WO2023040396A1 - 一种万古霉素水溶液组合物 - Google Patents

一种万古霉素水溶液组合物 Download PDF

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WO2023040396A1
WO2023040396A1 PCT/CN2022/100188 CN2022100188W WO2023040396A1 WO 2023040396 A1 WO2023040396 A1 WO 2023040396A1 CN 2022100188 W CN2022100188 W CN 2022100188W WO 2023040396 A1 WO2023040396 A1 WO 2023040396A1
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vancomycin
pharmaceutical composition
methyl
composition according
alanine
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PCT/CN2022/100188
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English (en)
French (fr)
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朱逸凡
范敏华
陆平
赵振坤
徐沧朔
石慧
沈乐
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浙江普利药业有限公司
海南普利制药股份有限公司
安徽普利药业有限公司
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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
    • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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

Definitions

  • the invention relates to the technical field of medicine, in particular to a vancomycin aqueous solution composition.
  • Vancomycin hydrochloride (3S-(3R*,6S*(S*),7S*,22S*,23R*,26R*,36S*,38aS*))-3-(2-Amino-2-oxoethyl )-44-((2-O-(3-amino-2,3,6-trideoxy-3-C-methyl-alpha-L-lyxo-hexopyranosyl)-beta-D-glucopyranosyl)oxy)-10,19 -dichloro-2,3,4,5,6,7,23,24,25,26,36,37,38,38a-tetradecahydro-7,22,28,30,32-pentahydro-6-((4 -methyl-2-(methylamino)-1-oxopentyl)amino)-2,5,24,38,39-pentaoxo-22H-8,11:18,21-dietheno-23,36-(iminome
  • Vancomycin hydrochloride is a glycopeptide antibiotic from Streptomyces orientalis or Agrothrix sp.
  • the mechanism of action of vancomycin hydrochloride is the blocking of alanylalanine that binds with high affinity to the polyterminal of the precursor peptide of sensitive bacterial cell wall
  • the synthesis of high-molecular peptidoglycan that constitutes the bacterial cell wall hinders the synthesis of the bacterial cell wall; in addition, vancomycin may also change the permeability of the bacterial cell membrane and selectively inhibit the synthesis of RNA.
  • vancomycin hydrochloride The characteristic of vancomycin hydrochloride is that it only has a strong bactericidal effect on Gram-positive bacteria, and the bacteria do not produce drug resistance to this product, and there is no cross-resistance with other antibiotics; it is mainly used clinically: from methicillin-resistant Infection caused by Staphylococcus aureus (MRSA), vancomycin-sensitive methicillin-resistant coagulase-negative staphylococcus (MRCNS), vancomycin-sensitive penicillin-resistant Streptococcus pneumoniae (PRSP). It is the drug of choice for infections caused by methicillin-resistant Staphylococcus aureus and methicillin-resistant coagulase-negative staphylococcus.
  • MRSA Staphylococcus aureus
  • MRCNS vancomycin-sensitive methicillin-resistant coagulase-negative staphylococcus
  • PRSP vancomycin-sensitive penicillin-resistant Streptococcus pneumoniae
  • vancomycin hydrochloride is relatively poor, especially in the state of aqueous solution. It can be observed that the color turns red gradually at room temperature. This may be due to the phenolic and diphenolic groups that exist in the molecular structure of vancomycin. When exposed to light, it is easily hydrated or oxidized to quinone and turns red.
  • vancomycin is composed of a heptapeptide containing an asparagine, and it is also prone to degradation reactions in aqueous solution.
  • the asparagine side chain in its structure is prone to deamination, hydrolysis and rearrangement reactions, resulting in unstable formulations.
  • Vancomycin is degraded to the following major degradation impurities: Des-(amido)-succinimidyl-vancomycin B (RS2), CDP-1major ((1.2M)-[L- ⁇ -Asp 3 ]vancomycin B , CDP-IM) and CDP-1minor ([L- ⁇ -Asp 3 ] vancomycin B, CDP-Im).
  • CDP-1m ([L- ⁇ -Asp 3 ]vancomycin B(CDP-I minor)
  • CDP-1M ((1.2M)-[L- ⁇ -Asp 3 ]vancomycin B, CDP-I major) vancomycin hydrochloride marketed formulations include lyophilized powder for injection or frozen solution, oral dry mix and capsules, Ophthalmic vancomycin ointment (oily base, anhydrous), most vancomycin exists in anhydrous form. Due to the stability of vancomycin aqueous solution, the preparation of direct-use vancomycin injection, vancomycin eye drops, vancomycin topical gel/emulsion/spray and other dosage forms has brought great challenges, which limits the use of vancomycin Development and use of other dosage forms.
  • the existing freeze-dried powder injection of vancomycin needs to be dispersed and diluted before use, and the use steps are relatively cumbersome; although Baxter has developed vancomycin injection, it requires cryopreservation, and it is very inconvenient to take out and thaw into a solution before use ; Moreover, due to stability issues, the diluted vancomycin injection should be used as soon as possible to prevent the formation of impurities and visible foreign matter after long-term storage.
  • Staphylococcus aureus is the main pathogen causing trauma, chronic wounds, and Surgical Site Infection (SSI).
  • Vancomycin can effectively inhibit MRSA, so vancomycin Susin is expected to become an effective drug for treating MRSA infection in wounds and chronic wounds of eyes, ears and other parts, as well as preventing and reducing the risk of MRSA infection in surgical sites.
  • the stability of vancomycin aqueous solution limits the development of vancomycin ophthalmic preparations and vancomycin topical gel/emulsion/spray.
  • vancomycin ointment for ophthalmology it is inconvenient to administer by adopting oily base (Vaseline, liquid paraffin), and it affects vision after administration.
  • the stable vancomycin solution makes it possible to develop vancomycin injections, ophthalmic preparations, ear preparations, nasal cavity preparations, etc., which help reduce the work intensity of medical staff and reduce safety risks caused by stability , Improve the convenience of use, expand the scope of use of vancomycin, and better exert the efficacy of vancomycin.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising vancomycin or a pharmaceutically acceptable salt thereof, N-methylalanine, and water.
  • N-methylalanine can improve the stability of vancomycin in aqueous solution state.
  • the concentration of vancomycin or its pharmaceutically acceptable salt is 0.1-30% w/w, more preferably, the concentration of said vancomycin or its pharmaceutically acceptable salt is 0.1-15% w/w.
  • the concentration of N-methylalanine is 0.1-30% w/w, more preferably, the concentration of N-methylalanine is 0.1-15% w/w.
  • the pH of the composition is 3-9, more preferably the pH is 3-6.
  • the pH can be adjusted using acids or bases. For example but not limited to hydrochloric acid, acetic acid, sodium hydroxide.
  • the N-methylalanine is N-methyl-DL-alanine, N-methyl-D-alanine or N-methyl-L-alanine. More preferably, the N-methylalanine is N-methyl-D-alanine.
  • the molar ratio of the N-methyl-amino acid and vancomycin is (0.1-40): 1, more preferably, the molar ratio of the N-methyl-amino acid and vancomycin is (0.5 -20):1.
  • the composition may contain pH regulators, ion chelating agents, osmotic pressure regulators, preservatives and other components.
  • the pH regulator includes but not limited to: acetic acid, sodium acetate, succinic acid, amino acid, malic acid, lactic acid, citric acid, sodium citrate, sodium dihydrogen phosphate, disodium hydrogen phosphate, phosphoric acid, boric acid one or more of .
  • the ion chelating agent includes, but is not limited to: one or more of disodium edetate, citric acid, and the like.
  • the preservative includes, but is not limited to: one or more of benzalkonium chloride, cresol, phenol, paraben, benzyl alcohol, EDTA, and the like.
  • the osmotic pressure regulator includes but not limited to: sodium chloride, glucose and the like.
  • Another aspect of the present invention provides a use of the pharmaceutical composition for preparing medicines for treating or preventing bacterial infections including Staphylococcus infections.
  • the bacterial infection is caused by methicillin-resistant Staphylococcus strains (MRSA).
  • MRSA methicillin-resistant Staphylococcus strains
  • test results show that the vancomycin in the pharmaceutical composition of the present invention can exist stably after 10 days under the condition of 25° C./60% RH.
  • the pharmaceutical composition of the present invention can well improve the stability of the vancomycin gel formulation under the condition of 25° C./60% RH, and keep it stable for at least 30 days.
  • the pharmaceutical composition of the present invention can well improve the stability of the vancomycin eye drop formulation under the condition of 25° C./60% RH, and keep it stable for at least 30 days.
  • the pharmaceutical composition of the present invention can well improve the stability of the vancomycin injection formulation under the condition of 25° C./60% RH, and keep it stable for at least 30 days.
  • the vancomycin solution preparation of the present invention can exhibit the same antibacterial activity as the vancomycin aqueous solution without N-methyl-alanine at the same vancomycin concentration.
  • the pharmaceutical preparations of the invention can be administered in undiluted or diluted form prior to administration. Dilution can be done with 5% or 10% dextrose solution or another injectable diluent or infusion solution. Administration routes may include, but are not limited to, injection, instillation, inhalation, oral, ear, nasal, topical, ophthalmic, vaginal and rectal administration, and the like.
  • the pharmaceutical formulations of the invention may be delivered using a needle/syringe, infusion set, catheter, applicator, bottle, nebulizer, inhalation device or as a wound dressing.
  • the pharmaceutical composition of the present invention may be filled in glass vials, syringes, dropper bottles, tubes, applicators, unit dispensers, infusion bags, nebulizers, inhalation devices or other pharmaceutical containers.
  • the pharmaceutical composition can be filled with an inert gas such as nitrogen for protection.
  • the pharmaceutical composition of the present invention can be used to prepare dosage forms such as injections, ophthalmic preparations, ear preparations, and nasal cavity preparations.
  • the aqueous solution of the vancomycin pharmaceutical composition provided by the invention is stable under non-freezing conditions, and can effectively inhibit the physical and chemical degradation of the vancomycin due to the presence of N-methyl-alanine.
  • the vancomycin aqueous solution provided by the invention has excellent potential in the development of vancomycin injections, ophthalmic preparations, ear preparations, nasal cavity preparations and the like.
  • Fig. 1 is the HPLC spectrogram of the detection result after 10 days under the condition of 25°C/60%RH of the F-4 prescription.
  • Fig. 2 is the HPLC spectrogram of the detection results after 10 days under the condition of 25°C/60%RH for F-20 prescription.
  • Fig. 3 is the HPLC spectrogram of the detection results after 30 days under the condition of 25°C/60%RH of the F-25 prescription.
  • Fig. 4 is the HPLC spectrogram of the test results after 30 days under the condition of 25°C/60%RH for F-29 prescription.
  • Figure 5 is the HPLC spectrogram of the detection results after 30 days under the condition of 25°C/60%RH for the F-32 prescription.
  • Solution A Accurately measure 4.0ml of triethylamine, add water to 2000ml, adjust pH to 3.20 with phosphoric acid;
  • Embodiment 1 The influence of different amino acids on the stability of vancomycin
  • Embodiment 2 the impact of N-methyl-alanine on the stability of vancomycin
  • Example 3 The experimental method is as in Example 1, and the stabilizer (amino acid) and corresponding test results are listed in Table 3.
  • N-methyl-DL-alanine is a derivative of alanine, and its stabilizing effect on vancomycin is better than that of alanine. Among them, the effect of N-methyl-D-alanine is particularly prominent.
  • the data corresponding to the F-20 (N-methyl-DL-alanine) HPLC spectrogram (Fig. 2) is shown in Table 4:
  • Embodiment 3 the impact of N-methyl-alanine on the stability of vancomycin gel
  • Peak name R RT min Area% Area 1 RS2 4.594 0.219 58915 2 CDP-1 7.222 0.402 108293 3 Vancomycin HCL 8.631 95.28 25694407
  • Embodiment 4 the influence of N-methyl-alanine on the stability of vancomycin eye drops
  • Embodiment 5 The impact of N-methyl-alanine on the stability of vancomycin injection
  • Embodiment 5 Effect of N-methyl-alanine on the stability of vancomycin injection
  • Embodiment 6 PK test of vancomycin injection
  • Group 1 mice were given a single intravenous injection of vancomycin (5 mg/ml) dissolved in normal saline, and the second group (G2) animals were given a single intravenous injection of vancomycin reference preparations (Xellia Corporation). , batch number 1V14003), the third group (G3) animals were given a single intravenous injection of self-made vancomycin injection (50mg/ml vancomycin, 53.4mg/ml N-methyl-D-alanine), three groups The dosage was consistently 20mg/kg. After the administration of each group, plasma samples were collected at 0.083, 0.167, 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours. An established LC-MS/MS method was used to detect the drug concentration of vancomycin in plasma samples.

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Abstract

本发明涉及医药技术领域，具体涉及一种万古霉素水溶液组合物。所述药物组合物包含万古霉素或其可药用的盐，N-甲基丙氨酸，水。采用N-甲基丙氨酸可以提高万古霉素水溶液状态下的稳定性。

Description

一种万古霉素水溶液组合物 技术领域
本发明涉及医药技术领域，具体涉及一种万古霉素水溶液组合物。
背景技术
盐酸万古霉素化学名为：
Chemical name of Vancomycin hydrochloride:(3S-(3R*,6S*(S*),7S*,22S*,23R*,26R*,36S*,38aS*))-3-(2-Amino-2-oxoethyl)-44-((2-O-(3-amino-2,3,6-trideoxy-3-C-methyl-alpha-L-lyxo-hexopyranosyl)-beta-D-glucopyranosyl)oxy)-10,19-dichloro-2,3,4,5,6,7,23,24,25,26,36,37,38,38a-tetradecahydro-7,22,28,30,32-pentahydroxy-6-((4-methyl-2-(methylamino)-1-oxopentyl)amino)-2,5,24,38,39-pentaoxo-22H-8,11:18,21-dietheno-23,36-(iminomethano)-13,16:31,35-dimetheno-1H,16H-(1,6,9)oxadiazacyclohexadecino(4,5-m)(10,2,16)benzoxadiazacyclotetracosine-26-carboxylic acid；Molecular weight:1485.7；Molecular formula:C 66H 76Cl 3N 9O 24,chemical structure formula:
Figure PCTCN2022100188-appb-000001
盐酸万古霉素是一种来自东方链霉菌或土壤丝菌属的糖肽类抗生素，盐酸万古霉素作用机制是高亲和力结合到敏感细菌细胞壁前体肽聚末端的丙氨酰丙氨酸阻断构成细菌细胞壁的高分子肽聚糖合成，阻碍细菌细胞壁合成；此外，万古霉素也可能改变细菌细胞膜渗透性，并选择性地抑制RNA的合成。
盐酸万古霉素作用特点是仅对革兰阳性菌有较强的杀菌作用，细菌对本品不产生耐药性，且与其他抗生素无交叉耐药性；临床主要应用于：由耐甲氧西林金黄色葡萄球菌(MRSA)、对万古霉素敏感的耐甲氧西林凝固酶阴性葡萄球菌MRCNS)、对万古霉素敏感的耐青霉素肺炎链球菌(PRSP)引起的感染。是耐甲氧西林金黄色葡萄球菌，耐甲氧西林凝固酶阴性葡萄球菌等所致感染的首选药物。
但是盐酸万古霉素稳定性较差，尤其是在水溶液状态下，常温下即可观察到颜色逐渐变红，这可能是由于万古霉素分子结构中存在的酚基及二酚基，酚类水溶液遇光易水合或氧化成醌而呈红色。
同时，万古霉素结构由含一个天冬酰胺的七肽组成，在水溶液中还易发生降解反应。在水溶液状态下，其结构中的天冬酰胺侧链易发生脱氨、水解及重排反应，导致处方不稳定。万古霉素降解为以下主要降解杂质：Des-(酰胺基)-琥珀酰亚胺基-万古霉素B(RS2)，CDP-1major((1.2M)-[L-β-Asp 3]vancomycin B,CDP-IM)和CDP-1minor([L-β-Asp 3]vancomycin B,CDP-Im)。
Figure PCTCN2022100188-appb-000002
Des-(酰胺基)-琥珀酰亚胺基-万古霉素B(RS2)
Figure PCTCN2022100188-appb-000003
CDP-1m([L-β-Asp 3]vancomycin B(CDP-I minor)
Figure PCTCN2022100188-appb-000004
CDP-1M((1.2M)-[L-β-Asp 3]vancomycin B,CDP-I major)盐酸万古霉素已上市剂型包括注射用冻干粉针或冷冻溶液、口服 干混剂和胶囊、眼用万古霉素软膏(油性基质，无水)，万古霉素多数以无水形式存在。因万古霉素水溶液稳定性的问题，制备直接使用的万古霉素注射液、万古霉素滴眼液、万古霉素外用凝胶/乳剂/喷剂等剂型带来巨大挑战，限制了万古霉素其它剂型的开发及使用。
现有的万古霉素冻干粉针剂，使用前需分散、稀释，使用步骤较为繁琐；Baxter虽然开发出万古霉素注射液，但要求冷冻保存，使用前取出解冻成溶液再使用，非常不方便；而且，因稳定性问题，稀释后的万古霉素注射液应尽快使用，以防长时间放置后生成杂质及可见异物。
金黄色葡萄球菌，尤其是耐甲氧西林金黄色葡萄球菌，是导致创伤、慢性创面、手术部位感染(Surgical Site Infection，SSI)的主要致病菌，万古霉素能有效抑制MRSA，因此万古霉素有望成为治疗眼部、耳部及其它部位创伤及慢性创面的MRSA感染，以及预防和降低手术部位MRSA感染风险的有效药物。但是，万古霉素水溶液稳定性问题，限制了万古霉素眼用制剂、万古霉素外用凝胶/乳剂/喷剂的开发。虽然已有眼用万古霉素软膏，但其是通过采用油性基质(凡士林、液体石蜡)的方式，给药不便利，且给药后影响视线。
因此，有必要实现万古霉素在水溶液中的稳定。稳定的万古霉素溶液，使得开发出现用型的万古霉素注射液、眼用制剂、耳用制剂、鼻腔制剂等成为可能，有利于减少医护人员工作强度、减少因稳定性导致的安全性风险、提高使用便利性，拓展万古霉素的使用范围，更好地发挥万古霉素的功效。
发明内容
为了解决现有技术中存在的问题，本发明提供了一种药物组合物，所述药物组合物包含万古霉素或其可药用的盐，N-甲基丙氨酸，水。
采用N-甲基丙氨酸可以提高万古霉素水溶液状态下的稳定性。
优选的，所述药物组合物中：
万古霉素或其可药用的盐浓度为0.1-30％w/w，更为优选的，所述万古霉素或其可药用的盐浓为度0.1-15％w/w。
N-甲基丙氨酸浓度为0.1-30％w/w，更为优选的，所述N-甲基丙氨酸浓度为0.1-15％w/w。
优选的，所述组合物的pH为3-9，更为优选pH为3-6。可以使用酸或碱对pH进行调节。例如但不限于盐酸、乙酸、氢氧化钠。
所述N-甲基丙氨酸为N-甲基-DL-丙氨酸、N-甲基-D-丙氨酸或N-甲基-L-丙氨酸。更为优选的，所述N-甲基丙氨酸为N-甲基-D-丙氨酸。
优选的，所述N-甲基-氨基酸和万古霉素的摩尔比是(0.1-40)：1，更为优选的，所述N-甲基-氨基酸和万古霉素的摩尔比是(0.5-20)：1。
在本发明的有一个实施方案中，所述组合物可以含有pH调节剂、离子螯合剂、渗透压调节剂、防腐剂等组分。
示例性的，所述pH调节剂包括但不限于：乙酸、乙酸钠、琥珀酸、氨基酸、苹果酸、乳酸、柠檬酸、柠檬酸钠、磷酸二氢钠、磷酸 氢二钠、磷酸、硼酸中的一种或多种。
示例性的，所述离子螯合剂包括但不限于：依地酸二钠、柠檬酸等中的一种或多种。
示例性的，所述防腐剂包括但不限于：苯扎氯铵、甲酚、苯酚、对羟基苯甲酸酯、苄醇、EDTA等中的一种或多种。
示例性的，所述渗透压调节剂包括但不限于：氯化钠、葡萄糖等。
本发明的另一方面提供了一种所述药物组合物的用途，用于制备用于治疗或预防包括葡萄球菌感染在内的细菌感染药物中的用途。
优选的，所述细菌感染为耐甲氧西林葡萄球菌菌株(MRSA)引起的感染。
检测结果表明本发明的药物组合物，其中万古霉素在25℃/60％RH条件下，10天后检测能够稳定存在。
本发明的药物组合物，在25℃/60％RH条件下，能够很好的提高万古霉素凝胶剂处方的稳定性，至少在30天内保持稳定。
本发明的药物组合物，在25℃/60％RH条件下，能够很好的提高万古霉素滴眼液处方的稳定性，至少在30天内保持稳定。
本发明的药物组合物，在25℃/60％RH条件下，能够很好的提高万古霉素注射液处方的稳定性，至少在30天内保持稳定。
本发明的万古霉素溶液制剂能够表现出与相同的万古霉素浓度且没有N-甲基-丙氨酸的万古霉素水溶液具有相同的抗菌活性。
本发明的药物制剂可以在给药前以未稀释或稀释的形式进行给药。可以使用5％或10％右旋糖溶液或另一可注射稀释剂或输注液进 行稀释。给药途径可以包括但不限于注射、滴注、吸入、口服、耳部、鼻腔、局部、眼部、阴道和直肠给药等。可以将本发明的药物制剂使用针/注射器、输注器、导管、涂药器、瓶、喷雾器、吸入装置或以伤口敷料进行递送。
本发明的药物组合物，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。
本发明的药物组合物，可以用于制备注射液、眼用制剂、耳用制剂、鼻腔制剂等剂型。
本发明提供的万古霉素药物组合物水溶液，在非冷冻条件下是稳定的，由于N-甲基-丙氨酸的存在，可以有效的抑制万古霉素物理和化学降解。本发明提供的万古霉素水溶液，在开发出现用型的万古霉素注射液、眼用制剂、耳用制剂、鼻腔制剂等具有优异的潜能。
附图说明
图1为F-4处方25℃/60％RH条件下，10天后检测结果HPLC谱图。
图2为F-20处方25℃/60％RH条件下，10天后检测结果HPLC谱图。
图3为F-25处方25℃/60％RH条件下，30天后检测结果HPLC谱图。
图4为F-29处方25℃/60％RH条件下，30天后检测结果HPLC 谱图。
图5为F-32处方25℃/60％RH条件下，30天后检测结果HPLC谱图。
具体实施方式
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。
以下实施例HPLC分析条件为：
色谱柱：WelchUltimate XB-C18(250×4.6mm，5μm)
检测波长：280nm；
柱温：30℃；
流速：2.0ml/min；
进样量；20μl；
流动相：
溶液A：精密量取三乙胺4.0ml，加水至2000ml，磷酸调节pH至3.20；
溶液B：乙腈-四氢呋喃-溶液A＝55-10-935，磷酸调节pH至3.20；
溶液C：乙腈-四氢呋喃-溶液A＝290-10-700，磷酸调节pH至3.20；
洗脱梯度：
时间 溶液B(％) 溶液C(％)
0 100 0
12 100 0
20 0 100
23 100 0
32 100 0
实施例1：不同氨基酸对万古霉素稳定性的影响
配置盐酸万古霉素水溶液，其中盐酸万古霉素浓度为5％w/w，稳定剂(氨基酸)浓度为0.25％w/w，于25℃/60％RH条件下放置10天后使用HPLC方法对进行有关物质检测，组合物中应用不同的稳定剂(氨基酸)及相应的测试结果如表1所列。
表1
Figure PCTCN2022100188-appb-000005
Figure PCTCN2022100188-appb-000006
本研究发现丙氨酸能够使万古霉素的降低缓慢下来。而其他氨基酸作用较低，或者会加速降解。其中F-4(DL-丙氨酸)HPLC谱图(图1)对应的数据如表2：
表2
Peak Name R RT min Area％ Area
1 RS2 5.335 1.87 470871
2 CDP-1 8.749 0.76 191171
3 Vancomycin HCL 10.589 93.24 23585597
实施例2：N-甲基-丙氨酸在对万古霉素稳定性的影响
实验方法如实施例1，稳定剂(氨基酸)及相应的测试结果如表3所列。
表3
Figure PCTCN2022100188-appb-000007
Figure PCTCN2022100188-appb-000008
N-甲基-DL-丙氨酸是丙氨酸的一种衍生物，它对万古霉素的稳定效果要优于丙氨酸。其中N-甲基-D-丙氨酸的效果尤为突出。其中F-20(N-甲基-DL-丙氨酸)HPLC谱图(图2)对应的数据如表4：
表4
Peak Name R RT min Area％ Area
1 RS2 5.332 1.12 280162
2 CDP-1 8.762 0.71 177973
3 Vancomycin HCL 10.576 94.66 23824054
实施例3：N-甲基-丙氨酸在对万古霉素凝胶剂稳定性的影响
于烧杯中称取处方量N-甲基-丙氨酸，加入处方量的水、乙酸，搅拌使混合均匀；称取处方量的明胶，加入到上述溶液中，搅拌溶解；称取处方量的盐酸万古霉素，搅拌溶解。放置在加速条件25℃/60％RH下，30天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，结果如表5。
表5
Figure PCTCN2022100188-appb-000009
Figure PCTCN2022100188-appb-000010
实验结果表明，N-甲基-D-丙氨酸，25℃/60％RH条件下，能够很好的提高万古霉素明胶凝胶剂处方的稳定性，在至少30天内保持稳定，F-25处方25℃/60％RH条件下，30天后检测结果HPLC谱图(图3)对应数据如表6。
表6
Peak Name R RT min Area％ Area
1 RS2 4.594 0.219 58915
2 CDP-1 7.222 0.402 108293
3 Vancomycin HCL 8.631 95.28 25694407
实施例4：N-甲基-丙氨酸在对万古霉素滴眼液稳定性的影响
于烧杯中称取处方量N-甲基-丙氨酸，加入处方量的水，搅拌使混合均匀；称取处方量的苯扎氯胺、甘氨酸，加入到上述溶液中，搅拌溶解；称取处方量的盐酸万古霉素，搅拌溶解。放置在加速条件 25℃/60％RH下，30天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，结果如表7。
表7
Figure PCTCN2022100188-appb-000011
实验结果表明，N-甲基-D-丙氨酸，在25℃/60％RH条件下，能够很好的提高万古霉素滴眼液处方的稳定性，在至少30天内保持稳定，F-29处方25℃/60％RH条件下，30天后检测结果HPLC谱图(图4)对应数据如表8。
表8
Peak Name R RT min Area％ Area
1 RS2 5.304 1.20 295178
2 CDP-2 8.707 0.72 176521
3 Vancomycin HCL 10.558 94.63 23334406
实施例5：N-甲基-丙氨酸在对万古霉素注射液稳定性的影响
Embodiment 5:Effect of N-methyl-alanine on the stability of vancomycin injection
于烧杯中称取处方量N-甲基-丙氨酸，加入处方量的水，搅拌使混合均匀；称取处方量的聚乙二醇400、L-赖氨酸盐酸盐，加入到上述溶液中，搅拌溶解；称取处方量的盐酸万古霉素，搅拌溶解。放置在加速条件25℃/60％RH下，30天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，结果如表9。
表9
Figure PCTCN2022100188-appb-000012
实验结果表明，N-甲基-D-丙氨酸，在25℃/60％RH条件下，能够很好的提高万古霉素注射液处方的稳定性，在至少30天内保持稳 定，F-32处方25℃/60％RH条件下，30天后检测结果HPLC谱图(图5)对应的数据如表10。
表10
Peak Name R RT min Area％ Area
1 RS2 5.336 1.15 283427
2 CDP-1 8.731 0.72 177649
3 Vancomycin HCL 10.565 94.62 23387061
实施例6：万古霉素注射液PK试验
9只雄性SD大鼠被分成3组。第1组(G1)动物单次静脉推注给予生理盐水溶解的万古霉素(5mg/ml)，第2组(G2)动物单次静脉推注给予已上市万古霉素参比制剂(Xellia公司，批号1V14003)，第3组(G3)动物单次静脉推注给予自制万古霉素注射液(50mg/ml万古霉素，53.4mg/ml N-甲基-D-丙氨酸)，三组给药剂量一致为20mg/kg。每组给药后，于0.083、0.167、0.25、0.5、1、2、4、6、8、12和24h采集血浆样本。应用已建立的LC-MS/MS方法检测血浆样本中的万古霉素药物浓度。
结果显示，单次静脉推注万古霉素注射液后，在SD大鼠体内消除半衰期(T1/2)为0.678-0.842h,血液循环时间较短；表观分布容积(Vd)明显大于大鼠的全血体积，表明万古霉素全身分布较为广泛。比较G1、G2和G3组药代动力学参数，G3组与G1和G2组相比，在大鼠体内的药代动力学行为基本一致，没有明显差异。
Figure PCTCN2022100188-appb-000013
Figure PCTCN2022100188-appb-000014

Claims (15)

  1. 一种药物组合物，所述药物组合物包含万古霉素或其可药用的盐，N-甲基丙氨酸，水。
  2. 根据权利要求1所述的药物组合物，其中所述万古霉素或其可药用的盐浓度为0.1-30％w/w。
  3. 根据权利要求1所述的药物组合物，所述万古霉素或其可药用的盐浓度为0.1-15％w/w。
  4. 根据权利要求1所述的药物组合物，所述N-甲基-D-丙氨酸浓度为0.1-30％w/w。
  5. 根据权利要求1所述的药物组合物，所述N-甲基-D-丙氨酸浓度为0.1-15％w/w。
  6. 根据权利要求1所述的药物组合物，所述N-甲基丙氨酸为N-甲基-DL-丙氨酸、N-甲基-D-丙氨酸或N-甲基-L-丙氨酸。
  7. 根据权利要求1所述的药物组合物，其pH为3-9。
  8. 根据权利要求7所述的药物组合物，其pH为3-6。
  9. 根据权利要求7或8所述的药物组合物，可以使用酸或碱对pH进行调节。
  10. 根据权利要求9所述的药物组合物，所述酸或碱为盐酸、乙酸或氢氧化钠。
  11. 根据权利要求1所述的药物组合物，所述N-甲基丙氨酸为N-甲基-D-丙氨酸。
  12. 根据权利要求1-11任一权利要求所述的药物组合物，所述N-甲基-氨基酸和万古霉素的摩尔比是(0.1-40)：1。
  13. 根据权利要求12所述的药物组合物，所述N-甲基-氨基酸和万古霉素的摩尔比是(0.5-20)：1。
  14. 权利要求1-13任一权利要求所述的药物组合物的用途，在用于制备用于治疗或预防包括葡萄球菌感染、肺炎链球菌在内的细菌感染药物中的应用。
  15. 权利要求14所述的药物组合物的用途，所述细菌感染为耐甲氧西林葡萄球菌菌株(MRSA)、耐甲氧西林凝固酶阴性葡萄球菌或耐青霉素肺炎链球菌(PRSP)引起的感染。
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Citations (6)

* Cited by examiner, † Cited by third party
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JP2008201778A (ja) * 2007-01-25 2008-09-04 Mochida Pharmaceut Co Ltd バンコマイシン液状製剤
CN104884047A (zh) * 2012-11-29 2015-09-02 英斯梅德股份有限公司 稳定的万古霉素制剂
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008201778A (ja) * 2007-01-25 2008-09-04 Mochida Pharmaceut Co Ltd バンコマイシン液状製剤
CN104884047A (zh) * 2012-11-29 2015-09-02 英斯梅德股份有限公司 稳定的万古霉素制剂
CN107073072A (zh) * 2014-11-06 2017-08-18 埃克斯利亚制药有限公司 糖肽组合物
CN107106585A (zh) * 2015-02-06 2017-08-29 杭州美南医药科技有限公司 万古霉素的水溶液制剂
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