WO2023040397A1 - 一种万古霉素凝胶剂及其制备方法 - Google Patents
一种万古霉素凝胶剂及其制备方法 Download PDFInfo
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- WO2023040397A1 WO2023040397A1 PCT/CN2022/100192 CN2022100192W WO2023040397A1 WO 2023040397 A1 WO2023040397 A1 WO 2023040397A1 CN 2022100192 W CN2022100192 W CN 2022100192W WO 2023040397 A1 WO2023040397 A1 WO 2023040397A1
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- vancomycin
- acid
- gel
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- chitosan
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Classifications
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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
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- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- 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
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- 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 pharmaceutical preparations, in particular to a vancomycin gel and a preparation method thereof.
- vancomycin hydrochloride (Sa)-(3S,6R,7R,22R,23S,26S,36R,38aR)-44- ⁇ [2-O-(3amino-2,3,6-trideoxy-3 -C-methyl- ⁇ -L-lyxo-hexopyranosyl)- ⁇ -D-glucopyranosyl]-oxy ⁇ -3(carbamoylmethyl)-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-[(2R)-4-methyl-2-(methylamino]valeramido]-2,5,24 ,38,39-pentaoxo-22H-8,11:18,21-dietheno-23,36(iminometha-no)-13,16:31,35-dimetheno-1H,16H[1,
- Vancomycin is a glycopeptide compound, clinically used for infections caused by methicillin-resistant Staphylococcus aureus and other bacteria, such as clinically used for sepsis, infective endocarditis, osteomyelitis, arthritis, burns , surgical trauma and other superficial secondary infection, pneumonia, lung abscess, empyema, peritonitis, meningitis.
- Vancomycin has a strong effect on Gram-positive bacteria, and is mainly used clinically for methicillin-resistant Staphylococcus aureus (MRSA); for vancomycin-sensitive methicillin-resistant coagulase-negative staphylococcus (MRCNS); for vancomycin Infection caused by penicillin-resistant Streptococcus pneumoniae (PRSP).
- MRSA methicillin-resistant Staphylococcus aureus
- MRCNS vancomycin-sensitive methicillin-resistant coagulase-negative staphylococcus
- PRSP penicillin-resistant Streptococcus pneumoniae
- Staphylococcus aureus is one of the most common clinical pathogens, which can colonize the human skin and nasopharynx.
- the carrier rate of medical staff is as high as 70%, and it is an important pathogen that causes infections such as wounds, wounds, and surgical incisions;
- Non-standard application leads to the emergence of methicillin-resistant Staphylococcus aureus MRSA, which has become one of the most common drug-resistant pathogens in clinical practice and is one of the risk factors for postoperative surgical site infection.
- Vancomycin is only available in freeze-dried powder injection in China. There are oral powders and capsules on the market in the United States, freeze-dried powder injections and solutions for intravenous injection. The European Union has oral capsules and freeze-dried powder injections for intravenous injection. There are oral powders, freeze-dried powder injections for intravenous injection, and ophthalmic ointments on the market in Japan. The above dosage forms are not suitable for local treatment of wounds, infection and prevention of wounds. At the same time, local application of vancomycin can avoid side effects such as nephrotoxicity and ototoxicity caused by systemic exposure of intravenous administration, and improve safety.
- WO2016/071495 discloses an aqueous composition of vancomycin, using N-acetyl-D-alanine and lysine to prepare a stable aqueous vancomycin drug solution
- WO2014085526A1 uses lipid components , such as phosphatidylcholine, prepared a stable glycopeptide antibiotic composition for the therapy of lung diseases
- CN 113018417 A adopts molybdenum disulfide, vancomycin, chitosan hydrochloric acid solution and ⁇ -sodium glycerophosphate , specifically using the ultrasonic liquid phase exfoliation method to obtain thin-layer MoS 2 nanosheets, but its preparation process is complicated, industrial production is difficult, and the stability of vancomycin cannot be guaranteed.
- none of the above technical solutions can solve the problem that vancomycin is easily released from the hydrogel, resulting in the effect of initial burst release at the initial stage of hydrogel implantation, that is, the initial average drug release amount is far away. higher than the
- the duration of action of vancomycin in the above scheme is shorter. This solution can prolong the release time of vancomycin and increase the residence time at the application site.
- chitosan exerts a synergistic effect to promote the healing of wounds, surgical incisions and wounds, and also inhibits Gram-negative bacteria.
- the invention provides a vancomycin gel, which includes a matrix, an organic solvent, and an organic acid.
- the matrix is selected from one or more of chitosan, gelatin, xanthan gum, gum arabic, carrageenan, etc., preferably, the matrix is selected from chitosan, gelatin or chitosan, gelatin mixture.
- the organic solvent is selected from one or more of propylene glycol, isopropanol, ethanol, methanol and the like.
- the organic acid is selected from propylene glycol, isopropanol or a mixture of propylene glycol and isopropanol.
- the organic acid is selected from one or more of citric acid, succinic acid, amino acid, malic acid, acetic acid, lactic acid and the like.
- the organic acid is selected from acetic acid, lactic acid or a mixture of acetic acid and lactic acid.
- the vancomycin may be a pharmaceutically acceptable salt of vancomycin, such as vancomycin hydrochloride.
- Utilizing the vancomycin gel provided by the invention can effectively solve the continuous release of vancomycin from the hydrogel and overcome the explosive release phenomenon.
- the gel contains water.
- the content of the vancomycin or its pharmaceutically acceptable salt is 0.1-10% w/w, more preferably the content of the vancomycin is 0.1-5% w/w.
- the amount of the organic solvent is 0.1-70% w/w, more preferably, the amount of the organic solvent is 30%-70%.
- the amount of the base is 0.1-5% w/w, more preferably, the amount of the base is 0.1-2% w/w.
- the organic acid is acetic acid.
- Chitosan (1,4-alpha-acetamide-alpha-deoxy-beta-D-glucan) described in the present invention becomes polyglucosamine and chitosan again, and its structure is as follows:
- Chitosan It is the only natural alkaline polysaccharide found so far. It is widely distributed in seaweed, fungi, animal joints, and crustacean shells. It is a derivative obtained by deacetylation of chitin. Chitosan molecular weight contains a large number of cations and hydrogen bonds. The number-average molecular weight of chitosan can vary from 50 to 1000Kda. Generally, those with N-deacetylation degree ⁇ 55% are insoluble in 1% acetic acid called chitin, and those with N-deacetylation degree>55% are soluble in 1% acetic acid. The product is called chitosan. However, chitosan has a high viscosity and is prone to agglomeration and deformation. By adjusting the proportion of chitosan in the gel, the purpose of reducing burst release and prolonging the action time can be achieved.
- the N-deacetylation degree of the chitosan is >55%.
- the gelatin (Gelatin) of the present invention is a straight-chain polymer formed by cross-linking 18 amino acids and peptides, and contains arginyl-glycyl-aspartic acid (RGD) biologically active short peptides. Its protein structure determines that it has excellent biological properties, has a large number of cell recognition sites, has good cytocompatibility, can promote the division and growth of chondrocytes and is biodegradable, and is non-toxic and non-antigenic .
- RGD arginyl-glycyl-aspartic acid
- Gelatin is a partial hydrolysis product of collagen, it is insoluble in benzene, ether, acetone, petroleum ether, carbon tetrachloride and most non-polar organic solvents, soluble in water, acetic acid, glycerin, propylene glycol and mannitol and other solutions, However, gelatin has poor moisture resistance, low mechanical properties, and extremely low strength after swelling.
- chitosan and/or gelatin is used as a carrier to prepare a gel, and additives such as propylene glycol and organic acids are used at the same time.
- the resulting gel has excellent stability, has extended release characteristics, and increases the action time. .
- additives may be added to the gel of the present invention, such as but not limited to, preservatives, pH regulators or penetration enhancers.
- the preservative is more than one of ethylparaben, propylparaben, benzoic acid, sodium benzoate, sorbic acid and potassium sorbate.
- the pH regulator is any one of sodium hydroxide, potassium hydroxide, sodium bicarbonate, ethylenediamine, and triethanolamine.
- the penetration enhancer is laurocapram or volatile oil.
- the invention provides a preparation method of the gel, which comprises adding an organic solvent into the organic acid and water, stirring to mix uniformly; adding a matrix, stirring to dissolve; adding vancomycin or a medicinal salt thereof, Stir and dissolve to obtain the gel.
- the invention provides the use of the gel, which is used to prepare medicines for the treatment and prevention of surgical incisions, wounds and wound infections.
- the gel provided by the invention is placed under the condition of 25°C/60%RH for 30 days, and the total impurities do not exceed 10%.
- This product can be applied to surgical incisions, external wounds, etc., for the prevention and treatment of infection.
- Figure 1 shows that prescription F3-1 was placed under accelerated conditions of 25°C/60%RH, and samples were taken to detect related substances after 30 days, corresponding to the HPLC chromatogram.
- Figure 2 shows that prescription F4-1 was placed under accelerated conditions of 25°C/60%RH, and samples were taken to detect related substances after 30 days, corresponding to the HPLC chromatogram.
- Fig. 3 is a graph showing the cumulative penetration amount of prescriptions F5-1 and F5-2.
- HPLC analytical method used in the following examples:
- Solution A Accurately measure 4.0ml of triethylamine, add water to 2000ml, adjust pH to 3.20 with phosphoric acid;
- Embodiment 1 the stability of vancomycin and different concentration propylene glycol prescriptions
- adding propylene glycol can reduce the degradation of vancomycin in aqueous solution, reduce the growth of total impurities, and increase its stability.
- Embodiment 2 the stability of vancomycin in isopropanol, ethanol, acetic acid, citric acid, malic acid
- Configure prescriptions with different concentrations according to the data in Table 3: take the prescribed amount of propylene glycol in a beaker, add the prescribed amount of water, acetic acid (or citric acid, or L-malic acid), stir to mix evenly; weigh the prescribed amount of hydrochloric acid Vancomycin, stirred to dissolve.
- Example 2 the stability of isopropanol to vancomycin is not as good as that of propylene glycol. Compared with citric acid and L-malic acid, acetic acid can reduce the degradation of vancomycin in aqueous solution, reduce the growth of total impurities and increase its stability.
- Embodiment 3 the stability of vancomycin gel acetic acid prescription
- the prescriptions of different concentrations are configured: take the prescription amount of propylene glycol in a beaker, add the water and acetic acid of the prescription amount, stir and mix evenly; take the chitosan or gelatin of the prescription amount, and add it to the above solution. Stir to dissolve; weigh the prescribed amount of vancomycin hydrochloride, and stir to dissolve.
- Example 3 Compared with the vancomycin aqueous solution formulation F1-1, the growth of impurities was all reduced. Formulation F3-1 was the most stable and had the lowest degree of degradation. Compared with chitosan and gelatin, the formulation with chitosan is more stable and the total impurities are lower. See Figure 1 for the HPLC chromatogram, and see Table 7 for the corresponding data.
- the prescriptions of different concentrations are configured: take the prescription amount of propylene glycol in a beaker, add the water and lactic acid of the prescription amount, and stir to mix evenly; take the chitosan or gelatin of the prescription amount, and add it to the above solution. Stir to dissolve; weigh the prescribed amount of vancomycin hydrochloride, and stir to dissolve.
- the formulation F3-1 is the most stable and has the lowest degree of degradation. Compared with acetic acid and lactic acid, the formulations F3-1, F3-2, and F3-3 added with acetic acid had lower total impurities than the formulations F4-1, F4-2, and F4-3 added with lactic acid. Formulation stability was better with the addition of acetic acid.
- Embodiment 5 the stability of vancomycin different concentration prescription
- Embodiment 6 In vitro release of vancomycin gel
- Transdermal diffusion device The exposed skin area in the diffusion cell is 1cm 2 , and the volume of the receiving chamber is 10mL. Take about 0.3g of the gel, spread it evenly on the skin surface, add 10mL of the receiving solution into the receiving pool to ensure a stable contact between the liquid surface and the skin, place it in a constant temperature water bath at 25 ⁇ 0.5°C, and stir at a speed of 350r ⁇ min -1 . At 1, 2, 4, 6, and 8 hours after coating, 1 mL of the receiving solution was taken at each point, and 6 copies were paralleled at each time point. After sampling, 1 mL of the receiving solution was added to the receiving chamber, and filtered through a 0.22 ⁇ m microporous membrane. Store frozen for testing. Calculate the cumulative permeation amount (Q) of the drug per unit area according to the following formula:
- Q is the percutaneous cumulative permeation amount of the drug per unit area
- S is the effective permeation area
- V is the volume of the receiving solution in the receiving pool
- Ci is the drug concentration in the receiving solution from the first sampling to the last sampling
- l is the sampling volume, 1mL
- Cn is the concentration of the drug in the receiving solution at the time of sampling
- the cumulative penetration (mg ⁇ cm -2 ) of the prescriptions F4-1 and F4-2 is shown in Figure 3.
- the prescription F5-1 can effectively reduce the drug burst release and prolong the release time.
- XELLIA PHARMS APS approved the aqueous solution formulation of vancomycin hydrochloride by FDA in 2019, which contains 1.8mL polyethylene glycol 400, 1.36g N-acetyl-D-alanine, 1.26g L-lysine per 100ml solution Hydrochloride.
- This vancomycin injection formulation is not recommended for use during pregnancy because it contains polyethylene glycol (PEG 400) and N-acetyl-D-alanine (NADA), which have caused fetal malformations in animal reproduction studies.
- a 5% vancomycin formulation was prepared using this amount of excipients, as follows.
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Abstract
一种万古霉素凝胶剂,包括万古霉素及其可药用盐、基质、有机溶剂、有机酸。该万古霉素凝胶剂可用于伤口、手术切口等部位的预防、治疗敏感菌株的感染,促进伤口愈合,在2-8℃的稳定性至少在18个月以上。
Description
本发明涉及医药制剂技术领域,具体涉及一种万古霉素凝胶剂及其制备方法。
盐酸万古霉素化学名为:(Sa)-(3S,6R,7R,22R,23S,26S,36R,38aR)-44-{[2-O-(3amino-2,3,6-trideoxy-3-C-methyl-α-L-lyxo-hexopyranosyl)-β-D-glucopyranosyl]-oxy}-3(carbamoylmethyl)-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-[(2R)-4-methyl-2-(methylamino]valeramido]-2,5,24,38,39-pentaoxo-22H-8,11:18,21-dietheno-23,36(iminometha-no)-13,16:31,35-dimetheno-1H,16H[1,6,9]-oxadiazacyclohexadecino-[4,5-m][10,2,16]-benzoxa-diazacyclotetracosine-26-carboxylic acid,monohydrochloride,分子式为:C
66H
75Cl
2N
9O
24·HCl分子量为:1485.71,其结构式如下:
万古霉素为一种糖肽类化合物,临床用于耐甲氧西林金黄色葡萄球菌及其它细菌所致的感染,例如临床用于败血症、感染性心内膜炎、骨髓炎、关节炎、灼伤、手术创伤等浅表性继发感染、肺炎、肺脓肿、脓胸、腹膜炎、脑膜炎。
万古霉素自从20世纪50年代开始使用以来,已经成为“人类对付顽固性耐药菌株的最后一道防线”,是甲氧西林耐药金葡菌(MRSA),甲氧西林耐药凝固酶阴性葡萄球菌(MRCNS)等所致感染的首选药物。
万古霉素对革兰氏阳性菌有强烈作用,临床主要应用于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。
金黄葡萄球菌是临床最常见的病原菌之一,可定植于人体皮肤和鼻咽部,其中医务人员带菌率高达70%以上,是引起伤口、创面、手术切口等感染的重要病原菌;由于青霉素广泛及不规范的应用,导致出现耐甲氧西林金黄色葡萄球菌MRSA,成为临床最常见的耐药病原体之一,是术后手术部位感染的危险因素之一。
万古霉素在国内仅上市冻干粉针剂。美国上市有口服散剂、胶囊剂,静脉注射用的冻干粉针剂、溶液剂。欧盟有口服胶囊剂,静脉注射用的冻干粉针剂。日本上市有口服散剂,静脉注射用的冻干粉针剂,眼用软膏剂。以上剂型均不适合用于局部治疗伤口、创面的感染与预防。同时,局部应用万古霉素可以避免静脉注射给药的全身系统性暴露引起的肾毒性、耳毒性等副作用,提高安全性。
WO2016/071495公开了万古霉素的一种含水组合物,采用N-乙酰基-D-丙氨酸、赖氨酸,制备了一种稳定的含水万古霉素药物溶液;WO2014085526A1采用脂质组分,如磷脂酰胆碱,制备了稳定的糖肽类抗生素组合物,用于肺部疾病的疗法中;CN 113018417 A采用二硫化钼、万古霉素、壳聚糖盐酸溶液和β-甘油磷酸钠,具体是利用超声液相剥离法获得薄层MoS
2纳米片,但其制备工艺复杂,产业化生产困难,无法保证万古霉素的稳定性。但是以上技术方案均不能够解决万古霉素容易从水凝胶中释放,从而造成水凝胶植入的初期出现爆释的现象(the effect of initial burst release),即初期平均释药量远远高于平稳期。
并且以上方案的万古霉素作用持续时间较短。本方案可以延长万古霉素的释放时间,增加在使用部位的停留时间。同时,壳聚糖发挥协同作用,促进伤口、手术切口、创面愈合的同时,对革兰氏阴性菌也有抑制作用。
发明内容
为了解决现有技术中存在的问题,本发明提供了一种万古霉素凝胶剂,所述凝胶剂包括基质,有机溶剂,有机酸。
其中所述基质选自壳聚糖、明胶、黄原胶、阿拉伯胶、卡拉胶等中的一种或多种,优选的,所述基质选自壳聚糖、明胶或者壳聚糖、明胶的混合物。
所述有机溶剂选自丙二醇、异丙醇、乙醇、甲醇等中的一种或多种。优选的,所述有机酸选自丙二醇、异丙醇或丙二醇、异丙醇的混合物。
所述有机酸选自柠檬酸、琥珀酸、氨基酸、苹果酸、乙酸、乳酸等中的一种或多种。优选的,所述有机酸选自乙酸、乳酸或乙酸、乳酸的混合物。
所述万古霉素可以为万古霉素药学可接受盐,如盐酸万古霉素。
利用本发明提供的万古霉素凝胶剂,可以有效的解决万古霉素持续的从水凝胶中释放,克服爆释现象。
在一个优选的实施方案中,所述凝胶剂中含有水。
优选的,所述万古霉素或其药学可接受盐含量为0.1-10%w/w,更为优选的所述万古霉素含量为0.1-5%w/w。
优选的,所述有机溶剂的用量为0.1-70%w/w,更为优选的,所述有机溶剂用量为30%-70%。
优选的,所述基质的用量为0.1-5%w/w,更为优选的,所述基质的用量为0.1-2%w/w。
优选的,所述有机酸的为乙酸。
本发明所述壳聚糖(1,4-α-乙酞胺基-α-脱氧-β-D-葡聚糖),又成聚氨基葡萄糖、甲壳胺,其结构如下:
其为迄今为止发现的唯一天然碱性多糖,广泛分布于海藻、真菌、动物的关节、甲壳类动物外壳,是甲壳素脱乙酰化得到的衍生物。壳聚糖分子量上含有大量阳离子和氢键。壳聚糖的数均分子量可从50到1000Kda变化,一般将N-脱乙酰度<55%不溶于1%乙酸的称为甲壳素,将N-脱乙酰度>55%可溶于1%乙酸的产物称为壳聚糖。但是壳聚糖的粘度大,容易出现团聚和变形。通过调整壳聚糖在凝胶剂中的比例可以达到降低突释,延长作用时间的目的。
在本发明中,所述壳聚糖的N-脱乙酰度>55%。
本发明所述明胶(Gelatin)是由18中氨基酸与肽交联形成的直链聚合物,含有精氨酰-甘氨酰-天冬氨酸(RGD)生物活性短肽。其蛋白质结构决定了它具有优异的生物学性能,具有大量的细胞识别位点,有良好的细胞相容性,能够促进软骨细胞的分裂和生长以及生物可降解性,且无毒、无抗原性。明胶是胶原蛋白的部分水解产物,它不溶于苯、乙醚、丙酮、石油醚、四氯化碳及大部分非极性的有机溶剂,溶于水、醋酸、甘油、丙二醇和甘露醇等溶液,但是明胶抗潮性差,力学性能低,溶胀后强度极低。
在一个优选的实施方案中,以壳聚糖和/或明胶为载体,制备凝 胶剂,同时采用丙二醇、有机酸等添加剂,得到的凝胶剂稳定性优异,具有延长释放特点,增长作用时间。
进一步优选的,可以在本发明所述凝胶剂中增加其他添加剂,例如但不限于,防腐剂、pH调节剂或促渗剂等。所述防腐剂为羟苯乙酯、羟苯丙酯、苯甲酸、苯甲酸钠、山梨酸、山梨酸钾中的一种以上。
PH调节剂为氢氧化钠、氢氧化钾、碳酸氢钠、乙二胺、三乙醇胺中的任何一种。
所述促渗剂是月桂氮卓酮,或挥发油。
本发明提供了所述凝胶剂的制备方法,所述制备方法为将有机溶剂加入所述有机酸和水中,搅拌使混合均匀;加入基质,搅拌溶解;加入万古霉素或其药用盐,搅拌溶解得到所述凝胶剂。
本发明提供了所述凝胶剂的用途,用于制备用于手术切口、伤口、创面感染的治疗与预防的药物。
本发明提供的凝胶剂在25℃/60%RH条件下放置30天,总杂不超过10%;本产品可以涂抹在手术切口、外用创面上等,用于预防、治疗感染。
图1为处方F3-1放置在加速条件25℃/60%RH下,30天后取样检测有关物质,对应HPLC色谱图。
图2为处方F4-1放置在加速条件25℃/60%RH下,30天后取样检测有关物质,对应HPLC色谱图。
图3为处方F5-1、F5-2的累计渗透量曲线图。
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。
以下实施例所用HPLC分析方法:
色谱柱:Welch Ultimate 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1:万古霉素和不同浓度丙二醇处方的稳定性
按照表1的数据配置不同浓度的处方:于烧杯中称取处方量丙二醇,加入处方量的水,搅拌使混合均匀;称取处方量的盐酸万古霉素,搅拌溶解;
表1
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2。
表2
从实施例1的结果可以看出,加入丙二醇可以减少万古霉素在水 溶液中的降解,减少总杂的增长,增加其稳定性。
实施例2:万古霉素在异丙醇、乙醇、乙酸、柠檬酸、苹果酸中的稳定性
按照表3的数据配置不同浓度的处方:于烧杯中称取处方量丙二醇,加入处方量的水、乙酸(或者柠檬酸,或者L-苹果酸),搅拌使混合均匀;称取处方量的盐酸万古霉素,搅拌溶解。
表3
F2-1 | F2-2 | F2-3 | F2-4 | |
组分 | 百分比%(w/w) | 百分比%(w/w) | 百分比%(w/w) | 百分比%(w/w) |
万古霉素 | 5 | 5 | 5 | 5 |
异丙醇 | 40 | 0 | 0 | 0 |
乙酸 | 0 | 1 | 0 | 0 |
柠檬酸 | 0 | 0 | 1 | 0 |
L-苹果酸 | 0 | 0 | 0 | 1 |
水 | 55 | 94 | 94 | 94 |
共 | 100 | 100 | 100 | 100 |
放置在加速条件25℃/60%RH下,30天后取样检测有关物质,以峰面积归一化法计算杂质峰面积百分比,结果如表4。
表4
从实施例2的结果可以看出,异丙醇的对于万古霉素的稳定性不如丙二醇。乙酸与柠檬酸、L-苹果酸相比,可以减少万古霉素在水溶液中的降解,减少总杂的增长,增加其稳定性。
实施例3:万古霉素凝胶剂乙酸处方的稳定性
按照表5的数据配置不同浓度的处方:于烧杯中称取处方量丙二醇,加入处方量的水、乙酸,搅拌使混合均匀;称取处方量的壳聚糖或明胶,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。
表5
F3-1 | F3-2 | F3-3 | |
组分 | 百分比%(w/w) | 百分比%(w/w) | 百分比%(w/w) |
万古霉素 | 5 | 5 | 5 |
丙二醇 | 40 | 40 | 40 |
壳聚糖 | 0.5 | 0 | 0.5 |
明胶 | 0 | 0.5 | 0.5 |
乙酸 | 1 | 1 | 1 |
水 | 53.5 | 53.5 | 53 |
共 | 100 | 100 | 100 |
放置在加速条件25℃/60%RH下,30天后取样检测有关物质,以峰面积归一化法计算杂质峰面积百分比,结果如表6。
表6
从实施例3的结果可以看出,和万古霉素水溶液处方F1-1相比,杂质增长均有所降低。处方F3-1最稳定,降解程度最低。壳聚糖和明胶相比,加入壳聚糖的处方更稳定,总杂较低。HPLC色谱图见图1,对应的数据见表7。
表7
实验例4:万古霉素乳酸处方稳定性
按照表8的数据配置不同浓度的处方:于烧杯中称取处方量丙二醇,加入处方量的水、乳酸,搅拌使混合均匀;称取处方量的壳聚糖或明胶,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。
表8
F4-1 | F4-2 | F4-3 | |
组分 | 百分比%(w/w) | 百分比%(w/w) | 百分比%(w/w) |
万古霉素 | 5 | 5 | 5 |
丙二醇 | 40 | 40 | 40 |
壳聚糖 | 0.5 | 0 | 0.5 |
明胶 | 0 | 0.5 | 0.5 |
乳酸 | 1 | 1 | 1 |
水 | 53.5 | 53.5 | 53 |
共 | 100 | 100 | 100 |
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
从实施例3、4的实验结果可以看出,和万古霉素水溶液处方1相比,处方F3-1最稳定,降解程度最低。乙酸和乳酸相比,加入乙酸的处方F3-1、F3-2、F3-3均比加入乳酸的处方F4-1、F4-2、F4-3的总杂较低。加入乙酸的处方稳定性更好。
实施例5:万古霉素不同浓度处方的稳定性
按照表10的数据配置不同浓度万古霉素的处方:于烧杯中称取处方量丙二醇,加入处方量的水、乙酸,搅拌使混合均匀;称取处方量的壳聚糖或明胶,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。
表10
F5-1 | F5-2 | F5-3 | |
组分 | 百分比%(w/w) | 百分比%(w/w) | 百分比%(w/w) |
万古霉素 | 0.5 | 0.5 | 3 |
丙二醇 | 40 | 40 | 40 |
壳聚糖 | 0.5 | 0 | 0.5 |
明胶 | 0 | 0.5 | 0.5 |
乙酸 | 1 | 1 | 1 |
水 | 53.5 | 53.5 | 53.5 |
共 | 100 | 100 | 100 |
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11。
表11
以上结果可以看出,处方F5-1最稳定,降解程度最低。壳聚糖 和明胶相比,加入壳聚糖的处方,总杂较低。如图2或表12。
表12
实施例6:万古霉素凝胶剂体外释放
采用处方F5-1、F5-2,Franz扩散池法,用人工膜(0.45μm,聚砜)和HPLC测定法,考察二者在pH 7.4磷酸盐缓冲溶液介质中的透过率。
TP3A ZTY智能透皮试验仪(上海越众仪器设备有限公司)。
透皮扩散装置:扩散池中暴露的皮肤面积为1cm
2,接受室容积为10mL。取凝胶剂约0.3g,均匀涂抹在皮肤表面,向接收池中加入接受液10mL,保证液面与皮肤的稳定接触,置于25±0.5℃恒温水浴中,搅拌速度为350r·min
-1。于涂布后的1、2、4、6、8h,各点取接受液1mL,每个时间点平行6份,取样后即向接受室内补充1mL接受液,经0.22μm微孔滤膜过滤,冷冻保存待测。按下列公式计算单位面积药物的累积渗透量(Q):
Q=[C
n×V+Σ(C
i×1)]/S
其中,Q为药物单位面积经皮累积渗透量;S为有效渗透面积;V为接收池中接收液的体积;Ci为第1次至上次取样时接收液中的药物浓度;l为取样体积,1mL;Cn为该次取样时接收液中药物的浓度,处方F4-1、F4-2的累计渗透量(mg·cm
-2)如图3所示。
由以上结果可知,处方F5-1能有效的降低药物突释,延长释放时间。
对比实施例1
XELLIA PHARMS APS在2019年FDA批准了盐酸万古霉素的水溶液制剂,该制剂每100ml溶液中含有1.8mL聚乙二醇400、1.36g N-乙酰-D-丙氨酸、1.26g L-赖氨酸盐酸盐。这种万古霉素注射液配方不建议在怀孕期间使用,因为它含有聚乙二醇(PEG 400)和N-乙酰-D-丙氨酸(NADA),在动物生殖研究中会导致胎儿畸形。采用该辅料用量制备了5%万古霉素制剂,如下。
组成 | 对比处方 |
盐酸万古霉素 | 5g |
聚乙二醇400 | 1.8mL |
N-乙酰-D-丙氨酸 | 1.36g |
L-赖氨酸盐酸盐 | 1.26g |
盐酸或氢氧化钠 | 调节pH至4.5to5.5 |
共 | 100ml溶液 |
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,结果如下:
该对比处方在25℃/60%RH下,30天后总杂已经达到16.56%。相同条件下,自制制剂的总杂大大降低,稳定性好于该处方。
Claims (15)
- 一种万古霉素凝胶剂,包括基质,有机溶剂,有机酸。
- 根据权利要求1所述的万古霉素凝胶剂,其中所述基质选自壳聚糖、明胶、黄原胶、阿拉伯胶、虫胶等中的一种或多种。
- 根据权利要求2所述的万古霉素凝胶剂,其中所述基质选自壳聚糖、明胶或者壳聚糖、明胶的混合物。
- 根据权利要求1所述的万古霉素凝胶剂,其中所述有机溶剂选自丙二醇、异丙醇、乙醇、甲醇等中的一种或多种。
- 根据权利要求4所述的万古霉素凝胶剂,其中所述有机溶剂选自丙二醇、异丙醇或丙二醇、异丙醇的混合物。
- 根据权利要求1所述的万古霉素凝胶剂,其中所述有机酸选自柠檬酸、琥珀酸、氨基酸、苹果酸、乙酸、乳酸等中的一种或多种。
- 根据权利要求6所述的万古霉素凝胶剂,其中所述有机酸选自乙酸、乳酸或乙酸、乳酸的混合物。
- 根据权利要求7所述的万古霉素凝胶剂,所述万古霉素可以为万古霉素药学可接受盐。
- 根据权利要求1所述的万古霉素凝胶剂,所述凝胶剂中含有水。
- 根据权利要求8所述的万古霉素凝胶剂,所述万古霉素或其药学可接受盐含量为0.1-10%w/w。
- 根据权利要求1所述的万古霉素凝胶剂,所述有机溶剂的用量为0.1-70%w/w。
- 根据权利要求1所述的万古霉素凝胶剂,所述基质的用量为0.1-5%w/w。
- 根据权利要求2所述的万古霉素凝胶剂,所述壳聚糖的N-脱乙酰度>55%。
- 权利要求1-13任一权利要求所述凝胶剂的制备方法,为将有机溶剂加入所述有机酸和水中,搅拌使混合均匀;加入基质,搅拌溶解;加入万古霉素或其药用盐,搅拌溶解得到所述凝胶剂。
- 权利要求1-13任一权利要求所述凝胶剂的用途,用于制备用于手术切口、伤口、创面感染的治疗与预防的药物。
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JP2008050298A (ja) * | 2006-08-24 | 2008-03-06 | Neige Corporation:Kk | 皮膚貼付用外用ゲル組成物 |
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