising administering to the subject a dose of at least about 30 μg once a week, the dose comprising a pharmaceutical composition comprising SEQ ID NO: 1. In some embodiments, a method is provided for treating a subject having hypoparathyroidism, the method comprising administering to the subject a dose of at least about 30 μg once a week, the dose comprising a pharmaceutical composition comprising SEQ ID NO: 1, the dose comprising SEQ ID NO: 2 having a release half-life of more than about 100 hours. In some cases, the dose is at least about 50 μg. In some cases, the dose is at least about 100 μg. In some cases, the dose is at least about 200 μg. In some cases, the dose is at least about 300 μg. In some cases, the dose is at least about 400 μg. In some cases, the dose is at least about 500 μg. In some cases, the dose is at least about 600 μg. In some cases, the dose is up to about 1000 μg. In some cases, the dose is up to about 900 μg. In some cases, the dose is up to about 700 μg. In some cases, the dose is up to about 600 μg. In some cases, the dose is up to about 500 μg. In some cases, the dose is up to about 460 μg. In some cases, the dose is up to about 400 μg. In some cases, the dose is approximately 50 μg, 150 μg, 200 μg, 300 μg, 400 μg, 460 μg, 600 μg, or 900 μg. In some cases, the dose is approximately 50 μg. In some cases, the dose is approximately 150 μg. In some cases, the dose is approximately 200 μg.In some cases, the dose is approximately 300 μg. In some cases, the dose is approximately 400 μg. In some cases, the dose is approximately 460 μg. In some cases, the dose is approximately 600 μg. In some cases, the dose is approximately 900 μg. In some cases, the dose is less than approximately 1000 μg. In some cases, the dose is less than approximately 900 μg. In some cases, the dose is less than 600 μg. In some cases, the dose is approximately 30 μg to 1000 μg. In some cases, the dose is approximately 30 μg to 900 μg. In some cases, the dose is approximately 30 μg to 800 μg. In some cases, the dose is approximately 30 μg to 700 μg. In some cases, the dose is approximately 30 μg to 600 μg. In some cases, the dose is approximately 30 μg to 500 μg. In some cases, the dose is approximately 30 μg to 400 μg. In some cases, the dose is approximately 30 μg to 300 μg. In some cases, the dose is approximately 30 μg to 200 μg. In some cases, the dose is approximately 30 μg to 100 μg. In some cases, the dose is approximately 30 μg to 50 μg. In some cases, the dose is approximately 50 μg to 1000 μg. In some cases, the dose is approximately 50 μg to 900 μg. In some cases, the dose is approximately 50 μg to 800 μg. In some cases, the dose is approximately 50 μg to 700 μg. In some cases, the dose is approximately 50 μg to 600 μg. In some cases, the dose is approximately 50 μg to 500 μg. In some cases, the dose is approximately 50 μg to 460 μg. In some cases, the dose is approximately 50 μg to 400 μg. In some cases, the dose is approximately 50 μg to 300 μg. In some cases, the dose is approximately 50 μg to 200 μg. In some cases, the dose is approximately 50 μg to 100 μg. In some cases, the dose is approximately 50 μg to 75 μg. In some cases, the dose is approximately 100 μg to 1000 μg. In some cases, the dose is approximately 100 μg to 900 μg. In some cases, the dose is approximately 100 μg to 800 μg. In some cases, the dose is approximately 100 μg to 700 μg.In some cases, the dose is approximately 100 μg to 600 μg. In some cases, the dose is approximately 100 μg to 500 μg. In some cases, the dose is approximately 100 μg to 460 μg. In some cases, the dose is approximately 100 μg to 400 μg. In some cases, the dose is approximately 100 μg to 300 μg. In some cases, the dose is approximately 100 μg to 200 μg. In some cases, the dose is approximately 100 μg to 100 μg. In some cases, the dose is approximately 100 μg to 75 μg. In some cases, the dose is approximately 200 μg to 1000 μg. In some cases, the dose is approximately 200 μg to 900 μg. In some cases, the dose is approximately 200 μg to 800 μg. In some cases, the dose is approximately 200 μg to 700 μg. In some cases, the dose is approximately 200 μg to 600 μg. In some cases, the dose is approximately 200 μg to 500 μg. In some cases, the dose is approximately 200 μg to 460 μg. In some cases, the dose is approximately 200 μg to 400 μg. In some cases, the dose is approximately 200 μg to 300 μg. In some cases, the dose is approximately 300 μg to 1000 μg. In some cases, the dose is approximately 300 μg to 900 μg. In some cases, the dose is approximately 300 μg to 800 μg. In some cases, the dose is approximately 300 μg to 700 μg. In some cases, the dose is approximately 300 μg to 600 μg. In some cases, the dose is approximately 300 μg to 500 μg. In some cases, the dose is approximately 300 μg to 460 μg. In some cases, the dose is approximately 300 μg to 400 μg. In some cases, the dose is approximately 400 μg to 1000 μg. In some cases, the dose is approximately 400 μg to 900 μg. In some cases, the dose is approximately 400 μg to 800 μg. In some cases, the dose is approximately 400 μg to 700 μg. In some cases, the dose is approximately 400 μg to 600 μg. In some cases, the dose is approximately 400 μg to 500 μg. In some cases, the dose is approximately 400 μg to 460 μg. In some cases, the dose is approximately 460 μg to 1000 μg.In some cases, the dose is approximately 460 μg to 900 μg. In some cases, the dose is approximately 460 μg to 800 μg. In some cases, the dose is approximately 460 μg to 700 μg. In some cases, the dose is approximately 460 μg to 600 μg. In some cases, the dose is approximately 460 μg to 500 μg. In some cases, the dose is approximately 500 μg to 1000 μg. In some cases, the dose is approximately 500 μg to 900 μg. In some cases, the dose is approximately 500 μg to 800 μg. In some cases, the dose is approximately 500 μg to 700 μg. In some cases, the dose is approximately 500 μg to 600 μg. In some cases, the dose is approximately 600 μg to 1000 μg. In some cases, the dose is approximately 600 μg to 900 μg. In some cases, the dose is approximately 600 μg to 800 μg. In some cases, the dose is approximately 600 μg to 700 μg. In some cases, the dose is approximately 700 μg to 1000 μg. In some cases, the dose is approximately 700 μg to 900 μg. In some cases, the dose is approximately 700 μg to 800 μg. In some cases, the method is for treating hypoparathyroidism in subjects requiring treatment for hypoparathyroidism. In some cases, the method is for treating osteoporosis or osteopenia in subjects requiring treatment for osteoporosis or osteopenia. In some cases, the dose is administered once a week for two weeks. In some cases, the dose is administered once a week for three weeks. In some cases, the dose is administered once a week for four weeks. In some cases, the dose is administered once a week for 5 weeks. In some cases, the dose is administered once a week for 6 weeks. In some cases, the dose is administered once a week for 7 weeks. In some cases, the dose is administered once a week for 8 weeks. In some cases, the dose is administered once a week for 9 weeks. In some cases, the dose is administered once a week for 10 weeks. In some cases, the dose is administered once a week for 11 weeks. In some cases, the dose is administered once a week for 12 weeks. In some cases, the dose is administered once a week for 13 weeks.In some cases, the dose is administered once a week for 14 weeks. In some cases, the dose is administered once a week for 15 weeks. In some cases, the dose is administered once a week for 16 weeks. In some cases, the dose is administered once a week for 17 weeks. In some cases, the dose is administered once a week for 18 weeks. In some cases, the dose is administered once a week for 19 weeks. In some cases, the dose is administered once a week for 20 weeks. In some cases, the dose is administered once a week for 21 weeks. In some cases, the dose is administered once a week for 22 weeks. In some cases, the dose is administered once a week for 23 weeks. In some cases, the dose is administered once a week for 24 weeks. In some cases, the dose is administered once a week for 25 weeks. In some cases, the dose is administered once a week for 26 weeks. In some cases, the dose is administered once a week for 27 weeks. In some cases, the dose is administered once a week for 28 weeks. In some cases, the dose is administered once a week for 29 weeks. In some cases, the dose is administered once a week for 30 weeks. In some cases, the dose is administered once a week for 31 weeks. In some cases, the dose is administered once a week for 32 weeks. In some cases, the dose is administered once a week for 33 weeks. In some cases, the dose is administered once a week for 34 weeks. In some cases, the dose is administered once a week for 35 weeks. In some cases, the dose is administered once a week for 36 weeks. In some cases, the dose is administered once a week for 37 weeks. In some cases, the dose is administered once a week for 38 weeks. In some cases, the dose is administered once a week for 39 weeks. In some cases, the dose is administered once a week for 40 weeks. In some cases, the dose is administered once a week for 41 weeks. In some cases, the dose is administered once a week for 42 weeks. In some cases, the dose is administered once a week for 43 weeks. In some cases, the dose is administered once a week for 44 weeks. In some cases, the dose is administered once a week for 45 weeks. In some cases, the dose is administered once a week for 46 weeks. In some cases, the dose is administered once a week for 47 weeks.In some cases, the dose is administered once a week for 48 weeks. In some cases, the dose is administered once a week for 49 weeks. In some cases, the dose is administered once a week for 50 weeks. In some cases, the dose is administered once a week for 51 weeks. In some cases, the dose is administered once a week for 52 weeks. In some cases, the dose is administered once a week for one year. In some cases, the dose is administered once a week for two weeks. It is administered annually. In some cases, the dosage is once a week for three years. In some cases, the dosage is once a week for four years. In some cases, the dosage is once a week for five years.

[0130] In some embodiments, the dose is administered once a week for eight weeks as a fixed dose, followed by a four-week titration period. In some cases, the fixed dose is approximately 400 μg to approximately 800 μg. In some cases, the fixed dose is 400 μg. In some cases, the fixed dose is 600 μg. In some cases, the fixed dose is 800 μg. The four-week titration period is an up-titration for subjects who cannot discontinue active vitamin D and / or reduce calcium supplements.

[0131] In some embodiments, the Disclosure provides a method for treating a subject having a disease or illness associated with an insufficient level of PTH (hypoparathyroidism), or a disease that responds to PTH therapy, such as osteoporosis, the method comprising administering to the subject a dose of at least about 30 μg once weekly, the dose comprising SEQ ID NO: 1. In some cases, the amount of the dose may be as described elsewhere in this Spec. In some cases, a method for treating hypoparathyroidism is provided, in which a patient requiring treatment for hypoparathyroidism is administered compound 1 (SEQ ID NO: 1) in an amount effective in treating or preventing hypoparathyroidism or alleviating a medical condition associated with hypoparathyroidism, according to any of the methods described herein.

[0132] In some embodiments, the subject requiring treatment has osteoporosis. In some embodiments, the subject requiring treatment has osteopenia. In some cases, the subject requiring treatment is a postmenopausal woman. In some cases, the subject requiring treatment has glucocorticoid-induced osteoporosis. In some cases, the subject requiring treatment has glucocorticoid-induced osteopenia.

[0133] In some embodiments, a method for treating osteoporosis is provided, which includes the step of treating a subject in need of treatment for osteoporosis by weekly subcutaneous injection of compound 1 (SEQ ID NO: 1) described in this disclosure.

[0134] In some embodiments, a method for treating renal impairment is provided, which includes the step of treating a subject requiring treatment for renal impairment by weekly subcutaneous injection of compound 1 (SEQ ID NO: 1) described in this disclosure.

[0135] In some embodiments, a method for treating renal failure is provided, which includes the step of treating a subject requiring treatment for renal failure by weekly subcutaneous injection of compound 1 (SEQ ID NO: 1) described in this disclosure.

[0136] In another embodiment, the Disclosure provides a method for treating osteoporosis, the method comprising the step of treating a subject in need of treatment for osteoporosis by weekly subcutaneous injection of compound 1 (SEQ ID NO: 1) described in the Disclosure.

[0137] In some embodiments, type I collagen telopeptides can be used as bone resorption biomarkers. In some cases, the bone resorption biomarkers are selected from carboxy-terminal crosslinked (CTX-1) and amino-terminal crosslinked (NTX-1) forms. In some cases, both CTX-1 and NTX-1 are released during collagen degradation. In some cases, ELISA can be used to measure CTX-1 using a monoclonal antibody against the octapeptide sequence in the α-1(I) chain of the β-isoform (EKAHD-β-GGR). In some cases, CTX-1 is a specific and sensitive biomarker of bone resorption that can rapidly indicate a response to bisphosphonate therapy for postmenopausal osteoporosis. In some cases, serum CTX-1 is affected by food intake, and since food intake substantially reduces CTX-1 levels, blood withdrawal must be performed in a fasting state.

[0138] In some embodiments, a method is provided for treating a subject having hypoparathyroidism, the method comprising the steps of (a) determining the subject's CTX-1 level after administering SEQ ID NO: 1 once weekly to the subject, and (b) providing the subject with a continued weekly dose of SEQ ID NO: 1, wherein the CTX-1 level is less than approximately 900 pg / mL. In some cases, the CTX-1 level is less than approximately 850 pg / mL. In some cases, the CTX-1 level is less than approximately 800 pg / mL. In some cases, the CTX-1 level is less than approximately 700 pg / mL. In some cases, the CTX-1 level is less than approximately 600 pg / mL. In some cases, the CTX-1 level is less than approximately 500 pg / mL. In some cases, the CTX-1 level is less than approximately 450 pg / mL. In some cases, the CTX-1 level is less than approximately 400 pg / mL. In some cases, the CTX-1 level is less than approximately 300 pg / mL. In some cases, the CTX-1 level is less than approximately 200 pg / mL. In some cases, the CTX-1 level is greater than approximately 100 pg / mL. In some cases, the CTX-1 level is greater than approximately 200 pg / mL. In some cases, the CTX-1 level is greater than approximately 300 pg / mL. In some cases, the CTX-1 level is greater than approximately 400 pg / mL. In some cases, the CTX-1 level is greater than approximately 500 pg / mL. In some cases, the CTX-1 level is greater than approximately 600 pg / mL. In some cases, the CTX-1 level is greater than approximately 700 pg / mL. In some cases, the CTX-1 level is between approximately 50 pg / mL and approximately 1000 pg / mL. In some cases, CTX-1 levels are approximately 50 pg / mL to 900 pg / mL. In some cases, CTX-1 levels are approximately 50 pg / mL to 800 pg / mL. In some cases, CTX-1 levels are approximately 50 pg / mL to 700 pg / mL. In some cases, CTX-1 levels are approximately 50 pg / mL to 600 pg / mL. In some cases, CTX-1 levels are approximately 50 pg / mL to 500 pg / mL.In some cases, the CTX-1 level is approximately 50 pg / mL to 400 pg / mL. In some cases, the CTX-1 level is approximately 50 pg / mL to 300 pg / mL. In some cases, the CTX-1 level is approximately 200 pg / mL to 1000 pg / mL. In some cases, the CTX-1 level is approximately 200 pg / mL to 900 pg / mL. In some cases, the CTX-1 level is approximately 200 pg / mL to 800 pg / mL. In some cases, the CTX-1 level is approximately 200 pg / mL to 700 pg / mL. In some cases, the CTX-1 level is approximately 200 pg / mL to 600 pg / mL. In some cases, the CTX-1 level is approximately 200 pg / mL to 500 pg / mL. In some cases, the CTX-1 level is approximately 200 pg / mL to 400 pg / mL. In some cases, the CTX-1 level is approximately 200 pg / mL to 300 pg / mL. In some cases, the CTX-1 level is approximately 300 pg / mL to 1000 pg / mL. In some cases, the CTX-1 level is approximately 300 pg / mL to 900 pg / mL. In some cases, the CTX-1 level is approximately 300 pg / mL to 800 pg / mL. In some cases, the CTX-1 level is approximately 300 pg / mL to 700 pg / mL. In some cases, the CTX-1 level is approximately 300 pg / mL to 600 pg / mL. In some cases, the CTX-1 level is approximately 300 pg / mL to 500 pg / mL. In some cases, the CTX-1 level is approximately 500 pg / mL to 1000 pg / mL. In some cases, the CTX-1 level is approximately 500 pg / mL to 900 pg / mL. In some cases, the CTX-1 level is approximately 500 pg / mL to 800 pg / mL. In some cases, the CTX-1 level is approximately 500 pg / mL to 700 pg / mL. In some cases, the CTX-1 level is approximately 500 pg / mL to 600 pg / mL. In some cases, the dose of SEQ ID NO: 1 is 1000 μg or less once a week.In some cases, the dose of SEQ ID NO: 1 is once a week, as described elsewhere in this specification. In some cases, the determination step further includes obtaining a biological sample from the subject and measuring the level of CTX-1 in the sample from the subject. In some cases, the method further includes (c) administering the subject a therapeutically effective dose of an anti-resorptive medication. In some cases, the CTX-1 level is measured between 1 and 30 days. In some cases, the CTX-1 level is measured between 1 and 15 days. In some cases, the CTX-1 level is measured between 15 and 30 days. In some cases, the CTX-1 level is measured between 12 and 25 days. In some cases, the dose is 200 μg, and this dose, including SEQ ID NO: 1, is administered to the subject before determining the level of CTX-1 in the subject. In some cases, the dose is 400 μg, and this dose, including SEQ ID NO: 1, is administered to the subject before determining the level of CTX-1 in the subject. In some cases, a dose of 600 μg, including SEQ ID NO: 1, is administered to subjects before determining their CTX-1 levels. In some cases, a dose of 900 μg, including SEQ ID NO: 1, is administered to subjects before determining their CTX-1 levels. In some cases, CTX-1 levels are measured using ELISA.

[0139] In some embodiments, type I collagen may be found in the organic bone matrix (>90%) that develops in bone derived from type I procollagen. In some cases, procollagen type I is synthesized by fibroblasts and osteoblasts. In some cases, procollagen type I has N-terminal and C-terminal elongations, which are removed by specific proteases during the conversion of procollagen to collagen. In some cases, type I procollagen, including P1CP and P1NP, is subsequently conjugated into the bone matrix. In some cases, P1NP, a biomarker of bone formation, is a specific indicator of type I collagen deposition. In some cases, P1NP is released into the intracellular space during type I collagen formation, and eventually exists in the bloodstream. In some cases, P1NP is typically released in trimer structures (derived from trimer collagen structures) and then rapidly degraded to monomeric form by thermal decomposition. In some cases, antibodies against P1NP are used to detect the trimer structure of P1NP by enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay. In some cases, P1NP has been demonstrated to be a more sensitive bone biomarker for measuring the rate of bone formation in osteoporosis.

[0140] In some embodiments, a method is provided for treating a subject having hypoparathyroidism, the method comprising: (a) determining the level of the subject's procollagen type I N-terminal propeptide (P1NP) after weekly administration of SEQ ID NO: 1 to the subject; and (b) providing the subject with a continued weekly administration of SEQ ID NO: 1, wherein the P1NP level in the subject is greater than approximately -50 μg / L. In some cases, the P1NP level in the subject is greater than approximately -40 μg / L. In some cases, the P1NP level in the subject is greater than approximately -30 μg / L. In some cases, the P1NP level in the subject is greater than approximately -20 μg / L. In some cases, the P1NP level in the subject is greater than approximately -10 μg / L. In some cases, the P1NP level in the subject is less than approximately -30 μg / L. In some cases, the P1NP level in the subject is less than approximately -20 μg / L. In some cases, the P1NP level is less than approximately -10 μg / L in the subject. In some cases, the P1NP level is less than approximately -5 μg / L in the subject. In some cases, the P1NP level is approximately -5 μg / L to -50 μg / L. In some cases, the P1NP level is approximately -5 μg / L to -40 μg / L. In some cases, the P1NP level is approximately -5 μg / L to -30 μg / L. In some cases, the P1NP level is approximately -5 μg / L to -20 μg / L. In some cases, the P1NP level is approximately -5 μg / L to -10 μg / L. In some cases, the P1NP level is approximately -10 μg / L to -50 μg / L. In some cases, the P1NP level is approximately -10 μg / L to -40 μg / L. In some cases, P1NP levels are approximately -10 μg / L to -30 μg / L. In some cases, P1NP levels are approximately -10 μg / L to -20 μg / L. In some cases, P1NP levels are approximately -20 μg / L to -50 μg / L. In some cases, P1NP levels are approximately -20 μg / L to -40 μg / L. In some cases, P1NP levels are approximately -20 μg / L to -30 μg / L. In some cases, P1NP levels are measured for 1 to 30 days.In some cases, P1NP levels are measured for 1 to 15 days. In some cases, P1NP levels are measured for 15 to 30 days. In some cases, P1NP levels are measured for 12 to 25 days. In some cases, a dose of 200 μg, containing SEQ ID NO: 1, is administered to the subject before determining the P1NP level in the subject. In some cases, a dose of 400 μg, containing SEQ ID NO: 1, is administered to the subject before determining the P1NP level in the subject. In some cases, a dose of 600 μg, containing SEQ ID NO: 1, is administered to the subject before determining the P1NP level in the subject. In some cases, a dose of 900 μg, containing SEQ ID NO: 1, is administered to the subject before determining the P1NP level in the subject. In some cases, P1NP levels are measured using an Elecsys 2010 automated analyzer.

[0141] In some embodiments, any one of the methods described herein results in an increase in the serum calcium level of the subject. In some cases, serum calcium is the maximum increase in serum calcium (E max,adj It is assessed by ( ). In some cases, serum calcium is assessed by the total serum calcium level between injections (AUEC0-τ, adj). In some cases, the maximum increase in albumin-adjusted serum calcium is observed approximately 48 hours after injection. In some cases, the increase in serum calcium is almost maximum after the third week injection.

[0142] The compounds described herein may be used in the preparation of pharmaceuticals for the prevention or treatment of diseases or illnesses. Furthermore, in a subject requiring treatment for any of the diseases or illnesses described herein, a method for treating any of the diseases or illnesses described herein includes administering to the subject a therapeutically effective dose of a pharmaceutical composition containing at least one of the compounds described herein (e.g., Compound 1), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

[0143] The compounds described herein may be administered for prophylactic and / or therapeutic purposes. In therapeutic use, the composition is administered to a subject already suffering from a disease or illness in an amount sufficient to cure or at least partially cessate the symptoms of the disease or illness. The effective amount for this use depends on the severity and course of the disease or illness, previous treatments, the subject's health status, weight, and response to the drug, as well as the judgment of the physician administering the treatment.

[0144] In some embodiments, the compounds of the Disclosure (e.g., Compound 1) may be administered alone or in combination with other agents, such as calcitonin, bisphosphonates, SERMs (e.g., raloxifene), hormone replacement therapy (HRT), calcium, vitamin D1, vitamin D2, vitamin D3, vitamin D4, and antiresorptive agents including estrogen. The compounds of the Disclosure may be administered co-administered with other agents. Alternatively, the compounds of the Disclosure may be administered sequentially with other agents, for example, the compounds of the Disclosure may be administered alone over a period of one week to one year, followed by administration of other agents either together with or in the absence of the compounds.

[0145] In prophylactic use, compositions containing the compounds described herein are administered to subjects who are susceptible to or otherwise at risk of a particular disease, disorder, or illness. Such amounts are defined as “prophylactically effective amounts or doses.” In this use, the exact amount also depends on the subject’s health condition, weight, etc. When used in a subject, the effective amount for this use depends on the severity and course of the disease, disorder, or illness, previous treatments, the subject’s health condition and response to the drug, and the judgment of the treating physician.

[0146] If the disease in question does not improve, the compound may, at the physician's discretion, be administered chronically, i.e., over the lifetime of the subject, for a long period of time, in order to improve, or otherwise control or limit the disease or symptoms of the disease in question.

[0147] Once improvement in the target disease occurs, a maintenance dose is administered as needed. Subsequently, the dose, frequency, or both may be reduced as a function of symptoms to a level at which the improved disease, disability, or condition is maintained. However, the patient may require long-term, intermittent treatment in the event of any symptom relapse.

[0148] The amount of a given drug corresponding to such quantities varies depending on factors such as the specific compound, disease, or the disease and its severity, and the identity of the subject or host requiring treatment (e.g., body weight). Nevertheless, it can be determined in a manner recognized in the art, for example, according to the specific drug administered, the route of administration, the condition being treated, and the specific circumstances surrounding the case, including the subject or host being treated. However, generally, doses used for adult human treatment are typically in the range of about 0.02 to about 5000 mg per day, and in some embodiments, about 1 to about 1500 mg per day. The desired dose may be presented as a single dose, or as divided doses administered simultaneously (or over a short period) or at appropriate intervals, for example, as sub-doses two, three, four or more times per day.

[0149] The pharmaceutical compositions described herein may be in unit dosage forms suitable for single-dose administration of precise amounts. In a unit dosage form, the formulation is divided into unit doses containing appropriate amounts of one or more compounds. A unit dose may be in the form of a package containing individual amounts of the formulation. Non-limiting examples include packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions may be packaged in single-dose, non-reclosable containers. Alternatively, reclosable containers for multiple doses may be used, typically containing preservatives in the composition. As just one example, formulations for parenteral injection may be provided in unit dosage forms, including but not limited to ampoules, or in multi-dose containers with added preservatives.

[0150] The toxicity and therapeutic efficacy of such treatment regimens are LD 50 (A lethal dose for 50% of the population) and ED 50 This can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including but not limited to determining the therapeutically effective dose in 50% of the population. The dose ratio between the toxic effect and the therapeutic effect is the therapeutic index, which is the LD 50 and ED 50 It can be expressed as a ratio between [a certain value] and [another value]. Compounds exhibiting a high therapeutic index are preferred. Data obtained from cell culture assays and animal studies can be used when formulating a range of dosages for use in humans. Doses of such compounds are preferably ED with minimal toxicity. 50 It is within the range of circulating concentrations, including [the substance]. The dosage may vary within this range depending on the dosage form used and the route of administration utilized.

[0151] In certain embodiments, the present invention provides a method for treating or preventing a disease, condition, or disease in a subject requiring treatment or prevention of such disease, condition, or disease, the method comprising administering to the subject an effective amount of one of the compounds of the embodiments of the present invention or a pharmaceutically acceptable salt thereof. The disease, condition, or disease may be selected from the group described elsewhere in this specification.

[0152] The following embodiments further illustrate the present invention, but should not be interpreted as limiting its scope. [Examples]

[0153] The following synthesis schemes are provided for illustrative purposes only, and not as an limitation. The following examples illustrate various methods for preparing the compounds described herein. Those skilled in the art will understand that these compounds can be prepared by similar methods or by combining other methods known to those skilled in the art. Those skilled in the art will also understand that they can be prepared in a manner similar to those described below, using appropriate starting materials and, if necessary, by modifying the synthesis route. Generally, starting materials and reagents can be obtained from commercial suppliers, synthesized according to sources known to those skilled in the art, or prepared as described herein.

[0154] Example 1: Synthesis Procedure Compound 1 (SEQ ID NO: 1) was synthesized using the same synthetic procedure as described in WO2021242756A2 (PCT / US2021 / 034055) and US20230285578A1.

[0155] [Table 1-1]

[0156] [Table 1-2]

[0157] Example 2: A Phase I, randomized, double-blind, placebo-controlled study evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of Compound 1 in single-dose and multiple-ascending dose studies in healthy participants. Compound 1 (SEQ ID NO: 1) was investigated as a potential therapy for the treatment of hypoparathyroidism. Compound 1 was administered subcutaneously.

[0158] Patients: Adults aged 21-60.

[0159] standard:

[0160] Inclusion Criteria: Healthy men and women aged 20-60 (including both ends of the age range) who are not likely to become pregnant. • Obesity index ranging from 20.0 to 32.0 kg / m2 (including both extremes). • Physical examination, electrocardiogram, laboratory tests, or vital signs showed no clinically significant findings. • The subject has signed informed consent.

[0161] Exclusion Criteria: • Any history of serious illness or disability. • Acute illness within 30 days of administration of the first dose of the study drug. • Positive screening results for HIV, hepatitis B, or hepatitis C. • A positive test result for a history of substance abuse (drugs or alcohol) within the past year, current substance abuse, or a drug being screened for abuse. • Use of nicotine-containing or vaping products within 3 months prior to screening or check-in. • Use of cannabis within 45 days prior to check-in. • Blood donation (donation) of blood collected within 3 months prior to screening, plasma collected within 2 weeks prior to screening, or platelets collected within 6 weeks prior to screening. • Participation in any other investigational study drug trial in which you received the investigational drug within the past 30 days.

[0162] Study Design: This study was designed to determine the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of compound 1 versus placebo in healthy participants (Figure 1).

[0163] Primary Objective: • Evaluate the safety and tolerability of compound 1 versus placebo in healthy participants. Secondary Objective: • To evaluate the pharmacokinetic and pharmacodynamic effects of compound 1 versus placebo in healthy participants.

[0164] Adverse Events:

[0165] Compound 1 demonstrated good tolerability over 4 weeks at the different doses tested (Table 2). There were no serious or treatment emergent adverse events (TEAEs). No symptomatic hypercalcemia occurred. The only adverse events leading to discontinuation of the study drug were COVID-19 in 4 cases and hypercalcemia in 2 cases. COVID-19 was the only TEAE occurring in ≥3 participants (any cohort).

[0166] [Table 2]

[0167] Example 3: PK Assessments Compound 1 was administered subcutaneously to subjects at different doses, and blood samples were collected to complete pharmacokinetic (PK) evaluations. PK evaluations were calculated using standard methods. PK data are presented in Figure 2 and Table 3 below. Compounds 1 and 2 showed linear and dose-proportional plasma concentrations.

[0168] The peak-to-trough ratio was calculated using the ratio between the highest and lowest plasma concentrations of compound 2 at steady state. As shown in Figure 2, the peak-to-trough ratio for the active drug is approximately 1.47–1.79, depending on the highest and lowest plasma concentrations.

[0169] The half-lives of compound 1 and compound 2 were calculated using standard methods and are shown in Table 3. Furthermore, Figure 2 shows that repeated administration of compound 1 leads to the accumulation of the active drug (compound 2) until a steady state is achieved.

[0170] [Table 3]

[0171] PD Assessments:

[0172] Compound 1 was subcutaneously injected into subjects at different doses, and blood samples were collected to complete pharmacodynamic (PD) evaluations. The C-terminal telopeptide (CTX) biomarker was measured and is shown in Figure 3. The procollagen type I N-terminal propeptide (P1NP) biomarker was measured and is shown in Figure 4.

[0173] PD assessment also included evaluation of changes in albumin-regulated serum calcium levels and suppression of endogenous PTH secreted by the parathyroid gland (Figure 7). Serum calcium levels were measured to assess the maximum increase in serum calcium (E max,adjThe data was evaluated in a dose-dependent and time-dependent manner by either (Figure 6A) or the total serum calcium level between injections (AUEC0-τ,adj) (Figure 6B).

[0174] Example 4: Phase 2, randomized, double-blind, placebo-controlled trial of compound 1 in adult patients with hypoparathyroidism. This study will investigate the safety, tolerability, and efficacy of three doses of compound 1 (SEQ ID NO: 1) over a 12-week period. The primary endpoint of the Phase 2 clinical trial is the proportion of patients who, after 12 weeks of treatment, can discontinue active vitamin D and reduce calcium supplements to ≤1000 mg per day while maintaining normal serum calcium levels. Secondary endpoints include the safety and tolerability of compound 1, as well as characterization of its pharmacokinetic and pharmacodynamic activity (including urinary calcium, serum phosphorus, 1,25-dihydroxyvitamin D, and bone biomarkers), and its impact on quality of life using outcome tools reported to patients. The primary goal of the Phase 2 clinical trial is to define a dose of compound 1 that is effective, safe, and well-tolerated, while enabling careful intake of active vitamin D and calcium supplements and maintaining normal serum and urinary calcium levels.

[0175] Patients will be randomized to receive weekly subcutaneous injections of placebo, as well as 400 μg, 600 μg, and 800 μg of Compound 1 (1:1:1:1). The 12-week treatment period will consist of an 8-week fixed dose period and a 4-week titration period. Patients who were unable to discontinue active vitamin D and / or reduce calcium supplements during the dose adjustment period may have their investigational drug dose increased using a protocol-specified algorithm. Patients who complete the 12-week treatment period will be eligible to participate in a 104-week long-term extension study.

Claims

1. A pharmaceutical composition comprising Sequence ID No. 1, wherein the pharmaceutical composition is suitable for subcutaneous administration once a week, and Sequence ID No. 2 has a release half-life of more than approximately 100 hours.

2. The pharmaceutical composition according to claim 1, wherein the release half-life is more than approximately 130 hours.

3. The pharmaceutical composition according to claim 1 or 2, wherein the release half-life is more than approximately 140 hours.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the release half-life is less than 250 hours.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the release half-life is less than 200 hours.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein Sequence ID 2 is generated in vivo by the self-cleavage of Sequence ID 1.

7. A pharmaceutical composition according to any one of claims 1 to 6, further comprising a pharmaceutically acceptable excipient.

8. A pharmaceutical composition according to any one of claims 1 to 7, for use in the treatment of hypoparathyroidism in subjects requiring treatment for hypoparathyroidism.

9. A pharmaceutical composition according to any one of claims 1 to 7, for use in the treatment of osteoporosis or osteopenia in subjects requiring treatment for osteoporosis or osteopenia.

10. A method for treating hypoparathyroidism, the method comprising the step of administering a pharmaceutical composition according to any one of claims 1 to 7 to a subject requiring treatment for hypoparathyroidism.

11. A method for treating osteoporosis or osteopenia, the method comprising the step of administering a pharmaceutical composition according to any one of claims 1 to 7 to a subject requiring treatment for osteoporosis or osteopenia.

12. A method for treating a subject having hypoparathyroidism, osteoporosis, or osteopenia, the method comprising administering to the subject a dose of at least about 30 μg once a week, wherein the dose comprises the pharmaceutical composition according to any one of claims 1 to 7.

13. A method for treating a subject having hypoparathyroidism, osteoporosis, or osteopenia, the method comprising administering to the subject a dose of at least about 30 μg once a week, wherein the dose comprises SEQ ID NO:

1.

14. The method according to claim 13, wherein the dose is at least about 50 μg.

15. The method according to claim 13 or 14, wherein the dose is at least about 200 μg.

16. The method according to any one of claims 13 to 15, wherein the dose is at least about 400 μg.

17. The method according to any one of claims 13 to 16, wherein the dose is a maximum of about 1000 μg.

18. The method according to any one of claims 13 to 17, wherein the dose is a maximum of about 900 μg.

19. The method according to any one of claims 13 to 18, wherein the dose is a maximum of about 600 μg.

20. The method according to claim 13, wherein the dose is approximately 50 μg, approximately 150 μg, approximately 200 μg, approximately 300 μg, approximately 400 μg, approximately 460 μg, approximately 600 μg, or approximately 900 μg.

21. The method according to claim 13, wherein the dose is approximately 50 μg.

22. The method according to claim 13, wherein the dose is approximately 150 μg.

23. The method according to claim 13, wherein the dose is approximately 200 μg.

24. The method according to claim 13, wherein the dose is approximately 300 μg.

25. The method according to claim 13, wherein the dose is approximately 400 μg.

26. The method according to claim 13, wherein the dose is approximately 460 μg.

27. The method according to claim 13, wherein the dose is approximately 600 μg.

28. The method according to claim 13, wherein the dose is approximately 900 μg.

29. The method according to any one of claims 13 to 28, for treating hypoparathyroidism in a subject requiring treatment for hypoparathyroidism.

30. The method according to any one of claims 13 to 28, for treating osteoporosis or osteopenia in subjects requiring treatment for osteoporosis or osteopenia.

31. A pharmaceutical composition comprising Sequence ID No. 1, wherein the pharmaceutical composition is suitable for subcutaneous administration once a week, and after administration of Sequence ID No. 1, the pharmacokinetic profile of Sequence ID No. 2 exhibits a peak-to-trough ratio of less than approximately 2 in plasma.

32. The pharmaceutical composition according to claim 31, wherein the peak-to-trough ratio in plasma is less than approximately 1.

8.

33. The pharmaceutical composition according to claim 31 or 32, wherein the peak-to-trough ratio in plasma is less than approximately 1.

6.

34. The pharmaceutical composition according to any one of claims 31 to 33, wherein the peak-to-trough ratio in plasma is greater than approximately 1.

1.

35. The pharmaceutical composition according to any one of claims 31 to 34, wherein the peak-to-trough ratio in plasma is greater than approximately 1.

2.

36. The pharmaceutical composition according to any one of claims 31 to 35, wherein the peak-to-trough ratio in plasma is approximately 1.

4.

37. The pharmaceutical composition according to any one of claims 31 to 35, wherein the peak-to-trough ratio in plasma is approximately 1.

5.

38. The pharmaceutical composition according to any one of claims 31 to 37, wherein the peak-to-trough ratio is measured in a steady state after subcutaneous administration of the pharmaceutical composition.

39. The pharmaceutical composition according to any one of claims 31 to 38, wherein the peak-to-trough ratio is measured approximately 250 hours after subcutaneous administration of the pharmaceutical composition.

40. The pharmaceutical composition according to any one of claims 31 to 39, wherein the peak-to-trough ratio is measured approximately 200 hours after subcutaneous administration of the pharmaceutical composition.

41. The pharmaceutical composition according to any one of claims 31 to 40, wherein the peak-to-trough ratio is measured approximately 48 hours after subcutaneous administration of the pharmaceutical composition.

42. The pharmaceutical composition according to any one of claims 31 to 41, wherein the subcutaneous administration is by subcutaneous injection.

43. The pharmaceutical composition according to any one of claims 31 to 42, wherein the subcutaneous administration is performed using a pen device.

44. The pharmaceutical composition according to any one of claims 31 to 43, wherein the subcutaneous administration is to a human being.

45. The pharmaceutical composition according to any one of claims 31 to 44, wherein the subcutaneous administration is to monkeys.

46. A method for treating a subject with hypoparathyroidism, wherein the method is: (a) A step of determining the level of CTX-1 in the subject when SEQ ID NO: 1 is administered to the subject once a week, (b) A step of providing the subject with a weekly continuous dose of SEQ ID NO: 1, wherein the level of CTX-1 is less than approximately 900 pg / mL. Methods that include...

47. The method according to claim 46, wherein the level of CTX-1 is less than 400 pg / mL.

48. The method according to claim 46 or 47, wherein a dose containing SEQ ID NO: 1 is administered to the subject, and the dose is less than 1000 μg once a week.

49. The method according to any one of claims 46 to 48, wherein the determining step further comprises obtaining a biological sample from the subject and measuring the level of CTX-1 in the biological sample from the subject.

50. (c) The method according to any one of claims 46 to 49, further comprising the step of administering a bone resorption inhibitor to the subject in a therapeutically effective amount.

51. A method for treating a subject with hypoparathyroidism, wherein the method is: (a) A step of determining the level of procollagen type I N-terminal propeptide (P1NP) in the subject when SEQ ID NO: 1 is administered to the subject weekly, (b) A step of providing the subject with a weekly continuous administration of SEQ ID NO: 1, wherein the level of P1NP in the subject is greater than approximately -50 μg / L. Methods that include...

52. The method according to claim 51, wherein a dose containing SEQ ID NO: 1 is administered to the subject, and the dose is less than 1000 μg once a week.

53. The method according to claim 51 or 52, wherein the determining step further comprises obtaining a biological sample from the subject and measuring the level of P1NP in the biological sample from the subject.

54. (c) The method according to claim 53, further comprising the step of administering a bone resorption inhibitor to the subject in a therapeutically effective amount.

55. A pharmaceutical composition comprising SEQ ID NO: 1, wherein the pharmaceutical composition is suitable for subcutaneous administration once a week, and SEQ ID NO: 2 indicates that when a dose containing SEQ ID NO: 1 is administered to a target, the maximum plasma concentration (C) is approximately 6 nmol / L. ｍａｘ A pharmaceutical composition having ) and the dose being 200 μg to 900 μg.

56. The pharmaceutical composition according to claim 55, wherein the aforementioned dose is administered once a week.

57. The maximum plasma concentration (C) of Sequence ID No. 2 ｍａｘ The pharmaceutical composition according to claim 55 or 56, wherein the maximum concentration is approximately 5 nmol / L.

58. The maximum plasma concentration (C) of Sequence ID No. 2 ｍａｘ The pharmaceutical composition according to any one of claims 55 to 57, wherein the amount is at least about 0.8 nmol / L.

59. SEQ ID NO: 1 has a maximum plasma concentration of approximately 20 nmol / L (C ｍａｘ A pharmaceutical composition according to any one of claims 55 to 58, having the following characteristics:

60. SEQ ID NO: 1 indicates a maximum plasma concentration (C) of at least approximately 3 nmol / L. ｍａｘ A pharmaceutical composition according to any one of claims 55 to 59, having the following characteristics:

61. The pharmaceutical composition according to any one of claims 55 to 60, wherein the ratio of Cmax of SEQ ID NO:1 to SEQ ID NO:2 is about 3 to about 7.

62. The pharmaceutical composition according to any one of claims 55 to 61, wherein the ratio of Cmax of SEQ ID NO:1 to SEQ ID NO:2 is about 4 to about 6.

63. A pharmaceutical composition comprising Sequence ID No. 1, wherein the pharmaceutical composition is suitable for subcutaneous administration once a week, and Sequence ID No. 2 has a half-life of more than approximately 100 hours.

64. The pharmaceutical composition according to claim 63, wherein the half-life is more than approximately 130 hours.

65. The pharmaceutical composition according to claim 63 or 64, wherein the release half-life is more than approximately 140 hours.

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