WO2023213293A1 - 一种二肽衍生物组合物及其制备方法和用途 - Google Patents

一种二肽衍生物组合物及其制备方法和用途 Download PDF

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Publication number
WO2023213293A1
WO2023213293A1 PCT/CN2023/092238 CN2023092238W WO2023213293A1 WO 2023213293 A1 WO2023213293 A1 WO 2023213293A1 CN 2023092238 W CN2023092238 W CN 2023092238W WO 2023213293 A1 WO2023213293 A1 WO 2023213293A1
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preparation
composition
liver failure
pharmaceutical composition
accounts
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English (en)
French (fr)
Inventor
章莉
李艳杰
刘红
凌飒
吴海燕
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Beijing Continent Pharmaceuticals Co Ltd
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Beijing Continent Pharmaceuticals Co Ltd
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Priority to JP2024565298A priority Critical patent/JP7829735B2/ja
Priority to KR1020247036784A priority patent/KR20240167928A/ko
Priority to US18/863,006 priority patent/US20250313593A1/en
Priority to EP23799279.7A priority patent/EP4520344A4/en
Publication of WO2023213293A1 publication Critical patent/WO2023213293A1/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • 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
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame

Definitions

  • the invention belongs to the field of pharmaceutical preparations, and specifically relates to a dipeptide derivative composition and its preparation method and use.
  • Liver failure refers to severe liver damage caused by a variety of factors, resulting in serious impairment or decompensation of the liver's own functions such as synthesis, detoxification, excretion, and biotransformation. Clinically, it appears as thrombin mechanism disorders, jaundice, hepatic encephalopathy, A group of symptoms manifested by dehydration. The mortality rate of liver failure is extremely high.
  • Patent applications CN201110025509.8 and CN201110025516.8 disclose a dipeptide derivative that can be used to treat liver failure. Its structure is as follows:
  • This dipeptide derivative is 3-(2-benzyloxycarbonylamino-3-methyl-butylamino)-5-fluoro-4-oxo-pentanoic acid (F573), which can significantly inhibit or reverse liver disease. Failure, it has a significant effect on liver failure and has no obvious toxicity to cells.
  • This dipeptide derivative is easily destroyed by various enzymes in the oral cavity and gastrointestinal tract, and is easily ineffective due to the first-pass action of the liver. Therefore, it is not suitable to be designed as an oral dosage form. Research has found that the dipeptide derivative has poor stability in aqueous solutions and cannot withstand moist heat sterilization. Therefore, it is necessary to develop an injection dosage form with high stability, low impurity content, and low side effects.
  • the present invention provides a pharmaceutical composition, including the following components:
  • the antioxidant is selected from one, two or more types of ascorbic acid, sodium edetate, sodium bisulfite, and sodium metabisulfite.
  • the composition optionally further includes component (d) pH adjuster; in some embodiments, the pH adjuster is an alkaline reagent selected from the group consisting of sodium hydroxide, potassium hydroxide, One, two or more of sodium bicarbonate, potassium bicarbonate, or disodium hydrogen phosphate.
  • the pH adjuster is an alkaline reagent selected from the group consisting of sodium hydroxide, potassium hydroxide, One, two or more of sodium bicarbonate, potassium bicarbonate, or disodium hydrogen phosphate.
  • the component (a) accounts for about 0.5% to about 10.0% (w/w) of the total composition, such as 0.5%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0% (w/w).
  • the component (a) accounts for about 2.0% to about 5.0% (w/w) of the total composition;
  • the component (b) accounts for about 0.5% to about 15.0% (w/w) of the total composition, such as 0.5%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%, 11.0%, 12.0%, 13.0% , 14.0%, 15.0% (w/w).
  • the component (b) accounts for about 3.0% to about 10.0% (w/w) of the total composition;
  • the component (c) accounts for about 0.01% to about 0.50% (w/w) of the total composition, such as 0.01%, 0.05%, 0.10%, 0.15%, 0.20%, 0.25%, 0.30%, 0.40%, 0.50% (w/w).
  • the component (c) accounts for about 0.05% to about 0.30% (w/w) of the total composition;
  • the pH value of the composition is greater than 7.0.
  • the pH value range of the composition is selected from 7.0-9.0, such as 7.0, 7.1, 7.2, 7.3, 7.4, 7.5 , 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, preferably 7.5-8.5.
  • the composition is a freeze-dried powder for injection.
  • the present invention provides a preparation method of the pharmaceutical composition, comprising the following steps:
  • step (a2) Add a prescribed amount of the compound of formula I to the solution obtained in step (a1) to dissolve it.
  • the preparation method of the pharmaceutical composition further includes the following steps:
  • step (a3) Sterilize and filter the liquid obtained in step (a2) and freeze-dry.
  • a prescription amount of antioxidant and glycine is added to the pH adjuster; preferably, the pH adjuster is in the form of an aqueous solution with a concentration of 0.5-3mol/L, for example is 0.5mol/L, 1.0mol/L, 1.5mol/L, 2.0mol/L, 3.0mol/L; more preferably, the pH adjuster is a 1mol/L sodium bicarbonate aqueous solution; in some embodiments , the pH value of the liquid obtained in step (a1) is greater than 7.0, preferably the pH value range is 7.0-9.0, and more preferably, it is 7.5-8.5;
  • step (a2) the temperature of the solution obtained in step (a1) is controlled at 8-15°C, and then a prescription amount of the compound of formula I is added; in some embodiments, the solution of formula I is first The compound is passed through a 80-200 mesh sieve (for example, it can be selected from a 100 mesh sieve), and then added to the solution obtained in step (a1);
  • nitrogen protection is used during steps (a1) and (a2).
  • microporous membrane sterilization filtration is used.
  • the microporous filter membrane is a polyethersulfone microporous filter membrane.
  • the preparation method of the pharmaceutical composition includes the following steps:
  • a butyl rubber stopper is added to an appropriate height and freeze-dried.
  • it also includes, after freeze-drying, box pressing, unboxing, capping, light inspection, labeling, packaging, sample delivery, and finished product storage after passing the inspection.
  • the present invention provides the use of the pharmaceutical composition in the preparation of a medicament for preventing or treating liver failure.
  • the liver failure includes: acute liver failure, subacute liver failure, acute-on-chronic liver failure, and chronic liver failure.
  • the medicine is also used to improve the survival rate of patients with liver failure; and/or to improve liver function indicators in patients with liver failure.
  • the improved liver function indicators include: reducing alanine aminotransferase (ALT), reducing aspartate aminotransferase (AST), and/or reducing total bilirubin (TBil).
  • the invention provides a stable composition of a dipeptide derivative of formula I, which has good compatibility with excipients.
  • the freeze-dried preparation prepared according to the composition has low impurity content and is durable under high humidity, strong light and low temperature storage conditions. All have good stability.
  • Example 2 Powder for injection (prepared with F573 + non-aqueous solvent)
  • each set contains 1 bottle of sterilized powder containing 30 mg of the main drug and 2 ml of non-aqueous solvent. It is ready to use. Add an appropriate amount of analgesic (benzyl alcohol). You need to first use 90% ethanol. The solution is used as a solvent to dissolve, crystallize, remove carbon, and dry the F573 raw material. It was found that processing the raw materials such as recrystallization and carbon removal would result in a yield of about 50% and may cause problems such as changes in crystal form. Therefore, F573 is not suitable for development into the above dosage forms.
  • analgesic benzyl alcohol
  • mannitol can be used as a carrier to form a uniform skeleton; amino acids can not only be used as skeleton agents for lyophilized agents, but also as common protein protective agents.
  • the terminal filter uses a 0.22 ⁇ m polyethersulfone microporous filter membrane (filter element) for sterilization filtration, filling, and at the same time, a butyl rubber plug is added to an appropriate height, and freeze-dried to obtain a block.

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  • Engineering & Computer Science (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
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Abstract

本发明涉及一种二肽衍生物组合物及其制备方法和用途，所述组合物包含(a)式I化合物，(b)甘氨酸和(c)抗氧化剂，所述组合物具有良好的辅料相容性，依据该组合物制备得到的冻干制剂杂质含量低，在高湿、强光以及低温贮存条件下均具有良好稳定性。

Description

一种二肽衍生物组合物及其制备方法和用途
本申请要求2022年5月6日向中国国家知识产权局提交的，专利申请号为202210532274.X，发明名称为“一种二肽衍生物组合物及其制备方法和用途”的在先申请的优先权。所述申请的全文通过引用的方式结合于本申请中。
技术领域
本发明属于药物制剂领域，具体涉及一种二肽衍生物组合物及其制备方法和用途。
背景技术
肝衰竭是指由多种因素引起的严重肝脏损害，导致肝脏本身合成、解毒、排泄和生物转化等功能发生严重障碍或失代偿，临床上出现以凝血酶机制障碍、黄疸、肝性脑病、脱水等表现的一组症候群。肝衰竭的病死率极高。
专利申请CN201110025509.8、CN201110025516.8披露了一种可用于治疗肝衰竭的二肽衍生物，其结构如下所示：
该二肽衍生物化学名称为3-(2-苄氧羰基氨基-3-甲基-丁酰胺基)-5-氟-4-氧代-戊酸(F573)，其能够显著抑制或逆转肝衰竭，对于肝衰竭有显著的疗效，并且对细胞没有明显的毒性。
该二肽衍生物容易在口腔和胃肠道环境中，被口腔及胃肠道中的各种酶破坏，又因肝脏首过作用易失效。所以，不适宜设计为口服剂型。且经研究发现，该二肽衍生物在水溶液中稳定性差，同时不能耐受湿热灭菌，因而需要开发一种稳定性高，杂质含量低，且副作用低的注射剂型。
发明内容
为改善现有技术中存在的问题，第一方面，本发明提供一种药物组合物，包括如下组分：
(a)式I化合物，结构如下：
(b)甘氨酸；
(c)抗氧化剂。
根据本发明的实施方案，所述抗氧化剂选自抗坏血酸、依地酸钠、亚硫酸氢钠、焦亚硫酸钠中的一种，两种或更多种。
根据本发明的实施方案，所述组合物任选进一步包括组分(d)pH调节剂；在一些实施方案中，所述pH调节剂为碱性试剂，选自氢氧化钠、氢氧化钾、碳酸氢钠、碳酸氢钾或磷酸氢二钠中的一种，两种或更多种。
根据本发明的实施方案，所述组分(a)占组合物总量的约0.5％至约10.0％(w/w)，例如为0.5％，1.5％，2.0％，2.5％，3.0％，3.5％，4.0％，4.5％，5.0％，6.0％，7.0％，8.0％，9.0％，10.0％(w/w)。优选的，所述组分(a)占组合物总量的约2.0％至约5.0％(w/w)；
根据本发明的实施方案，所述组分(b)占组合物总量的约0.5％至约15.0％(w/w)，例如为0.5％，1.5％，2.0％，2.5％，3.0％，3.5％，4.0％，4.5％，5.0％，5.5％，6.0％，6.5％，7.0％，7.5％，8.0％，8.5％，9.0％，9.5％，10.0％，11.0％，12.0％，13.0％，14.0％，15.0％(w/w)。优选的，所述组分(b)占组合物总量的约3.0％至约10.0％(w/w)；
根据本发明的实施方案，所述组分(c)占组合物总量的约0.01％至约0.50％(w/w)，例如为0.01％，0.05％，0.10％，0.15％，0.20％，0.25％，0.30％，0.40％，0.50％(w/w)。优选的，所述组分(c)占组合物总量的约0.05％至约0.30％(w/w)；
根据本发明的实施方案，所述组合物的pH值大于7.0，在一些实施方案中，所述组合物的pH值范围选自7.0-9.0，例如为7.0，7.1，7.2，7.3，7.4，7.5，7.6，7.7，7.8，7.9，8.0，8.1，8.2，8.3，8.4，8.5，8.6，8.7，8.8，8.9，9.0，优选的为7.5-8.5。
根据本发明的实施方案，所述组合物为冻干粉针剂。
第二方面，本发明提供一种所述药物组合物的制备方法，包括如下步骤：
(a1)加入处方量的抗氧化剂、甘氨酸，并任选加入pH调节剂，混合均匀；
(a2)向步骤(a1)得到的溶液中，加入处方量的式I化合物，使其溶解。
根据本发明的实施方案，所述药物组合物的制备方法，进一步包括如下步骤：
(a3)将步骤(a2)得到的液体进行除菌过滤，冻干。
根据本发明的实施方案，所述步骤(a1)中，将处方量的抗氧化剂、甘氨酸加入pH调节剂中；优选的，所述pH调节剂以水溶液形式，浓度为0.5-3mol/L，例如为0.5mol/L，1.0mol/L,1.5mol/L，2.0mol/L，3.0mol/L；更优选的，所述pH调节剂为1mol/L的碳酸氢钠水溶液；在一些实施方案中，步骤(a1)得到的液体pH值大于7.0，优选pH值范围为7.0-9.0，更优选的，为7.5-8.5；
根据本发明的实施方案，所述步骤(a2)中，将步骤(a1)得到的溶液温度控制在8～15℃，再加入处方量的式I化合物；在一些实施方案中，先将式I化合物过80-200目筛(例如可选自100目筛)，再加入到步骤(a1)得到的溶液中；
根据本发明的实施方案，所述步骤(a1)、(a2)过程中采用氮气保护。
根据本发明的实施方案，所述步骤(a3)中，采用微孔滤膜除菌过滤。优选的，所述微孔滤膜为聚醚砜微孔滤膜。
根据本发明一个优选的方案，所述药物组合物的制备方法包括如下步骤：
称取处方量的焦亚硫酸钠和甘氨酸加入碳酸氢钠溶液中搅拌使其完全溶解，调节pH值为7.0-9.0；将溶液温度控制在8～15℃，然后加入处方量F573，搅拌30-50分钟使溶解，整个配液过程进行氮气保护，除菌过滤，灌装，同时加开花丁基胶塞至适当高度，冻干。优选的，还包括冻干后，箱内压塞、出箱、轧盖、灯检、贴签、包装、送样、检验合格后成品入库。
第三方面，本发明提供所述药物组合物在制备用于预防或治疗肝衰竭的药物中的用途。
根据本发明的实施方案，所述的肝衰竭包括：急性肝衰竭、亚急性肝衰竭、和慢加急性肝衰竭、慢性肝衰竭。
根据本发明的实施方案，所述的药物还用于提高肝衰竭病人的生存率；和/或用于改善肝衰竭病人的肝功能指标。在一些实施方案中，所述的改善肝功能指标包括：降低降低丙氨酸转氨酶(ALT)、降低天冬氨酸转氨酶(AST)和/或降低总胆红素(TBil)。
有益效果
本发明提供了一种式I的二肽衍生物的稳定组合物，具有良好的辅料相容性，依据该组合物制备得到的冻干制剂杂质含量低，在高湿、强光以及低温贮存条件下均具有良好稳定性。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本 发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
试剂：3-(2-苄氧羰基氨基-3-甲基-丁酰胺基)-5-氟-4-氧代-戊酸(简称F573，由北京康蒂尼药业股份有限公司提供)结构如下：
仪器设备：LYO-25药用真空冷冻干燥机，岛津20A高效液相色谱仪，HP1100高效液相色谱仪，Mettler AE240天平。
实施例1 F573注射液制备
1.1以制备F573的注射液为目的，筛选注射溶剂
表A-1溶剂影响
结果显示：F573在丙二醇/水溶液(80％/20％；调节pH至4.0～5.0)中完全溶解。
1.2 F573注射液的稳定性考察
将F573溶解于丙二醇/水溶液(80％/20％；调节pH至4.0～5.0)中，在120℃，15min条件下高温灭菌15分钟，然后进行检测(结果参见下表1-2)。
表A-2 F573溶液高温灭菌前后考察结果
结果显示：高温灭菌后的样品，有关物质增加了约50％，F573含量降低了约50％。可见F573在水溶液中稳定性差，同时不能耐受湿热灭菌，因此不宜开发成小容量注射剂或大容量注射剂。
实施例2粉针剂(F573+非水溶剂配制使用)
制备复合包装的F573粉针剂，即每套含1瓶含30mg主药的灭菌粉末和2ml非水溶剂，即配制即用，酌加适量的止痛剂(苯甲醇)，需要首先采用90％乙醇溶液作为溶剂，对F573原料进行溶解、结晶、除炭、干燥等处理。结果发现，对原料进行重结晶以及除炭等处理工艺，将导致收率约为50％，且可能引起晶型改变等问题。因此，F573不宜开发为上述剂型。
实施例3冻干组合物配方研究
3.1辅料影响实验
在冻干制剂中，甘露醇可以作为载体用于形成均匀骨架；而氨基酸不仅可用作冻干剂的骨架剂，也是常见的蛋白质保护剂。选择F573不添加其它辅料以及分别添加精氨酸，甘氨酸，甘露醇的配方，采用如下冻干工艺制备：将F573过100目筛，备用。称取适量的碳酸氢钠配制成1mol/L的溶液，备用。称取处方量的精氨酸、甘氨酸或者甘露醇加入上述碳酸氢钠溶液中搅拌使其完全溶解；将溶液温度控制在8～15℃，然后加入处方量F573，边加边搅拌，搅拌40分钟使溶解，整个配液过程进行氮气保护。终端过滤器采用0.22μm的聚醚砜微孔滤膜(滤芯)进行除菌过滤，灌装，同时加开花丁基胶塞至适当高度，冻干，得到块状物。
研究结果如下表B-1所示，可以看出甘氨酸更适合作为骨架剂。
表B-1

3.2 F573与辅料相容性试验结果，将F573与甘氨酸、焦亚硫酸钠分别进行配伍研究，如下表B-2、B-3所示，可见F573适于和甘氨酸、焦亚硫酸钠配伍。
表B-2 F573与甘氨酸相容性试验结果
表B-3 F573与焦亚硫酸钠相容性试验结果
3.3处方优化实验
选择焦亚硫酸钠和甘氨酸作为F573冻干制剂的辅料，并对这2个因素进行考察以便进一 步优化配方，每因素分别设3个水平，以正交表L9(34)安排9个处方进行实验，以冻干针物理外观、复溶时间及pH值作为评价指标，对结果进行分析，实验因素水平的分配见表C-1，实验结果及统计分析见表C-2、表C-3。
表C-1因素水平表
表C-2处方优化试验结果
注：综合评价中，外观占50％，复溶时间占40％，pH值占10％。
表C-3方差分析
实施例4冻干制剂F-1
4.1 F-1的制备
制剂处方F-1(1000支用量)
F573 30g
甘氨酸 50g
焦亚硫酸钠 1g
碳酸氢钠 适量
注射用水加至 1000ml。
将F573过100目筛，备用。称取适量的碳酸氢钠配制成1mol/L的溶液，备用。另称取处方量的焦亚硫酸钠和甘氨酸加入上述碳酸氢钠溶液中搅拌使其完全溶解，调节pH值为7.5-8.5；将溶液温度控制在8～15℃，然后加入处方量F573，边加边搅拌，搅拌40分钟使溶解，整个配液过程进行氮气保护。检测，pH、含量合格后过滤。终端过滤器采用聚醚砜微孔滤膜(滤芯)进行除菌过滤，药液可见异物检查合格后入盛药用大理瓶，调整装量后灌装，同时加开花丁基胶塞至适当高度。冻干、箱内压塞、出箱、轧盖、灯检、贴签、包装、送样、检验合格后成品入库。成品置4-8℃下保存。
4.2取三批按照上述F-1制备工艺的样品，分别考察制剂在高湿、强光以及在低温贮存条件下的长期稳定性，检测结果如下所示。结果表明：注射用F573的各项检查项目均符合药典对于制剂稳定性的规定。
表D-1三批样品检测结果

表D-2注射用F573(20110501)90.0％高湿度(25℃)条件下的稳定性试验结果
表D-3.注射用F573(20110501)4500lx强光照射条件下稳定性试验结果
表D-4注射用F573(20110501)在冰箱贮存(2～8℃)条件下长期试验结果
表D-5.注射用F573(20110502)在冰箱贮存(2～8℃)条件下长期试验结果
表D-6.注射用F573(20110503)在冰箱贮存(2～8℃)条件下长期试验结果
以上，对本发明示例性的实施方式进行了说明。但是，本发明的保护范围不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (11)

  1. 一种药物组合物，包括如下组分：
    (a)式I化合物，结构如下：
    (b)甘氨酸；
    (c)抗氧化剂。
  2. 根据权利要求1的药物组合物，其特征在于，所述抗氧化剂选自抗坏血酸、依地酸钠、亚硫酸氢钠、焦亚硫酸钠中的一种，两种或更多种。
  3. 根据权利要求1的药物组合物，其特征在于，所述组合物任选进一步包括组分(d)pH调节剂；在一些实施方案中，所述pH调节剂为碱性试剂，选自氢氧化钠、氢氧化钾、碳酸氢钠、碳酸氢钾或磷酸氢二钠中的一种，两种或更多种。
  4. 根据权利要求1的药物组合物，其特征在于，
    所述组分(a)占组合物总量的0.5％至10.0％(w/w)；优选的，所述组分(a)占组合物总量的2.0％至5.0％(w/w)；
    所述组分(b)占组合物总量的约0.5％至约15.0％(w/w)；优选的，所述组分(b)占组合物总量的3.0％至约10.0％(w/w)；
    所述组分(c)占组合物总量的0.01％至0.50％(w/w)；优选的，所述组分(c)占组合物总量的0.05％至0.30％(w/w)。
  5. 根据权利要求1的药物组合物，其特征在于，所述组合物的pH值大于7.0，优选的，为7.0-9.0，更优选的，为7.5-8.5。
  6. 根据权利要求1的药物组合物，其特征在于，所述组合物为冻干粉针剂。
  7. 根据权利要求1-6任一项所述的药物组合物的制备方法，其特征在于，包括如下步骤：
    (a1)加入处方量的抗氧化剂、甘氨酸，并任选加入pH调节剂，混合均匀；
    (a2)向步骤(a1)得到的溶液中，加入处方量的式I化合物，使其溶解；
    优选的，所述制备方法还包括如下步骤：
    (a3)将步骤(a2)得到的液体进行除菌过滤，冻干。
  8. 根据权利要求7所述的制备方法，其特征在于，
    所述步骤(a1)中，将处方量的抗氧化剂、甘氨酸加入pH调节剂中；
    所述步骤(a2)中，将步骤(a1)得到的溶液温度控制在8～15℃，再加入处方量的式I化合物。
  9. 根据权利要求7所述的制备方法，其特征在于，包括如下步骤：
    称取处方量的焦亚硫酸钠和甘氨酸加入碳酸氢钠溶液中搅拌使其完全溶解，调节pH值为7.0-9.0；将溶液温度控制在8～15℃，然后加入处方量F573，搅拌30-50分钟使溶解，整个配液过程进行氮气保护，除菌过滤，灌装，同时加开花丁基胶塞至适当高度，冻干。
  10. 根据权利要求1-6任一项所述的药物组合物在制备用于预防或治疗肝衰竭的药物中的用途。
  11. 根据权利要求10所述的用途，其特征在于，所述的肝衰竭包括：急性肝衰竭、亚急性肝衰竭、和慢加急性肝衰竭、慢性肝衰竭；优选的，所述的药物还用于提高肝衰竭病人的生存率；和/或用于改善肝衰竭病人的肝功能指标；更优选的，所述的改善肝功能指标包括：降低降低丙氨酸转氨酶(ALT)、降低天冬氨酸转氨酶(AST)和/或降低总胆红素(TBil)。
PCT/CN2023/092238 2022-05-06 2023-05-05 一种二肽衍生物组合物及其制备方法和用途 Ceased WO2023213293A1 (zh)

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