WO2021248532A1 - Voriconazole preparation for external use and preparation method therefor - Google Patents
Voriconazole preparation for external use and preparation method therefor Download PDFInfo
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- 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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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- the invention relates to an antifungal drug preparation, in particular to a voriconazole external preparation and a preparation method thereof.
- Voriconazole is a second-generation triazole antifungal drug. It overcomes the problems of the first-generation antifungal drugs, such as fluconazole and itraconazole, with insufficient antibacterial spectrum, low bioavailability and drug resistance.
- first-generation antifungal drugs such as fluconazole and itraconazole
- Skin fungal infections can be clinically divided into superficial mycoses (the infected areas are limited to the stratum corneum, hair, and nails), subcutaneous mycosis (infection of the dermis and subcutaneous tissues), and systemic mycoses (also known as invasive Fungal disease).
- External preparations for superficial mycosis are the main ones.
- Commonly used drugs include external preparations such as ketoconazole, ciclopirox and terbinafine. Among them, imidazoles represented by ketoconazole account for the largest proportion. Due to the greater hepatotoxicity of ketoconazole, its oral dosage form has been discontinued in Europe, Australia and China. In 2017, China transferred ketoconazole-related non-prescription drugs such as lotions and ointments out of the non-prescription drug catalog to implement prescription monitoring and management.
- Voriconazole is a derivative of fluconazole with a broader antibacterial spectrum and has a bactericidal effect against Aspergillus; it has antibacterial activity against Candida, Cytospora and Fusarium; it also has antibacterial activity against Cryptococcus, biphasic fungi, etc. Good antibacterial activity.
- Voriconazole oral and injection have been used clinically for a long time, and the safety is better than imidazole antifungal drugs represented by ketoconazole.
- the in vitro antibacterial activity test shows that it has good antibacterial activity against fungi that cause skin infections, and may be a safe and effective method for treating intractable infections (such as onychomycosis) or skin fungal infections in patients with immunodeficiency.
- intractable infections such as onychomycosis
- skin fungal infections in patients with immunodeficiency.
- oral or injection voriconazole is not easy to directly target the affected area. If voriconazole is prepared as an external preparation, it can be directly targeted at the affected area and can be treated more effectively.
- voriconazole is relatively poor, especially in the state of aqueous solution, voriconazole is easy to hydrolyze, after the reverse aldol reaction product recombination, generate inactive isomer impurities. Therefore, it is difficult to prepare voriconazole into long-term stable water-containing ointments, injections, and eye drops.
- the logD of voriconazole is 1.8, which is a semi-polar compound with poor solubility. Its solubility in aqueous solution is only 0.65mg/ml, and it cannot be solubilized by conventional methods such as oil, surfactant or miscibility with water. The co-solvent for solubilization.
- the purpose of the present invention is to provide a voriconazole external preparation, which can be used to treat superficial fungal infections directly on the affected area, and solves the problem of poor solubility of voriconazole and instability in water, and provides a good stability and good solubility , Voriconazole topical preparation with high intradermal distribution.
- Another object of the present invention is to provide a preparation method of voriconazole external preparation.
- the external preparation of voriconazole includes at least voriconazole, a matrix material and a solubilizer, wherein the solubilizer is an isopropyl ester or hydrocarbon solvent.
- the isopropyl ester is diisopropyl adipate.
- the hydroxy solvent is hexadecane.
- the matrix material is one of myristyl alcohol, cetyl alcohol, stearyl alcohol and mixtures thereof, emulsifying wax, microcrystalline wax, paraffin wax or liquid paraffin, petrolatum, mineral oil, beeswax, lanolin, and lanolin. kind or mixed.
- the voriconazole external preparation of the present invention comprises 0.3% to 3% of voriconazole, 67% to 94% of matrix material, and 5% to 30% of solubilizer in weight percentage.
- the invention also discloses a preparation method of voriconazole external preparation, which comprises the following steps:
- the external preparation of voriconazole of the present invention provides an antifungal dosage form for external use of voriconazole, which can more effectively target the affected area and solves the problem of poor stability of voriconazole during the preparation process of the external preparation of voriconazole.
- voriconazole is easily hydrolyzed and undergoes retro-aldol reaction product Recombination to produce inactive isomeric impurities.
- it is found that voriconazole has good solubility and stability in esters and alkane auxiliary materials, especially after adding isopropyl esters and hydroxy solvents, the effect is obvious.
- step (3) Mixing: the drug solution obtained in step (1) is slowly poured into the melted matrix under stirring, and stirred evenly. Cool down at room temperature to get.
- Example 2 Experiment on the solubility of voriconazole in different solvents
- voriconazole has the highest solubility in diisopropyl adipate.
- voriconazole After 7 days of acceleration in different solvents, voriconazole has good compatibility and stability in diisopropyl oxalate and hexadecane, and it is not easy to degrade.
- the voriconazole ointment obtained from prescription 1, prescription 2, and prescription 3 of Example 1 was placed under accelerated conditions for 7 days, and then the appearance and related substances were tested.
- Example 1 The voriconazole ointment obtained in Example 1 has no significant increase in total impurities after 7 days of acceleration, showing good compatibility.
- Example 5 Using an in vitro skin permeability test to evaluate the in vitro transdermal permeability of different formulations.
- the device can absorb about 0.2-0.3ml Spread the sample evenly on the skin surface (the amount of sample added is about 300mg); weigh the weight of the diffusion cell after adding the sample, and deduct the weight before adding the sample to get the sample weight; after the sample is added, use a sealing film to seal it. Avoid the sample from drying out during the experiment.
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Abstract
Description
本发明涉及抗真菌类药物制剂，尤其涉及伏立康唑外用制剂及其制备方法。The invention relates to an antifungal drug preparation, in particular to a voriconazole external preparation and a preparation method thereof.
伏立康唑化学名为：(2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4triazol-1-yl)-2-butanol，分子式为：C 16H 14F 3N 5O分子量为：349.3。 Voriconazole chemical name: (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4triazol-1-yl)-2 -butanol, molecular formula: C 16 H 14 F 3 N 5 O molecular weight: 349.3.
伏立康唑为第二代三唑类抗真菌药物，它克服了第一代抗真菌药，如氟康唑、伊曲康唑抗菌谱不够广、生物利用度低及耐药性问题。用于治疗成人及2周岁以上儿童的侵袭性曲霉病、非中性粒细胞减少症和其他深层组织念珠菌感染中的念珠菌血症、食管念珠菌病，以及由尖端赛多孢子菌和镰刀菌属(包括腐皮镰刀菌)引起的严重真菌感染。Voriconazole is a second-generation triazole antifungal drug. It overcomes the problems of the first-generation antifungal drugs, such as fluconazole and itraconazole, with insufficient antibacterial spectrum, low bioavailability and drug resistance. For the treatment of invasive aspergillosis, non-neutropenia and other deep tissue candida infections in adults and children over the age of 2 years Severe fungal infections caused by bacteria (including Fusarium solani).
皮肤真菌感染临床上根据其感染部位可分为浅表真菌病(感染部位限于角质层、毛发、指甲)、皮下真菌病(真皮及皮下组织的感染)及系统性真菌病(又称为侵袭性真菌病)。浅表真菌病以外用制剂为主，常用药物包括：酮康唑、环吡酮和特比萘芬等外用制剂，其中以酮康唑为代表的咪唑类药物占比最大。由于酮康唑肝毒性较大，其口服给药剂型在欧洲、澳大利亚和中国相继停止使用。2017年中国将酮康唑相关非处方药如洗剂、软膏调出非处方药目录实施处方监测管理。Skin fungal infections can be clinically divided into superficial mycoses (the infected areas are limited to the stratum corneum, hair, and nails), subcutaneous mycosis (infection of the dermis and subcutaneous tissues), and systemic mycoses (also known as invasive Fungal disease). External preparations for superficial mycosis are the main ones. Commonly used drugs include external preparations such as ketoconazole, ciclopirox and terbinafine. Among them, imidazoles represented by ketoconazole account for the largest proportion. Due to the greater hepatotoxicity of ketoconazole, its oral dosage form has been discontinued in Europe, Australia and China. In 2017, China transferred ketoconazole-related non-prescription drugs such as lotions and ointments out of the non-prescription drug catalog to implement prescription monitoring and management.
伏立康唑已上市剂型包括用于静脉给药的冻干粉针、口服给药的片剂和干混悬剂，商品名为：Vefend。伏立康唑为氟康唑衍生物，其抗菌谱更广，对曲霉属具有杀菌作用；对念珠菌属、赛多孢霉属和镰刀菌属有抗菌活性；对隐球菌属、双相真菌等也有很好的抗菌活性。Carrillo-Munoz et.al.的研究表明：伏立康唑念珠菌、白色念珠菌、假丝酵母等引起灰指甲的真菌体外抑菌活性好于特比奈芬、伊曲康唑。Bueno J G et.al [3]测定了伏立康唑对引起甲真菌病的皮肤真菌(如红毛滴虫、趾间滴虫等)的抑菌活性，其MIC几何平均值为0.037-0.107g/mL，抑菌活性较好。其研究也表明：伏立康唑对其他相关的皮肤真菌也有较高的抗 真菌活性。Muangkaew W et.al.对临床常见皮肤病的真菌(包括：毛癣菌、红毛癣菌、孢子菌等)，分别用不同抗真菌药对其进行体外抑菌试验。结果表明：伏立康唑对念珠菌的抑菌效果优于氟康唑、伊曲康唑和特比奈芬。 The marketed dosage forms of voriconazole include freeze-dried powder injections for intravenous administration, tablets and dry suspensions for oral administration, and the trade name is Vefend. Voriconazole is a derivative of fluconazole with a broader antibacterial spectrum and has a bactericidal effect against Aspergillus; it has antibacterial activity against Candida, Cytospora and Fusarium; it also has antibacterial activity against Cryptococcus, biphasic fungi, etc. Good antibacterial activity. The study of Carrillo-Munoz et.al. shows that the fungi that cause onychomycosis such as Candida voriconazole, Candida albicans, and Candida albicans have better in vitro antibacterial activities than terbinafine and itraconazole. Bueno J G et.al [3] measured the antibacterial activity of voriconazole against skin fungi that cause onychomycosis (such as Trichomonas trichomonas, Trichomonas interdigital, etc.), and its geometric mean MIC is 0.037-0.107g/mL, The antibacterial activity is better. Its research also shows that: Voriconazole also has higher antifungal activity against other related skin fungi. Muangkaew W et.al. conducted in vitro antibacterial tests on fungi of common clinical skin diseases (including: Trichophyton, Rhodophyton, spore bacteria, etc.) with different antifungal drugs. The results show that the antibacterial effect of voriconazole on Candida is better than fluconazole, itraconazole and terbinafine.
伏立康唑口服和注射剂在临床上应用时间较长，安全性优于以酮康唑代表的咪唑类抗真菌药。体外抑菌活性试验表明：其对引皮肤感染的真菌具有较好的抑菌活性，可能是治疗顽固性感染(如甲癣)或免疫缺陷患者皮肤真菌感染的安全、有效手段。对于浅表性真菌感染口服或注射剂伏立康唑不容易直接针对患处，如果伏立康唑制备成外用制剂则可直接针对患处，能更有效进行治疗。Voriconazole oral and injection have been used clinically for a long time, and the safety is better than imidazole antifungal drugs represented by ketoconazole. The in vitro antibacterial activity test shows that it has good antibacterial activity against fungi that cause skin infections, and may be a safe and effective method for treating intractable infections (such as onychomycosis) or skin fungal infections in patients with immunodeficiency. For superficial fungal infections, oral or injection voriconazole is not easy to directly target the affected area. If voriconazole is prepared as an external preparation, it can be directly targeted at the affected area and can be treated more effectively.
但是，伏立康唑稳定性较差，尤其是在水溶液状态下，伏立康唑易于水解，经过逆醇醛反应产物重组，生成非活性的异构体杂质。因此，伏立康唑很难制备成有长期稳定的含水的软膏、注射液、滴眼液。此外，伏立康唑logD为1.8，为半极性化合物，其溶解性较差，在水溶液中的溶解度仅为0.65mg/ml，而且无法通过常规增溶方法，如油、表面活性剂或与水混溶的共溶剂进行增溶。However, the stability of voriconazole is relatively poor, especially in the state of aqueous solution, voriconazole is easy to hydrolyze, after the reverse aldol reaction product recombination, generate inactive isomer impurities. Therefore, it is difficult to prepare voriconazole into long-term stable water-containing ointments, injections, and eye drops. In addition, the logD of voriconazole is 1.8, which is a semi-polar compound with poor solubility. Its solubility in aqueous solution is only 0.65mg/ml, and it cannot be solubilized by conventional methods such as oil, surfactant or miscibility with water. The co-solvent for solubilization.
发明内容Summary of the invention
本发明的目的在于提供一种伏立康唑外用制剂，能直接针对患处，用于治疗浅表性真菌感染，且解决了伏立康唑溶解性差，在水中不稳定的问题，提供一种稳定性好，溶解性好，皮内分布高的伏立康唑外用制剂。The purpose of the present invention is to provide a voriconazole external preparation, which can be used to treat superficial fungal infections directly on the affected area, and solves the problem of poor solubility of voriconazole and instability in water, and provides a good stability and good solubility , Voriconazole topical preparation with high intradermal distribution.
本发明的另一目的在于提供一种伏立康唑外用制剂的制备方法。Another object of the present invention is to provide a preparation method of voriconazole external preparation.
为了解决背景技术中存在的问题，本发明采用如下技术方案：In order to solve the problems in the background art, the present invention adopts the following technical solutions:
伏立康唑外用制剂，至少包括伏立康唑、基质材料和增溶剂，其中所述的增溶剂是异丙酯类或烃类溶剂。The external preparation of voriconazole includes at least voriconazole, a matrix material and a solubilizer, wherein the solubilizer is an isopropyl ester or hydrocarbon solvent.
作为优选，所述的异丙酯类是已二酸二异丙酯。Preferably, the isopropyl ester is diisopropyl adipate.
作为优选，所述的羟类溶剂是十六烷。Preferably, the hydroxy solvent is hexadecane.
作为优选所述的基质材料是十四醇、十六醇、十八醇及其混合物、乳化蜡、微晶蜡、石蜡或液体石蜡、凡士林、矿物油、蜂蜡、羊毛脂、羊毛醇中的一种或多种混合。Preferably, the matrix material is one of myristyl alcohol, cetyl alcohol, stearyl alcohol and mixtures thereof, emulsifying wax, microcrystalline wax, paraffin wax or liquid paraffin, petrolatum, mineral oil, beeswax, lanolin, and lanolin. Kind or mixed.
本发明伏立康唑外用制剂，按重量百分比计包括伏立康唑0.3％～3％、基质材料67％～94％、增溶剂5％～30％。The voriconazole external preparation of the present invention comprises 0.3% to 3% of voriconazole, 67% to 94% of matrix material, and 5% to 30% of solubilizer in weight percentage.
本发明还公开伏立康唑外用制剂的制备方法，包括如下步骤：The invention also discloses a preparation method of voriconazole external preparation, which comprises the following steps:
(1)增溶剂中加入伏立康唑原料，搅拌溶解；(1) Add voriconazole raw material to the solubilizer, stir to dissolve;
(2)基质材料融化备用；(2) The matrix material is melted for use;
(3)混合搅拌即得。(3) Mix and stir to obtain.
本发明伏立康唑外用制剂，提供了伏立康唑外用抗真菌的剂型，能更有效针对患处，而且解决了伏立康唑外用制剂制备过程中伏立康唑稳定性差，尤其在有水状态下，伏立康唑易水解经过逆醇醛反应产物重组，生成非活性的异构体杂质。本发明在研究中发现伏立康唑在酯类和烷烃类辅料中具有良好的溶解度与稳定性，尤其在加入异丙酯类和羟类溶剂后，效果明显。The external preparation of voriconazole of the present invention provides an antifungal dosage form for external use of voriconazole, which can more effectively target the affected area and solves the problem of poor stability of voriconazole during the preparation process of the external preparation of voriconazole. Especially in the presence of water, voriconazole is easily hydrolyzed and undergoes retro-aldol reaction product Recombination to produce inactive isomeric impurities. In the research of the present invention, it is found that voriconazole has good solubility and stability in esters and alkane auxiliary materials, especially after adding isopropyl esters and hydroxy solvents, the effect is obvious.
下面结合实施例对本发明做进一步的说明。The present invention will be further described below in conjunction with embodiments.
实施例1：制备伏立康唑软膏剂Example 1: Preparation of voriconazole ointment
处方：prescription:
制备工艺：Preparation Process:
(1)于烧杯中称取处方量的增溶剂，60℃水浴加热，将处方量的伏立康唑加入搅拌使其尽可能全部溶解，保温备用；(1) Weigh the prescription amount of solubilizer in a beaker, heat it in a water bath at 60°C, add the prescription amount of voriconazole and stir to dissolve it as much as possible, and keep it warm for later use;
(2)60℃水浴加热，熔融基质，至完全融化，保温备用；(2) Heat in a 60℃ water bath to melt the substrate until it is completely melted, keep it warm for later use;
(3)混合：将步骤(1)获得的药物溶液，在搅拌状态下缓慢倒入融化的基质中，搅拌均匀。于室温下冷却，即得。(3) Mixing: the drug solution obtained in step (1) is slowly poured into the melted matrix under stirring, and stirred evenly. Cool down at room temperature to get.
实施例2：伏立康唑在不同溶剂中溶解度实验；Example 2: Experiment on the solubility of voriconazole in different solvents;
伏立康唑在不同溶剂中溶解度：Solubility of voriconazole in different solvents:
由上表可知，伏立康唑在已二酸二异丙酯中的溶解度最大。It can be seen from the above table that voriconazole has the highest solubility in diisopropyl adipate.
实验例3：相容性Experimental example 3: Compatibility
将伏立康唑溶解于下列溶剂中，配成近似饱和的含药溶液。含药溶液放置于加速条件下(40℃/75％RH)，7天后取出，参照以下液相色谱条件，进行有关物质检测。Dissolve voriconazole in the following solvents to form a nearly saturated drug-containing solution. The drug-containing solution was placed under accelerated conditions (40°C/75% RH), and then taken out after 7 days. Refer to the following liquid chromatographic conditions for related substance detection.
结果见下表：The results are shown in the table below:
结论：伏立康唑在不同的溶剂中在加速7天后，检测显示，伏立康唑在乙二酸二异丙酯和十六烷中具备较好的相容性和稳定性，不易降解。Conclusion: After 7 days of acceleration in different solvents, voriconazole has good compatibility and stability in diisopropyl oxalate and hexadecane, and it is not easy to degrade.
实施例4：稳定性实验：Example 4: Stability experiment:
将实施例1处方一、处方二、处方三获得的伏立康唑软膏于加速条件下放置7天，后进行外观和有关物质检测。The voriconazole ointment obtained from prescription 1, prescription 2, and prescription 3 of Example 1 was placed under accelerated conditions for 7 days, and then the appearance and related substances were tested.
结论：实施例1中所得的伏立康唑软膏在加速7天后，总杂增长不明显，显示具有较好的相容性。Conclusion: The voriconazole ointment obtained in Example 1 has no significant increase in total impurities after 7 days of acceleration, showing good compatibility.
实施例5：采用体外皮肤渗透性试验，评价不同配方的体外经皮渗透性。Example 5: Using an in vitro skin permeability test to evaluate the in vitro transdermal permeability of different formulations.
实验过程：experiment procedure:
(1)取出冷冻的猪皮，室温条件下于0.9％的生理盐水中解冻；解冻后，采用电推子剃除猪皮表的猪皮，用手术剪除皮下脂肪组织，备用；(1) Take out the frozen pig skin and thaw it in 0.9% normal saline at room temperature; after thawing, use electric clippers to shave off the pig skin, and surgically cut off the subcutaneous fat tissue for use;
(2)将实验用皮铺于Franz立式扩散池的接收室，采用手术剪，修剪边缘，边缘余量不少于5mm；修剪完成后，用夹具夹紧。并精密称定整套扩散池的重量。(2) Spread the experimental leather in the receiving room of the Franz vertical diffusion cell, use surgical scissors to trim the edge, and the margin of the edge is not less than 5mm; after the trimming is completed, clamp it with a clamp. And accurately weigh the whole set of diffusion cell.
(3)采用1ml注射器，用美工刀切除注射器前部，使前端开口，以便吸取及挤出样品，并减小挤压应力对待待测试样品性能的影响；用该装置吸收约0.2-0.3ml的样品，均匀涂布于皮肤表面(样品加入量约300mg)；称取加样后扩散池的重量，扣减加样前的重量后，即得到样品重量；加样结束后，采用封口膜封口，避免样品在实验过程中变干。(3) Using a 1ml syringe, cut off the front part of the syringe with a utility knife to make the front end open so that the sample can be sucked and extruded, and the influence of the compression stress on the performance of the sample to be tested is reduced; the device can absorb about 0.2-0.3ml Spread the sample evenly on the skin surface (the amount of sample added is about 300mg); weigh the weight of the diffusion cell after adding the sample, and deduct the weight before adding the sample to get the sample weight; after the sample is added, use a sealing film to seal it. Avoid the sample from drying out during the experiment.
(4)以pH7.2的磷酸盐缓冲液为接收介质，试验温度32℃±1℃；(4) Use phosphate buffer of pH 7.2 as the receiving medium, and the test temperature is 32℃±1℃;
(5)6小时后，分别提取角质层及表皮。采用提取介质，提取并测定其中的药物浓度。(5) After 6 hours, extract the stratum corneum and epidermis. Using the extraction medium, extract and determine the drug concentration in it.
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| WO2010084505A2 (en) * | 2008-06-06 | 2010-07-29 | Glenmark Pharmaceuticals Limited | Stable topical formulation comprising voriconazole |
| CN101909634A (en) * | 2008-01-03 | 2010-12-08 | 陶氏制药科学公司 | Compositions and methods for treating nail disease |
| CN103429246A (en) * | 2010-12-29 | 2013-12-04 | 战略科学与技术有限责任公司 | Transdermal delivery of treatments for fungal infections and other indications |
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| AU3673195A (en) * | 1994-10-13 | 1996-05-06 | Hisamitsu Pharmaceutical Co., Inc. | External preparation for nail ringworm |
| EP1617818A1 (en) * | 2003-04-29 | 2006-01-25 | Baxter International Inc. | Formulation to render an antimicrobial drug potent against organisms normally considered to be resistant to the drug |
| RU2014149993A (en) * | 2012-05-11 | 2016-07-10 | Сипла Лимитед | PHARMACEUTICAL COMPOSITION |
| KR101799008B1 (en) * | 2015-03-12 | 2017-11-17 | 동아제약 주식회사 | Pharmaceutical composition for treating fungal infections of keratinous tissue |
| CN108567782A (en) * | 2018-07-05 | 2018-09-25 | 江苏先声药业有限公司 | A kind of posaconazole externally-applied medicinal composition, preparation method and the usage |
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| CN101909634A (en) * | 2008-01-03 | 2010-12-08 | 陶氏制药科学公司 | Compositions and methods for treating nail disease |
| WO2010084505A2 (en) * | 2008-06-06 | 2010-07-29 | Glenmark Pharmaceuticals Limited | Stable topical formulation comprising voriconazole |
| CN103429246A (en) * | 2010-12-29 | 2013-12-04 | 战略科学与技术有限责任公司 | Transdermal delivery of treatments for fungal infections and other indications |
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