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WO2018176891A1 - 以麦羟硅钠石为乳化剂的Pickering乳液模板法制备的纳米杂化药物载体及其制法 - Google Patents

以麦羟硅钠石为乳化剂的Pickering乳液模板法制备的纳米杂化药物载体及其制法 Download PDF

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WO2018176891A1
WO2018176891A1 PCT/CN2017/114187 CN2017114187W WO2018176891A1 WO 2018176891 A1 WO2018176891 A1 WO 2018176891A1 CN 2017114187 W CN2017114187 W CN 2017114187W WO 2018176891 A1 WO2018176891 A1 WO 2018176891A1
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drug
plga
hybrid
organic
water
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French (fr)
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戈明亮
曹罗香
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South China University of Technology SCUT
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South China University of Technology SCUT
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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
    • A61K31/33—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
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5115—Inorganic compounds
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • 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
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)

Definitions

  • the invention relates to the field of pharmaceutical carriers, in particular to a pickering with sulphate as an emulsifier Nano-hybrid drug carrier prepared by emulsion template method and preparation method thereof.
  • the biodegradable nano drug carrier has become a research hotspot by slowing the degradation of the drug, reducing the phagocytosis of the drug by the reticuloendothelial phagocytic system, improving the bioavailability, prolonging the circulation time in the body and increasing the cell permeability.
  • Polylactic acid - Glycolic acid copolymer PLGA It has good biocompatibility, can be degraded in vivo, is non-toxic and harmless to the body, can delay drug release time, improve drug half-life and reduce drug toxicity, and is widely used in nano drug delivery carrier.
  • the presence of drug burst release limits its industrial application. It has been reported to control the burst release by controlling the size of nanospheres, microsphere structure modification, polymer combination, and additives.
  • Emulsion is a thermodynamically unstable system, and an emulsifier must be added to the system to obtain a stable emulsion by reducing the interfacial tension between the two phases.
  • an emulsifier must be removed from the sample, otherwise it will cause harm to the human body, affecting and destroying the subsequent application of the emulsion.
  • the emulsifier will induce tissue inflammation or even cell damage, which is prepared by an emulsifier.
  • the use of traditional emulsions in pharmaceutical preparations is limited.
  • the solid particles can prevent the emulsion droplets from coalescing through the interfacial action, so that it can be prepared instead of the traditional emulsifier. Pickering lotion.
  • Solid material magadiite can be synthesized from pure chemical reagents to obtain high purity and stable products, and synthesized magadiite
  • the raw materials are widely available at low prices and at low cost.
  • Sodium hydroxyapatite is non-toxic and does not cause adverse reactions to the human body. Interactions between clay and drugs can occur. Structured clays have been applied to drug delivery systems.
  • Magadiite was used as an emulsifier to prepare a stable Pickering emulsion.
  • the PLGA-magadiite nanohybrid drug carrier was prepared by emulsification-volatilization method.
  • the emulsion has the advantages of no pollution, environmental friendliness, little toxicity to human body, strong stability, etc.
  • concentration of the nanoparticle emulsifier or the oil-water ratio of the emulsion By adjusting the concentration of the nanoparticle emulsifier or the oil-water ratio of the emulsion, the size regulation of the emulsion particles is realized, and the drug loading efficiency is improved.
  • the drug carrier composition comprises: organic methicillite, PLGA, medicine.
  • Method for preparing nano hybrid drug carrier by Pickering emulsion template method based on hydroxyammite emulsifier Includes the following steps:
  • the temperature of the internal phase is volatilized first, so that the PLGA is slowly precipitated and solidified, and magadiite
  • the nano-hybrid is formed, and the drug is contained in the hybrid, and then the water is dried to obtain a nano-hybrid drug carrier, that is, PLGA-magadiite nano-hybrid drug controlled release microsphere.
  • the model drug is a water-insoluble drug, and the volume ratio of the oil to water in step 2) is less than 1.
  • the model drug is levonorgestrel or paclitaxel.
  • the oil phase is dichloromethane or ethyl acetate.
  • the organic magnesite is one of the sodium hydroxysilicate stone modified by an organic quaternary phosphonium salt (phosphorus refers to PH4 + ), an organic quaternary ammonium salt and a silane.
  • organic quaternary phosphonium salt phosphorus refers to PH4 +
  • organic quaternary ammonium salt a silane.
  • the PLGA Preferably, the PLGA, the model drug, and the organic methicillite.
  • Method for preparing nano hybrid drug carrier by Pickering emulsion template method based on hydroxyammite emulsifier Includes the following steps:
  • the model drug is a water-soluble drug, and the volume ratio of the oil to water in step 2) is greater than 1.
  • the model drug is doxorubicin.
  • the oil phase is dichloromethane or ethyl acetate.
  • the organic magnesite is one of sodium hydroxysilicate, modified by an organic quaternary phosphonium salt, an organic quaternary ammonium salt and a silane.
  • the PLGA Preferably, the PLGA, the model drug, and the organic methicillite.
  • a nanohybrid drug carrier prepared by the method described above.
  • the nanohybrid drug carrier comprises the following components: organic methicillite, PLGA and a drug.
  • the structure of the nanohybrid drug carrier is divided into two types, which are respectively prepared by O/W type Pickering emulsion template method. Preparation of PLGA-magadiite nano-hybrid drug controlled release microspheres and W/O type Pickering emulsion template method PLGA-magadiite Nano-hybrid drug controlled release membrane.
  • the invention uses organic magadiite as an emulsifier to dissolve and disperse the organic solvent of PLGA as an oil phase preparation. Pickering drug emulsion, and then using solvent evaporation method to prepare PLGA-magadiite nano-hybrid drug controlled release carrier.
  • O/W type Pickering emulsion template preparation Preparation of PLGA-magadiite nano-hybrid drug controlled release microspheres and W/O type Pickering emulsion template method PLGA-magadiite Nano-hybrid drug controlled release membrane.
  • the drug carrier of the invention has the advantages of slowing down drug degradation, reducing drug phagocytosis by the reticuloendothelial phagocytic system, improving bioavailability, prolonging circulation time in the body and improving cell permeability;
  • the emulsion is a template, which has the advantages of no pollution, environmental friendliness, little toxicity to the human body and strong stability compared with the traditional emulsion.
  • the size regulation of the emulsion particles is achieved by adjusting the concentration of the nanoparticle emulsifier or the oil-water ratio of the emulsion. Can improve drug loading efficiency.
  • the invention has important research value and application value in biological, pharmaceutical, material and other related fields such as drug carrier, sustained-release material and catalyst carrier.
  • the present invention has the following advantages:
  • the nanohybrid drug carrier prepared by the invention is a microsphere or a porous membrane structure, and the preparation process is mild and easy to operate;
  • the invention adopts organic magadiite as an emulsifier, and can obtain a stable Pickering emulsion of O/W and W/O type by modifying magadiite with different organic reagents to obtain organic magadiite having different three-phase contact angle ⁇ values;
  • the invention adopts PLGA which is biodegradable in vitro and in vivo.
  • the polymer is non-toxic to the body and has good compatibility with the human body.
  • Figure 1 is a microscopic schematic diagram of a process for preparing PLGA-magadiite nanohybrid drug controlled release microspheres
  • Figure 2 is a microscopic schematic diagram of a process for preparing a PLGA-magadiite nanohybrid drug controlled release membrane
  • Figure 3 a is an SEM image of pure magadiite
  • Figure 3b is an SEM image of a magadiite modified with cetyltriphenyl quaternary phosphonium salt
  • Figure 4 is a polarizing microscope image of the emulsion
  • Figure 5 shows the TEM image of 5-fluorouracil encapsulated with PLGA-m agadiite.
  • Hybrid ultrasound to obtain a stable uniform milky white Pickering emulsion (see Figure 4 for a polarized microscope)
  • the solvent phase volatilization method was used to remove the ethyl acetate from the oil phase, and finally dried under vacuum at 80 ° C to obtain a nano-hybrid drug controlled release microsphere containing the drug levonorgestrel.
  • Its structure is shown in Figure 1.
  • the modified organic magnesite is supported by a hard phase, and is entangled with PLGA to form microspheres, and the drug is contained in the microspheres.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

一种以麦羟硅钠石为乳化剂的Pickering乳液模板法制备的纳米杂化药物载体及其治法，以有机麦羟硅钠石为乳化剂，可溶解分散PLGA的有机溶剂为油相制备Pickering药物乳液，再利用溶剂挥发法制备PLGA-麦羟硅钠石纳米杂化药物控释载体。

Description

以麦羟硅钠石为乳化剂的Pickering乳液模板法制备的纳米杂化药物载体及其制法
技术领域
本发明涉及药物载体领域，具体涉及一种以麦羟硅钠石为乳化剂的 Pickering 乳液模板法制备的纳米杂化药物载体及其制法。
背景技术
传统药物无控释性及组织特异性，给药后初期药物大量释放，对机体带来危害，全身释药也对正常器官组织造成损害；同时机体对药物分解排泄快，导致只有多次给药才能使药物浓度达到一定的治疗水平，这在肿瘤患者的化疗过程中尤其多见。因此将这些药物制成缓释制剂，保护其结构不被周围环境破坏，保持应有的药效，减少服药次数、提高生物利用度、降低药物的毒副作用等对治疗患者有很大的现实意义。生物可降解纳米药物载体具有减缓药物降解、减少药物被网状内皮吞噬系统吞噬、提高生物利用度、延长体内循环时间和提高细胞渗透性等优点而成为研究热点。聚乳酸 - 羟基乙酸共聚物 PLGA 具有良好的生物相容性，可体内降解，对机体无毒无害，可延缓药物释放时间，提高药物半衰期，降低药物毒性，被广泛应用于纳米药物缓释载体。然而存在的药物突释现象限制其工业化应用，有报道采用控制纳米微球粒径、微球结构修饰、聚合物联用、选用添加剂等方法控制突释。
乳液是一种热力学不稳定体系，必须向体系中加入乳化剂，通过减少两相之间的界面张力，才能获得稳定的乳液。然而，过量的非食品级传统乳化剂必须从样品中去除，否则会对人体产生伤害，影响和破坏乳液后续的应用，如乳化剂会诱导组织发炎甚至造成细胞损伤，这使得由乳化剂制备的传统乳液在医药制剂方面的应用受到限制。固体颗粒可通过界面作用阻止乳液液滴聚结，从而可代替传统的乳化剂制备稳定的 Pickering 乳液。固体物质 magadiite 可采用纯的化学试剂为原料进行合成，从而得到高纯度和稳定的产物，且合成 magadiite 的原料来源广泛与价格便宜，成本低。麦羟硅钠石无毒，不会对人体产生不良的反应，黏土与药物之间可发生相互作用，已经有结构相似的粘土应用于药物缓释体系，本发明使用 magadiite 作为乳化剂制备稳定的 Pickering 乳液，利用乳化 - 挥发法制备 PLGA-magadiite 纳米杂化药物载体。充分利用 Pickering 乳液具有无污染、环境友好、对人体毒害作用小、稳定性强等优点，通过调节纳米颗粒乳化剂的浓度或者乳液的油水比，实现对乳液粒子的尺寸调控，提高药物装载效率。
发明内容
本发明的目的在于提供一种基于麦羟硅钠石（ magadiite ）乳化剂的 Pickering 乳液模板法制备的纳米杂化药物载体及其制法，该药物载体组成包括：有机麦羟硅钠石、 PLGA 、 药物。
本发明的目的通过以下技术方案实现。
一种基于麦羟硅钠石乳化剂的 Pickering 乳液模板法制备纳米杂化药物载体的方法， 包括以下步骤：
1 ）将 PLGA 、模型药物、接触角 θ<90° 的有机麦羟硅钠石加入到油相中，机械搅拌和超声分散至均匀，得到混合物 A ；
2 ）将混合物 A 加入到去离子水中，搅拌，超声分散，得稳定的 O/W 型 Pickering 乳液；
3 ）采用溶剂挥发法，先升温将内相的有机溶剂挥发，使得 PLGA 慢慢析出固化，与 magadiite 形成纳米杂化物，药物内含于杂化物中，再干燥去除水，得到纳米杂化药物载体，即 PLGA-magadiite 纳米杂化药物控释微球 。
优选的，所述模型药物为非水溶性药物，步骤 2 ）中油水体积比小于 1 。
优选的，所述模型药物为左炔诺孕酮或紫杉醇。
优选的，所述油相为二氯甲烷或乙酸乙酯。
优选的，所述有机麦羟硅钠石是麦羟硅钠石经有机季磷盐（磷是指PH4+)、有机季铵盐和硅烷改性中的一种。
优选的，所述 PLGA 、模型药物、有机麦羟硅钠石。
一种基于麦羟硅钠石乳化剂的 Pickering 乳液模板法制备纳米杂化药物载体的方法， 包括以下步骤：
1 ）将 PLGA 与接触角 θ>90° 的有机麦羟硅钠石加入到油相中，机械搅拌和超声分散至均匀，得到混合物 B ；
2 ）把混合物 B 加入溶有模型药物的去离子水中，强烈搅拌与超声分散，得稳定的 W/O 型 Pickering 乳液；
3 ）然后用溶剂挥发法将外相的有机溶剂挥发，， PLGA 析出与 magadiite 形成纳米杂化物，药物内含于杂化物中，再升温干燥去除内相中的水，可得到纳米杂化药物控释载体，即 PLGA-magadiite 纳米杂化药物控释膜 。
优选的，所述模型药物为水溶性药物，步骤 2 ）中油水体积比大于 1 。
优选的，所述模型药物为阿霉素。
优选的，所述油相为二氯甲烷或乙酸乙酯。
优选的，所述有机麦羟硅钠石是麦羟硅钠石经有机季磷盐、有机季铵盐和硅烷改性中的一种。
优选的，所述 PLGA 、模型药物、有机麦羟硅钠石。
由以上所述的方法制备的纳米杂化药物载体。
优选的，该纳米杂化药物载体包括以下组分：有机麦羟硅钠石、 PLGA 和药物。
该纳米杂化药物载体的 结构分为两种，分别是 O/W 型 Pickering 乳液模板法制备 PLGA-magadiite 纳米杂化药物控释微球和 W/O 型 Pickering 乳液模板法制备 PLGA-magadiite 纳米杂化药物控释膜。
本发明以有机 magadiite 为乳化剂，可溶解分散 PLGA 的有机溶剂为油相制备 Pickering 药物乳液，再利用溶剂挥发法制备 PLGA-magadiite 纳米杂化药物控释载体。通过加入具有不同亲水亲油值的有机 magadiite ，从而调节油 / 水界面使之具有不同的三相接触角 θ ，制备两种具有不同结构的纳米杂化药物载体： O/W 型 Pickering 乳液模板法制备 PLGA-magadiite 纳米杂化药物控释微球和 W/O 型 Pickering 乳液模板法制备 PLGA-magadiite 纳米杂化药物控释膜。
本发明的药物载体具有减缓药物降解、减少药物被网状内皮吞噬系统吞噬、提高生物利用度、延长体内循环时间和提高细胞渗透性等优点；以 Pickering 乳液为模板，相比于传统乳液，具有无污染、环境友好、对人体毒害作用小、稳定性强等优点；通过调节纳米颗粒乳化剂的浓度或者乳液的油水比，实现对乳液粒子的尺寸调控，可提高药物装载效率。本发明在药物载体、缓释材料、催化剂载体等生物、医药、材料等相关领域都具有重要的研究价值和应用价值。
与现有技术相比，本发明具有以下优势：
1. 本发明制备的 纳米杂化药物载体 为微球或多孔膜结构，且该制备过程条件温和，操作简便；
2. 本发明采用有机 magadiite 作为乳化剂，可通过用不同的有机试剂改性 magadiite ，得到具有不同三相接触角 θ 值的有机 magadiite ，制备 O/W 和 W/O 型的稳定 Pickering 乳液；
3. 本发明采用体内体外都可生物降解的 PLGA 聚合物，对身体无毒害作用，且与人体有很好的相容性。
附图说明
图 1 为制备 PLGA-magadiite 纳米杂化 药 物控释微球的过程的微观示意图；
图 2 为制备 PLGA-magadiite 纳米杂化药物控释膜的过程的微观示意图；
图 3 a 为纯的 magadiite 的 SEM 图；
图 3 b 为十六烷基三苯基季磷盐改性的 magadiite 的 SEM 图；
图 4 为乳液的偏光显微镜图；
图 5 为 PLGA- m agadiite 包裹药物 5- 氟尿嘧啶的 TEM 图。
具体实施方式
下面结合附图和实例对本发明的具体实施作进一步说明，但本发明的实施方式不限于此。
实施例 1
称取 5g 麦羟硅钠石（ SEM 图见 图 3a ）和 1g 十六烷基 三苯基溴化磷放入到 500ml 的烧杯中，加入 100ml 的去离子水，将烧杯置于磁力搅拌水浴锅中于 80 ℃下搅拌 24 小时，待反应结束后，将产物过滤并用去离子水洗涤 3 次，将得到的滤液在 80 ℃下干燥 6h ，之后研磨得到 有机麦羟硅钠石（ SEM 图见 图 3b ） 。称取 2mg 左炔诺孕酮和 1g 有机麦羟硅钠石 以及 1g 的 PLGA 混合溶于 50ml 乙酸乙酯中，混合后置于 100ml 的烧杯中，放于磁力搅拌水浴锅中在室温下搅拌 6h 之后，置于超声环境（ 40KHz ）下超声 3h ，之后加入到去离子水中，水油体积比为 1:2 。混合超声得到稳定均一乳白色的 Pickering 乳液（偏光显微镜图见图 4 ），采用溶剂挥发法除去油相乙酸乙酯，最后在真空 80 ℃下干燥，得到包有药物左炔诺孕酮的 纳米杂化药物控释微球 。其结构示意图如图 1 所示，改性的有机麦羟硅钠石为硬相起支撑作用，和 PLGA 缠绕形成微球，药物包含于微球内。
实施例 2
称取 5g 麦羟硅钠石和 1 g 十六烷基三甲基溴化铵放入到 500ml 的烧杯中，加入 100ml 的去离子水，将烧杯置于磁力搅拌水浴锅中于 80 ℃下搅拌 24 小时，待反应结束后，将产物过滤并用去离子水洗涤 3 次，将得到的滤液在 80 ℃下干燥 6h ，之后研磨得到 有机麦羟硅钠石 。称取 1g 有机麦羟硅钠石 以及 1g 的 PLGA 混合溶于 50ml 二氯甲烷中，超声混合后置于 100ml 的烧杯中，将 2mg 阿霉素溶于 50ml 去离子水中，将油相和水相混合，水油 体积比 为 2:1 ，置于超声环境 （ 40KHz ） 下超声 3h 得到稳定的 乳白色 的 Pickering 乳液。之后，用溶剂挥发法除去油相二氯甲烷，最后在真空 80 ℃下干燥，得到含有药物阿霉素的纳米杂化药物控释膜。 其结构示意图如图 2 所示。
实施例 3
称取 5g 麦羟硅钠石和 1g 十六烷基三甲基季磷盐放入到 500ml 的烧杯中，加入 100ml 的去离子水，将烧杯置于磁力搅拌水浴锅中于 80 ℃下搅拌 24 小时，待反应结束后，将产物过滤并用去离子水洗涤 3 次，将得到的滤液在 80 ℃下干燥 6h ，之后研磨得到 有机麦羟硅钠石 。称取 2mg 5- 氟尿嘧啶 和 1g 有机麦羟硅钠石 以及 1g 的 PLGA 混合溶于 50ml 乙酸乙酯中，超声混合均匀后置于 100ml 的烧杯中，放于磁力搅拌水浴锅中在室温下搅拌 6h 之后，置于超声环境 （ 40KHz ） 下超声 3h ，之后加入到去离子水中，水油 体积比 为 8:9 。混合超声得到稳定均一 乳白色 的 Pickering 乳液，采用溶剂挥发法除去油相乙酸乙酯，最后在真空 80 ℃下干燥，得到包有药物 5- 氟尿嘧啶 的纳米杂化药物控释微球。图 5 为 PLGA- m agadiite 包裹药物 5- 氟尿嘧啶的 TEM 图。
本发明的上述实施例仅仅是为清楚地说明本发明所作的举例，而并非是对本发明的实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明权利要求的保护范围之内。

Claims (10)

  1. 一种以麦羟硅钠石为乳化剂的 Pickering 乳液模板法制备纳米杂化药物载体的方法，其特征在于， 包括以下步骤：
    1 ）将 PLGA 、模型药物、接触角 θ<90° 的有机麦羟硅钠石加入到油相中，机械搅拌和超声分散至均匀，得到混合物 A ；
    2 ）将混合物 A 加入到去离子水中，搅拌，超声分散，得稳定的 O/W 型 Pickering 乳液；
    3 ）采用溶剂挥发法，先升温将内相的有机溶剂挥发，再干燥去除水，得到纳米杂化药物载体，即 PLGA-magadiite 纳米杂化药物控释微球 。
  2. 一种以麦羟硅钠石为乳化剂的 Pickering 乳液模板法制备纳米杂化药物载体的方法，其特征在于， 包括以下步骤：
    1 ）将 PLGA 与接触角 θ>90° 的有机麦羟硅钠石加入到油相中，机械搅拌和超声分散至均匀，得到混合物 B ；
    2 ）把混合物 B 加入溶有模型药物的去离子水中，搅拌与超声分散，得稳定的 W/O 型 Pickering 乳液；
    3 ）然后用溶剂挥发法将外相的有机溶剂挥发，再升温干燥去除内相中的水，可得到纳米杂化药物控释载体，即 PLGA-magadiite 纳米杂化药物控释膜 。
  3. 根据权利要求 1 所述的方法，其特征在于， 所述模型药物为非水溶性药物，步骤 2 ）中油水体积比小于 1 。
  4. 根据权利要求 2 所述的方法，其特征在于， 所述模型药物为水溶性药物，步骤 2 ）中油水体积比大于 1 。
  5. 根据权利要求 1 所述的方法，其特征在于，所述模型药物为左炔诺孕酮或紫杉醇。
  6. 根据权利要求 2 所述的方法，其特征在于，所述模型药物为阿霉素。
  7. 根据权利要求 1 或 2 所述的方法，其特征在于，所述油相为二氯甲烷或乙酸乙酯。
  8. 根据权利要求 1 或 2 所述的方法，其特征在于，所述有机麦羟硅钠石是麦羟硅钠石经有机季磷盐、有机季铵盐和硅烷中的一种改性得到。
  9. 由权利要求 1-8 任一项所述的方法制备的纳米杂化药物载体。
  10. 根据权利要求 9 所述的纳米杂化药物载体，其特征在于，该纳米杂化药物载体包括以下组分：有机麦羟硅钠石、 PLGA 和药物。
PCT/CN2017/114187 2017-03-29 2017-12-01 以麦羟硅钠石为乳化剂的Pickering乳液模板法制备的纳米杂化药物载体及其制法 Ceased WO2018176891A1 (zh)

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