WO2024037451A1 - 一种稳定的奥利万星药物水溶液及其制备方法 - Google Patents

一种稳定的奥利万星药物水溶液及其制备方法 Download PDF

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WO2024037451A1
WO2024037451A1 PCT/CN2023/112556 CN2023112556W WO2024037451A1 WO 2024037451 A1 WO2024037451 A1 WO 2024037451A1 CN 2023112556 W CN2023112556 W CN 2023112556W WO 2024037451 A1 WO2024037451 A1 WO 2024037451A1
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oritavancin
aqueous solution
streptococcus
staphylococcus
bacteroides
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PCT/CN2023/112556
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English (en)
French (fr)
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朱逸凡
范敏华
赵振坤
陆平
徐沧朔
石慧
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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
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Publication of WO2024037451A1 publication Critical patent/WO2024037451A1/zh

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    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7024—Esters of saccharides
    • 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
    • A61K9/08—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
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention belongs to the technical field of pharmaceutical preparations, and specifically relates to a stable oritavancin drug aqueous solution and a preparation method thereof.
  • Oritavancin is: [4”R]-22-O-(3-amino-2,3,6-trideoxy-3-C-methyl- ⁇ -Larabino-hexopyranosyl)-N3-[ (4'-chloro[1,1'-biphenyl]-4-yl)methyl]vancomycin phosphate[1:2][salt], the molecular formula is: C 86 H 97 N 10 O 26 C l3 ⁇ 2H 3 PO 4 , The molecular weight is: 1989.09, and its phosphate form structural formula is as follows:
  • Oritavancin is a new semi-synthetic lipoglycopeptide antibiotic. Oritavancin has been shown to be effective in the treatment of adult patients 18 years and older with acute bacterial skin infections and skin structure infections (ABSSSI) caused or suspected to be caused by susceptible isolates of specified Gram-positive microorganisms . In 2014, the U.S. Food and Drug Administration (FDA) approved oritavancin for the treatment of infectious diseases caused or suspected to be caused by susceptible strains of specified Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA). Adults with acute bacterial skin infections and skin structure infections. Current oritavancin preparations are freeze-dried powder injections, which need to be diluted at least once before use, making clinical use inconvenient and error-prone.
  • ABSSSI acute bacterial skin infections and skin structure infections
  • MRSA methicillin-resistant Staphylococcus aureus
  • CN106620649A discloses that oritavancin shows significant activity against many bacteria.
  • the application text describes methods for treating, preventing, and preventing bacterial infections and diseases in animals, including humans, using a single dose of oritavancin over a course of treatment.
  • CN108712909A discloses a freeze-dried powder preparation containing oritavancin and a ⁇ -cyclodextrin derivative.
  • CN105641679A provides a stable oritavancin pharmaceutical composition: oritavancin, mannitol, phosphoric acid and water for injection. However, its preferred form is lyophilized powder.
  • Oritavancin is only available abroad as freeze-dried powder for injection, for intravenous injection. Oritavancin freeze-dried powder will show rapid degradation when reconstituted, and oritavancin aqueous solution will also degrade during short-term storage. Therefore, oritavancin is not suitable for long-term storage in aqueous solution. Therefore, we continue to develop a ready-to-use injection (RTU). Compared with freeze-dried powder for injection, RTU does not require a reconstitution step and can be directly used clinically, reducing medication errors.
  • the present invention uses N-methyl-D-alanine as a stabilizer, which can reduce the degradation rate of oritavancin in aqueous solution and prepare a stable aqueous solution of oritavancin. preparation. Therefore, the present invention provides a stable aqueous pharmaceutical solution of oritavancin, which includes components: oritavancin or a pharmaceutically acceptable salt thereof, N-methyl-D-alanine, and water.
  • the pharmaceutically acceptable salts are acid salts and/or alkali salts, and the acid salts can, for example, form pharmaceutically acceptable acid addition salts using inorganic acids and organic acids.
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid , methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.
  • the base salt can use inorganic bases and organic bases to form pharmaceutically acceptable salts.
  • Inorganic bases from which salts can be derived include, for example, bases containing sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc.; particularly preferred are ammonium, potassium, sodium, calcium salts and magnesium salts.
  • treatment of oritavancin with an inorganic base removes labile hydrogens from oritavancin to provide inorganic cations including inorganic cations such as Li + , Na + , K + , Mg 2+ , and Ca 2+ , etc. ) salt form.
  • Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, substituted amines, cyclic amines, basic ion exchange resins and the like, in particular such as isopropylamine, trimethylamine, diethylamine, triethylamine, triethylamine, etc. Propylamine and ethanolamine.
  • the content of oritavancin or its pharmaceutical salt is 0.1-30% w/w, preferably 0.1-25% w/w, preferably 0.1-20% w/w, preferably 0.1-15% w/ w, preferably 0.1-10% w/w, more preferably 0.1-5% w/w.
  • the content of N-methyl-D-alanine is 0.1-60% w/w, preferably 0.5-60% w/w, and further preferably 1-60% w/w.
  • an organic solvent can be added to the aqueous oritavancin drug solution.
  • the organic solvent can be commonly used in liquid preparations, such as ethanol, glycerol, propylene glycol, dimethyl sulfoxide, and polyethylene glycol. .
  • the preferred pH of the aqueous solution preparation of oritavancin is 3-8, and more preferably 4-7.
  • the final aqueous solution formulation of oritavancin has a pH of about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6 , about 6.5, about 7, about 7.5, or about 8; preferably about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, or about 7.
  • the oritavancin pharmaceutical aqueous solution of the present invention may further include one or a combination of any two or more of solubilizers, surfactants, buffers, antioxidants, preservatives, and chelating agents.
  • the solubilizing agent is selected from ionic surfactants or nonionic surfactants, such as sodium lauryl sulfate, Tween 80, Span 20, etc., and its dosage is usually 0.01 to 20.0g/100mL.
  • ionic surfactants or nonionic surfactants such as sodium lauryl sulfate, Tween 80, Span 20, etc.
  • dosage is usually 0.01 to 20.0g/100mL.
  • the description of the solubilizer here is only for illustrative purposes and does not constitute a limitation on the scope of the present invention. Any suitable solubilizer known to those skilled in the art is suitable for use in the present invention.
  • Various buffers and methods can be used for adjusting the pH, including acetate buffers, citrate buffers, phosphate buffers, tartrates, amino acid salts, and borate buffers. Acids or bases can be used to adjust the pH of these formulations, as desired.
  • the antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene. Its dosage is usually 0.001 ⁇ 5.0g/100mL.
  • the preservatives include, but are not limited to, benzalkonium chloride, polyhexamethylene hydrochloride (PHMB), chlorobutanol, thimerosal, phenylmercury, acetate, phenylmercuric nitrate, ethylparaben, p-hydroxybenzoic acid
  • esters, benzoic acid and its salts, sorbic acid, chlorobutanol, benzyl alcohol, phenylethyl alcohol, chlorhexidine acetate and quaternary ammonium compound cationic surfactants the dosage is usually 0.005 ⁇ 10.0g/100mL.
  • the description of the preservatives here is only for illustrative purposes and does not constitute a limitation on the scope of the present invention. Any suitable preservative known to those skilled in the art is suitable for use in the present invention.
  • the chelating agent includes various dicarboxylic acids, tricarboxylic acids and aminopolycarboxylic acids, such as ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis( ⁇ -aminoethyl ether)-N,N,N', N'-tetraacetic acid (EGTA) and penta(carboxymethyl)diethylenetriamine (DTPA) and their salts and hydrates; monomeric polyacids such as EDTA, cyclohexanediaminetetraacetic acid (CDTA) may also be included , Hydroxyethylethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), dimercaptopropanesulfonic acid (DMPS), dimercaptosuccinic acid (DMSA), aminotrimethylenephosphonic acid (ATPA), citric acid, which are acceptable for ophthalmology of salt, and combinations of any of the foregoing.
  • chelating agents include pyrophosphates, tripolyphosphates and hexametaphosphates, chelating antibiotics such as chloroquine and tetracyclines, containing two or more chelating nitrogen atoms within the imino group or in the aromatic ring.
  • Nitrogen-containing chelating agents for example, diimine, 2,2'-bipyridyl, etc.
  • various polyamines such as Cyclam (1,4,7,11-tetraazacyclotetradecane) , N-(C1 to C30 alkyl) substituted cyclamine (e.g., cetyl cycloamine, tetramethylhexadecyl cycloamine), diethylenetriamine (DETA), spermine , diethylnorspermine (DENSPM), diethylhomo-spermine (DEHOP) and deferoxamine (N'-[5-[[4-[[5-(acetylhydroxylamino) )pentyl]amino]-1,4-dioxybutyl]hydroxy-amino]pentyl]-N'-(5-aminopentyl)-N-hydroxybutyl diamide. Its dosage is usually 0.01 ⁇ 5.0g/100mL.
  • Another aspect of the present invention provides a method for preparing an aqueous drug solution of oritavancin, which involves weighing the prescription amount of N-methyl-D-alanine, adding it to water, stirring to dissolve, and then weighing the prescription amount of N-methyl-D-alanine. oritavancin, stir and dissolve to obtain the oritavancin drug aqueous solution.
  • auxiliary materials include but are not limited to the solubilizer, surfactant, buffer, antioxidant, preservative, chelating agent and any of them. A combination of two or more.
  • the oritavancin pharmaceutical aqueous solution disclosed herein can be oral liquid, injection, eye drops, topical gel, topical emulsion, or spray.
  • Administration of formulations prepared from aqueous pharmaceutical solutions of oritavancin disclosed herein may be performed via any acceptable mode of administration used for agents with similar uses, including but not limited to oral, subcutaneous, intravenous, intranasal, topical, Dermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration.
  • Another aspect of the present invention provides an application of the oritavancin drug aqueous solution in preparing a drug for treating bacterial infections.
  • the infection can be in any tissue or tissues of the subject.
  • the oritavancin aqueous solution provided by the present invention can be used to treat subjects suffering from the following infections: bloodstream infection (BSI), catheter-related bloodstream infection (CRBSI), osteomyelitis, prosthetic joint infection, pneumonia, joint Interstitial and device infections.
  • BBI bloodstream infection
  • CRBSI catheter-related bloodstream infection
  • osteomyelitis prosthetic joint infection
  • pneumonia joint Interstitial and device infections.
  • the oritavancin pharmaceutical aqueous solution provided by the present invention can be used to treat subjects suffering from the following infections: complicated skin infections and skin structure infections (cSSSI) and complicated and uncomplicated skin infections and soft tissue infections (SSTI), including abscesses , ulcers, burns, cellulitis, deep bacterial infections (such as severe abscesses, infected ulcers, severe burns, or deep and extensive cellulitis). Treatment may also be performed along with surgical procedures for bacterial infections.
  • cSSSI complicated skin infections and skin structure infections
  • SSTI complicated and uncomplicated skin infections and soft tissue infections
  • abscesses , ulcers, burns, cellulitis, deep bacterial infections (such as severe abscesses, infected ulcers, severe burns, or deep and extensive cellulitis). Treatment may also be performed along with surgical procedures for bacterial infections.
  • the subject may be an animal, such as a mammal or a human.
  • Examples of bacterial infections include Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Gram acidophilus Klebsiella oxytoc, Serratia marcescens, Francisella tularensis, Morganella morganii
  • the bacterial infection treated by the oritavancin aqueous solution provided by the present invention may be caused by bacteria of any phenotype or genotype provided above, or by any other bacteria capable of causing bacterial infection.
  • the infection treated may be caused by more than one bacterial species, or by more than one phenotype or genotype of a single bacterial species.
  • the infections treated may be complicated skin infections and skin structure infections.
  • the oritavancin pharmaceutical aqueous solution obtained by the present invention uses N-methyl-D-alanine as a stabilizer and has the following beneficial effects: the oritavancin pharmaceutical aqueous solution provided by the present invention is stable at 25°C Under the conditions, the growth rate of impurities in aqueous solution is greatly reduced, and the change of impurities in 30 days is less than 0.1%; it is highly safe and stable. Even if it is stored at room temperature, the maximum impurity is less than 0.1%. It is a ready-to-use injection (RTU) with good stability. Compared with freeze-dried powder for injection, RTU does not require a reconstitution step and can be directly used clinically, reducing medication errors.
  • RTU ready-to-use injection
  • Figure 1 shows the HPLC chromatogram of prescription 17 at 25°C-60 days.
  • Figure 2 shows the HPLC chromatogram of prescription 16 at 25°C-60 days.
  • Figure 3 shows the HPLC chromatogram of prescription 15 at 25°C-60 days.
  • HPLC method used in the present invention to detect the stability of oritavancin:
  • Solution A Precisely measure 4.0mL of triethylamine, add water to 2000mL, and adjust the pH to 3.20 with phosphoric acid;
  • Nmethyl D-alanine has the best effect and relative purity.
  • the relative purity is 98.6%.
  • the relative purity is the ratio of the purity after being left for a period of time to the initial purity. For example, the relative purity of prescription 5 is 97.6%/99.0%.
  • Figure 1 shows the HPLC chromatogram of prescription 17 at 25°C-60 days.
  • the integral data are as follows:
  • Figure 2 shows the HPLC chromatogram of prescription 16 at 25°C-60 days.
  • the integral data are as follows:
  • Figure 3 shows the HPLC chromatogram of prescription 15 at 25°C-60 days.
  • the integral data are as follows:
  • N-methyl-D-alanine can reduce the degradation of oritavancin at different concentrations in aqueous solutions, reduce the growth of total impurities, and increase its stability.
  • Example 5 Stability of oritavancin after adding stabilizer and different organic solvent formulations

Abstract

一种稳定的奥利万星药物水溶液及其制备方法，所述的奥利万星的水溶液包括：奥利万星或其药用盐，N-甲基-D-丙氨酸，水。

Description

一种稳定的奥利万星药物水溶液及其制备方法 技术领域
本发明属于医药制剂技术领域，具体涉及一种稳定的奥利万星药物水溶液及其制备方法。
背景技术
奥利万星(Oritavancin)化学名为：[4”R]-22-O-(3-amino-2,3,6-trideoxy-3-C-methyl-α-Larabino-hexopyranosyl)-N3-[(4’-chloro[1,1’-biphenyl]-4-yl)methyl]vancomycin phosphate[1:2][salt]，分子式为：C86H97N10O26Cl3·2H3PO4，分子量为：1989.09，其磷酸盐形式结构式如下：
奥利万星(Oritavancin)是新型的半合成脂糖肽类抗生素。奥利万星已被证明可有效治疗患有由指定的革兰氏阳性微生物的敏感性分离株引起或疑似引起的急性细菌性皮肤感染和皮肤结构感染(ABSSSI)的18岁及以上的成年患者。2014年美国食品与药物管理局(FDA)批准奥利万星用于治疗患有由指定的革兰氏阳性微生物(包括耐甲氧西林金黄色葡萄球菌(MRSA)的敏感性菌株引起或疑似引起急性细菌性皮肤感染和皮肤结构感染的成人。目前的奥利万星制剂均为冻干粉针剂，使用前需要至少一次稀释，临床使用不便，易出现差错。
CN106620649A公开了奥利万星显示针对许多细菌的显著活性。该申请文本描述了在疗程内使用单剂量奥利万星治疗、预防和防止动物(包括人类)的细菌感染和疾病的方法。
CN108712909A公开了包含奥利万星和β-环糊精衍生物的冻干粉末制剂。
CN105641679A提供一种稳定的奥利万星药物组合物：奥利万星、甘露醇、磷酸和注射用水。但是其优选形式为冻干粉针。
奥利万星在国外仅上市冻干粉针剂，静脉注射用。奥利万星冻干粉针在复溶时即会表现出快速降解，且奥利万星水溶液在短暂存储过程中也会出现降解，因此，奥利万星不适合在水溶液中长期储存。因此继续开发一种即用型注射液(RTU，Ready-To-Use)，相比于冻干粉针剂，RTU无需复溶步骤，可直接临床使用，减少了用药差错。
发明内容
为了解决现有技术中存在的问题，本发明采用N-甲基-D-丙氨酸作为稳定剂，能够降低奥利万星在水溶液中的降解速率，制备得到稳定的奥利万星的水溶液制剂。因此本发明提供了一种稳定的奥利万星药物水溶液，包括组分：奥利万星或其药用盐，N-甲基-D-丙氨酸，水。
所述药用盐为酸盐和/或碱盐，所述酸盐例如可以用无机酸和有机酸形成药学上可接受的酸加成盐。可以衍生盐的无机酸包括例如，盐酸、氢溴酸、硫酸、硝酸、磷酸等。可以衍生盐的有机酸包括例如，乙酸、丙酸、乙醇酸、丙酮酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸等。所述碱盐可以使用无机碱和有机碱形成药学上可接受的盐。可以衍生盐的无机碱包括例如，含有钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝等的碱；特别优选的是铵盐、钾盐、钠盐、钙盐和镁盐。在一些实施方案中，用无机碱处理奥利万星会从奥利万星中失去不稳定的氢以提供包括无机阳离子(诸如Li+、Na+、K+、Mg2+和Ca2+等)的盐形式。可以衍生盐的有机碱包括例如，伯胺、仲胺和叔胺，取代的胺、环胺，碱性离子交换树脂等，特别是诸如异丙胺、三甲胺、二乙胺、三乙胺、三丙胺和乙醇胺。
其中所述奥利万星或其药用盐含量为0.1-30％w/w，优选为0.1-25％w/w，优选为0.1-20％w/w，优选为0.1-15％w/w，优选为0.1-10％w/w，进一步优选为0.1-5％w/w。
其中所述N-甲基-D-丙氨酸含量为0.1-60％w/w，优选为0.5-60％w/w，进一步优选为1-60％w/w。
进一步的，可以在所述的奥利万星药物水溶液中加入有机溶剂，所述有机溶剂可以为液体制剂中常用的，比如可以为乙醇、甘油、丙二醇、二甲基亚砜、聚乙二醇。
所述奥利万星的水溶液制剂优选的pH为3-8，进一步优选为4-7。在具体的实施方案中，最终奥利万星的水溶液制剂的pH为约1、约1.5、约2、约2.5、约3、约3.5、约4、约4.5、约5、约5.5、约6、约6.5、约7、约7.5、或约8；优选为约4、约4.5、约5、约5.5、约6、约6.5、约7。
本发明所述的奥利万星药物水溶液可以进一步包括增溶剂、表面活性剂、缓冲剂、抗氧化剂、防腐剂、螯合剂中的一种或其中任意两种以上的组合。
所述增溶剂自离子型表面活性剂或非离子型表面活性剂，例如十二烷基硫酸钠、吐温80、司盘20等，其用量通常为0.01～20.0g/100mL。此处仅仅是为了示例性地对增溶剂进行说明，并不构成对本发明保护范围的限制。本领域技术人员所知的任何合适的增溶剂均适用于本发明。
可以使用各种缓冲剂和方法用于调节pH，缓冲剂包括乙酸盐缓冲剂、柠檬酸盐缓冲剂、磷酸盐缓冲剂、酒石酸盐、氨基酸盐和硼酸盐缓冲剂。根据需要，可以使用酸或碱来调节这些制剂的pH。
所述抗氧化剂包括但不限于焦亚硫酸钠、硫代硫酸钠、乙酰半胱氨酸、丁基化羟基苯甲醚和丁基化羟基甲苯。其用量通常为0.001～5.0g/100mL。
所述防腐剂包括但不限于苯扎氯铵、聚已亚甲基盐酸(PHMB)、氯丁醇、硫柳汞、苯汞、乙酸盐、硝酸苯汞、尼泊金乙酯、对羟基苯甲酸酯类、苯甲酸及其盐、山梨酸、三氯叔丁醇、苯甲醇、苯乙醇、醋酸洗必泰及季铵化合物类阳离子型表面活性剂中的一种或多种，其用量通常为0.005～10.0g/100mL。此处仅仅是为了示例性地对防腐剂进行说明，并不构成对本发明保护范围的限制。本领域技术人员所知的任何合适的防腐剂均适用于本发明。
所述螯合剂，包括各种二羧酸、三羧酸和氨基多羧酸，例如乙二胺四乙酸(EDTA)、乙二醇-双(β-氨基乙醚)-N,N,N',N'-四乙酸(EGTA)和五(羧甲基)二亚乙基三胺(DTPA)以及其盐和水合物；还可以包括单体多元酸例如EDTA、环己二胺四乙酸(CDTA)、羟乙基乙二胺三乙酸 (HEDTA)、二乙烯三胺五乙酸(DTPA)、二巯基丙磺酸(DMPS)、二巯基丁二酸(DMSA)、氨基三亚甲基膦酸(ATPA)、柠檬酸、其眼用可接受的盐、以及前述任何一种的组合。其他合适的螯合剂包括焦磷酸盐，三聚磷酸盐和六偏磷酸盐，螯合抗生素例如氯喹和四环素，在亚氨基内或在芳环中含有两个或多于两个螯合氮原子的含氮螯合剂(例如，二亚胺、2,2'-联吡啶等)，以及各种多胺例如环拉胺(Cyclam)(1,4,7,11-四氮杂环十四烷)、N-(C1至C30烷基)取代的环拉胺(例如，十六烷基环拉胺、四甲基十六烷基环拉胺)、二亚乙基三胺(DETA)、精胺、二乙基去甲精胺(DENSPM)、二乙基高精胺(diethylhomo-spermine)(DEHOP)和去铁胺(N'-[5-[[4-[[5-(乙酰基羟基氨基)戊基]氨基]-1,4-二氧基丁基]羟基-氨基]戊基]-N'-(5-氨基戊基)-N-羟基丁基二酰胺。其用量通常为0.01～5.0g/100mL。
本发明的另一方面，提供了一种奥利万星药物水溶液的制备方法，称取处方量的N-甲基-D-丙氨酸，加入水中，搅拌使溶解，然后称取处方量的奥利万星，搅拌溶解得到所述的奥利万星药物水溶液。
在有其他辅料存在的情况下，进一步的包括加入其他辅料的步骤，所述辅料包括但不限于所述的增溶剂、表面活性剂、缓冲剂、抗氧化剂、防腐剂、螯合剂及他们的任一两种或两种以上的组合。
本文公开的奥利万星药物水溶液可以为口服液，注射剂，滴眼液，外用凝胶，外用乳剂，喷剂。
本文公开的奥利万星药物水溶液制备得到的制剂的施用可以经由用于具有类似用途的试剂的任何可接受的施用方式进行，包括但不限于口服、皮下、静脉内、鼻内、局部、经皮、腹膜内、肌肉内、肺内、阴道、直肠或眼内施用。
本发明的另一方面提供了一种所述奥利万星药物水溶液在制备治疗细菌感染药物中的应用。感染可以在对象的任何组织或组织中。例如，可将本发明提供的奥利万星水溶液用于治疗患有以下感染的对象：血流感染(BSI)、导管相关血流感染(CRBSI)、骨髓炎、假体关节感染、肺炎、关节间隙感染和装置感染。
本发明提供的奥利万星药物水溶液可以用于治疗患有以下感染的对象：复杂的皮肤感染和皮肤结构感染(cSSSI)以及复杂的和不复杂的皮肤感染和软组织感染(SSTI)，包括脓肿、溃疡、烧伤、蜂窝组织炎、深部细菌感染(诸如重度脓肿、感染性溃疡、重度烧伤或深部和广泛性蜂窝组织炎)。也可以将治疗方法伴随针对细菌感染的外科手术来实施。
在一些具体的实施方案中，对象可以是动物，例如哺乳动物、人。
细菌感染的实例包括绿脓假单胞菌(Pseudomonas aeruginosa)、荧光假单胞菌(Pseudomonas fluorescens)、食酸假单胞菌(Pseudomonas acidovorans)、产碱假单胞菌(Pseudomonas alcaligenes)、恶臭假单胞菌(Pseudomonas putida)、嗜麦芽寡养单胞菌(Stenotrophomonas maltophilia)、洋葱伯克霍尔德菌(Burkholderia cepacia)、嗜水气单胞菌(Aeromonas hydrophilia)、大肠杆菌(Escherichia coli)、弗氏柠檬酸杆菌(Citrobacter freundii)、鼠伤寒沙门氏菌(Salmonella typhimurium)、伤寒沙门氏菌(Salmonella typhi)、副伤寒沙门菌(Salmonella paratyphi)、肠炎沙门氏菌(Salmonellaenteritidis)、痢疾志贺氏菌(Shigella dysenteriae)、弗氏志贺菌(Shigellaflexneri)、宋内志贺菌(Shigella sonnei)、阴沟肠杆菌(Enterobacter cloacae)、产气肠杆菌(Enterobacter aerogenes)、肺炎克雷白氏杆菌(Klebsiella pneumoniae)、产酸克雷白氏杆菌(Klebsiella oxytoc)、粘质沙雷氏菌(Serratia marcescens)、土拉弗朗西斯菌(Francisella tularensis)、摩氏摩根菌(Morganella morganii)、奇异变形杆菌(Proteusmirabilis)、普通变形杆菌(Proteus vulgaris)、产碱普罗威登斯菌(Providenciaalcalifaciens)、雷氏普罗威登斯菌(Providencia rettgeri)、斯氏普罗威登斯菌(Providencia stuartii)、鲍氏不动杆菌(Acinetobacter baumannii)、乙酸钙不动杆菌(Acinetobacter calcoaceticus)、溶血不动杆菌(Acinetobacter haemolyticus)、小肠结肠炎耶尔森氏菌(Yersinia enterocolitica)、鼠疫耶尔森氏菌(Yersinia pestis)、假结核耶尔森氏菌(Yersinia pseudotuberculosis)、中间耶尔森氏菌(Yersiniaintermedia)、百日咳博德特氏菌(Bordetella pertussis)、副百日咳博德特氏菌(Bordetella parapertussis)、支气管炎博德特氏菌(Bordetella bronchiseptica)、流感嗜血杆菌(Haemophilus influenzae)、副流感嗜血杆菌(Haemophilus parainfluenzae)、溶血嗜血杆菌(Haemophilus haemolyticus)、副溶血嗜血杆菌(Haemophilusparahaemolyticus)、杜克雷嗜血杆菌(Haemophilus ducreyi)、多杀巴斯德菌(Pasteurella multocida)、溶血巴斯德菌(Pasteurella haemolytica)、粘膜炎布兰汉球菌(Branhamella catarrhalis)、幽门螺杆菌(Helicobacter pylori)、胎儿弯曲杆菌(Campylobacter fetus)、空肠弯曲杆菌(Campylobacter jejuni)、大肠弯曲杆菌(Campylobacter coli)、伯氏疏螺旋体(Borrelia burgdorferi)、霍乱弧菌(Vibriocholerae)、副溶血弧菌(Vibrio parahaemolyticus)、嗜肺军团菌(Legionellapneumophila)、单核细胞增多性李斯特氏菌(Listeria monocytogenes)、淋病奈瑟氏菌(Neisseria gonorrhoeae)、脑膜炎奈瑟氏菌(Neisseria meningitidis)、金氏菌属(Kingella)、莫拉克斯氏菌属(Moraxella)、阴道加德菌(Gardnerella vaginalis)、脆弱拟杆菌(Bacteroides fragilis)、狄氏拟杆菌(Bacteroides distasonis)、拟杆菌3452A同源群(Bacteroides 3452A homology group)、普通拟杆菌(Bacteroides vulgatus)、卵形拟杆菌(Bacteroides ovalus)、多形拟杆菌(Bacteroides thetaiotaomicron)、单形拟杆 菌(Bacteroides uniformis)、埃氏拟杆菌(Bacteroides eggerthii)、内脏拟杆菌(Bacteroides splanchnicus)、艰难梭菌(Clostridium difficile)、结核分枝杆菌(Mycobacterium tuberculosis)、鸟分枝杆菌(Mycobacterium avium)、胞内分枝杆菌(Mycobacterium intracellulare)、麻风分枝杆菌(Mycobacterium leprae)、白喉棒状杆菌(Corynebacterium diphtheriae)、溃疡棒状杆菌(Corynebacterium ulcerans)、肺炎链球菌(Streptococcus pneumoniae)、无乳链球菌(Streptococcus agalactiae)、酿脓链球菌(Streptococcus pyogenes)、中间链球菌(Streptococcus intermedius)、中间链球菌(Streptococcus intermedius)、星座链球菌(Streptococcus constellatus)、停乳链球菌(Streptococcus dysgalactiae)、停乳链球菌似马亚种(Streptococcus dysgalactiaesubsp.equisimilis)、粪肠球菌(Enterococcus faecalis)、屎肠球菌(Enterococcusfaecium)、耐万古霉素粪肠球菌(vancomycin-resistant Enterococcus faecalis)、屎肠球菌(Enterococcus faecium)、耐万古霉素屎肠球菌(vancomycin-resistantEnterococcus faecium)、金黄色葡萄球菌(Staphylococcus aureus)、耐甲氧西林金黄色葡萄球菌(methicillin-resistant Staphylococcus aureus)、耐万古霉素金黄色葡萄球菌(vancomycin-resistant Staphylococcus aureus)、万古霉素中度耐受金黄色葡萄球菌(vancomycin-intermediate Staphylococcus aureus)、万古霉素异质性中度耐受金黄色葡萄球菌(vancomycin hetero-intermediate Staphylococcus aureus)、表皮葡萄球菌(Staphylococcus epidermidis)、腐生葡萄球菌(Staphylococcus saprophyticus)、中间葡萄球菌(Staphylococcus intermedius)、猪葡萄球菌猪亚种(Staphylococcus hyicussubsp.hyicus)、溶血葡萄球菌(Staphylococcus haemolyticus)、人葡萄球菌(Staphylococcus hominis)或解糖葡萄球菌(Staphylococcus saccharolyticus)及其组合。
本发明提供的奥利万星水溶液所治疗的细菌感染可能由上述提供的任何表型或基因型的细菌引起，或者由上述能够引起细菌感染的任何其他细菌引起。在本发明中，所治疗的感染可能是由多于一种细菌种类所致，或由单一细菌种类的多于一种表型或基因型所致。例如，所治疗的感染可以是复杂的皮肤感染和皮肤结构感染。
本发明在大量实验的基础上得到的奥利万星药物水溶液，以N-甲基-D-丙氨酸作为稳定剂，具有的有益效果：本发明提供的奥利万星药物水溶液在25℃条件下，极大的降低杂质在水溶液中的增长速度，30天杂质变化小于0.1％；安全性高，稳定性好，即使常温保存，最大杂质小于0.1％。其为稳定性好的即用型注射液(RTU，Ready-To-Use)，相比于冻干粉针剂，RTU无需复溶步骤，可直接临床使用，减少了用药差错。
附图说明
图1为处方17，25℃-60天HPLC图谱。
图2为处方16，25℃-60天HPLC图谱。
图3为处方15，25℃-60天HPLC图谱。
具体实施方式
为了更好的理解本发明，下面结合具体的实施方式，对本发明的内容做进一步说明，但是具体的内容并不是对本发明的限制。
本发明检测奥利万星稳定性所使用的HPLC方法：
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：
实施例1：奥利万星和不同氨基酸及其衍生物处方的稳定性
制备步骤：
1、于烧杯中称取处方量的氨基酸或其衍生物，加入处方量的水，搅拌使溶解；
2、称取处方量的奥利万星，搅拌溶解；
3、放置在25℃下，一定时间后取样检测，计算相对于初始的百分比，结果如下。
以上结果可以看出，加入氨基酸或其衍生物可以降低奥利万星在水溶液中的降解，减少总杂的增长，增加其稳定性，其中N甲基D-丙氨酸效果最好，相对纯度为98.6％，所述的相对纯度为放置一段时间后的纯度与初始纯度的比值，例如，处方5的相对纯度为97.6％/99.0％。
实施例2：奥利万星和不同有机溶剂处方的稳定性
制备步骤：
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；
2、称取处方量的奥利万星，搅拌溶解；
3、放置在25℃下，一定时间后取样检测，计算相对于初始的百分比，结果如下。
以上结果可以看出，向奥利万星水溶液处方中加入少量的N,N二甲基乙酰胺、聚乙二醇400、丙二醇、乙醇，奥利万星即有结晶析出，说明奥利万星与以上有机溶剂的物理相容性较差。在较低浓度的甘油中，未出现絮状沉淀，但对于奥利万星的降解的抑制作用有限。
实验例3：不同浓度稳定剂对奥利万星处方稳定性影响
制备步骤：
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；
2、称取处方量的奥利万星，搅拌溶解；
3、放置在25℃下，一定时间后取样检测，根据面积归一化计算峰面积百分比，结果如下。
以上结果可以看出，和奥利万星水溶液处方1相比，在不同比例浓度稳定剂N-甲基-D-丙氨酸存在下，处方14-17在60天内的降解均较低，可以保持稳定较长时间。
图1为处方17，25℃-60天HPLC图谱，积分数据如下：
图2为处方16，25℃-60天HPLC图谱，积分数据如下：
图3为处方15，25℃-60天HPLC图谱，积分数据如下：
实施例4：不同浓度奥利万星和N-甲基-D-丙氨酸处方的稳定性
制备步骤：
1、于烧杯中称取处方量的N-甲基-D-丙氨酸，加入处方量的水，搅拌使溶解；
2、称取处方量的奥利万星，搅拌溶解；
3、放置在25℃下，一定时间后取样检测，计算相对于初始的百分比，结果如下。
以上结果可以看出，加入N-甲基-D-丙氨酸可以降低不同浓度奥利万星在水溶液中的降解，减少总杂的增长，增加其稳定性。
实施例5：奥利万星中加入稳定剂后和不同有机溶剂处方的稳定性
制备步骤：
1、于烧杯中称取处方量的有机溶剂和N-甲基-D-丙氨酸或N-乙酰-D-丙氨酸，加入50mL的注射用水中，搅拌使溶解；
2、称取处方量的奥利万星，搅拌溶解；
3、放置在25℃下，一定时间后取样检测，计算相对于初始的百分比，结果如下。
以上结果可以看出，和奥利万星水溶液处方中加入少量的N,N二甲基乙酰胺、聚乙二醇400、丙二醇、乙醇，原本有奥利万星结晶析出，但是加入稳定剂后明显有改善作用，但是N-乙酰-D-丙氨酸改善无明显作用，N-甲基-D-丙氨酸改善效果明显，并且能够抑制奥利万星的降解。

Claims (11)

  1. 一种稳定的奥利万星药物水溶液，包括组分：奥利万星或其药用盐，N-甲基-D-丙氨酸，水。
  2. 根据权利要求1所述的药物水溶液，所述药用盐为酸盐或碱盐。
  3. 根据权利要求1所述的药物水溶液，其中所述奥利万星或其药用盐含量为0.1-30％w/w，优选为0.1-25％w/w，优选为0.1-20％w/w，优选为0.1-15％w/w，优选为0.1-10％w/w，进一步优选为0.1-5％w/w。
  4. 根据权利要求1所述的药物水溶液，其中所述N-甲基-D-丙氨酸含量为0.1-60％w/w，优选为0.5-60％w/w，进一步优选为1-60％w/w。
  5. 根据权利要求1所述的药物水溶液，进一步包含有机溶剂，所述有机溶剂选自但不限于乙醇、甘油、丙二醇、二甲基亚砜、聚乙二醇。
  6. 根据权利要求1-5所述的药物水溶液，pH为3-8。
  7. 根据权利要求6所述的药物水溶液，可以进一步包括增溶剂、表面活性剂、缓冲剂、抗氧化剂、防腐剂、螯合剂中的一种或其中任一两种以上的组合。
  8. 权利要求1-7任一权利要求所述的药物水溶液的制备方法，称取处方量的N-甲基-D-丙氨酸或其他辅料(如果存在的情况下)，加入水中搅拌使溶解，然后称取处方量的奥利万星，搅拌溶解得到所述的奥利万星药物水溶液。
  9. 权利要求1-7任一权利要求所述的药物水溶液的用途，用于制备口服液，注射剂，滴眼液，外用凝胶，外用乳剂，喷剂。
  10. 权利要求1-7和9任一权利要求所述的药物水溶液在制备治疗细菌感染药物中的应用。
  11. 根据权利要求10所述的应用，其中所述细菌感染括绿脓假单胞菌(Pseudomonas aeruginosa)、荧光假单胞菌(Pseudomonas fluorescens)、食酸假单胞菌(Pseudomonas acidovorans)、产碱假单胞菌(Pseudomonas alcaligenes)、恶臭假单胞菌(Pseudomonas putida)、嗜麦芽寡养单胞菌(Stenotrophomonas maltophilia)、洋葱伯克霍尔德菌(Burkholderia cepacia)、嗜水气单胞菌(Aeromonas hydrophilia)、大肠杆菌(Escherichia coli)、弗氏柠檬酸杆菌(Citrobacter freundii)、鼠伤寒沙门氏菌(Salmonella typhimurium)、伤寒沙门氏菌(Salmonella typhi)、副伤寒沙门菌(Salmonella paratyphi)、肠炎沙门氏菌(Salmonellaenteritidis)、痢疾志贺氏菌(Shigella dysenteriae)、 弗氏志贺菌(Shigellaflexneri)、宋内志贺菌(Shigella sonnei)、阴沟肠杆菌(Enterobacter cloacae)、产气肠杆菌(Enterobacter aerogenes)、肺炎克雷白氏杆菌(Klebsiella pneumoniae)、产酸克雷白氏杆菌(Klebsiella oxytoc)、粘质沙雷氏菌(Serratia marcescens)、土拉弗朗西斯菌(Francisella tularensis)、摩氏摩根菌(Morganella morganii)、奇异变形杆菌(Proteusmirabilis)、普通变形杆菌(Proteus vulgaris)、产碱普罗威登斯菌(Providenciaalcalifaciens)、雷氏普罗威登斯菌(Providencia rettgeri)、斯氏普罗威登斯菌(Providencia stuartii)、鲍氏不动杆菌(Acinetobacter baumannii)、乙酸钙不动杆菌(Acinetobacter calcoaceticus)、溶血不动杆菌(Acinetobacter haemolyticus)、小肠结肠炎耶尔森氏菌(Yersinia enterocolitica)、鼠疫耶尔森氏菌(Yersinia pestis)、假结核耶尔森氏菌(Yersinia pseudotuberculosis)、中间耶尔森氏菌(Yersiniaintermedia)、百日咳博德特氏菌(Bordetella pertussis)、副百日咳博德特氏菌(Bordetella parapertussis)、支气管炎博德特氏菌(Bordetella bronchiseptica)、流感嗜血杆菌(Haemophilus influenzae)、副流感嗜血杆菌(Haemophilus parainfluenzae)、溶血嗜血杆菌(Haemophilus haemolyticus)、副溶血嗜血杆菌(Haemophilusparahaemolyticus)、杜克雷嗜血杆菌(Haemophilus ducreyi)、多杀巴斯德菌(Pasteurella multocida)、溶血巴斯德菌(Pasteurella haemolytica)、粘膜炎布兰汉球菌(Branhamella catarrhalis)、幽门螺杆菌(Helicobacter pylori)、胎儿弯曲杆菌(Campylobacter fetus)、空肠弯曲杆菌(Campylobacter jejuni)、大肠弯曲杆菌(Campylobacter coli)、伯氏疏螺旋体(Borrelia burgdorferi)、霍乱弧菌(Vibriocholerae)、副溶血弧菌(Vibrio parahaemolyticus)、嗜肺军团菌(Legionellapneumophila)、单核细胞增多性李斯特氏菌(Listeria monocytogenes)、淋病奈瑟氏菌(Neisseria gonorrhoeae)、脑膜炎奈瑟氏菌(Neisseria meningitidis)、金氏菌属(Kingella)、莫拉克斯氏菌属(Moraxella)、阴道加德菌(Gardnerella vaginalis)、脆弱拟杆菌(Bacteroides fragilis)、狄氏拟杆菌(Bacteroides distasonis)、拟杆菌3452A同源群(Bacteroides 3452A homology group)、普通拟杆菌(Bacteroides vulgatus)、卵形拟杆菌(Bacteroides ovalus)、多形拟杆菌(Bacteroides thetaiotaomicron)、单形拟杆菌(Bacteroides uniformis)、埃氏拟杆菌(Bacteroides eggerthii)、内脏拟杆菌(Bacteroides splanchnicus)、艰难梭菌(Clostridium difficile)、结核分枝杆菌(Mycobacterium tuberculosis)、鸟分枝杆菌(Mycobacterium avium)、胞内分枝杆菌(Mycobacterium intracellulare)、麻风分枝杆菌(Mycobacterium leprae)、白喉棒状杆菌(Corynebacterium diphtheriae)、溃疡棒状杆菌(Corynebacterium ulcerans)、肺炎链球菌(Streptococcus pneumoniae)、无乳链球菌(Streptococcus agalactiae)、酿脓链球菌(Streptococcus pyogenes)、中间链球菌(Streptococcus intermedius)、中间链球菌(Streptococcus intermedius)、星座链球菌(Streptococcus constellatus)、停乳链球菌(Streptococcus dysgalactiae)、停乳链球菌似马 亚种(Streptococcus dysgalactiaesubsp.equisimilis)、粪肠球菌(Enterococcus faecalis)、屎肠球菌(Enterococcusfaecium)、耐万古霉素粪肠球菌(vancomycin-resistant Enterococcus faecalis)、屎肠球菌(Enterococcus faecium)、耐万古霉素屎肠球菌(vancomycin-resistantEnterococcus faecium)、金黄色葡萄球菌(Staphylococcus aureus)、耐甲氧西林金黄色葡萄球菌(methicillin-resistant Staphylococcus aureus)、耐万古霉素金黄色葡萄球菌(vancomycin-resistant Staphylococcus aureus)、万古霉素中度耐受金黄色葡萄球菌(vancomycin-intermediate Staphylococcus aureus)、万古霉素异质性中度耐受金黄色葡萄球菌(vancomycin hetero-intermediate Staphylococcus aureus)、表皮葡萄球菌(Staphylococcus epidermidis)、腐生葡萄球菌(Staphylococcus saprophyticus)、中间葡萄球菌(Staphylococcus intermedius)、猪葡萄球菌猪亚种(Staphylococcus hyicussubsp.hyicus)、溶血葡萄球菌(Staphylococcus haemolyticus)、人葡萄球菌(Staphylococcus hominis)或解糖葡萄球菌(Staphylococcus saccharolyticus)及其组合。
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WO2017143169A1 (en) * 2016-02-18 2017-08-24 The Medicines Company Oritavancin formulations
WO2018053140A1 (en) * 2016-09-14 2018-03-22 Children's Medical Center Corporation Compositions with permeation enhancers for drug delivery
CN109069580A (zh) * 2016-05-09 2018-12-21 埃克斯利亚制药有限公司 稳定化的糖肽抗生素配制品
EP4014965A1 (en) * 2020-12-16 2022-06-22 EVER Valinject GmbH Aqueous solution

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WO2017143169A1 (en) * 2016-02-18 2017-08-24 The Medicines Company Oritavancin formulations
CN108712909A (zh) * 2016-02-18 2018-10-26 梅琳塔治疗公司 奥利万星制剂
CN109069580A (zh) * 2016-05-09 2018-12-21 埃克斯利亚制药有限公司 稳定化的糖肽抗生素配制品
WO2018053140A1 (en) * 2016-09-14 2018-03-22 Children's Medical Center Corporation Compositions with permeation enhancers for drug delivery
EP4014965A1 (en) * 2020-12-16 2022-06-22 EVER Valinject GmbH Aqueous solution

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