WO2023173615A1 - Stable ester peptide drug aqueous solution - Google Patents

Stable ester peptide drug aqueous solution Download PDF

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WO2023173615A1
WO2023173615A1 PCT/CN2022/100169 CN2022100169W WO2023173615A1 WO 2023173615 A1 WO2023173615 A1 WO 2023173615A1 CN 2022100169 W CN2022100169 W CN 2022100169W WO 2023173615 A1 WO2023173615 A1 WO 2023173615A1
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aqueous solution
amino acid
ring
ester
peptide
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PCT/CN2022/100169
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French (fr)
Chinese (zh)
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赵振坤
陆平
朱逸凡
范敏华
徐沧朔
石慧
沈乐
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海南普利制药股份有限公司
浙江普利药业有限公司
安徽普利药业有限公司
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Publication of WO2023173615A1 publication Critical patent/WO2023173615A1/en

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    • 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
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • 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
    • 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
    • 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
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic 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
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics

Definitions

  • the invention belongs to the medical field, and specifically relates to a stable aqueous solution of ester peptide drugs, aiming to solve the stability problem of ester peptide drugs, including daptomycin.
  • Lipopeptides represent a class of powerful anti-infective drugs that exhibit efficient antibacterial and antifungal activity against multi-drug-resistant bacteria.
  • lipopeptide drugs available on the market such as daptomycin, Telavancin, Caspofungin, Micafungin, Arni Anidulafungin to fight aggressive, often life-threatening infections.
  • Daptomycin is a cyclic ester peptide compound.
  • FDA Food and Drug Administration
  • injectable daptomycin (trade name: Cubicin) through an expedited review process for the treatment of concurrent skin and skin structure infections caused by some Gram-positive susceptible strains, such as Abscesses, surgical incision infections, and skin ulcers.
  • Daptomycin interferes with the transport of amino acids in the cell membrane, thereby hindering the biosynthesis of bacterial cell wall peptidoglycan and changing the properties of the cytoplasmic membrane; in addition, it can also achieve sterilization by damaging the bacterial cell membrane and leaking its contents. Purpose. It may therefore be difficult for bacteria to develop resistance to daptomycin.
  • Daptomycin is potent against Gram-positive bacteria and is used to treat the following infections:
  • CSSSI Complex skin and soft tissue infections: Treat Staphylococcus aureus (including methicillin-resistant strains) that are sensitive to this product, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subsp. equi and Complicated skin and soft tissue infections caused by Enterococcus faecalis (vancomycin-susceptible strains only).
  • Staphylococcus aureus including methicillin-sensitive and methicillin-resistant bloodstream infection (bacteremia), and associated right-sided infective endocarditis.
  • daptomycin is difficult to stabilize in solution, especially in aqueous solutions, because daptomycin is prone to hydrolytic degradation and is known to degrade in slightly acidic solutions via aspartate on the asp-9 residue. Degraded by acyl transpeptide action. Therefore, daptomycin is only available as freeze-dried powder for injection at home and abroad, for intravenous injection. Daptomycin lyophilized powder will show rapid degradation when reconstituted, and daptomycin aqueous solution will also degrade during short-term storage. Therefore, daptomycin is not suitable for long-term storage in aqueous solution.
  • daptomycin formulated as a reconstituted solution i.e., daptomycin in an aqueous state
  • daptomycin in an aqueous state has a stability of 5 days under refrigerated conditions and a maximum stability of 2 days at room temperature.
  • the main degradation products of daptomycin are the intralipid hydrolyzate of daptomycin, the ⁇ -isomer of daptomycin and dehydrated daptomycin.
  • Their structural formulas are as follows:
  • Kirsch disclosed that during the purification of daptomycin, dehydrated daptomycin and the ⁇ -isomer of daptomycin were produced (Pharmaceutical Research, 6:387-393, 1989, Kirsch). Kirsch describes methods to minimize the levels of dehydrated daptomycin and ⁇ -isomer by controlling pH conditions and temperature conditions. However, Kirsch is unable to stabilize daptomycin and does not prevent the conversion of daptomycin to anhydrodaptomycin and its subsequent isomerization to the ⁇ -isomer. Kirsch also cannot prevent the degradation of daptomycin into other degradation products unrelated to anhydrodaptomycin and the ⁇ -isomer. US Patent No.
  • 6,696,412 discloses several additional impurities present in the fermentation product from which daptomycin is derived, and provides a method to produce purified daptomycin of increased purity.
  • the additional impurities include lactone hydrolysis products of daptomycin. It is disclosed that the daptomycin purification method may include forming daptomycin micelles, removing low molecular weight contaminants by filtration, and then converting the micellar filtrate containing daptomycin into a non-micelle state, and then performing Anion exchange and reverse osmosis diafiltration are used to obtain high-purity daptomycin, which is then freeze-dried, which is a complicated process.
  • WO2014041425 discloses a freeze-dried daptomycin formulation containing additives, which may be antioxidants, organic acids or glucose derivatives.
  • WO2013103801 discloses a powder formulation containing daptomycin and polyethylene glycol.
  • WO20111063419 discloses a freeze-dried preparation of daptomycin with a shorter reconstitution time.
  • ester peptide drugs including ester peptide drugs and amino acid derivatives.
  • the ester peptide drug is selected from the group consisting of daptomycin, Telavancin, Caspofungin, Micafungin, Anidulafungin, etc., preferably daptomycin. Mycin.
  • amino acid derivatives contain free sulfhydryl groups or N-acetyl-glycine, N-acetyl-valine, N-acetyl-tyrosine, N-acetyl-alanine, N-acetyl-methionine, N-methyl- A type of cysteine.
  • amino acid derivative has the following structure of formula I:
  • R 1 is selected from hydrogen, C 1 -C 3 alkyl, halogen
  • R 2 and R 3 are each independently selected from COR 4 , hydrogen, C 1 -C 6 alkyl, and at least R 2 and R 3
  • One is COR 4 , where R 4 is selected from C 1 -C 6 alkyl, aryl, alkaryl, the aryl or alkaryl may have 1-3 substituents, and the substituents
  • the group is selected from halogen, nitro, alkanoyl, C 1 -C 6 linear or branched alkyl.
  • the C 1 -C 3 alkyl group is selected from methyl, ethyl, propyl, and isopropyl.
  • the halogen is selected from Cl, Br, I.
  • the C 1 -C 6 alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, and hexyl.
  • the aryl group is selected from benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, furan ring, thiophene ring, pyrazole ring, imidazole ring or triazole ring.
  • the alkylaryl group has the general formula (CH 2 ) nAr, wherein n is 1-5, preferably 1-3, and Ar is selected from the group consisting of benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, and furan ring, thiophene ring, pyrazole ring, imidazole ring or triazole ring.
  • the R 1 is selected from hydrogen, methyl, ethyl, and chlorine.
  • the R 4 is selected from methyl, ethyl, and propyl.
  • one of R 2 and R 3 is hydrogen.
  • amino acid derivative has the following structure:
  • R 1 , R 2 and R 4 are the same as before.
  • R 1 is hydrogen, methyl, or halogen
  • R 2 is hydrogen or methyl
  • R 4 is methyl, ethyl, propyl, or benzyl.
  • the amino acid derivative is N-acetyl-cysteine.
  • the N-acetyl-cysteine can be a mixture of D-form or L-form or DL.
  • the present invention provides a stable ester peptide drug aqueous solution, including ester peptide drugs and amino acid derivatives.
  • the impurity growth rate of the ester peptide drug aqueous solution is within 0.01% w/w/day, preferably Within 0.007% w/w/day. Preferably, the impurity growth rate is within 0.005% w/w/day.
  • adding N-acetylcysteine can stabilize daptomycin, and can effectively reduce or inhibit the ⁇ -isoforms of daptomycin lactone hydrolyzate and daptomycin.
  • the daptomycin composition exhibits excellent stability, exemplarily, it is stable at 2-8°C for at least 12 months, at least 18 months, at least 24 months, or at least 32 months.
  • the proportion of peptide ester drugs in the aqueous solution of peptide ester drugs is about 0.1-50% w/w.
  • the proportion of peptide ester drugs is about 0.1-30% w/w. More preferably, the proportion of peptide ester drugs is about 0.1-30% w/w.
  • Ester drugs account for about 0.1-20% w/w, and most preferably, the peptide ester drugs account for about 0.5-10% w/w.
  • the amino acid derivatives account for about 0.01-50% w/w, preferably, the amino acid derivatives account for about 0.01-10% w/w, and more preferably, the amino acid derivatives account for About 0.01-5% w/w, more preferably, the amino acid derivative accounts for about 0.01-2% w/w.
  • This value means that the error change after measurement does not exceed plus or minus 10%. It can be plus or minus 9%, plus or minus 8%, plus or minus 7%, Plus or minus 6%, plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2%, or plus or minus 1%, preferably plus or minus 5%.
  • the molar dosage ratio of the peptide ester drugs to the amino acid derivatives is 1: (2-40); Preferably, the molar dosage ratio of the peptide ester drugs to the amino acid derivatives is 1: (10-30). ), more preferably, the molar dosage ratio of the peptide ester drugs to the amino acid derivatives is 1: (15-20); the most optimal is the molar dosage ratio of the peptide ester drugs to the amino acid derivatives It's 1:20.
  • the aqueous peptide ester drug solution includes polyol.
  • the polyol is selected from mannitol, sorbitol, sucrose, and trehalose.
  • the aqueous solution of the ester peptide drug includes an organic solvent.
  • the organic solvent is selected from: dimethylacetamide, isopropyl alcohol, ethanol, benzyl alcohol, 2-methyl-1-propanol, tert-butanol, ethylene glycol, propylene glycol, glycerol, polysorbate, such as Polysorbate 20, polysorbate 40 and polysorbate 80, polyethylene glycol (PEG), such as polyethylene glycol 200 (PEG 200), polyethylene glycol 300 (PEG 300), polyethylene glycol One or more mixtures of alcohol 400 (PEG 400) and polyethylene glycol 600 (PEG 600).
  • PEG polyethylene glycol
  • the pharmaceutical excipient can be, for example, a carrier, antioxidant, surfactant, lipid , sugar, organic acids, complexing agents, preservatives, stabilizers, solubilizers, surfactants, buffers, diluents, binders, etc.
  • the aqueous ester peptide drug solution of the present invention can be filled in glass vials, syringes, drop bottles, tubes, applicators, unit dispensers, infusion bags, sprayers, inhalation devices or other drug containers.
  • the pharmaceutical composition can be filled and protected with an inert gas such as nitrogen.
  • the aqueous ester peptide drug solution of the present invention can be used to prepare injections, eye preparations, ear preparations, nasal preparations and other dosage forms.
  • the invention provides a method for preparing an aqueous solution of ester peptide drugs, which includes the following steps:
  • Step a Weigh the prescribed amount of amino acid derivatives in a beaker, add the prescribed amount of water, stir to dissolve, and obtain an amino acid derivative solution;
  • Step b Weigh the prescribed amount of ester peptide drugs, stir and dissolve it in the amino acid derivative solution obtained in step a above;
  • the preparation method includes the step of adding other pharmaceutical excipients.
  • the present invention provides the use of the aqueous ester peptide pharmaceutical solution in the preparation of a medicament for the treatment of microbial infections, particularly caused by Gram-positive organisms.
  • the present invention provides the use of the aqueous ester peptide drug solution in the preparation of drugs for the treatment of skin and soft tissue infections (cSSTI) and Staphylococcus aureus bloodstream infections (bacteremia).
  • cSSTI skin and soft tissue infections
  • bacteremia Staphylococcus aureus bloodstream infections
  • ester peptide drug aqueous solution provided by the present invention can be prepared into solid preparations, such as powders, granules, tablets, capsules, freeze-dried powders, etc., without adding water.
  • the peptide ester drug aqueous solution formula provided by the present invention can greatly reduce the growth rate of impurities in the aqueous solution under the condition of 8°C.
  • the obtained aqueous solution can be used to prevent and treat infections of sensitive strains, and at the same time, the stability of the aqueous solution at 2-8°C is at least 12 months.
  • the aqueous solution provided by the present invention does not require a reconstitution step and can be directly used clinically, reducing medication errors.
  • Figure 1 is the HPLC spectrum of prescription 7 at 40°C/24h.
  • Figure 2 is the HPLC spectrum of prescription 20 at 8°C/30 days.
  • Figure 3 is the HPLC spectrum of prescription 21 at 8°C/60 days.
  • Figure 4 is the HPLC chromatogram of prescription 21 at 8°C/12 months.
  • HPLC analysis conditions of the following examples are:
  • Liquid chromatograph Waters UPLC, column Waters ACQUITY UPLC@BEH shield RP18, mobile phase is as follows:
  • Anhydrous sodium sulfate solution Weigh 3.46g of anhydrous sodium sulfate, dissolve it in 1000ml of purified water, and adjust the pH to 3.4 with phosphoric acid.
  • Peak Name RRT min Area% Area 1 Internal lipid hydrolyzate 13.061 0.11 17276 2 Daptomycin 17.406 93.70 14613658 3 beta isomer 18.709 0.63 97481 4 Dehydrated Daptomycin 20.617 1.98 309056
  • prescription 14 is the most stable and has the lowest degradation rate.
  • prescription 21 is the most stable and has the lowest degradation rate.
  • HPLC spectrum of prescription 20, 8°C/30 days is shown in Figure 2, and its corresponding data is as follows:
  • Peak Name RRT min Area% Area 1 Internal lipid hydrolyzate 12.745 0.12 18675 2 Daptomycin 16.817 97.45 14957632 3 beta isomer 18.617 0.03 5090 4 Dehydrated Daptomycin 19.878 0.74 113375
  • Prescription 21 The daptomycin composition is placed at 8°C, and the stability is investigated at 2 months, 4 months, 6 months, 9 months, and 12 months.
  • the peak area percentage of impurities is calculated by normalizing the peak area. , the results are as follows.
  • the impurity growth rate does not extend with the extension of storage time, but shows a downward trend, and the total impurity growth rate can be effectively controlled at 0.7%w/ w range.
  • Peak Name RRT min Area% Area 1 Internal lipid hydrolyzate 12.734 0.11 19051 2 Daptomycin 16.815 97.02 16285372 3 beta isomer 18.599 0.03 5086 4 Dehydrated Daptomycin 19.857 0.74 124064
  • the amino acid derivative has the following general structure:
  • R 1 , R 2 and R 3 are the same as before.
  • the total impurity content of each prescription on day 0 is different because different starting materials are used.

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Abstract

The present invention belongs to the medical field, and particularly relates to a stable ester peptide drug aqueous solution. The stable ester peptide drug aqueous solution comprises an ester peptide drug and an amino acid derivative, wherein the amino acid derivative comprises free sulfhydryl. The formula of the ester peptide drug aqueous solution provided by the present invention can greatly reduce the growth speed of impurities in the aqueous solution under the condition of 2-8 °C. The stability at 2-8 °C is kept for at least 12 months or more.

Description

一种稳定的酯肽类药物水溶液A stable aqueous solution of ester peptide drugs
本申请主张如下优先权：This application claims the following priority rights:
本申请要求于2022年3月18日提交中国专利局、申请号为202210271021.1、申请名称为“一种稳定的酯肽类药物水溶液”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。This application claims priority to the Chinese patent application submitted to the China Patent Office on March 18, 2022, with the application number 202210271021.1 and the application name "A stable aqueous solution of ester peptide drugs", the entire content of which is incorporated herein by reference. Applying.
技术领域Technical field
本发明属于医疗领域，具体涉及一种稳定的酯肽类药物水溶液，旨在解决酯肽类药物的稳定性问题，包括达托霉素。The invention belongs to the medical field, and specifically relates to a stable aqueous solution of ester peptide drugs, aiming to solve the stability problem of ester peptide drugs, including daptomycin.
背景技术Background technique
脂肽(Lipopeptide)代表一类强效抗感染药物，其对多重耐药菌表现出高效的抗菌作用以及抗真菌活性。现在市场上有可获得的各种各样的脂肽药物如达托霉素(Daptomycin)、泰拉万星(Telavancin)、卡泊芬净(Caspofungin)、米卡芬净(Micafungin)、阿尼芬净(Anidulafungin)，以对抗侵袭性的通常危及生命的感染。Lipopeptides represent a class of powerful anti-infective drugs that exhibit efficient antibacterial and antifungal activity against multi-drug-resistant bacteria. There are various lipopeptide drugs available on the market such as daptomycin, Telavancin, Caspofungin, Micafungin, Arni Anidulafungin to fight aggressive, often life-threatening infections.
达托霉素(Daptomycin)化学名为：The chemical name of Daptomycin is:
N-decanoyl-L-tryptophyl-D-asparaginyl-L-aspartyl-L-threonylglycyl-L-ornithyl-L-aspartyl-D-alanyl-L-aspartylglycyl-D-seryl-threo-3-methyl-L-glutamyl-3-anthraniloyl-L-alanine ε 1-lactone，分子式为：C 72H 101N 17O 26，分子量为：1620.67，结构式如下： N-decanoyl-L-tryptophyl-D-asparaginyl-L-aspartyl-L-threonylglycyl-L-ornithyl-L-aspartyl-D-alanyl-L-aspartylglycyl-D-seryl-threo-3-methyl-L-glutamyl- 3-anthraniloyl-L-alanine ε 1 -lactone, the molecular formula is: C 72 H 101 N 17 O 26 , the molecular weight is: 1620.67, and the structural formula is as follows:
Figure PCTCN2022100169-appb-000001
Figure PCTCN2022100169-appb-000001
达托霉素(Daptomycin，DAP)为一种环酯肽类化合物。2003年，美国食品与药物管理局(FDA)经过快速审理程序批准注射用达托霉素(商品名Cubicin)用于治疗由一些革兰氏阳性敏感菌株引起的并发性皮肤及皮肤结构感染，如脓肿、手术切口感染和皮肤溃疡。达托霉素通过扰乱细胞膜对氨基酸的转运，从而阻碍细菌细胞壁肽聚糖的生物合成，改变细胞质膜的性质；另外，它还能通过破坏细菌的细胞膜，使其内容物外泄而达到杀菌的目的。因此细菌对达托霉素产生耐药性可能会比较困难。Daptomycin (DAP) is a cyclic ester peptide compound. In 2003, the U.S. Food and Drug Administration (FDA) approved injectable daptomycin (trade name: Cubicin) through an expedited review process for the treatment of concurrent skin and skin structure infections caused by some Gram-positive susceptible strains, such as Abscesses, surgical incision infections, and skin ulcers. Daptomycin interferes with the transport of amino acids in the cell membrane, thereby hindering the biosynthesis of bacterial cell wall peptidoglycan and changing the properties of the cytoplasmic membrane; in addition, it can also achieve sterilization by damaging the bacterial cell membrane and leaking its contents. Purpose. It may therefore be difficult for bacteria to develop resistance to daptomycin.
达托霉素对革兰氏阳性菌有强烈作用，用于治疗下列感染：Daptomycin is potent against Gram-positive bacteria and is used to treat the following infections:
1、复杂性皮肤及软组织感染(CSSSI):治疗由对本品敏感的金黄色葡萄球菌(包括甲氧西林耐药菌株)、化脓链球菌无乳链球菌、停乳链球菌似马亚种及粪肠球菌(仅用于万古霉素敏感的菌株)导致的复杂性肤及软组织感染。1. Complex skin and soft tissue infections (CSSSI): Treat Staphylococcus aureus (including methicillin-resistant strains) that are sensitive to this product, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subsp. equi and Complicated skin and soft tissue infections caused by Enterococcus faecalis (vancomycin-susceptible strains only).
2、金黄色葡萄球菌(包括甲氧西林敏感和甲氧西林耐药)血流感染(菌血症)，以及伴发的右侧感染性心内膜炎。2. Staphylococcus aureus (including methicillin-sensitive and methicillin-resistant) bloodstream infection (bacteremia), and associated right-sided infective endocarditis.
根据现有文献，在溶液，尤其是在水性溶液中，达托霉素难以稳定，因为达托霉素易于水解降解，并且已知在微酸性溶液中通过asp-9残基上的天冬氨酰转肽作用而降解。因此达托霉素在国内外仅上市冻干粉针剂，静脉注射用。达托霉素冻干粉针在复溶时即会表现出快速降解，且达托霉素水溶液在短暂存储过程中也会出现降解，因此，达托霉素不适合在水溶液中长期储存。目前，以重构溶液的形式(即，含水状态的达托霉素)配制的市售的达托霉素在冷藏条件下的稳定性为5天，而在室温下最大稳定性为2天。达托霉素主要降解物是达托霉素的内脂水解物、达托霉素的β-异构体和脱水达托霉素，其结构式依次如下：According to the existing literature, daptomycin is difficult to stabilize in solution, especially in aqueous solutions, because daptomycin is prone to hydrolytic degradation and is known to degrade in slightly acidic solutions via aspartate on the asp-9 residue. Degraded by acyl transpeptide action. Therefore, daptomycin is only available as freeze-dried powder for injection at home and abroad, for intravenous injection. Daptomycin lyophilized powder will show rapid degradation when reconstituted, and daptomycin aqueous solution will also degrade during short-term storage. Therefore, daptomycin is not suitable for long-term storage in aqueous solution. Currently, commercially available daptomycin formulated as a reconstituted solution (i.e., daptomycin in an aqueous state) has a stability of 5 days under refrigerated conditions and a maximum stability of 2 days at room temperature. The main degradation products of daptomycin are the intralipid hydrolyzate of daptomycin, the β-isomer of daptomycin and dehydrated daptomycin. Their structural formulas are as follows:
Figure PCTCN2022100169-appb-000002
Figure PCTCN2022100169-appb-000002
Figure PCTCN2022100169-appb-000003
Figure PCTCN2022100169-appb-000003
例如Kirsch披露了在纯化达托霉素过程中产生脱水达托霉素和达托霉素的β-异构体(Pharmaceutical Research,6:387-393,1989,Kirsch)。Kirsch描述了通过控制pH条件和温度条件而使脱水达托霉素和β-异构体的水平最小化的方法。然而，Kirsch不能使达托霉素稳定且不能防止达托霉素向脱水达托霉素的转化及其随后向β-异构体的异构化。Kirsch也不能防止达托霉素降解为与脱水达托霉素和β-异构体不相关的其它降解产物。美国专利US6696412披露了存在于发酵产物中的若干额外的杂质，其中达托霉素由所述发酵产物衍生得到，且该专利提供了产生增加的纯度的纯化达托霉素的方法。所述额外的杂质包括达托霉素的内酯水解产物。其公开了所述达托霉素纯化方法可包括形成达托霉素胶束、通过滤过除去低分子量污染物，然后将含有达托霉素的胶束滤液转化为非胶束状态，接着进行阴离子交换和反渗透渗滤以获得高纯度达托霉素，然后将其冻干，工艺复杂。For example, Kirsch disclosed that during the purification of daptomycin, dehydrated daptomycin and the β-isomer of daptomycin were produced (Pharmaceutical Research, 6:387-393, 1989, Kirsch). Kirsch describes methods to minimize the levels of dehydrated daptomycin and β-isomer by controlling pH conditions and temperature conditions. However, Kirsch is unable to stabilize daptomycin and does not prevent the conversion of daptomycin to anhydrodaptomycin and its subsequent isomerization to the β-isomer. Kirsch also cannot prevent the degradation of daptomycin into other degradation products unrelated to anhydrodaptomycin and the β-isomer. US Patent No. 6,696,412 discloses several additional impurities present in the fermentation product from which daptomycin is derived, and provides a method to produce purified daptomycin of increased purity. The additional impurities include lactone hydrolysis products of daptomycin. It is disclosed that the daptomycin purification method may include forming daptomycin micelles, removing low molecular weight contaminants by filtration, and then converting the micellar filtrate containing daptomycin into a non-micelle state, and then performing Anion exchange and reverse osmosis diafiltration are used to obtain high-purity daptomycin, which is then freeze-dried, which is a complicated process.
WO2014041425公开了包含添加剂的冻干达托霉素制剂，所述辅料可以是抗氧化剂、有机酸或葡萄糖衍生物。WO2013103801公开了包含达托霉素和聚乙二醇的粉末制剂。WO20111063419公开了一种达托霉素冻干制剂，具有更短的复溶时间。虽然这些专利申请试图改善达托霉素的稳定性，但是均不可避免复溶步骤，以及错配的风险。WO2014041425 discloses a freeze-dried daptomycin formulation containing additives, which may be antioxidants, organic acids or glucose derivatives. WO2013103801 discloses a powder formulation containing daptomycin and polyethylene glycol. WO20111063419 discloses a freeze-dried preparation of daptomycin with a shorter reconstitution time. Although these patent applications attempt to improve the stability of daptomycin, the reconstitution step and the risk of mismatching are unavoidable.
发明内容Contents of the invention
为了解决现有技术中存在的问题，本发明采用如下技术方案：In order to solve the problems existing in the prior art, the present invention adopts the following technical solutions:
一种稳定的酯肽类药物水溶液，包括酯肽类药物、氨基酸衍生物。A stable aqueous solution of ester peptide drugs, including ester peptide drugs and amino acid derivatives.
所述酯肽类药物选自达托霉素、泰拉万星(Telavancin)、卡泊芬净(Caspofungin)、米卡芬净(Micafungin)、阿尼芬净(Anidulafungin)等，优选为达托霉素。The ester peptide drug is selected from the group consisting of daptomycin, Telavancin, Caspofungin, Micafungin, Anidulafungin, etc., preferably daptomycin. Mycin.
所述氨基酸衍生物含有游离巯基或N-乙酰-甘氨酸，N-乙酰-缬氨酸，N-乙酰-酪氨酸、N-乙酰-丙氨酸，N-乙酰-蛋氨酸，N-甲基-半胱氨酸中的一种。The amino acid derivatives contain free sulfhydryl groups or N-acetyl-glycine, N-acetyl-valine, N-acetyl-tyrosine, N-acetyl-alanine, N-acetyl-methionine, N-methyl- A type of cysteine.
优选的，所述氨基酸衍生物具有如下式I结构：Preferably, the amino acid derivative has the following structure of formula I:
Figure PCTCN2022100169-appb-000004
Figure PCTCN2022100169-appb-000004
其中R 1选自氢，C 1-C 3的烷基，卤素；R 2和R 3各自独立的选自COR 4，氢，C 1-C 6的烷基，且R 2和R 3中至少有一个为COR 4，其中R 4选自C 1-C 6的烷基，芳基，烷芳基，所述芳基或烷芳基可用带有1-3个取代基团，所述取代基团选自卤素、硝基、烷酰基、C 1-C 6的直链或支链烷基。 Wherein R 1 is selected from hydrogen, C 1 -C 3 alkyl, halogen; R 2 and R 3 are each independently selected from COR 4 , hydrogen, C 1 -C 6 alkyl, and at least R 2 and R 3 One is COR 4 , where R 4 is selected from C 1 -C 6 alkyl, aryl, alkaryl, the aryl or alkaryl may have 1-3 substituents, and the substituents The group is selected from halogen, nitro, alkanoyl, C 1 -C 6 linear or branched alkyl.
示例性的，所述C 1-C 3的烷基选自甲基，乙基，丙基，异丙基。 Illustratively, the C 1 -C 3 alkyl group is selected from methyl, ethyl, propyl, and isopropyl.
示例性的，所述卤素选自Cl，Br，I。Illustratively, the halogen is selected from Cl, Br, I.
示例性的，所述C 1-C 6的烷基选自甲基，乙基，丙基，异丙基，正丁基，异丁基，叔丁基，戊基，己基。所述芳基选自苯环、吡啶环、嘧啶环、吡嗪环、哒嗪环、呋喃环、噻吩环、吡唑环、咪唑环或***环。 Illustratively, the C 1 -C 6 alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, and hexyl. The aryl group is selected from benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, furan ring, thiophene ring, pyrazole ring, imidazole ring or triazole ring.
所述烷芳基具有通式(CH 2)nAr，其中n为1-5，优选为1-3，Ar选自选自苯环、吡啶环、嘧啶环、吡嗪环、哒嗪环、呋喃环、噻吩环、吡唑环、咪唑环或***环。 The alkylaryl group has the general formula (CH 2 ) nAr, wherein n is 1-5, preferably 1-3, and Ar is selected from the group consisting of benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, and furan ring, thiophene ring, pyrazole ring, imidazole ring or triazole ring.
优选的，所述R 1选自氢、甲基、乙基、氯。 Preferably, the R 1 is selected from hydrogen, methyl, ethyl, and chlorine.
优选的，所述R 4选自甲基，乙基，丙基。 Preferably, the R 4 is selected from methyl, ethyl, and propyl.
优选的，所述R 2和R 3其中有一个为氢。 Preferably, one of R 2 and R 3 is hydrogen.
优选的，所述氨基酸衍生物具有如下结构：Preferably, the amino acid derivative has the following structure:
Figure PCTCN2022100169-appb-000005
Figure PCTCN2022100169-appb-000005
其中R 1、R 2和R 4的定义与前文相同。 The definitions of R 1 , R 2 and R 4 are the same as before.
优选的，R 1为氢、甲基、卤素；R 2为氢、甲基；R 4为甲基，乙基、丙基、苄基。 Preferably, R 1 is hydrogen, methyl, or halogen; R 2 is hydrogen or methyl; R 4 is methyl, ethyl, propyl, or benzyl.
优选的，所述氨基酸衍生物为N-乙酰-半胱氨酸。Preferably, the amino acid derivative is N-acetyl-cysteine.
优选的，所述N-乙酰-半胱氨酸可以为D型或L型或DL的混合物。Preferably, the N-acetyl-cysteine can be a mixture of D-form or L-form or DL.
另一方面，本发明提供了一种稳定的酯肽类药物水溶液，包括酯肽类药物、氨基酸衍生物，所述酯肽类药物水溶液杂质增长率在0.01％w/w/天以内，优选的0.007％w/w/天以内。优选的，杂质增长率在0.005％w/w/天以内。On the other hand, the present invention provides a stable ester peptide drug aqueous solution, including ester peptide drugs and amino acid derivatives. The impurity growth rate of the ester peptide drug aqueous solution is within 0.01% w/w/day, preferably Within 0.007% w/w/day. Preferably, the impurity growth rate is within 0.005% w/w/day.
在一个优选的技术方案中，加入N-乙酰半胱氨酸可以起到稳定达托霉素的作用，并能够有效降低或抑制达托霉素内脂水解物、达托霉素的β-异构体和脱水达托霉素的产生：In a preferred technical solution, adding N-acetylcysteine can stabilize daptomycin, and can effectively reduce or inhibit the β-isoforms of daptomycin lactone hydrolyzate and daptomycin. Generation of conformation and dehydration of daptomycin:
Figure PCTCN2022100169-appb-000006
Figure PCTCN2022100169-appb-000006
Figure PCTCN2022100169-appb-000007
Figure PCTCN2022100169-appb-000007
在稳定性试验中，该达托霉素组合物展现优异的稳定性，示例性的，在2-8℃稳定至少12个月，至少18个月、至少24个月或至少32个月。In the stability test, the daptomycin composition exhibits excellent stability, exemplarily, it is stable at 2-8°C for at least 12 months, at least 18 months, at least 24 months, or at least 32 months.
优选的，所述肽酯类药物水溶液中肽酯类药物占比约0.1-50％w/w，优选的，肽酯类药物占比约0.1-30％w/w，更为优选的，肽酯类药物占比约0.1-20％w/w，最为优选的，所述肽酯类药物占比约0.5-10％w/w。Preferably, the proportion of peptide ester drugs in the aqueous solution of peptide ester drugs is about 0.1-50% w/w. Preferably, the proportion of peptide ester drugs is about 0.1-30% w/w. More preferably, the proportion of peptide ester drugs is about 0.1-30% w/w. Ester drugs account for about 0.1-20% w/w, and most preferably, the peptide ester drugs account for about 0.5-10% w/w.
优选的，所述氨基酸衍生物占比约0.01-50％w/w，优选的，所述氨基酸衍生物占比约0.01-10％w/w，更为优选的，所述氨基酸衍生物占比约0.01-5％w/w，更为优选的，所述氨基酸衍生物占比约0.01-2％w/w。Preferably, the amino acid derivatives account for about 0.01-50% w/w, preferably, the amino acid derivatives account for about 0.01-10% w/w, and more preferably, the amino acid derivatives account for About 0.01-5% w/w, more preferably, the amino acid derivative accounts for about 0.01-2% w/w.
其中“约”是指处于如本领域的普通技术人员所确定的特定值的可接受误差范围之内，所述特定值的部分取决于所述值是如何测量或测定的，即所述测量***的限制。在特定测定、结果或实施方案的上下文中，除非实施例或说明书其它地方内另有明确说明，否则“约”意指在根据本领域惯例的一个标准偏差之内，或多至5％的范围。另外，本发明中数值为仪器测量值，存在一定程度的误差，一般而言，正负10％均属于合理误差范围内。当然需要考虑该数值所用之处的上下文，例如，各组分占比，该数值为测量后误差变化不超过正负10％，可以为正负9％、正负8％、正负7％、正负6％、正负5％、正负4％、正负3％、正负2％或正负1％，优选正负5％。Where "about" means within the acceptable error range for a particular value as determined by one of ordinary skill in the art, which particular value depends in part on how the value is measured or determined, i.e. the measurement system limits. In the context of a particular assay, result, or embodiment, unless expressly stated otherwise in the examples or elsewhere in the specification, "about" means within one standard deviation, or a range of up to 5%, in accordance with common practice in the art . In addition, the numerical values in the present invention are instrument measurement values, and there is a certain degree of error. Generally speaking, plus or minus 10% is within a reasonable error range. Of course, the context in which this value is used needs to be considered. For example, the proportion of each component. This value means that the error change after measurement does not exceed plus or minus 10%. It can be plus or minus 9%, plus or minus 8%, plus or minus 7%, Plus or minus 6%, plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2%, or plus or minus 1%, preferably plus or minus 5%.
优选的，所述肽酯类药物与氨基酸衍生物的摩尔用量比为1：(2-40)；优选的，所述肽酯类药物与氨基酸衍生物的摩尔用量比为1：(10-30)，更为优选的，所述肽酯类药物与氨基酸衍生物的摩尔用量比为1：(15-20)；最优为优选的，所述肽酯类药物与氨基酸衍生物的摩尔用量比为1：20。Preferably, the molar dosage ratio of the peptide ester drugs to the amino acid derivatives is 1: (2-40); Preferably, the molar dosage ratio of the peptide ester drugs to the amino acid derivatives is 1: (10-30). ), more preferably, the molar dosage ratio of the peptide ester drugs to the amino acid derivatives is 1: (15-20); the most optimal is the molar dosage ratio of the peptide ester drugs to the amino acid derivatives It's 1:20.
进一步优选的，所述肽酯类药物水溶液包括多元醇。Further preferably, the aqueous peptide ester drug solution includes polyol.
优选的，所述多元醇选自甘露醇，山梨醇，蔗糖，海藻糖。Preferably, the polyol is selected from mannitol, sorbitol, sucrose, and trehalose.
进一步优选的，所述酯肽类药物水溶液中包括有机溶剂。Further preferably, the aqueous solution of the ester peptide drug includes an organic solvent.
所述有机溶剂选自：二甲基乙酰胺，异丙醇，乙醇，苄醇，2-甲基-1-丙醇，叔丁醇，乙二醇，丙二醇，甘油，聚山梨醇酯，如聚山梨醇酯20，聚山梨醇酯40和聚山梨醇酯80，聚乙二醇(PEG)，如聚乙二醇200(PEG 200)，聚乙二醇300(PEG 300)，聚乙二醇400(PEG 400)和聚乙二醇600(PEG 600)中的一种或一种以上的混合物。The organic solvent is selected from: dimethylacetamide, isopropyl alcohol, ethanol, benzyl alcohol, 2-methyl-1-propanol, tert-butanol, ethylene glycol, propylene glycol, glycerol, polysorbate, such as Polysorbate 20, polysorbate 40 and polysorbate 80, polyethylene glycol (PEG), such as polyethylene glycol 200 (PEG 200), polyethylene glycol 300 (PEG 300), polyethylene glycol One or more mixtures of alcohol 400 (PEG 400) and polyethylene glycol 600 (PEG 600).
进一步，为了药用目的，本领域的技术人员可以在本发明的技术方案的基础上添加至少一种其他药用辅料，所述药用辅料例如可以为载体，抗氧化剂，表面活性剂，脂质，糖，有机酸，络合剂，防腐剂，稳定剂，增溶剂，表面活性剂，缓冲剂，稀释剂，粘合剂等。Further, for pharmaceutical purposes, those skilled in the art can add at least one other pharmaceutical excipient on the basis of the technical solution of the present invention. The pharmaceutical excipient can be, for example, a carrier, antioxidant, surfactant, lipid , sugar, organic acids, complexing agents, preservatives, stabilizers, solubilizers, surfactants, buffers, diluents, binders, etc.
本发明的酯肽类药物水溶液，可以填装在玻璃小瓶、注射器、滴瓶、管、涂药器、单位分配器、输注袋、喷雾器、吸入装置或其它药物容器中。选择性的，所述药物组合物可以用诸如氮气的惰性气体进行填充保护。The aqueous ester peptide drug solution of the present invention can be filled in glass vials, syringes, drop bottles, tubes, applicators, unit dispensers, infusion bags, sprayers, inhalation devices or other drug containers. Optionally, the pharmaceutical composition can be filled and protected with an inert gas such as nitrogen.
本发明的酯肽类药物水溶液，可以用于制备注射液、眼用制剂、耳用制剂、鼻腔制剂等剂型。The aqueous ester peptide drug solution of the present invention can be used to prepare injections, eye preparations, ear preparations, nasal preparations and other dosage forms.
本发明提供了一种酯肽类药物水溶液的制备方法，包括如下步骤：The invention provides a method for preparing an aqueous solution of ester peptide drugs, which includes the following steps:
步骤a：于烧杯中称取处方量的氨基酸衍生物，加入处方量的水，搅拌使溶解，得到氨基酸衍生物溶液；Step a: Weigh the prescribed amount of amino acid derivatives in a beaker, add the prescribed amount of water, stir to dissolve, and obtain an amino acid derivative solution;
步骤b：称取处方量的酯肽类药物，搅拌溶解于上述步骤a得到的氨基酸衍生物溶液；Step b: Weigh the prescribed amount of ester peptide drugs, stir and dissolve it in the amino acid derivative solution obtained in step a above;
进一步的，所述制备方法包括加入其它药用辅料的步骤。Further, the preparation method includes the step of adding other pharmaceutical excipients.
本发明提供了应用所述酯肽类药物水溶液在用于制备治疗特别是由革兰氏阳性生物体引起的微生物感染的药物中的应用。The present invention provides the use of the aqueous ester peptide pharmaceutical solution in the preparation of a medicament for the treatment of microbial infections, particularly caused by Gram-positive organisms.
最后，本发明在一个方面提供了应用所述酯肽类药物水溶液在用于制备治疗皮肤和软组织感染(cSSTI)、金黄色葡萄球菌血流感染(菌血症)的药物中的应用。Finally, in one aspect, the present invention provides the use of the aqueous ester peptide drug solution in the preparation of drugs for the treatment of skin and soft tissue infections (cSSTI) and Staphylococcus aureus bloodstream infections (bacteremia).
同时需要注意，利用本发明提供的酯肽类药物水溶液的配方，在不加入水分的情况下，可以制备成固体制剂，如散剂、颗粒剂、片剂、胶囊剂，冻干粉等。At the same time, it should be noted that the formula of the ester peptide drug aqueous solution provided by the present invention can be prepared into solid preparations, such as powders, granules, tablets, capsules, freeze-dried powders, etc., without adding water.
本发明提供的肽酯类药物水溶液配方在8℃条件下，能够极大的降低杂质在水溶液中的增长速度。所得到的水溶液可以用于预防、治疗敏感菌株的感染，同时所述水溶液在2-8℃的稳定性至少在12个月以上。相比于冻干粉针剂，本发明提供的水溶液无需复溶步骤，可直接临床使用，减少了用药差错。The peptide ester drug aqueous solution formula provided by the present invention can greatly reduce the growth rate of impurities in the aqueous solution under the condition of 8°C. The obtained aqueous solution can be used to prevent and treat infections of sensitive strains, and at the same time, the stability of the aqueous solution at 2-8°C is at least 12 months. Compared with freeze-dried powder for injection, the aqueous solution provided by the present invention does not require a reconstitution step and can be directly used clinically, reducing medication errors.
附图说明Description of the drawings
图1为处方7在40℃/24h的HPLC谱图。Figure 1 is the HPLC spectrum of prescription 7 at 40°C/24h.
图2为处方20在8℃/30天的HPLC谱图。Figure 2 is the HPLC spectrum of prescription 20 at 8°C/30 days.
图3为处方21在8℃/60天的HPLC谱图。Figure 3 is the HPLC spectrum of prescription 21 at 8°C/60 days.
图4为处方21在8℃/12月的HPLC图谱。Figure 4 is the HPLC chromatogram of prescription 21 at 8°C/12 months.
具体实施方式Detailed ways
为了更好地理解本发明的技术方案，下面结合具体的实施例对本发明的技术方案做进一步说明，所述实施例仅仅是帮助理解本发明，不应视为对本发明的具体限制。In order to better understand the technical solutions of the present invention, the technical solutions of the present invention will be further described below with reference to specific examples. The examples are only to help understand the present invention and should not be regarded as specific limitations of the present invention.
以下实施例HPLC分析条件为：The HPLC analysis conditions of the following examples are:
液相色谱仪Waters UPLC，色谱柱Waters ACQUITY UPLC@BEH shield RP18，流动相如下：Liquid chromatograph Waters UPLC, column Waters ACQUITY UPLC@BEH shield RP18, mobile phase is as follows:
无水硫酸钠溶液：称取无水硫酸钠3.46g，用1000ml纯化水溶解，磷酸调节pH至3.4。Anhydrous sodium sulfate solution: Weigh 3.46g of anhydrous sodium sulfate, dissolve it in 1000ml of purified water, and adjust the pH to 3.4 with phosphoric acid.
流动相A，无水硫酸钠溶液：乙腈＝74:26比例混合；Mobile phase A, anhydrous sodium sulfate solution: acetonitrile = 74:26 ratio mixture;
流动相B，无水硫酸钠溶液：乙腈＝50:50比例混合；Mobile phase B, anhydrous sodium sulfate solution: acetonitrile = 50:50 ratio mixture;
等度洗脱，流动相A：B＝66:34。Isocratic elution, mobile phase A:B=66:34.
取待测样品，加10％乙腈稀释至1mg/ml，进样检测，柱温30℃，检测器UV，进样量2微升，检测波长223nm，流速0.2mL/min。Take the sample to be tested, add 10% acetonitrile and dilute it to 1mg/ml, inject the sample for detection, the column temperature is 30°C, the detector is UV, the injection volume is 2 microliters, the detection wavelength is 223nm, and the flow rate is 0.2mL/min.
实施例1：达托霉素和不同氨基酸的稳定性Example 1: Stability of daptomycin and different amino acids
Figure PCTCN2022100169-appb-000008
Figure PCTCN2022100169-appb-000008
制备步骤：Preparation steps:
1、于烧杯中称取处方量的氨基酸化合物，加入处方量的水，搅拌使溶解；1. Weigh the prescribed amount of amino acid compound in a beaker, add the prescribed amount of water, and stir to dissolve;
2、称取处方量的达托霉素，搅拌溶解于上述步骤1得到的氨基酸化合物溶液；2. Weigh the prescribed amount of daptomycin, stir and dissolve it in the amino acid compound solution obtained in step 1 above;
3、放置在40℃下，一定时间后取样检测有关物质，以峰面积归一化化计算杂质峰面积百分比，结果如下。3. Place it at 40°C. After a certain period of time, take samples to detect relevant substances. Calculate the impurity peak area percentage by normalizing the peak area. The results are as follows.
总杂General miscellaneous 处方1Prescription 1 处方2 Prescription 2 处方3 Prescription 3 处方4 Prescription 4 处方5Prescription 5 处方6Prescription 6 处方7Prescription 7
0天0 days 2.342.34 2.412.41 2.332.33 2.332.33 2.482.48 2.422.42 2.312.31
24h24h 7.487.48 7.777.77 10.5010.50 7.847.84 7.337.33 7.557.55 6.306.30
增长量Increment 5.145.14 5.365.36 8.178.17 5.515.51 4.854.85 5.135.13 3.993.99
以上结果可以看出，加入半胱氨酸可以稍微降低达托霉素在水溶液中的降解，减少总杂的增长，增加其稳定性，但是杂质增长率依然很高。It can be seen from the above results that adding cysteine can slightly reduce the degradation of daptomycin in aqueous solution, reduce the growth of total impurities, and increase its stability, but the growth rate of impurities is still high.
处方7，40℃/24h HPLC谱图见图1，其对应的数据如下：Recipe 7, 40℃/24h HPLC spectrum is shown in Figure 1, and its corresponding data is as follows:
PeakPeak NameName RRT minRRT min Area％ Area% AreaArea
11 内脂水解物Internal lipid hydrolyzate 13.06113.061 0.110.11 1727617276
22 达托霉素Daptomycin 17.40617.406 93.7093.70 1461365814613658
33 β异构体beta isomer 18.70918.709 0.630.63 9748197481
44 脱水达托霉素Dehydrated Daptomycin 20.61720.617 1.981.98 309056309056
实施例2：达托霉素和不同有机溶剂处方的稳定性Example 2: Stability of daptomycin and different organic solvent formulations
Figure PCTCN2022100169-appb-000009
Figure PCTCN2022100169-appb-000009
制备步骤：Preparation steps:
1、于烧杯中称取处方量的有机溶剂，加入50ml的注射用水中，搅拌使溶解；1. Weigh the prescribed amount of organic solvent in a beaker, add 50 ml of water for injection, and stir to dissolve;
2、称取处方量的达托霉素，搅拌溶解于上述步骤1得到的溶液中；2. Weigh the prescribed amount of daptomycin, stir and dissolve it in the solution obtained in step 1 above;
3、放置在40℃下，一定时间后取样检测有关物质，以峰面积归一化化计算杂质峰面积百分比，结果如下。3. Place it at 40°C. After a certain period of time, take samples to detect relevant substances. Calculate the impurity peak area percentage by normalizing the peak area. The results are as follows.
总杂General miscellaneous 处方8Prescription 8 处方9Prescription 9 处方10Prescription 10 处方11Prescription 11 处方12Prescription 12
0天0 days 2.652.65 2.782.78 3.153.15 2.802.80 2.842.84
24h24h 8.038.03 7.847.84 7.337.33 7.557.55 7.217.21
增长量Increment 5.385.38 5.065.06 4.184.18 4.754.75 4.374.37
以上结果可以看出，和达托霉素水溶液处方1相比，加入丙二醇、甘油，达托霉素的杂质增长稍微降低。It can be seen from the above results that compared with the daptomycin aqueous solution prescription 1, the impurity growth of daptomycin is slightly reduced by adding propylene glycol and glycerin.
实验例3：达托霉素和氨基酸衍生物的稳定性Experimental Example 3: Stability of daptomycin and amino acid derivatives
Figure PCTCN2022100169-appb-000010
Figure PCTCN2022100169-appb-000010
制备步骤：Preparation steps:
1、于烧杯中称取处方量的氨基酸衍生物，加入50ml的注射用水中，搅拌使溶解；1. Weigh the prescribed amount of the amino acid derivative in a beaker, add it to 50 ml of water for injection, and stir to dissolve;
2、称取处方量的达托霉素，搅拌溶解于上述步骤1得到的溶液中；2. Weigh the prescribed amount of daptomycin, stir and dissolve it in the solution obtained in step 1 above;
3、放置在8℃下，一定时间后取样检测有关物质，以峰面积归一化化计算杂质峰面积百分比，结果如下。3. Place it at 8°C. After a certain period of time, take samples to detect the relevant substances. Calculate the impurity peak area percentage by normalizing the peak area. The results are as follows.
Figure PCTCN2022100169-appb-000011
Figure PCTCN2022100169-appb-000011
以上结果可以看出，和达托霉素水溶液处方1相比，处方14最稳定，降解速率最低。It can be seen from the above results that compared with daptomycin aqueous solution prescription 1, prescription 14 is the most stable and has the lowest degradation rate.
实验例4：达托霉素处方的稳定性Experimental Example 4: Stability of daptomycin prescription
Figure PCTCN2022100169-appb-000012
Figure PCTCN2022100169-appb-000012
制备步骤：Preparation steps:
1、于烧杯中称取处方量的N-乙酰-L-半胱氨酸、甘露醇、甘油，加入50ml的注射用水中，搅拌使溶解；1. Weigh the prescribed amount of N-acetyl-L-cysteine, mannitol, and glycerol in a beaker, add 50 ml of water for injection, and stir to dissolve;
2、称取处方量的达托霉素，搅拌溶解于上述步骤1得到的溶液中；2. Weigh the prescribed amount of daptomycin, stir and dissolve it in the solution obtained in step 1 above;
3、放置在8℃下，一定时间后取样检测有关物质，以峰面积归一化化计算杂质峰面积百分比，结果如下。3. Place it at 8°C. After a certain period of time, take samples to detect the relevant substances. Calculate the impurity peak area percentage by normalizing the peak area. The results are as follows.
总杂General miscellaneous 处方19Prescription 19 处方20Prescription 20 处方21Prescription 21 处方22Prescription 22
0天0 days 2.332.33 2.142.14 2.252.25 2.152.15
30天30 days 3.563.56 2.452.45 2.392.39 2.752.75
增长量Increment 1.231.23 0.310.31 0.140.14 0.600.60
速率/天Rate/day 0.040.04 0.010.01 0.0050.005 0.020.02
以上结果可以看出，和达托霉素水溶液处方1相比，处方21最稳定，降解速率最低。处方20，8℃/30天的HPLC谱图见图2，其对应的数据如下：It can be seen from the above results that compared with the daptomycin aqueous solution prescription 1, prescription 21 is the most stable and has the lowest degradation rate. The HPLC spectrum of prescription 20, 8℃/30 days is shown in Figure 2, and its corresponding data is as follows:
PeakPeak NameName RRT minRRT min Area％ Area% AreaArea
11 内脂水解物Internal lipid hydrolyzate 16.70016.700 0.0450.045 86528652
22 达托霉素Daptomycin 22.53622.536 97.5597.55 1882361818823618
33 β异构体beta isomer 24.95624.956 0.040.04 76337633
44 脱水达托霉素Dehydrated Daptomycin 26.87326.873 1.201.20 230937230937
实施例5：不同酯肽类药物稳定性比较Example 5: Comparison of stability of different ester peptide drugs
 ​ 处方23Prescription 23 处方24Prescription 24 处方25Prescription 25 处方21Prescription 21
组分Components 百分比％(w/w)Percent %(w/w) 百分比％(w/w)Percent %(w/w) 百分比％(w/w)Percent %(w/w) 百分比％(w/w)Percent %(w/w)
泰拉万星Terravan 55 // // //
卡泊芬净Caspofungin // 55 // //
米卡芬净micafungin // // 55 //
达托霉素Daptomycin // // // 55
N乙酰-L-半胱氨酸N-acetyl-L-cysteine 摩尔比＝1:20Molar ratio=1:20 摩尔比＝1:20Molar ratio=1:20 摩尔比＝1:20Molar ratio=1:20 摩尔比＝1:20Molar ratio=1:20
甘露醇Mannitol 5％5% 5％5% 5％5% 5％5%
甘油glycerin 10％10% 10％10% 10％10% 10％10%
注射用水Water for Injection 50ml50ml 50ml50ml 50ml50ml 50ml50ml
制备步骤：Preparation steps:
1、于烧杯中称取处方量的N-乙酰-L-半胱氨酸、甘露醇、甘油，加入50ml的注射用水中，搅拌使溶解；1. Weigh the prescribed amount of N-acetyl-L-cysteine, mannitol, and glycerol in a beaker, add 50 ml of water for injection, and stir to dissolve;
2、称取处方量酯肽药物，搅拌溶解于上述步骤1得到的溶液中；2. Weigh the prescribed amount of ester peptide drug, stir and dissolve it in the solution obtained in step 1 above;
3、放置在8℃下，一定时间后取样检测有关物质，以峰面积归一化化计算杂质峰面积百分比，结果如下。3. Place it at 8°C. After a certain period of time, take samples to detect the relevant substances. Calculate the impurity peak area percentage by normalizing the peak area. The results are as follows.
总杂General miscellaneous 处方23Prescription 23 处方24Prescription 24 处方25Prescription 25 处方21Prescription 21
0天0 days 2.132.13 2.112.11 2.202.20 2.252.25
60天60 days 2.462.46 2.462.46 2.562.56 2.552.55
增长量Increment 0.330.33 0.350.35 0.360.36 0.310.31
速率/天Rate/day 0.0050.005 0.0060.006 0.0060.006 0.0050.005
处方21，8℃/60天的HPLC谱图见图3，其对应的数据如下：The HPLC spectrum of prescription 21, 8℃/60 days is shown in Figure 3, and its corresponding data is as follows:
PeakPeak NameName RRT minRRT min Area％ Area% AreaArea
11 内脂水解物Internal lipid hydrolyzate 12.74512.745 0.120.12 1867518675
22 达托霉素Daptomycin 16.81716.817 97.4597.45 1495763214957632
33 β异构体beta isomer 18.61718.617 0.030.03 50905090
44 脱水达托霉素Dehydrated Daptomycin 19.87819.878 0.740.74 113375113375
实施例6：不同浓度达托霉素稳定性比较Example 6: Comparison of stability of daptomycin at different concentrations
Figure PCTCN2022100169-appb-000013
Figure PCTCN2022100169-appb-000013
制备步骤：Preparation steps:
1、于烧杯中称取处方量的N-乙酰-L-半胱氨酸、甘露醇、甘油，加入50ml的注射用水中，搅拌使溶解；1. Weigh the prescribed amount of N-acetyl-L-cysteine, mannitol, and glycerol in a beaker, add 50 ml of water for injection, and stir to dissolve;
2、称取处方量达托霉素，搅拌溶解于上述步骤1得到的溶液中；2. Weigh the prescribed amount of daptomycin, stir and dissolve it in the solution obtained in step 1 above;
3、放置在8℃下，一定时间后取样检测有关物质，以峰面积归一化化计算杂质峰面积百分比，结果如下。3. Place it at 8°C. After a certain period of time, take samples to detect the relevant substances. Calculate the impurity peak area percentage by normalizing the peak area. The results are as follows.
总杂General miscellaneous 处方21Prescription 21 处方26Prescription 26 处方27Prescription 27 处方28Prescription 28
0天0 days 2.252.25 2.312.31 2.122.12 2.272.27
60天60 days 2.552.55 2.632.63 2.552.55 2.682.68
增长量Increment 0.310.31 0.320.32 0.340.34 0.410.41
速率/天Rate/day 0.0050.005 0.0050.005 0.0060.006 0.0070.007
从以上实验结果可以得出，当处方中达托霉素的量增加到30％w/w时，杂质的增长率依然能够控制在0.007范围以内。From the above experimental results, it can be concluded that when the amount of daptomycin in the prescription is increased to 30% w/w, the growth rate of impurities can still be controlled within the range of 0.007.
实施例7：不同时间达托霉素稳定性比较Example 7: Comparison of daptomycin stability at different times
处方21达托霉素组合物放置在8℃下，在2个月、4个月、6个月、9个月、12个月稳定性考察，以峰面积归一化化计算杂质峰面积百分比，结果如下。Prescription 21: The daptomycin composition is placed at 8°C, and the stability is investigated at 2 months, 4 months, 6 months, 9 months, and 12 months. The peak area percentage of impurities is calculated by normalizing the peak area. , the results are as follows.
总杂General miscellaneous 2个月2 months 4个月4 months 6个月6 months 9个月9 months 12个月12 months
0天0 days 2.252.25 2.252.25 2.252.25 2.252.25 2.252.25
总增长量total growth 0.310.31 0.480.48 0.540.54 0.560.56 0.730.73
速率/天Rate/day 0.0050.005 0.0040.004 0.0030.003 0.0020.002 0.0020.002
从以上实验结果可以得出，随着储存时间的延长，杂质增长率并没有随着储存的时间延长而延长，而是呈现下降的趋势，而总杂质增长率可以有效的控制在0.7％w/w范围内。From the above experimental results, it can be concluded that with the extension of storage time, the impurity growth rate does not extend with the extension of storage time, but shows a downward trend, and the total impurity growth rate can be effectively controlled at 0.7%w/ w range.
处方21在8℃/12月HPLC图谱见图4，其对应的数据如下：The HPLC chromatogram of prescription 21 at 8℃/12 months is shown in Figure 4, and its corresponding data is as follows:
PeakPeak NameName RRT minRRT min Area％ Area% AreaArea
11 内脂水解物Internal lipid hydrolyzate 12.73412.734 0.110.11 1905119051
22 达托霉素Daptomycin 16.81516.815 97.0297.02 1628537216285372
33 β异构体beta isomer 18.59918.599 0.030.03 50865086
44 脱水达托霉素Dehydrated Daptomycin 19.85719.857 0.740.74 124064124064
实施例8：达托霉素组合物在不同氨基酸衍生物中稳定性比较Example 8: Comparison of the stability of daptomycin compositions among different amino acid derivatives
所述氨基酸衍生物具有如下通式结构：The amino acid derivative has the following general structure:
Figure PCTCN2022100169-appb-000014
Figure PCTCN2022100169-appb-000014
其中R 1、R 2和R 3的定义与前文相同。 The definitions of R 1 , R 2 and R 3 are the same as before.
Figure PCTCN2022100169-appb-000015
Figure PCTCN2022100169-appb-000015
制备步骤：Preparation steps:
1、于烧杯中称取处方量的氨基酸衍生物、甘露醇、甘油，加入50ml的注射用水中，搅拌使溶解；1. Weigh the prescribed amount of amino acid derivatives, mannitol, and glycerin in a beaker, add 50 ml of water for injection, and stir to dissolve;
2、称取处方量达托霉素，搅拌溶解于上述步骤1得到的溶液中；2. Weigh the prescribed amount of daptomycin, stir and dissolve it in the solution obtained in step 1 above;
3、放置在8℃下，一定时间后取样检测有关物质，以峰面积归一化化计算杂质峰面积百分比，结果如下。3. Place it at 8°C. After a certain period of time, take samples to detect the relevant substances. Calculate the impurity peak area percentage by normalizing the peak area. The results are as follows.
总杂General miscellaneous 处方21Prescription 21 处方29Prescription 29 处方30Prescription 30 处方31Prescription 31 处方32Prescription 32
0天0 days 2.252.25 2.052.05 2.182.18 2.312.31 2.192.19
60天60 days 2.562.56 2.482.48 2.712.71 2.672.67 2.682.68
增长量Increment 0.310.31 0.430.43 0.530.53 0.360.36 0.490.49
速率/天Rate/day 0.0050.005 0.0070.007 0.0090.009 0.0060.006 0.0080.008
从以上实验结果可以得出，使用不同的带有游离巯基的氨基酸衍生物时，杂质的增长率依然能够控制在0.009％w/w/天范围以内。From the above experimental results, it can be concluded that when using different amino acid derivatives with free thiol groups, the growth rate of impurities can still be controlled within the range of 0.009% w/w/day.
另外需要说明的是，在本发明的各实施例中各处方在0天时总杂含量不同是因为使用了不同的起始物料。In addition, it should be noted that in each embodiment of the present invention, the total impurity content of each prescription on day 0 is different because different starting materials are used.

Claims (32)

  1. 一种稳定的酯肽类药物水溶液，包括酯肽类药物、氨基酸衍生物，其中所述氨基酸衍生物含有游离巯基或N-乙酰-甘氨酸，N-乙酰-缬氨酸，N-乙酰-酪氨酸、N-乙酰-丙氨酸，N-乙酰-蛋氨酸，N-甲基-半胱氨酸中的一种。A stable aqueous solution of ester peptide drugs, including ester peptide drugs and amino acid derivatives, wherein the amino acid derivatives contain free sulfhydryl groups or N-acetyl-glycine, N-acetyl-valine, and N-acetyl-tyrosine Acid, one of N-acetyl-alanine, N-acetyl-methionine, and N-methyl-cysteine.
  2. 根据权利要求1所述的水溶液，其中所述酯肽类药物选自达托霉素、泰拉万星(Telavancin)、卡泊芬净(Caspofungin)、米卡芬净(Micafungin)、阿尼芬净(Anidulafungin)，优选为达托霉素。The aqueous solution according to claim 1, wherein the ester peptide drug is selected from the group consisting of daptomycin, Telavancin, Caspofungin, Micafungin, and Anidifine Anidulafungin, preferably daptomycin.
  3. 根据权利要求1所述的水溶液，所述氨基酸衍生物具有如下式I结构：The aqueous solution according to claim 1, the amino acid derivative has the following formula I structure:
    Figure PCTCN2022100169-appb-100001
    Figure PCTCN2022100169-appb-100001
    其中R 1选自氢，C 1-C 3的烷基，卤素；R 2和R 3各自独立的选自COR 4，氢，C 1-C 6的烷基，且R 2和R 3中至少有一个为COR 4，其中R 4选自C 1-C 6的烷基，芳基，烷芳基，所述芳基或烷芳基可用带有1-3个取代基团，所述取代基团选自卤素、硝基、烷酰基、C 1-C 6的直链或支链烷基。 Wherein R 1 is selected from hydrogen, C 1 -C 3 alkyl, halogen; R 2 and R 3 are each independently selected from COR 4 , hydrogen, C 1 -C 6 alkyl, and at least R 2 and R 3 One is COR 4 , where R 4 is selected from C 1 -C 6 alkyl, aryl, alkaryl, the aryl or alkaryl may have 1-3 substituents, and the substituents The group is selected from halogen, nitro, alkanoyl, C 1 -C 6 linear or branched alkyl.
  4. 根据权利要求3所述的水溶液，其中所述C 1-C 3的烷基选自甲基，乙基，丙基，异丙基；所述卤素选自Cl，Br，I；所述C 1-C 6的烷基选自甲基，乙基，丙基，异丙基，正丁基，异丁基，叔丁基，戊基，己基。所述芳基选自苯环、吡啶环、嘧啶环、吡嗪环、哒嗪环、呋喃环、噻吩环、吡唑环、咪唑环或***环。 The aqueous solution according to claim 3, wherein the C 1 -C 3 alkyl group is selected from methyl, ethyl, propyl, isopropyl; the halogen is selected from Cl, Br, I; the C 1 -C 6 alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl. The aryl group is selected from benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, furan ring, thiophene ring, pyrazole ring, imidazole ring or triazole ring.
  5. 根据权利要求3所述的水溶液，其中所述烷芳基具有通式(CH 2)nAr，其中n为1-5，Ar选自选自苯环、吡啶环、嘧啶环、吡嗪环、哒嗪环、呋喃环、噻吩环、吡唑环、咪唑环或***环。 The aqueous solution according to claim 3, wherein the alkylaryl group has the general formula (CH 2 )nAr, wherein n is 1-5, Ar is selected from the group consisting of benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridine ring, Azine ring, furan ring, thiophene ring, pyrazole ring, imidazole ring or triazole ring.
  6. 根据权利要求3所述的水溶液，所述R 1选自氢、甲基、乙基、氯；所述R 4选自甲基，乙基，丙基；且所述R 2和R 3其中有一个为氢。 The aqueous solution according to claim 3, said R 1 is selected from hydrogen, methyl, ethyl, chlorine; said R 4 is selected from methyl, ethyl, propyl; and said R 2 and R 3 have One is hydrogen.
  7. 根据权利要求1-3任一权利要求所述的水溶液，所述氨基酸衍生物具有如下结构：According to the aqueous solution of any one of claims 1-3, the amino acid derivative has the following structure:
    Figure PCTCN2022100169-appb-100002
    Figure PCTCN2022100169-appb-100002
    其中R 1、R 2和R 4的定义与权利要求3的定义相同。 The definitions of R 1 , R 2 and R 4 are the same as those in claim 3.
  8. 根据权利要求7所述的水溶液，其中所述R 1选自氢、甲基、卤素；R 2选自氢、甲基、乙基；R 4选自甲基，乙基、丙基、苄基。 The aqueous solution according to claim 7, wherein R1 is selected from hydrogen, methyl, and halogen; R2 is selected from hydrogen, methyl, and ethyl; R4 is selected from methyl, ethyl, propyl, and benzyl .
  9. 根据权利要求7所述的水溶液，所述氨基酸衍生物为N-乙酰-半胱氨酸。The aqueous solution according to claim 7, wherein the amino acid derivative is N-acetyl-cysteine.
  10. 根据权利要求9所述的水溶液，所述N-乙酰-半胱氨酸为D型，L型或DL的混合物。The aqueous solution according to claim 9, wherein the N-acetyl-cysteine is a mixture of D-form, L-form or DL.
  11. 根据权利要求1所述的水溶液，所述酯肽类药物水溶液杂质增长率在0.01％w/w/天以内。According to the aqueous solution of claim 1, the impurity growth rate of the ester peptide drug aqueous solution is within 0.01% w/w/day.
  12. 根据权利要求11所述的水溶液，所述酯肽类药物水溶液杂质增长率在0.007％w/w/天以内。According to the aqueous solution of claim 11, the impurity growth rate of the ester peptide drug aqueous solution is within 0.007% w/w/day.
  13. 根据权利要求11所述的水溶液，所述酯肽类药物水溶液杂质增长率在0.005％w/w/天以内。According to the aqueous solution of claim 11, the impurity growth rate of the ester peptide drug aqueous solution is within 0.005% w/w/day.
  14. 根据权利要求1所述的水溶液，所述肽酯类药物水溶液中肽酯类药物占比约0.1-50％w/w。According to the aqueous solution of claim 1, the proportion of peptide ester drugs in the aqueous solution of peptide ester drugs is about 0.1-50% w/w.
  15. 根据权利要求1所述的水溶液，所述肽酯类药物占比约0.1-30％w/w。According to the aqueous solution of claim 1, the peptide ester drug accounts for about 0.1-30% w/w.
  16. 根据权利要求1所述的水溶液，所述肽酯类药物占比约0.1-20％w/w。According to the aqueous solution of claim 1, the peptide ester drug accounts for about 0.1-20% w/w.
  17. 根据权利要求1所述的水溶液，所述肽酯类药物占比约0.5-10％w/w。According to the aqueous solution of claim 1, the peptide ester drug accounts for about 0.5-10% w/w.
  18. 根据权利要求1所述的水溶液，所述氨基酸衍生物占比约0.01-50％w/w.According to the aqueous solution of claim 1, the amino acid derivative accounts for about 0.01-50% w/w.
  19. 根据权利要求1所述的水溶液，所述氨基酸衍生物占比约0.01-10％w/w。According to the aqueous solution of claim 1, the amino acid derivative accounts for about 0.01-10% w/w.
  20. 根据权利要求1所述的水溶液，所述氨基酸衍生物占比约0.01-5％w/w。According to the aqueous solution of claim 1, the amino acid derivative accounts for about 0.01-5% w/w.
  21. 根据权利要求1所述的水溶液，所述氨基酸衍生物占比约0.01-2％w/w。According to the aqueous solution of claim 1, the amino acid derivative accounts for about 0.01-2% w/w.
  22. 根据权利要求1所述的水溶液，所述肽酯类药物与氨基酸衍生物的摩尔用量比为1：(2-40)。According to the aqueous solution of claim 1, the molar dosage ratio of the peptide ester drug and the amino acid derivative is 1: (2-40).
  23. 根据权利要求1所述的水溶液，所述肽酯类药物与氨基酸衍生物的摩尔用量比为1：(10-30)。According to the aqueous solution of claim 1, the molar dosage ratio of the peptide ester drug and the amino acid derivative is 1: (10-30).
  24. 根据权利要求1所述的水溶液，所述肽酯类药物与氨基酸衍生物的摩尔用量比为1：(15-20)。According to the aqueous solution of claim 1, the molar dosage ratio of the peptide ester drug and the amino acid derivative is 1: (15-20).
  25. 根据权利要求1所述的水溶液，所述肽酯类药物与氨基酸衍生物的摩尔用量比为1：20。According to the aqueous solution of claim 1, the molar dosage ratio of the peptide ester drug and the amino acid derivative is 1:20.
  26. 根据权利要求1所述的水溶液，所述肽酯类药物水溶液包括多元醇。The aqueous solution according to claim 1, wherein the peptide ester drug aqueous solution includes a polyol.
  27. 根据权利要求26所述的水溶液，所述多元醇选自甘露醇，山梨醇，蔗糖，海藻糖.The aqueous solution according to claim 26, wherein the polyol is selected from the group consisting of mannitol, sorbitol, sucrose, and trehalose.
  28. 根据权利要求26所述的水溶液，进一步包括有机溶剂。The aqueous solution of claim 26, further comprising an organic solvent.
  29. 根据权利要求28所述的水溶液，所述有机溶剂选自：二甲基乙酰胺，异丙醇，乙醇，苄醇，2-甲基-1-丙醇，叔丁醇，乙二醇，丙二醇，甘油，聚山梨醇酯，如聚山梨醇酯20，聚山梨醇酯40和聚山梨醇酯80，聚乙二醇(PEG)，如聚乙二醇200(PEG 200)，聚乙二醇300(PEG 300)，聚乙二醇400(PEG 400)和聚乙二醇600(PEG 600)中的一种或一种以上的混合物。The aqueous solution according to claim 28, the organic solvent is selected from: dimethylacetamide, isopropyl alcohol, ethanol, benzyl alcohol, 2-methyl-1-propanol, tert-butanol, ethylene glycol, propylene glycol , glycerin, polysorbates such as polysorbate 20, polysorbate 40 and polysorbate 80, polyethylene glycol (PEG) such as polyethylene glycol 200 (PEG 200), polyethylene glycol 300 (PEG 300), one or more mixtures of polyethylene glycol 400 (PEG 400) and polyethylene glycol 600 (PEG 600).
  30. 权利要求1-29任一权利要求所述的酯肽类药物水溶液的制备方法，包括如下步骤：The preparation method of the ester peptide drug aqueous solution according to any one of claims 1 to 29 includes the following steps:
    步骤a：于烧杯中称取处方量的氨基酸衍生物，加入处方量的水，搅拌使溶解，得到氨基酸衍生物溶液；Step a: Weigh the prescribed amount of amino acid derivatives in a beaker, add the prescribed amount of water, stir to dissolve, and obtain an amino acid derivative solution;
    步骤b：称取处方量的酯肽类药物，搅拌溶解于上述步骤a得到的氨基酸衍生物溶液；Step b: Weigh the prescribed amount of ester peptide drugs, stir and dissolve it in the amino acid derivative solution obtained in step a above;
    进一步的，所述制备方法包括加入其它药用辅料的步骤。Further, the preparation method includes the step of adding other pharmaceutical excipients.
  31. 应用权利要求1-29任一权利要求所述酯肽类药物水溶液在用于制备治疗特别是由革兰氏阳性生物体引起的微生物感染的药物中的应用。Application of the aqueous ester peptide drug solution of any one of claims 1 to 29 in the preparation of a drug for the treatment of microbial infections caused by gram-positive organisms.
  32. 根据权利要求31所述的应用，为治疗皮肤和软组织感染(cSSTI)或金黄色葡萄球菌血流感染(菌血症)。Use according to claim 31 for the treatment of skin and soft tissue infections (cSSTI) or Staphylococcus aureus bloodstream infections (bacteremia).
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