WO2017107908A1 - 艾沙康唑的微粒给药组合物 - Google Patents

艾沙康唑的微粒给药组合物 Download PDF

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WO2017107908A1
WO2017107908A1 PCT/CN2016/111230 CN2016111230W WO2017107908A1 WO 2017107908 A1 WO2017107908 A1 WO 2017107908A1 CN 2016111230 W CN2016111230 W CN 2016111230W WO 2017107908 A1 WO2017107908 A1 WO 2017107908A1
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esaconazole
microparticle
administration composition
injection
group
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PCT/CN2016/111230
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French (fr)
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潘弘
韩建生
尹大全
乔燕萍
李晨曦
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上海医药集团股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers

Definitions

  • the invention relates to a microparticle administration composition of esaconazole, belonging to the technical field of pharmaceutical preparations.
  • Isacconazole (English name Isavuconazole, research and development code BAL4815, CAS number 241479-67-4, chemical name (1R, 2R)-4-[2-[2-hydroxy-1-methyl-3-[1 , 2,4]triazol-1-yl-2-(2,5-difluoro-phenyl)-propyl]-thiazolyl-4-yl]-benzonitrile, which inhibits sterol 14 ⁇ -desorption
  • the base enzyme (the microsomal P450 enzyme required for the biosynthesis of fungal ergosterol) has a strong broad-spectrum antifungal activity. However, due to the poor water solubility of esaconazole, its drug-forming properties are greatly limited.
  • esaconazole sulfate (English name Isavuconazonium Sulfate, code name BAL8557).
  • esaconazole sulphate was marketed in the United States under the trade name Cresemba for the life-threatening invasive fungal infection in patients with immune dysfunction. The indications were invasive aspergillosis and invasive mucormycosis.
  • Each of the Cresemba capsules contained 186 mg of esaconazole sulphate (equivalent to 100 mg of esaconazole), and each bottle of Cresemba lyophilized powder contained 372 mg of esaconazole bisulphate (equivalent to 200 mg of esaconazole).
  • the water-soluble prodrug is a racemic mixture of two epimers which can be rapidly and quantitatively converted into the active ingredient ixaconazole in vivo to exert significant anti-multi-fungal activity.
  • Cresemba uses a water-soluble prodrug to indirectly solve the problem of poor water solubility of the active ingredient esaconazole
  • the physicochemical stability of the water-soluble prodrug esaconazole bismuth sulfate is poor, especially Cresemba freeze-dried.
  • the bag After the powder injection preparation is reconstituted with water for injection, it may cause particulate matter or discoloration.
  • the bag must be gently mixed or rolled to reduce the formation of particles, avoid unnecessary vibration or shake the solution vigorously. This puts higher requirements on the dosing process in clinical use, and also increases the risk of degradation of the drug due to instability or improper operation before use. Therefore, there is an urgent need in the art to solve the problem that the water solubility of esaconazole is not favorable for administration, and the preparation or other solution for improving the stability of the drug can be ensured to ensure the safety of the drug.
  • an object of the present invention is to provide a microparticle administration composition of esaconazole, which is prepared by using esaconazole to prepare a microparticle delivery system, which solves the problem of esaconazole.
  • the problem of poor water solubility and inability to inject directly increases the stability of the active ingredient during administration.
  • Fat emulsions, liposomes, polymeric micelles, nanoparticles and microspheres are all pharmaceutically acceptable microparticle delivery vehicles by loading esaconazole into fat emulsions, liposomes, polymeric micelles, The microparticles and microspheres and other microparticles are used to ensure the stability of the esaconazole before and after administration, and finally the drug safety of the drug is achieved.
  • a microparticle administration composition of esaconazole comprising esaconazole and a microparticle carrier, wherein the microparticle carrier is selected from the group consisting of fat emulsion, liposome, polymer micelle, nanoparticle, microsphere or other pharmacy An acceptable microparticle delivery vehicle.
  • the weight percentage of esaconazole is from 1% to 20%.
  • the micro-administration composition of the present invention is esaconazole fat emulsion, including esaconazole, injectable oil, emulsifier, stabilizer Isotonicity adjusting agent, pH adjusting agent and water for injection; and each of the above-mentioned esaconazole fat emulsion contains 0.01 to 4 g of active ingredient of oxaconazole, 5 to 30 g of oil for injection, 0.5 to 5 g of emulsifier, and is stable.
  • the agent is 0 to 1 g
  • the isotonicity adjusting agent is 1 to 5 g
  • the pH adjusting agent is adjusted to a pH of 4.0 to 8.0, and the remaining amount of water for injection.
  • the oil for injection is selected from the group consisting of soybean oil for injection, medium chain oil for injection, or a combination of mass ratio of 1:0.5 to 1:2.
  • the medium chain oil for injection is preferably a medium chain triglyceride for injection.
  • the emulsifier is selected from the group consisting of egg yolk lecithin for injection.
  • the stabilizer is selected from the group consisting of phosphatidylglycerol, oleic acid, sodium oleate or a combination thereof, and the phosphatidylglycerol is selected from the group consisting of dimyristoyl phosphatidylglycerol (DMPG), dipalmitoylphosphatidylglycerol (DPPG), and two oils.
  • DMPG dimyristoyl phosphatidylglycerol
  • DPPG dipalmitoylphosphatidylglycerol
  • the isotonicity adjusting agent is selected from any one or a mixture of glycerin, mannitol, sorbitol, glucose, and sucrose for injection, and is preferably glycerin for injection.
  • the pH adjusting agent is selected from the group consisting of sodium hydroxide, sodium hydrogencarbonate or hydrochloric acid.
  • the micro-administration composition of esaconazole of the present invention is esaconazole liposome, including: ixaconazole, phosphatidylcholine, phospholipid Acylglycerol, cholesterol, antioxidant, lyoprotectant and buffer salt; the esaconazole liposome contains 200 mg of eswaconazole and phosphatidylcholine 400 mg to 4 g, phosphatidylglycerol 160 mg ⁇ 1.6 g, cholesterol 100 mg to 1 g, antioxidant 1 mg to 20 mg, lyophilized protective agent 1 g to 20 g, and buffer salt 0 mg to 2 g.
  • the phosphatidylcholine is selected from the group consisting of egg yolk phosphatidylcholine (EPC), hydrogenated soybean phosphatidylcholine (HSPC), distearoylphosphatidylcholine (DSPC), dipalmitoylphosphatidylcholine (DPPC). , dioleoylphosphatidylcholine (DOPC) or dimyristoylphosphatidylcholine (DMPC), preferably hydrogenated soybean phosphatidylcholine, distearoylphosphatidylcholine or dipalmitoylphosphatidylcholine .
  • EPC egg yolk phosphatidylcholine
  • HSPC hydrogenated soybean phosphatidylcholine
  • DSPC distearoylphosphatidylcholine
  • DPPC dipalmitoylphosphatidylcholine
  • DOPC dioleoylphosphatidylcholine
  • DMPC dimyristoylphosphatidyl
  • the phosphatidylglycerol is selected from the group consisting of dimyristoyl phosphatidylglycerol (DMPG), dipalmitoylphosphatidylglycerol (DPPG), dioleoylphosphatidylglycerol (DOPG), and distearoylphosphatidylglycerol (DSPG). Any one or more of a mixture, preferably distearoylphosphatidylglycerol or dipalmitoylphosphatidylglycerol.
  • the antioxidant is selected from the group consisting of vitamin E.
  • the lyoprotectant is selected from the group consisting of sucrose, trehalose or mannitol, preferably sucrose.
  • the buffer salt is selected from the group consisting of phosphate, acetate, citrate or succinate, preferably citrate or succinate.
  • the micro-administration composition of the esaconazole of the present invention is an isaconazole polymer micelle, including: esaconazole, high amphiphilic Molecular polymer; and oxaconazole and amphiphilic polymer
  • the molar ratio of the polymer is from 1:1 to 1:50.
  • the amphiphilic polymer is selected from the group consisting of methoxypolyethylene glycol 2000-distearoylphosphatidylethanolamine (mPEG2000-DSPE) or methoxypolyethylene glycol 2000-polyester block copolymer.
  • the molecular weight range is selected from 2700 to 30,000, preferably from 3,000 to 6,000.
  • the microparticle administration composition of the present invention is esaconazole nanoparticle, including: esaconazole, albumin; and the active component of esaconazole and white
  • the molar ratio of protein is 1:1 to 1:50.
  • the microparticle-administering composition of the present invention is an ixaconazole microsphere, including: ixaconazole, a biodegradable polymer; and
  • the molar ratio of the azole active ingredient to the biodegradable high molecular polymer is from 1:1 to 1:100.
  • the biodegradable high molecular polymer is selected from a blocked or uncapped lactide-glycolide copolymer (PLGA), wherein the molar ratio of lactide to glycolide is selected from 75:25 or 50:50.
  • the intrinsic viscosity is 0.2 to 0.6 dl/g, and the weight average molecular weight is 15,000 to 85,000.
  • the invention also provides a method for preparing the microparticle administration composition of the ixaconazole, which comprises:
  • the colostrum is obtained by an online shearing mechanism, and the water for injection is supplemented to a prescribed amount, and an appropriate amount of a pH adjusting agent is added to adjust the pH to 4.0 to 8.0;
  • the emulsion obtained in the step (3) is homogenized by a high-pressure homogenizer, and the pressure is 700 bar to 900 bar, and the temperature is maintained at 40 to 60 ° C to obtain a fat emulsion intermediate;
  • the fat emulsion intermediate is filtered, dispensed, and sterilized;
  • the liposome crude suspension is homogenized by a microfluidizer homogenizer, the homogenization pressure is 1500 bar to 2000 bar, and the control homogenization temperature is lower than 40 ° C;
  • the homogenization pressure is 1500 bar to 2000 bar, and the dichloromethane is removed by evaporation through a layer plate;
  • step (2) adding the solution of step (1) to the high shear aqueous phase at a shear rate of 6000 to 9000 rpm;
  • the invention comprises the esaconazole microparticle administration composition by the active ingredient esaconazole in the microparticles of the fat emulsion, the liposome, the polymer micelle, the nanoparticle or the microsphere, and the esaconazole microparticle administration composition is added, and the Aisacon is added.
  • the water solubility of the azole Compared with the existing water-soluble prodrug technology, the microparticle administration composition has a more stable preparation form, is more convenient to use, and reduces the unsafe hidden danger of clinical medication.
  • the colostrum is obtained by an in-line shearing mechanism, and the water for injection is supplemented to 1000 mL, and an appropriate amount of sodium hydroxide solution is added to adjust the pH to 6.8;
  • the emulsion obtained in the step (3) is homogenized by a high-pressure homogenizer for 6 cycles, the pressure is 700 bar, and the temperature is maintained at 45 ° C to obtain a fat emulsion intermediate;
  • the liposome crude suspension is passed through a microfluidizer for 2 cycles, the homogenization pressure is 1500 bar, and the control homogenization temperature is lower than 40 ° C;
  • albumin nanosuspension is filtered through a 0.22 ⁇ m filter and packed in 20 mL/pack;
  • step (2) adding the solution of step (1) to the high shear aqueous phase, the final volume is 500 ml, and the shear rate is 9000 rpm;

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Abstract

艾沙康唑的微粒给药组合物，包括由艾沙康唑和辅料构成的脂肪乳、脂质体、聚合物胶束、纳米粒和微球等微粒给药组合物，微粒给药组合物用于治疗重度系统性真菌病。

Description

艾沙康唑的微粒给药组合物 技术领域
本发明涉及艾沙康唑的微粒给药组合物，属于药物制剂技术领域。
背景技术
艾沙康唑(英文名Isavuconazole，研发代号BAL4815，CAS号为241479-67-4，化学名为(1R,2R)-4-[2-[2-羟基-1-甲基-3-[1,2,4]三唑-1-yl-2-(2,5-二氟-苯基)-丙基]-噻唑基-4-基]-苄腈)，可以抑制固醇14α-脱甲基酶(真菌麦角固醇生物合成过程中必需的微粒体P450酶)，因此具有较强的广谱抗真菌活性。但由于艾沙康唑的水溶性不佳，其成药性受到极大限制。
Basilea制药公司将其改造成水溶性前药：艾沙康唑鎓硫酸酯(英文名Isavuconazonium Sulfate，研发代号BAL8557)。2015年艾沙康唑鎓硫酸酯在美国以Cresemba商品名上市，用于出现免疫功能不全患者危及生命的侵袭性真菌感染，适应症为侵袭性曲霉菌病和侵袭性毛霉菌病。其中每颗Cresemba胶囊含186mg艾沙康唑鎓硫酸酯(相当于100mg艾沙康唑)，每瓶Cresemba冻干粉针含372mg艾沙康唑鎓硫酸酯(相当于200mg艾沙康唑)。该水溶性前药为两种差向异构体的外消旋混合物，在体内能迅速且定量地转化为活性成分艾沙康唑，发挥显著的抗多种真菌活性。
Cresemba采用水溶性前药的方式虽然间接解决了活性成分艾沙康唑水溶性不佳的问题，但该水溶性前药艾沙康唑鎓硫酸酯的理化稳定性较差，尤其是Cresemba冻干粉针制剂在加入注射用水复溶重建后，有可能产生颗粒物或变色，在注射制剂稀释和制备过程中，必须轻轻混合或滚动袋以减少颗粒的形成，避免不必要振动或剧烈摇动溶液。这对临床使用中的配液过程提出了较高的要求，也增加了药品在使用前由于不稳定或操作不当而产生降解的隐患。因此，本领域急需既能解决艾沙康唑水溶性不佳不利于给药的问题，又能提高该药稳定性的制剂或其他解决方案，以确保该药的使用安全性。
发明内容
针对现有技术存在的上述问题，本发明的目的是提供一种艾沙康唑的微粒给药组合物，以艾沙康唑制备成微粒给药系统的制剂方式，既解决了艾沙康唑水溶性不佳不能直接注射的问题，又提高了该活性成分在给药过程中的稳定性。脂肪乳、脂质体、聚合物胶束、纳米粒和微球都是药学上可接受的微粒给药载体，通过将艾沙康唑包载入脂肪乳、脂质体、聚合物胶束、纳米粒和微球等微粒给药载体，保证了艾沙康唑给药前后的稳定性，最终实现该药的用药安全性。
为实现上述发明目的，本发明采用的技术方案如下：
一种艾沙康唑的微粒给药组合物，包括艾沙康唑和微粒给药载体，微粒给药载体选自脂肪乳、脂质体、聚合物胶束、纳米粒、微球或其他药学上可接受的微粒给药载体。
在所述艾沙康唑的微粒给药组合物中，艾沙康唑的重量百分比为1％～20％。
当所述微粒给药载体为脂肪乳时，本发明所述艾沙康唑的微粒给药组合物即为艾沙康唑脂肪乳，包括艾沙康唑、注射用油、乳化剂、稳定剂、等渗调剂、pH调节剂及注射用水；且每100mL所述的艾沙康唑脂肪乳中含有艾沙康唑活性成分0.01～4g、注射用油5～30g、乳化剂0.5～5g、稳定剂0～1g、等渗调节剂1～5g、pH调节剂调节pH至4.0～8.0、注射用水余量。
所述的注射用油选自注射用大豆油、注射用中链油、或两者质量比1:0.5～1:2的组合。注射用中链油优选为注射用中链甘油三酯。所述的乳化剂选自注射用蛋黄卵磷脂。所述的稳定剂选自磷脂酰甘油、油酸、油酸钠或其组合，磷脂酰甘油选自为二肉豆蔻酰磷脂酰甘油(DMPG)、二棕榈酰磷脂酰甘油(DPPG)、二油酰磷脂酰甘油(DOPG)、二硬脂酰磷脂酰甘油(DSPG)中的任意一种或几种的混合物。所述的等渗调节剂选自注射用甘油、甘露醇、山梨糖醇、葡萄糖、蔗糖中的任意一种或几种的混合物，优选为注射用甘油。所述的pH调节剂选自氢氧化钠、碳酸氢钠或盐酸。
当所述微粒给药载体为脂质体时，本发明所述艾沙康唑的微粒给药组合物即为艾沙康唑脂质体，包括：艾沙康唑、磷脂酰胆碱、磷脂酰甘油、胆固醇、抗氧剂、冻干保护剂及缓冲盐；所述的艾沙康唑脂质体每含200mg艾沙康唑的同时，含磷脂酰胆碱400mg～4g、磷脂酰甘油160mg～1.6g、胆固醇100mg～1g、抗氧剂1mg～20mg、冻干保护剂1g～20g、缓冲盐0mg～2g。
所述的磷脂酰胆碱选自蛋黄磷脂酰胆碱(EPC)、氢化大豆磷脂酰胆碱(HSPC)、二硬脂酰磷脂酰胆碱(DSPC)、二棕榈酰磷脂酰胆碱(DPPC)、二油酰磷脂酰胆碱(DOPC)或二肉豆蔻酰磷磷脂酰胆碱(DMPC)，优选为氢化大豆磷脂酰胆碱、二硬脂酰磷脂酰胆碱或二棕榈酰磷脂酰胆碱。所述的磷脂酰甘油选自二肉豆蔻酰磷脂酰甘油(DMPG)、二棕榈酰磷脂酰甘油(DPPG)、二油酰磷脂酰甘油(DOPG)、二硬脂酰磷脂酰甘油(DSPG)中的任意一种或几种的混合物，优选为二硬脂酰磷脂酰甘油或二棕榈酰磷脂酰甘油。所述的抗氧剂选自维生素E。所述的冻干保护剂选自蔗糖、海藻糖或甘露醇，优选为蔗糖。所述缓冲盐选自磷酸盐、醋酸盐、枸橼酸盐或琥珀酸盐，优选为枸橼酸盐或琥珀酸盐。
当所述微粒给药载体为聚合物胶束时，本发明所述艾沙康唑的微粒给药组合物即为艾沙康唑聚合物胶束，包括：艾沙康唑、两亲性高分子聚合物；且艾沙康唑与两亲性高分子 聚合物的摩尔比例为1:1～1:50。
所述的两亲性高分子聚合物选自甲氧基聚乙二醇2000-二硬脂酰磷脂酰乙醇胺(mPEG2000-DSPE)或甲氧基聚乙二醇2000-聚酯嵌段共聚物。其分子量范围选自2700～30000，优选为3000～6000。
当所述微粒给药载体为纳米粒时，本发明所述的微粒给药组合物即为艾沙康唑纳米粒，包括：艾沙康唑、白蛋白；且艾沙康唑活性成分与白蛋白的摩尔比例为1:1～1:50。
当所述微粒给药载体为微球时，本发明所述的微粒给药组合物即为艾沙康唑微球，包括：艾沙康唑、可生物降解高分子聚合物；且艾沙康唑活性成分与可生物降解高分子聚合物的摩尔比例为1:1～1:100。
所述的可生物降解高分子聚合物选自封端或未封端的丙交酯-乙交酯共聚物(PLGA)，其中丙交酯与乙交酯的摩尔比例选自75:25或50:50，其特性粘度为0.2～0.6dl/g，重均分子量为15000～85000。
本发明还提供了所述艾沙康唑的微粒给药组合物的制备方法，其包括：
A、按如下步骤制备艾沙康唑脂肪乳：
(1)将艾沙康唑、乳化剂和稳定剂溶解于注射用油中，60～70℃保温，全程充氮气保护；
(2)将等渗调节剂溶解于注射用水中，60～70℃保温；
(3)将步骤(1)和(2)的溶液混合后通过在线剪切机制得初乳，补足注射用水至处方量，并加适量pH调节剂调节pH值至4.0～8.0；
(4)将步骤(3)得到的乳液通过高压均质机均质，压力700bar～900bar，40～60℃保温，得到脂肪乳中间体；
(5)脂肪乳中间体经过滤、分装、灭菌；或
B、按如下步骤制备艾沙康唑脂质体：
(1)将艾沙康唑溶解于适量二氯甲烷中；
(2)将磷脂酰胆碱、胆固醇溶解于适量氯仿:甲醇(体积比1:3～3:1)中；
(3)将磷脂酰甘油溶解于适量氯仿:甲醇(体积比1:3～3:1)中；
(4)将以上三种溶液混匀，并加入抗氧剂，转移至旋转蒸发器中，蒸去有机溶剂，完全干燥后，加入含有冻干保护剂的水溶液，水化0.5～2h，得到脂质体粗混悬液；
(5)将脂质体粗混悬液通过微射流均质机均质，均质压力1500bar～2000bar，控制均质温度低于40℃；
(6)过滤；
(7)分装；
(8)冷冻干燥去除水分，即得注射用艾沙康唑脂质体；或
C、按如下步骤制备艾沙康唑聚合物胶束：
(1)将艾沙康唑和两亲性高分子聚合物溶解于适量二氯甲烷中；
(2)旋转蒸发去除二氯甲烷，加入注射用水，水化；
(3)0.22μm滤膜过滤后，分装；
(4)冷冻干燥去除水分，即得注射用艾沙康唑胶束；或
D、按如下步骤制备艾沙康唑白蛋白纳米粒：
(1)将艾沙康唑溶解于适量二氯甲烷中；
(2)将白蛋白溶解于注射用水中；
(3)将步骤(1)和(2)得到的溶液混合后迅速通过微射流均质机均质，均质压力1500bar～2000bar，经层板蒸发去除二氯甲烷；
(4)过滤后，分装；
(5)冷冻干燥去除水分，即得注射用艾沙康唑白蛋白纳米粒；或
E、按如下步骤制备艾沙康唑微球：
(1)将艾沙康唑和可生物降解高分子聚合物溶解于适量二氯甲烷；
(2)将步骤(1)的溶液加入至高剪切的水相中，剪切速率6000～9000rpm；
(3)蒸发去除有机溶剂后，分装；
(4)冷冻干燥去除水分，即得注射用艾沙康唑微球。
本发明通过脂肪乳、脂质体、聚合物胶束、纳米粒或微球等微粒给药载体包载活性成分艾沙康唑制成艾沙康唑微粒给药组合物，增加了艾沙康唑的水溶性。与现有水溶性前药技术相比，微粒给药组合物的制剂形式更稳定，使用更方便，减少了临床用药的不安全隐患。
具体实施方法
实施例1
艾沙康唑脂肪乳
处方：
Figure PCTCN2016111230-appb-000001
Figure PCTCN2016111230-appb-000002
制备工艺：
(1)将艾沙康唑、蛋黄卵磷脂和油酸溶解于注射用大豆油和注射用中链甘油三酯中，保温70℃，全程充氮气保护；
(2)将注射用甘油溶解于700mL注射用水中，保温70℃；
(3)将步骤(1)和(2)的溶液混合后通过在线剪切机制得初乳，补足注射用水至1000mL，并加适量氢氧化钠溶液调节pH值至6.8；
(4)将步骤(3)得到的乳液通过高压均质机均质6个循环，压力700bar，保温45℃，得到脂肪乳中间体；
(5)脂肪乳中间体经1μm聚丙烯滤膜过滤2次；
(6)按20mL/支灌装于中性硼硅玻璃安瓿瓶中并充氮封口；
(7)121℃旋转灭菌12min。
实施例2
注射用艾沙康唑脂质体
处方:
Figure PCTCN2016111230-appb-000003
制备工艺：
(1)将艾沙康唑溶解于适量二氯甲烷中；
(2)将氢化大豆卵磷脂、胆固醇溶解于适量氯仿:甲醇(体积比1:1)中；
(3)将二硬脂酰磷脂酰甘油溶解于适量氯仿:甲醇(体积比1:1)中；
(4)将以上三种溶液混匀，并加入维生素E，转移至旋转蒸发器中，蒸去有机溶剂，完全干燥后，加入蔗糖的水溶液，加水定容至1000ml，水化1h，得到脂质体粗混悬液；
(5)将脂质体粗混悬液通过微射流均质机2个循环，均质压力1500bar，控制均质温度低于40℃；
(6)按照1000mL/65cm2通过100nm聚碳酸酯膜过滤2次；
(7)以20mL/支灌装至50mL中性硼硅玻璃西林瓶中；
(8)冷冻干燥去除水分，即得注射用艾沙康唑脂质体。
实施例3
注射用艾沙康唑聚合物胶束
处方:
艾沙康唑      10g
mPEG2000-DSPE 150g
制备工艺：
(1)将艾沙康唑和mPEG2000-DSPE溶解于适量二氯甲烷中；
(2)旋转蒸发去除二氯甲烷，加入注射用水定容至1000ml，水化；
(3)0.22μm滤膜过滤后，按照20mL/支分装；
(4)冷冻干燥去除水分，即得注射用艾沙康唑胶束。
实施例4
注射用艾沙康唑白蛋白纳米粒
处方:
艾沙康唑  10g
白蛋白    100g
制备工艺：
(1)将艾沙康唑溶解于适量二氯甲烷中；
(2)将白蛋白溶解于1000ml注射用水中；
(3)将步骤(1)和(2)得到的溶液混合后迅速通过微射流均质机2个循环，均质压力1500bar，经层板蒸发去除二氯甲烷；
(4)白蛋白纳米混悬液经0.22μm滤膜过滤后，按照20mL/支分装；
(5)冷冻干燥去除水分，即得注射用艾沙康唑白蛋白纳米粒。
实施例5
注射用艾沙康唑微球
处方:
艾沙康唑          10g
PLGA(摩尔比50:50) 100g
制备工艺：
(1)将艾沙康唑和PLGA(封端，重均分子量为20000)按摩尔比50:50溶解于适量二氯甲烷；
(2)将步骤(1)的溶液加入至高剪切的水相中，终体积为500ml，剪切速率9000rpm；
(3)旋转蒸发去除有机溶剂后，分装；
(4)冷冻干燥去除水分，即得注射用艾沙康唑微球。
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本领域的技术人员在本发明所揭示的技术范围内，可不经过创造性劳动想到的变化或替换，都应涵盖在本发明的保护范围之内。

Claims (20)

  1. 一种艾沙康唑的微粒给药组合物，包括艾沙康唑和微粒给药载体，微粒给药载体选自脂肪乳、脂质体、聚合物胶束、纳米粒、微球或其他药学上可接受的微粒给药载体。
  2. 根据权利要求1所述的艾沙康唑的微粒给药组合物，其特征在于：艾沙康唑的重量百分比为1％～20％。
  3. 根据权利要求1所述的艾沙康唑的微粒给药组合物，其特征在于：所述微粒给药载体为脂肪乳，所述艾沙康唑的微粒给药组合物即为艾沙康唑脂肪乳，包括：艾沙康唑、注射用油、乳化剂、稳定剂、等渗调剂、pH调节剂及注射用水；且每100mL所述的艾沙康唑脂肪乳中含有：艾沙康唑0.01～4g、注射用油5～30g、乳化剂0.5～5g、稳定剂0～1g、等渗调节剂1～5g、pH调节剂调节pH至4.0～8.0、注射用水余量。
  4. 根据权利要求3所述的艾沙康唑的微粒给药组合物，其特征在于：所述的注射用油选自注射用大豆油、注射用中链油、或两者质量比1:0.5～1:2的组合。
  5. 根据权利要求3所述的艾沙康唑的微粒给药组合物，其特征在于：所述的乳化剂选自注射用蛋黄卵磷脂。
  6. 根据权利要求3所述的艾沙康唑的微粒给药组合物，其特征在于：所述的稳定剂选自磷脂酰甘油、油酸或油酸钠。
  7. 根据权利要求3所述的艾沙康唑的微粒给药组合物，其特征在于：所述的等渗调节剂选自注射用甘油。
  8. 根据权利要求3所述的艾沙康唑的微粒给药组合物，其特征在于：所述的pH调节剂选自氢氧化钠、碳酸氢钠或盐酸。
  9. 根据权利要求1所述的艾沙康唑的微粒给药组合物，其特征在于：所述微粒给药载体为脂质体，所述艾沙康唑的微粒给药组合物即为艾沙康唑脂质体，包括：艾沙康唑、磷脂酰胆碱、磷脂酰甘油、胆固醇、抗氧剂、冻干保护剂及缓冲盐；所述的艾沙康唑脂质体每含200mg艾沙康唑的同时，含磷脂酰胆碱400mg～4g、磷脂酰甘油160mg～1.6g、胆固醇100mg～1g、抗氧剂1mg～20mg、冻干保护剂1g～20g、缓冲盐0mg～2g。
  10. 根据权利要求9所述的艾沙康唑的微粒给药组合物，其特征在于：所述的磷脂酰胆碱选自氢化大豆磷脂酰胆碱、二硬脂酰磷脂酰胆碱或二棕榈酰磷脂酰胆碱。
  11. 根据权利要求9所述的艾沙康唑的微粒给药组合物，其特征在于：所述的磷脂酰甘油选自二硬脂酰磷脂酰甘油或二棕榈酰磷脂酰甘油。
  12. 根据权利要求9所述的艾沙康唑的微粒给药组合物，其特征在于：所述的抗氧剂为维生素E。
  13. 根据权利要求9所述的艾沙康唑的微粒给药组合物，其特征在于：所述的冻干保护剂选自蔗糖或海藻糖。
  14. 根据权利要求1所述的艾沙康唑的微粒给药组合物，其特征在于：所述微粒给药载体为胶束，所述艾沙康唑的微粒给药组合物即为艾沙康唑聚合物胶束，包括：艾沙康唑、两亲性高分子聚合物；且艾沙康唑与两亲性高分子聚合物的摩尔比例为1:1～1:50。
  15. 根据权利要求14所述的艾沙康唑的微粒给药组合物，其特征在于：所述的两亲性高分子聚合物选自甲氧基聚乙二醇2000-二硬脂酰磷脂酰乙醇胺或甲氧基聚乙二醇2000-聚酯嵌段共聚物。
  16. 根据权利要求15所述的艾沙康唑的微粒给药组合物，其特征在于：所述的两亲性高分子聚合物为甲氧基聚乙二醇2000-聚酯嵌段共聚物，其分子量为3000～5000，其中的甲氧基聚乙二醇与聚酯嵌段的比例为1:0.5～1:1.5，聚酯嵌段共聚物中的聚酯选自D,L-丙交酯、L-丙交酯、己内酯或乙交酯。
  17. 根据权利要求1所述的艾沙康唑的微粒给药组合物，其特征在于：所述微粒给药载体为纳米粒，所述艾沙康唑的微粒给药组合物即为艾沙康唑纳米粒，包括：艾沙康唑、白蛋白；且艾沙康唑与白蛋白的摩尔比例为1:1～1:50。
  18. 根据权利要求1所述的艾沙康唑的微粒给药组合物，其特征在于：所述微粒给药载体为微球，所述艾沙康唑的微粒给药组合物即为艾沙康唑微球，包括：艾沙康唑、可生物降解高分子聚合物；且艾沙康唑与可生物降解高分子聚合物的摩尔比例为1:1～1:100。
  19. 根据权利要求18所述的艾沙康唑的微粒给药组合物，其特征在于：所述的可生物降解高分子聚合物选自封端或未封端的丙交酯-乙交酯共聚物。
  20. 根据权利要求19所述的艾沙康唑的微粒给药组合物，其特征在于：所述封端或未封端的丙交酯-乙交酯共聚物中，丙交酯与乙交酯的摩尔比例选自75:25或50:50，所述封端或未封端的丙交酯-乙交酯共聚物特性粘度为0.2～0.6dl/g，重均分子量为15000～85000。
PCT/CN2016/111230 2015-12-25 2016-12-21 艾沙康唑的微粒给药组合物 WO2017107908A1 (zh)

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