WO2022257958A1 - 一种钙敏感受体激动剂的组合物及其应用 - Google Patents

一种钙敏感受体激动剂的组合物及其应用 Download PDF

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WO2022257958A1
WO2022257958A1 PCT/CN2022/097594 CN2022097594W WO2022257958A1 WO 2022257958 A1 WO2022257958 A1 WO 2022257958A1 CN 2022097594 W CN2022097594 W CN 2022097594W WO 2022257958 A1 WO2022257958 A1 WO 2022257958A1
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pharmaceutical composition
composition according
formula
compound
active ingredient
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PCT/CN2022/097594
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English (en)
French (fr)
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仝新勇
邹爱峰
王海凤
杨婷婷
杨怡
周银
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北京拓界生物医药科技有限公司
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Priority to CN202280032979.3A priority Critical patent/CN117295510A/zh
Priority to EP22819555.8A priority patent/EP4353248A1/en
Publication of WO2022257958A1 publication Critical patent/WO2022257958A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
    • A61P5/20—Drugs for disorders of the endocrine system of the parathyroid hormones for decreasing, blocking or antagonising the activity of PTH

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  • the disclosure belongs to the technical field of medicine, and relates to a composition of a calcium-sensing receptor agonist suitable for injection and an application thereof.
  • CaSR Calcium-sensing Receptor
  • GPCR G-Protein Coupled Receptor
  • parathyroid hormone In patients with chronic kidney disease, the need to achieve steady-state levels of calcium and phosphate ions results in a continuous secretion of parathyroid hormone from the parathyroid glands. This continuous secretion of parathyroid hormone is initially adaptive, but as chronic kidney disease progresses it eventually leads to parathyroid hyperplasia and excessive parathyroid hormone levels in the body and induces secondary parathyroid hormone The formation of hyperthyroidism. Studies have shown that persistent secondary hyperparathyroidism leads to the loss of calcium-sensing receptors and vitamin D receptors on the surface of parathyroid cells. These disease-induced downstream pathological effects further contribute to the dysregulation of parathyroid regulation of mineral homeostasis in the body.
  • Calcimimetic generally refers to compounds whose physiological function and mechanism of action are similar to calcium ions and can directly activate calcium-sensing receptors on the surface of parathyroid cells.
  • Cinacalcet hydrochloride is an organic small-molecule calcimimetic agent developed by Amgen, which can activate the calcium-sensing receptor on the surface of the parathyroid organ, inhibit the secretion level of parathyroid hormone and achieve the treatment of secondary parathyroid glands. Hyperfunction and other related metabolic diseases. Cinacalcet hydrochloride is clinically approved for the treatment of secondary hyperparathyroidism in dialysis patients with chronic kidney disease. Patients are administered orally, and the frequency of use is once or twice a day. The maximum dose can be 90 mg each time.
  • Cinacalcet hydrochloride has clinically demonstrated excellent efficacy in reducing plasma parathyroid hormone levels in patients with secondary hyperparathyroidism.
  • significant drug-induced side effects such as nausea, vomiting, and diarrhea associated with gastrointestinal side effects, were observed during patient use.
  • the oral administration of cinacalcet hydrochloride is a greater burden for chronic kidney disease patients on dialysis, and cinacalcet hydrochloride has been shown to inhibit cytochrome 450 and induce drug-drug interaction between.
  • calcium-sensing receptor agonist compounds that can be administered by intravenous injection, which can reduce the secretion of parathyroid hormone by activating the calcium-sensing receptor on the surface of parathyroid gland cells, thereby achieving the treatment of secondary parathyroid Hyperthyroidism and other related metabolic diseases.
  • Such calcium-sensing receptor agonist compounds can significantly improve the compliance and compliance of patients with chronic kidney disease.
  • WO2021115272 describes a series of polypeptide calcium-sensing receptor agonist compounds, wherein the compound of formula (I) has an agonist effect on human calcium-sensing receptors to reduce plasma parathyroid hormone and serum calcium ion levels, and can be used for secondary Treatment of metabolic diseases such as hyperparathyroidism and tumor-induced hypercalcemia.
  • the present disclosure provides a pharmaceutical composition of a calcium-sensing receptor agonist and its application.
  • the pharmaceutical composition provided by the disclosure has high stability, can be stored for a long time, can effectively reduce plasma parathyroid hormone, has low release level of histamine, and has few side effects.
  • the pharmaceutical composition provided by the disclosure has low sensitivity, good safety and no hemolysis in vivo.
  • the pharmaceutical composition provided by the present disclosure comprises an active ingredient, a buffer, and an osmotic pressure regulator, and the active ingredient is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
  • Amino acid sequences in this disclosure are represented by the standard one-letter or three-letter codes for amino acids, namely alanine (Ala, A), cysteine (Cys, C), arginine (Arg, R), D-2 - Aminobutyric acid (D-Abu).
  • the compound of formula (I) in the present disclosure can also be represented by the following sequence: Ac-c(C)-rr-(D-Abu)-rar-NH 2 .
  • the pH value of the composition is 2.0-3.5; in some embodiments, the pH value of the composition is 3.0-3.5; in some embodiments, the pH value of the composition is The value is 3.3.
  • the active ingredient is the hydrochloride of the compound of formula (I).
  • the number of the compound of formula (I) combined with hydrochloric acid in the hydrochloride of the compound of formula (I) can be 1-10 (can be any value between 1-10, that is, the average value), preferably
  • the number of hydrochloric acid is 4-8, more preferably 4-5
  • the optional number of hydrochloric acid includes but not limited to 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 , 8, 8.5, 9, 9.5, 10.
  • the content of the active ingredient is 1-10 mg/mL in terms of free base; in some embodiments, the content of the active ingredient is 2.5-10 mg/mL in terms of free base; in some embodiments In, the content of the active ingredient is 5 mg/mL in terms of free base, and the content of the active ingredient can be 1 mg/mL, 1.5 mg/mL, 2 mg/mL, 2.5 mg/mL, 3 mg/mL, 3.5 mg/mL in terms of free base mg/mL, 4mg/mL, 4.5mg/mL, 5mg/mL, 5.5mg/mL, 6mg/mL, 6.5mg/mL, 7mg/mL, 7.5mg/mL, 8mg/mL, 8.5mg/mL, 9mg /mL, 9.5mg/mL, 10mg/mL.
  • the buffer is selected from one or more of succinate, citrate, and phosphate; in some embodiments, the buffer is succinate.
  • the osmotic pressure regulator is selected from one or more of sodium chloride and glucose; in some embodiments, the osmotic pressure regulator is sodium chloride.
  • the pharmaceutical composition provided by the present disclosure further comprises a pH regulator, and the pH regulator is one or more of sodium hydroxide and hydrochloric acid.
  • the mass volume percentage of the buffering agent is 0.05% to 1%; in some embodiments, the mass volume percentage of the buffering agent is 0.1% to 0.5%; in some embodiments, The mass volume percentage of described buffering agent is 0.118%; Optional mass volume percentage is 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.11%, 0.115%, 0.118%, 0.12%, 0.13% %, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.35%, 0.40%, 0.45%, 0.50%.
  • the mass volume percentage of the osmotic pressure regulator is 0.5% to 2%; in some embodiments, the mass volume percentage of the osmotic pressure regulator is 0.5% to 1%; In some embodiments, the mass volume percentage of the osmotic pressure regulator is 0.85%; optional mass volume percentages are 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%.
  • the present disclosure provides a pharmaceutical composition, comprising 2.5-10 mg/m active ingredient in terms of free base, 0.1%-0.5% (w/v) buffer, 0.5%-1% (w/v) osmotic pressure regulator , the active ingredient is a compound shown in formula (I) or a pharmaceutically acceptable salt thereof, and in some embodiments the active ingredient is a hydrochloride salt of a compound of formula (I):
  • the buffering agent is one or more of succinate, citrate, and phosphate; in some embodiments, the buffering agent is succinate; the osmotic pressure regulator is sodium chloride, glucose One or more; In some embodiments, the buffer is sodium chloride succinate.
  • the pharmaceutical composition provided by the present disclosure when placed at a temperature of 2 to 8°C for 3 months, produces a total impurity content of ⁇ 10%; in some embodiments, at a temperature of 2 to 8°C, three 1, the content of total impurities produced is ⁇ 8%.
  • compositions provided by the present disclosure are suitable for injection.
  • the present disclosure provides a use of the above-mentioned composition in the preparation of a drug for reducing the level of parathyroid hormone in a subject and treating secondary hyperparathyroidism or tumor-induced hypercalcemia; in some embodiments , the hyperparathyroidism is secondary hyperparathyroidism in a subject suffering from chronic kidney disease.
  • Another aspect of the present disclosure provides a method for preparing the above-mentioned pharmaceutical composition, which includes mixing the prescribed amount of buffer, sodium chloride and water for injection, and stirring until completely dissolved; then mixing the prescribed amount of the compound of formula (I) with the above-mentioned solution , stir until completely dissolved; adjust the pH to the target pH value with sodium hydroxide, add water for injection to the full amount, continue stirring to mix evenly, sterilize and filter, and then fill.
  • the "mass volume percentage” (w/v) in the present disclosure refers to the mass (unit g) of the components contained in each 100 mL liquid system, ie g/100 mL.
  • Fig. 1 is the hemolytic effect of the compound of formula (I) on human red blood cells in vitro, wherein: *: positive control (polyethylene glycol octylphenyl ether), #: PBS buffer solution;
  • Fig. 2 is the effect that formula (I) compound reduces parathyroid hormone level in normal rat body
  • Fig. 3 is the efficacy of compounds of formula (I) in reducing serum calcium ion levels in normal rats.
  • Solid-phase peptide synthesis was performed using the Fmoc/tBu synthesis strategy on a Prelude-X automated peptide synthesizer, starting from Rink-amide MBHA resin (0.1 mmole) using 10 equivalents of HCTU and 4-methylmorpholine activated Amino acid residues (HCTU, 4-methylmorpholine and amino acid residues in a molar ratio of 1:2:1) were coupled in nitrogen, nitrogen-dimethylformamide at room temperature for 25 minutes.
  • the mixed solution obtained above was filtered through a 0.22um membrane, it was separated with a WATERS Prep150 preparative reversed-phase high-performance liquid chromatography system, and the buffer solution was A (0.1% trifluoroacetic acid, aqueous solution) and B (0.1% trifluoroacetic acid, 90 % acetonitrile, in water).
  • the preparation chromatographic column is X-SELECT OBD C-18 (WATERS) reversed-phase chromatographic column.
  • the detection wavelength of the chromatograph is set at 220nm, and the flow rate is 15mL/min.
  • Ac-c(C) means that the D-configuration cysteine (c) at the amino terminal is acetylated and linked to another cysteine in the L-configuration (C) through a disulfide bond;
  • r-NH 2 means that the D-configuration arginine (r) at the carboxy-terminus is amidated.
  • the compound of formula (I) is synthesized by a synthetic scheme similar to that of Example 1, and the purity and molecular weight of the synthetic polypeptide are determined by analytical ultra-high performance liquid chromatography and ultra-high performance liquid chromatography/mass spectrometry, wherein the purity of the compound of formula (I) is 95.79%, the molecular weight of the compound is: 1062.29Da.
  • composition of the prescription in the table above take about 70% of the total volume of water for injection, add the prescribed amount of buffer and sodium chloride, and stir until it is completely dissolved by visual inspection. Then add the formula (I) compound hydrochloride of prescription amount, stir until completely dissolved, adjust the pH to 3.3 ⁇ 0.10 with 1mol/L sodium hydroxide, add water for injection to the full amount. Continue to stir to combine well. After sterilizing and filtering, filling and stoppering are carried out.
  • the pH value screening experiment was carried out according to the prescription composition in Table 3. During preparation, the pH value is not adjusted, and the pH of the preparation solution is about 2.7. Adjust the pH value to 2.0, 3.0, 3.3, 3.5, 4.0, 4.5, 5.0, 6.0 with 1M sodium hydroxide or 1M hydrochloric acid respectively. The stability of the composition was investigated under the conditions of 2-8°C and 25°C, and the experimental results are shown in Table 4.
  • API content is 95.6%, total impurity 3.9%
  • the pH value when the pH value was higher than 3.5, the content of active ingredients decreased significantly, and the total impurities increased significantly.
  • the pH value when the pH value is between 3.0 and 3.5, the composition is placed at 2-8°C for 3M and 25°C for 1M content, the total impurities are relatively stable, and the stability of the preparation is better, so the pH value range of the pharmaceutical composition is preferably 3.0-3.5 .
  • Example 4 The composition prepared in Example 4 was administered to Beagle dogs for in vivo hemolysis research. Beagle dogs were administered a 5 mg/mL pharmaceutical composition by intravenous injection, and were continuously observed for 4 days after a single administration. After administration, the general state observation of the animals, hematology related to hemolysis, blood biochemistry, urine indicators and blood cell smears showed no abnormal changes related to the test product.
  • the HEK293/CaSR stably transfected cell line (source: Pharmaron) was cultured in complete medium (ingredients: DMEM, high glucose+10% FBS+2mM GlutaMAX+1X Penicillin-Streptomycin+200 ⁇ g/ml Hygromycin B), at 37°C , and incubate to 70%-90% confluence in a 5% CO2 environment.
  • the cell lines were digested with TrypLE and inoculated in 384-well cell culture plates, and cultured overnight at 37°C in 5% CO2.
  • the stimulation buffer HEPES 10mM, MgCl2 0.5mM, KCl 4.2mM, NaCl 146mM, glucose 5.5mM, LiCl 50mM, CaCl2 1.2mM
  • the stimulation buffer HEPES 10mM, MgCl2 0.5mM, KCl 4.2mM, NaCl 146mM, glucose 5.5mM, LiCl 50mM, CaCl2 1.2mM
  • different concentrations of the compounds to be tested were added at 37°C. Incubate for 60 minutes, and detect the production of IP-One in the cells according to the steps in the instructions of the Cisbio IP-One Tb kit.
  • software is used to calculate the EC50 value of each example to be tested on human calcium-sensing receptors, and to evaluate the agonist activity of the examples against human calcium-sensing receptors.
  • Signal readout for HTRF was performed using an EnVision detector with excitation at 320 nm and emission at 620 nm and 665 nm. Calculate the signal ratio (665nm/620nm*10,000), and use the four-parameter equation to perform nonlinear fitting between the signal ratio and the sample concentration in GraphPad Prism 6, and obtain the EC50 value of Example 1 to be tested. The specific values are shown in Table 1 below .
  • the compound of formula (I) of the present disclosure has excellent in vitro efficacy, corresponding to an EC50 value lower than 10uM in the in vitro evaluation of human calcium-sensing receptor agonist activity, which is equivalent to the activity of the positive drug etekatide.
  • rat peritoneal mast cells were isolated by lavage of rat peritoneum with lavage buffer (cold HBSS+25mM HEPES containing 5 U/mL heparin, pH 7.4). After separation, the cells were centrifuged, the lavage buffer was removed, and the stimulation buffer (HBSS+25mM HEPES+1mM CaCl2, pH 7.4) was added to resuspend the cells and washed twice.
  • lavage buffer cold HBSS+25mM HEPES containing 5 U/mL heparin, pH 7.4
  • Etecartide can obviously cause the release of histamine from rat peritoneal mast cells in vitro, which is specifically reflected in the fact that the relative histamine release multiple is higher than 1.50 relative to PBS buffer.
  • the compound of formula (I) greatly reduces the release level of histamine in rat peritoneal mast cells in vitro compared with etecartide.
  • red blood cells were resuspended by the compound solution of the example to be tested, polyethylene glycol octylphenyl ether-100 solution and PBS buffer respectively and incubated at 37°C for 1 hour. After incubation, centrifuge at 4°C for 10 minutes and extract the supernatant (100ul), transfer to a 96-well plate and measure the absorbance at 540nm to evaluate the hemolytic effect of the compound of formula (I) on red blood cells in vitro.
  • Formula (I) compound does not observe obvious erythrocyte hemolysis effect under the concentration of 100ug/ml, and corresponding polyethylene glycol octyl phenyl ether-100 solution observes obvious erythrocyte hemolysis effect under experimental conditions, see Attached Figure 1.
  • Rats Normal adult rats (Sprague Dawley, SD) of SPF grade were used in the experiment, weighing 250-350 grams, and were restored to normal diet for 7 days in the animal room. Rats were divided into random groups, 6 in each group, half male and half male, and numbered respectively. One day before the start of the experiment, 540 ⁇ L of blood was collected from each rat, and the plasma parathyroid hormone level and serum calcium ion concentration were measured as the control values before administration.
  • the plasma separation method is anticoagulated with K2-EDTA, blood is collected through the jugular vein, put on ice after collection, and then the whole blood is centrifuged at 6,800 rpm for 6 minutes at 2-8°C, and the upper layer is gently taken out to be the plasma, 2 Store at ⁇ 8°C.
  • the serum separation method is to collect blood through the jugular vein, let the whole blood stand at room temperature for 1 hour, then centrifuge at room temperature at 3,500rpm for 10 minutes, gently take out the upper layer, which is the serum, and store it at room temperature. The day before the experiment, the animals were fasted overnight and had free access to water.
  • ELISA Enzyme-linked immunosorbent assay, enzyme-linked immunosorbent assay.
  • the detailed steps are: use the streptavidin pre-coated reaction strip provided by the kit, and add 25 ⁇ L of standard substance, control substance or plasma sample to each well. Mix biotinylated rat parathyroid hormone antibody and rat parathyroid hormone/HRP-conjugated antibody 1:1, and add 100 ⁇ L of this mixed solution to each well. Seal the reaction strips with a sealing film, wrap the reaction strips with aluminum foil for storage in the dark, and oscillate on a horizontal shaker at 220 rpm for 3 h at room temperature.
  • the absorbance of each well was read at 450 nm, and the absorbance at 620 nm was used as the background subtraction.
  • 150 ⁇ L of horseradish peroxidase ELISA substrate plus 100 ⁇ L of ELISA stop solution was used as a blank control for absorbance measurement.
  • the determination of serum calcium ion concentration is carried out according to the steps of the relevant kit.
  • the compound of formula (I) completely reduces the plasma parathyroid hormone level of normal rats within 4 hours at a dose of 3 mg/kg, and the serum calcium ion level is also correspondingly reduced, see accompanying drawings 2 and 3.

Abstract

提供一种钙敏感受体激动剂的组合物及其应用。具体而言，提供一种多肽钙敏感受体激动剂的药物组合物，所述组合物包含活性成分、缓冲剂和渗透压调节剂。本组合物稳定性高，可长期储存，可有效降低血浆甲状旁腺激素，且组胺释放水平低。

Description

一种钙敏感受体激动剂的组合物及其应用 技术领域
本公开属于医药技术领域，涉及一种适于注射的钙敏感受体激动剂的组合物及其应用。
背景技术
钙敏感受体(Calsium-sensing Receptor,CaSR)是指分布在人体甲状旁腺器官细胞表面的一种A家族G-蛋白偶联受体(G-Protein Coupled Receptor,GPCR)。甲状旁腺激素的分泌受到甲状旁腺细胞表面钙敏感受体的高度调节从而维持人体矿物质的稳态水平，钙敏感受体通过持续监测人体内钙离子浓度的细微变化继而通过改变甲状旁腺激素的分泌水平进行相应的响应。
在慢性肾病患者中，体内对于实现钙离子和磷离子的稳态水平的需求导致了甲状旁腺激素持续地从甲状旁腺的分泌。这种持续的甲状旁腺激素的分泌一开始是适应性的，但随着慢性肾病的进展最终导致了甲状旁腺的增生以及体内过高的甲状旁腺激素水平并诱发了继发性甲状旁腺功能亢进的形成。有研究表明，持续的继发性甲状旁腺功能亢进会导致甲状旁腺细胞表面钙敏感受体和维生素D受体的缺失。这些由疾病引发的下游病理效应进一步导致了甲状旁腺对于体内矿物质稳态调节的失调。
拟钙剂泛指生理功能和作用机制类似于钙离子并可以直接激活甲状旁腺细胞表面钙敏感受体的化合物。盐酸西那卡塞是由安进公司开发的有机小分子拟钙剂，其可激活甲状旁腺器官表面的钙敏感受体，抑制甲状旁腺激素的分泌水平进而达到治疗继发性甲状旁腺功能亢进等相关代谢类疾病的目的。盐酸西那卡塞在临床上获批用于治疗慢性肾病透析患者中的继发性甲状旁腺功能亢进，患者采用口服给药的方式，使用频率为每天口服一到二次，最高剂量可为每次90毫克。盐酸西那卡塞在临床上展现出优异的降低继发性甲状旁腺功能亢进患者血浆甲状旁腺激素水平的疗效。然而，在患者使用过程中观测到明显的药物引发的副作用，例如与胃肠道副作用相关的恶心，呕吐以及腹泻。此外，盐酸西那卡塞口服给药的用药方式对于慢性肾病透析患者而言是一个较大的负担，并且盐酸西那卡塞已被证明可以抑制细胞色素450并诱发与此有关的药物与药物之间的相互作用。这些与盐酸西那卡塞使用相关的副作用在一定程度上降低了患者的依从性和顺应性。
因此，临床上急需具有可以通过静脉注射给药的钙敏感受体激动剂化合物，其可以通过激活甲状旁腺细胞表面的钙敏感受体从而降低甲状旁腺激素的分泌进而达到治疗继发性甲状旁腺功能亢进等相关代谢类疾病的疗效。这类钙敏感受 体激动剂化合物可以显著提升慢性肾病患者治疗的依从性和顺应性。
WO2021115272描述了一系列多肽钙敏感受体激动剂化合物，其中式(I)化合物对人类钙敏感受体具有激动剂作用从而降低血浆甲状旁腺激素和血清钙离子水平，并可以用于继发性甲状旁腺功能亢进，肿瘤引发的高钙血症等代谢类疾病的治疗。
Figure PCTCN2022097594-appb-000001
发明内容
本公开提供一种钙敏感受体激动剂的药物组合物及其应用。本公开提供的药物组合物稳定性高，可长期储存，可有效降低血浆甲状旁腺激素，且组胺释放水平低，副作用小。
本公开提供的药物组合物，敏感性低，安全性好，不会发生体内溶血。
本公开提供的药物组合物，包含活性成分、缓冲剂、渗透压调节剂，所述活性成分是式(I)所示的化合物或其可药用盐：
Figure PCTCN2022097594-appb-000002
本公开中的氨基酸序列采用氨基酸的标准单字母或三字母代码表示，即丙氨酸(Ala,A)，半胱氨酸(Cys,C)，精氨酸(Arg,R)，D-2-氨基丁酸(D-Abu)。本公开式(I)化合物还可用以下序列表示：Ac-c(C)-r-r-(D-Abu)-r-a-r-NH 2。
本公开提供的药物组合物，所述组合物的pH值为2.0～3.5；在一些实施方案中，所述组合物的pH值为3.0～3.5；在一些实施方案中，所述组合物的pH值为 为3.3。
本公开提供的药物组合物，所述活性成分是式(I)化合物的盐酸盐。
在某些实施方式中，所述式(I)化合物盐酸盐中式(I)化合物结合盐酸的个数可以为1-10(可以是1-10之间的任意数值，即平均值)，优选盐酸个数为4-8，更优选4-5，可选盐酸个数包括但不限于1、1.5、2、2.5、3、3.5、4、4.5、5、5.5、6、6.5、7、7.5、8、8.5、9、9.5、10。
本公开提供的药物组合物，所述活性成分的含量以游离碱计为1～10mg/mL；在一些实施方案中，活性成分的含量以游离碱计为2.5～10mg/mL；在一些实施方案中，活性成分的含量以游离碱计为5mg/mL，所述活性成分的含量以游离碱计可为1mg/mL、1.5mg/mL、2mg/mL、2.5mg/mL、3mg/mL、3.5mg/mL、4mg/mL、4.5mg/mL、5mg/mL、5.5mg/mL、6mg/mL、6.5mg/mL、7mg/mL、7.5mg/mL、8mg/mL、8.5mg/mL、9mg/mL、9.5mg/mL、10mg/mL。
本公开提供的药物组合物，所述缓冲剂选自琥珀酸盐、柠檬酸盐、磷酸盐中的一种或多种；在一些实施方案中，所述缓冲剂为琥珀酸盐。
本公开提供的药物组合物，所述渗透压调节剂选自氯化钠、葡萄糖中的一种或多种；在一些实施方案中，所述渗透压调节剂为氯化钠。
在一些实施方案中，本公开提供的药物组合物还包含pH调节剂，所述pH调节剂为氢氧化钠、盐酸中的一种或多种。
本公开提供的药物组合物，所述缓冲剂的质量体积百分比为0.05％～1％；在一些实施方案中，所述缓冲剂的质量体积百分比为0.1％～0.5％；在一些实施方案中，所述缓冲剂的质量体积百分比为0.118％；可选的质量体积百分比为0.05％、0.06％、0.07％、0.08％、0.09％、0.10％、0.11％、0.115％、0.118％、0.12％、0.13％、0.14％、0.15％、0.16％、0.17％、0.18％、0.19％、0.20％、0.21％、0.22％、0.23％、0.24％、0.25％、0.26％、0.27％、0.28％、0.29％、0.30％、0.35％、0.40％、0.45％、0.50％。
本公开提供的药物组合物，所述渗透压调节剂的的质量体积百分比为0.5％～2％；在一些实施方案中，所述渗透压调节剂的质量体积百分比为0.5％～1％；在一些实施方案中，所述渗透压调节剂的质量体积百分比为0.85％；可选的质量体积百分比为0.5％、0.55％、0.6％、0.65％、0.7％、0.75％、0.8％、0.85％、0.9％、0.95％、1％。
本公开提供一种药物组合物，包含以游离碱计2.5～10mg/m的活性成分、0.1％～0.5％(w/v)缓冲剂、0.5％～1％(w/v)渗透压调节剂，所述活性成分是式(I)所示的化合物或其可药用盐，在一些实施方案中活性成分为式(I)化合物的盐酸盐：
Figure PCTCN2022097594-appb-000003
所述缓冲剂为琥珀酸盐、柠檬酸盐、磷酸盐中的一种或多种；在一些实施方案中，缓冲剂为琥珀酸盐；所述渗透压调节剂为氯化钠、葡萄糖中的一种或多种；在一些实施方案中，缓冲剂为琥珀酸盐氯化钠。
本公开提供的药物组合物，在2～8℃温度的条件下放置3个月，产生的总杂质的含量≤10％；在一些实施方案中，在2～8℃温度的条件下放置3个月，产生的总杂质的含量≤8％。
在一些实施方案中，本公开提供的药物组合物是适于注射用的。
本公开提供一种上述组合物在制备用于降低受试者甲状旁腺激素水平，治疗继发性甲状旁腺功能亢进或肿瘤引发的高钙血症的药物中的用途；在一些实施方案中，所述甲状旁腺功能亢进为罹患慢性肾病的受试者的继发性甲状旁腺功能亢进。
本公开另一方面提供一种制备上述药物组合物的方法包括将处方量的缓冲剂、氯化钠和注射用水混合，搅拌至全部溶解；再将处方量的式(I)化合物与上述溶液混合，搅拌至完全溶解；用氢氧化钠调节pH至目标pH值，补加注射用水至全量，继续搅拌使其混合均匀，除菌过滤后，进行灌装。
在本公开的说明书和权利要求书中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。然而，为了更好地理解本公开，下面提供了部分相关术语的定义和解释。
本公开所述的“质量体积百分比”(w/v)是指每100mL液体体系中含有所述成分的质量(单位g)，即g/100mL。
WO2021115272公开的内容全文引用到本公开中。
附图说明
图1为式(I)化合物在体外针对人类红血细胞的溶血效应，其中：*：阳性对照(聚乙二醇辛基苯基醚)，#：PBS缓冲液；
图2为式(I)化合物在正常大鼠体内降低甲状旁腺激素水平的功效；
图3为式(I)化合物在正常大鼠体内降低血清钙离子水平的功效。
具体实施方式
以下将结合实施例更详细地解释本公开，本公开的实施例仅用于说明本公开的技术方案，并非限定本公开的实质和范围，本公开所用药用辅料均可通过商业途径购得。
1、实验试剂
序号 试剂 来源
1 Rink-amide MBHA树脂 西安蓝晓科技
2 HCTU 苏州昊帆科技
3 4-甲基吗啉 TCI Chemicals
4 乙腈(色谱级) Sigma-Aldrich
5 氮，氮-二甲基甲酰胺 国药试剂
6 二氯甲烷 国药试剂
7 三氟乙酸 TCI Chemicals
8 三异丙基硅烷 TCI Chemicals
9 甲基叔丁基醚 TCI Chemicals
10 4-甲基哌啶 TCI Chemicals
11 L-半胱氨酸 Sigma-Aldrich
12 Fmoc-D-Cys(Trt)-OH 吉尔生化
13 Fmoc-D-Arg(Pbf)-OH 吉尔生化
14 Fmoc-D-Ala-OH 吉尔生化
15 Fmoc-D-Abu-OH 吉尔生化
16 2，2-二吡啶二硫醚 吉尔生化
2、实验仪器
序号 仪器 来源
1 Prelude-X多通道多肽合成仪 Protein Technology
2 H-CLASS分析型超高效液相色谱 Waters
3 Xevo液相色谱/质谱联用 Waters
4 Labconco多功能冻干机 Thermo-Fisher Scientific
5 Prep150制备型高效液相色谱 Waters
6 多通道高速离心机 希格玛
在Prelude-X全自动多肽合成仪上使用Fmoc/tBu合成策略进行固相肽合成，从Rink-amide MBHA树脂(0.1mmole)开始，其中使用10当量的用HCTU和4-甲基吗啉活化的氨基酸残基(HCTU、4-甲基吗啉和氨基酸残基三者摩尔比为 1:2:1)在氮，氮-二甲基甲酰胺中在室温下进行25分钟偶联。
在完成上述肽-树脂的合成后，在含有90：5：5(v/v/v)的三氟乙酸：三异丙基硅烷：水和2，2-二吡啶二硫醚(1mmole)的溶液中，在室温，2小时同时完成多肽从固相树脂的切割，侧链保护基的去除以及D-Cys侧链巯基的活化。反应结束后过滤并用三氟乙酸洗涤树脂2次，合并滤液后加入大量冷冻甲基叔丁基醚析出固体，离心后除去上清液得到多肽的粗品并进行干燥称重。
将上述得到的多肽粗品和L-Cys(0.1mmole)溶解于PBS缓冲液(pH＝7.4)中，在室温下振荡反应并用超高效液相色谱监测实施例编号1的产生。反应完成后往混合液加入三氟乙酸(300ul)猝灭反应并用于后续纯化。
将上述得到的混合液经过0.22um膜过滤后用WATERS Prep150制备型反相高效液相色谱系统进行分离，缓冲液为A(0.1％三氟乙酸，水溶液)和B(0.1％三氟乙酸，90％乙腈，水溶液)。其中，制备色谱柱为X-SELECT OBD C-18(WATERS)反相色谱柱，纯化过程中色谱仪检测波长设定为220nm，流速为15mL/min。收集产物相关馏分冻干后得到实施例编号1的多肽纯品，收率45％。多肽纯品通过分析型超高效液相色谱和超高效液相色谱/质谱联用确定纯度及化合物身份，其中化合物纯度为96.78％，化合物分子量为：1109.60Da。
化合物编号 序列
1 Ac-c(C)-(D-Phg)-r-r-r-a-r-NH 2
“Ac-c(C)”表示氨基末端的D构型半胱氨酸(c)被乙酰化，并通过二硫键与L构型(C)的另一半胱氨酸连接；“r-NH 2”表示羧基末端的D构型精氨酸(r)被酰胺化。
实施例2
采用与实施例1类似的合成方案合成式(I)化合物，并用分析型超高效液相色谱和超高效液相色谱/质谱联用确定合成多肽的纯度和分子量，其中式(I)化合物纯度为95.79％，化合物分子量为：1062.29Da。
实施例3
式(I)化合物盐酸盐的制备
1、称取Rink Amide-AM树脂(1034.4g)加入到玻璃反应釜中，再加入DMF溶胀树脂。加入20％PIP/DMF(V/V)溶液，分别反应脱除Fmoc，然后用DMF 洗涤，茚三酮检测呈蓝色。称取Fmoc-D-Arg(Pbf)-OH(1167.6g)、Oxyma(383.6g)，使用DMF(5.0L)和DCM(5.0L)溶解，然后加入DIC(340.5g)。搅拌混匀加入到玻璃反应釜中反应，以茚三酮检测反应终点(如果树脂无色透明就终止反应，如果树脂有颜色则延长反应时间，下同)，反应结束后，依次使用DMF、IPA、DMF、IPA，DMF洗涤树脂。称取Ac 2O(368.1g)、DIEA(467.4g)加入DMF(5.0L)和DCM(5.0L)。搅拌混匀加入到玻璃反应釜中反应，取少量树脂茚三酮检测至反应终点，反应结束后，依次使用DMF、IPA、DMF、IPA，DMF洗涤树脂。
2、按照相同的偶联方法，依次偶联后续的氨基酸，得N-Ac-D-Cys(Trt)-D-Arg(Pbf)-D-Arg(Pbf)-D-Abu-D-Arg(Pbf)-D-Ala-D-Arg(Pbf)-Rink Amide Resin 2.5Kg。
3、将TFA/TIS/H2O(V:V:V＝97:2.5:0.5)裂解液加入到50L反应器中，再加入DPDS(793.2g)，搅拌溶解后。将2中的产物(2.5Kg)加入到反应器中，室温搅拌反应，过滤。滤液加入到IPE/ACN(V:V＝7:1)中，收集前体多肽850g，收率75.4％。
4、将6.73L水加入到20L反应器中，加入H-L-Cys-OH.HCl.H 2O(118.4g)，搅拌溶解后，加入3的前体多肽(850g)反应。结束后缓慢冲析入0.01moL/L的HCl/IPA溶液中，搅拌后离心，收集滤饼。干燥后得到目标多肽粗品700g，收率79％。
5、取4中的粗肽700g，使用汉邦纯化系统，波长254nm，填料C18，流动相0.1％TFA/H 2O和0.1％TFA/乙腈，进行纯化，收集目标峰馏分，得到纯化液90L，工序收率64.1％。
6、使用纳滤系统，流加盐酸溶液，同时除去样品溶液中的三氟乙酸根，得到式(I)化合物盐酸盐溶液，浓缩和冻干后，得到式(I)化合物盐酸盐240g，收率90％，质谱信号为1061.5367Da(理论值1061.5447Da)，HPLC纯度98.33％，总收率34.4％。
根据中国药典2020年版四部通则0701电位滴定法，测得式(I)化合物结合盐酸的个数为4.4。
实施例4
药物组合物制备工艺
Figure PCTCN2022097594-appb-000004
根据上表中的处方组成，取约总体积70％的注射用水，加入处方量缓冲剂和氯化钠，搅拌至目测全部溶解。再加入处方量的式(I)化合物盐酸盐，搅拌至完全溶解，用1mol/L氢氧化钠调节pH至3.3±0.10，补加注射用水至全量。继续搅拌使其混合均匀。除菌过滤后，进行灌装加塞。
实施例5
组合物pH值筛选
按表3处方组成开展pH值筛选实验。配制时，不调节pH值，制剂溶液pH2.7左右。分别用1M氢氧化钠或者1M盐酸分别调节pH值至2.0、3.0、3.3、3.5、4.0、4.5、5.0、6.0。考察2～8℃和25℃条件下组合物的稳定性，实验结果见表4。
表3组合物pH值筛选处方表
成分 用量
式(I)化合物 5mg/ml(以游离碱计)
琥珀酸 10mM
氯化钠 0.85％
氢氧化钠/盐酸 适量
pH值 2.0、3.0、3.3、3.5、4.0、4.5、5.0、6.0
注：API含量为95.6％，总杂3.9％
表4 pH值筛选一览表
Figure PCTCN2022097594-appb-000005
Figure PCTCN2022097594-appb-000006
结果表明：pH值高于3.5时，活性成分的含量明显下降，总杂明显增加。pH值在3.0～3.5之间时，组合物在2-8℃放置3M及25℃放置1M含量、总杂相对稳定，制剂稳定性较好，因此药物组合物的pH值范围优选为3.0～3.5。
实施例6
缓冲体系筛选
实验考察了不同缓冲体系下组合物的稳定性。处方筛选表见表5，实验结果见表6。
表5组合物缓冲体系筛选处方表
Figure PCTCN2022097594-appb-000007
表6组合物缓冲体系筛选一览表
Figure PCTCN2022097594-appb-000008
Figure PCTCN2022097594-appb-000009
由实验结果可知：3种缓冲盐中，式(I)化合物三种缓冲体系中，稳定性均良好。在25℃1M及2-8℃3M条件下，琥珀酸盐缓冲体系中总杂增加最少，含量稳定。
实施例7
将实施例4中制得的组合物，给药比格犬，进行体内溶血研究。比格犬静脉推注给予5mg/mL的药物组合物，单次给药后连续观察4天。给药后动物一般状态观察、溶血相关的血液学、血生化、尿液指标和血细胞涂片均未见供试品相关的异常改变。
上述结果表明，5mg/mL的式(I)化合物的药物组合物不会引起动物体内溶血。
实施例8
以下结合本公开中的具体实施例进一步描述解释本公开，但这些实施例并非意味着限制本公开的范围。
1、体外，体内生物学测试评价所需实验试剂
序号 试剂 来源
1 FBS,500ml ThermoFisher Scientific
2 DMEM,High Glucose,GlutaMAX,500ml ThermoFisher Scientific
3 Penicillin-Streptomycin,Liquid,100ml(100X) ThermoFisher Scientific
4 1X PBS pH 7.2-7.4(500ml) Solarbio
5 1X TrypLE Express Enzyme,no phenol red(500ml) ThermoFisher Scientific
6 Hygromycin B Gold solution(5g,1x 50ml,100mg/ml) Invivogen
7 HEPES,1M Gibco
8 MgCl 2,1M Sigma-Aldrich
9 KCl,1M Sigma-Aldrich
10 NaCl,5M Sigma-Aldrich
11 Glucose Sigma-Aldrich
12 LiCl,8M Sigma-Aldrich
13 CaCl 2,1M Sigma-Aldrich
14 IP-One-Gq Kit(1,000tests) Cisbio
2、实验仪器
序号 仪器 来源
1 EnVision检测器 Perkin Elmer
评估式(I)化合物对人类钙敏感受体(CaSR)的激动剂活性
实验方法：
将HEK293/CaSR稳转细胞株(来源：康龙化成)培养在完全培养基(成分：DMEM,high glucose+10％FBS+2mM GlutaMAX+1X Penicillin-Streptomycin+200μg/ml Hygromycin B)，于37℃，5％CO2环境中孵育至70％-90％融合度。细胞株经TrypLE消化处理后接种于384孔细胞培养板，在37℃，5％CO2中培养过夜。细胞换液后，加入刺激缓冲液(HEPES 10mM,MgCl2 0.5mM,KCl 4.2mM,NaCl 146mM,葡萄糖5.5mM,LiCl 50mM，CaCl2 1.2mM)和不同浓度的待测实施例化合物，并于37℃下孵育60分钟，按照Cisbio IP-One Tb试剂盒说明书中的步骤检测细胞中IP-One的产生。收集各实施例的原始数据后利用软件计算各待测实施例在人类钙敏感受体的EC50值，并以此评价实施例针对人类钙敏感受体的激动剂活性。
实验数据处理方法：
使用EnVision检测器进行HTRF的信号读取，激发波长为320nm，发射波长为620nm和665nm。计算信号比值(665nm/620nm*10,000)，并在GraphPad Prism 6中将信号比值与样品浓度使用四参数方程进行非线性拟合，得出待测实施例1的EC50值，具体数值见下表1。
表1体外钙敏感受体激动剂活性
实施例编号 序列 钙敏感受体EC 50(uM)
式(I)化合物 Ac-c(C)-r-r-(D-Abu)-r-a-r-NH 2 6.28
依特卡肽 Ac-c(C)-a-r-r-r-a-r-NH 2 6.78
依特卡肽类似物 Ac-c(C)-r-r-a-r-a-r-NH 2 6.74
本公开的式(I)化合物具有优良的体外功效，对应于在体外人类钙敏感受体激动剂活性评估中低于10uM的EC50值，与阳性药依特卡肽的活性相当。
评估式(I)化合物在大鼠腹膜肥大细胞上的体外组胺释放活性
实验方法和数据处理：
为评估部分待测实施例的体外组胺释放水平，通过灌洗缓冲液(含肝素5U/mL的冷HBSS+25mM HEPES，pH 7.4)灌洗大鼠腹膜分离大鼠腹膜肥大细胞。分离后，离心细胞，去除灌洗缓冲液，加入刺激缓冲液(HBSS+25mM HEPES+1mM CaCl2，pH 7.4)重悬细胞并洗涤两次。按105细胞/孔密度铺板(200μl/孔)，分别加入阳性对照Compound 48/80(终浓度4μg/mL)、待测实施例化合物(最终浓度10μM)或溶媒对照，37℃孵育15min。离心，取细胞上清液，按照LDN Histamine ELISA试剂盒(BAE-1000)说明书检测上清液的组胺浓度。具体数值见下表2。
表2体外组胺释放副反应水平
实施例编号 体外相对组胺释放倍数
PBS缓冲液 1.00
式(I)化合物 0.97
依特卡肽 1.70
依特卡肽会较明显地引起体外大鼠腹膜肥大细胞的组胺释放，具体体现在相对于PBS缓冲液时相对组胺释放倍数高于1.50。令人意想不到的是，式(I)化合物相对依特卡肽体外大鼠腹膜肥大细胞组胺释放水平大大降低。
评估式(I)化合物在体外对人红血细胞的溶血效应
实验方法和数据处理：
为评估实施例化合物在体外对红血细胞的溶血效应，取人全血(100ul)并与磷酸盐缓冲液混匀，在4℃条件下离心10分钟后丢弃上清液。用PBS缓冲液(900ul)重悬红细胞后在4℃条件下离心10分钟后丢弃上清液并重复上述步骤一次。将式(I)化合物溶解在1×PBS缓冲液中，终浓度为100ug/ml。分别利用待 测实施例化合物溶液，聚乙二醇辛基苯基醚-100溶液以及PBS缓冲液重悬红细胞并在37℃条件下孵育1小时。孵育后在4℃条件下离心10分钟并抽取上清液(100ul),转移至96孔板后在540nm处测定吸光度并以此评估式(I)化合物在体外对红血细胞的溶血效应。
3.3.3实验结果
式(I)化合物在100ug/ml的浓度下未观测到明显的红细胞溶血效应，与之相对应聚乙二醇辛基苯基醚-100溶液在实验条件下观测到明显的红细胞溶血效应，见附图1。
评估式(I)化合物在正常大鼠模型上单次给药后的体内药效
实验方法和数据处理：
试验选用SPF级正常成年大鼠(Sprague Dawley,SD)，体重为250～350克，在动物房中正常饮食恢复7天。大鼠随机分组，每组6只，雌雄各半，分别编号。实验开始前一天，每只大鼠采血540μL，检测血浆甲状旁腺素水平和血清钙离子浓度作为给药前的对照值。血浆分离方法为采用K2-EDTA抗凝、经颈静脉采血，采集后置于冰上，随后将全血在2～8℃条件下以6,800rpm离心6分钟，轻轻取出上层即为血浆，2～8℃保存。血清分离方法为经颈静脉采血，将全血室温静置1小时，然后在室温，3,500rpm转速下离心10分钟，轻轻取出上层，即为血清，室温保存。实验前一天开始，动物禁食过夜，自由饮水。采血后次日，式(I)化合物和依特卡肽溶于磷酸盐缓冲液(Phosphate buffered saline,PBS,Gibco)，每只大鼠静脉注射给予式(I)化合物及依特卡肽3mg/kg或等体积的PBS缓冲溶液，随后按照如下方法采血测定相应指标。给药后1小时、2小时、4小时分别采血100μL，按照上述方法分离血浆，采用Rat Intact PTH ELISA Kit(Quidel-Immunotopics,Cat.#:60-2500)，按照试剂盒说明书进行血浆甲状旁腺激素水平的测定(ELISA:Enzyme-linked immunosorbent assay，酶联免疫吸附测定)。详细步骤为：采用试剂盒提供的抗生蛋白链菌素预铺的反应条，每孔中加入25μL的标准品、对照品或血浆样品。按照1:1混合生物素化的大鼠甲状旁腺激素抗体和大鼠甲状旁腺激素/HRP结合抗体，并在每孔中加入100μL的此混合溶液。使用密封薄膜封闭反应条，并使用铝箔包裹反应条以避光保存，室温条件下在水平振荡器上振荡以220rpm的转速振荡3h。移去孔中溶液，以350μL的清洗工作液洗涤每孔，再移去孔中溶液；以同样方法洗涤总共5次，最后吸净每孔中的溶液。 在每个孔中加入150μL的辣根过氧化物酶ELISA底物。使用密封薄膜封闭反应条，并使用铝箔包裹反应条以避光保存，室温条件下在水平振荡器上以180～220rpm的转速振荡30min。在每个孔中加入100μL的ELISA终止液，室温条件下在水平振荡器上以180～220rpm的转速振荡1分钟。在加入ELISA终止液后的10min内，在450纳米处读取每个孔的吸光度，同时以620nm处的吸光度作为背景扣除。以150μL的辣根过氧化酶ELISA底物加上100μL的ELISA终止液作为吸光度测量的空白对照。根据标准品的吸光度绘制标准曲线，再将其它样品的吸光度结合标准曲线计算出血浆甲状旁腺激素的实际浓度，血清钙离子浓度的测定按相关试剂盒的步骤进行。
实验结果
式(I)化合物在3mg/kg的剂量下4小时内完全降低正常大鼠血浆甲状旁腺激素水平，血清钙离子水平也相应的得到降低，见附图2和附图3。

Claims (14)

  1. 一种药物组合物，包含活性成分、缓冲剂、渗透压调节剂，所述活性成分是式(I)所示的化合物或其可药用盐：
    Figure PCTCN2022097594-appb-100001
  2. 根据权利要求1所述的药物组合物，其特征在于，所述组合物的pH值为2.0～3.5，优选3.0～3.5，更优选为3.3。
  3. 根据权利要求1或2所述的药物组合物，其特征在于，所述活性成分是式(I)化合物的盐酸盐。
  4. 根据权利要求1-3任意一项所述的药物组合物，其特征在于，所述活性成分的含量以游离碱计为1～10mg/mL，优选为2.5～10mg/mL，更优选为5mg/mL。
  5. 根据权利要求1-4任意一项所述的药物组合物，其特征在于，所述缓冲剂为琥珀酸盐、柠檬酸盐、磷酸盐中的一种或多种，优选琥珀酸盐。
  6. 根据权利要求1-5任意一项所述的药物组合物，其特征在于，所述渗透压调节剂为氯化钠、葡萄糖中的一种或多种，优选氯化钠。
  7. 根据权利要求1-6任意一项所述的药物组合物，其特征在于，所述缓冲剂的质量体积百分比为0.05％～1％，优选0.1％～0.5％，更优选0.118％。
  8. 根据权利要求1-7任意一项所述的药物组合物，其特征在于，所述渗透压调节剂的质量体积百分比为0.5％～2％，优选0.5％～1％，更优选0.85％。
  9. 根据权利要求1-8任意一项所述的药物组合物，其特征在于，所述组合物还含有pH调节剂。
  10. 一种药物组合物，包含以游离碱计2.5～10mg/m的活性成分、0.1％～0.5％(w/v)缓冲剂、0.5％～1％(w/v)渗透压调节剂，所述活性成分是式(I)所示的化合物或其可药用盐，优选活性成分为式(I)化合物的盐酸盐：
    Figure PCTCN2022097594-appb-100002
    所述缓冲剂为琥珀酸盐、柠檬酸盐、磷酸盐中的一种或多种，优选琥珀酸盐；
    所述渗透压调节剂为氯化钠、葡萄糖中的一种或多种，优选氯化钠。
  11. 根据权利要求1-10任意一项所述的药物组合物，其特征在于，在2～8℃温度的条件下放置3个月，所述的药物组合物的总杂质的含量≤10％，优选≤8％。
  12. 根据权利要求1-11任意一项所述的药物组合物，所述药物组合物适于注射用。
  13. 一种制备如权利要求1-12任意一项所述的药物组合物的方法，包括将活性成分、缓冲剂、渗透压调节剂混合的步骤。
  14. 权利要求1-12中任意一项所述的药物组合物在制备用于降低受试者甲状旁腺激素水平，治疗继发性甲状旁腺功能亢进或肿瘤引发的高钙血症的药物中的用途。
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CN101668421A (zh) * 2006-11-16 2010-03-10 凯制药公司 用于治疗甲状旁腺功能亢进和高钙血症的聚阳离子钙调节肽
CN102711789A (zh) * 2009-07-29 2012-10-03 凯伊药品公司 用于降低甲状旁腺激素水平的治疗剂
CN104168955A (zh) * 2011-11-10 2014-11-26 凯伊药品公司 拟钙剂及其使用方法
WO2021115272A1 (zh) 2019-12-09 2021-06-17 北京拓界生物医药科技有限公司 钙敏感受体激动剂化合物及其应用

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CN102711789A (zh) * 2009-07-29 2012-10-03 凯伊药品公司 用于降低甲状旁腺激素水平的治疗剂
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WO2021115272A1 (zh) 2019-12-09 2021-06-17 北京拓界生物医药科技有限公司 钙敏感受体激动剂化合物及其应用

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