WO2019051733A1 - 一种依托泊苷胶束的制备方法 - Google Patents

一种依托泊苷胶束的制备方法 Download PDF

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WO2019051733A1
WO2019051733A1 PCT/CN2017/101790 CN2017101790W WO2019051733A1 WO 2019051733 A1 WO2019051733 A1 WO 2019051733A1 CN 2017101790 W CN2017101790 W CN 2017101790W WO 2019051733 A1 WO2019051733 A1 WO 2019051733A1
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parts
tpgs
micelle
same
etoposide
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顾崧
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顾崧
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention particularly relates to a method for preparing etoposide micelles.
  • VP-16 Etoposide
  • the sugar metabolite of podophyllotoxin is a semi-synthetic antitumor drug.
  • VP-16 has a good effect on small cell lung cancer, and the effective remission rate is 40%-85%. It is also effective for other tumors such as acute leukemia, ovarian cancer, testicular tumor, malignant lymphoma. At present, VP-16 injection is commonly used in clinical practice.
  • VP-16 is insoluble in water
  • the injection contains a large amount of anhydrous ethanol, Tween 80 and polyethylene glycol 400 as pharmaceutical excipients, which may cause hypersensitivity reaction.
  • Adverse reactions such as gastrointestinal irritation and hypertension make the injection difficult to be tolerated by patients. Therefore, it is urgent to develop a safe and effective VP-16 injection to reduce the adverse reactions of VP-16 injection.
  • D- ⁇ -tocopherol-polyethylene glycol succinate is a water-soluble natural vitamin E derivative consisting of a hydrophobic vitamin E segment and a hydrophilic polyethylene glycol segment. It can be self-assembled to form micelles, and has been used as a delivery carrier for the hydrophobic antitumor drugs paclitaxel, docetaxel, doxorubicin, and the like. Vitamin E is an essential vitamin for the human body, and polyethylene glycol has been approved by the US FDA for use in the human body. Therefore, TPGS is a safe material; as a drug carrier, adverse reactions caused by other excipients can be avoided.
  • the micelle preparation method is simple and does not use toxic solvents, which can improve the safety of the preparation; at the same time, its special "hydrophilic-hydrophobic" segment constitutes a "core-shell” structure, which makes it have excellent performance for loading hydrophobic drugs. Its nano-scale size ( ⁇ 100nm) and hydrophilic shell make it have long-circulating properties and passively target tumor tissue sites, thereby improving efficacy. Micellar has become a hot spot in current research.
  • the preparation method of the etoposide micelle comprises the following steps: dissolving 3-5 parts of VP-16 and 6-12 parts of TPGS in 20-30 parts of methanol, mixing uniformly, and vacuum-steaming at 30-40 ° C The solvent is removed to obtain a uniform mixed film containing VP-16 and TPGS; 80-90 parts of ultrapure water is added, and shaken in a 90-100 ° C water bath to obtain a clear transparent solution, and the solution is filtered with a microporous membrane. It is obtained by vacuum freeze-drying; each raw material is in parts by weight.
  • VP-16 and 9 parts of TPGS are dissolved in 25 parts of methanol.
  • the solvent is removed by vacuum distillation at 35 °C.
  • the preparation method is shaken in a 95 ° C water bath.
  • the pore size of the microporous membrane is 0.22 ⁇ m.
  • the VP-16-TPGS micelle prepared by the method has a small particle size, has a high drug loading amount and an encapsulation efficiency, and has economic value.
  • the preparation method of the etoposide micelle comprises the following steps: dissolving 4 parts of VP-16 and 9 parts of TPGS in 25 parts of methanol, uniformly mixing, and vacuum-removing the solvent at 35 ° C to obtain a uniform content.
  • Mixed film of VP-16 and TPGS adding 85 parts of ultrapure water, shaking in a 95 ° C water bath to obtain a clear transparent solution, using a 0.22 ⁇ m microporous membrane to filter the solution while hot, freeze-drying is obtained; For parts by weight.
  • the preparation method of the etoposide micelle comprises the following steps: dissolving 3 parts of VP-16 and 6 parts of TPGS in 20 parts of methanol, uniformly mixing, and vacuum-removing the solvent at 30 ° C to obtain a uniform content.
  • Mixed film of VP-16 and TPGS adding 80 parts of ultrapure water, shaking in a 90 ° C water bath to obtain a clear transparent solution, using a 0.22 ⁇ m microporous membrane to filter the solution while hot, freeze-drying is obtained; For parts by weight.
  • the preparation method of the etoposide micelle comprises the following steps: dissolving 5 parts of VP-16 and 12 parts of TPGS in 30 parts of methanol, uniformly mixing, and vacuum-removing the solvent at 40 ° C to obtain a uniform content.
  • Mixed film of VP-16 and TPGS adding 90 parts of ultrapure water, shaking in a 100 ° C water bath to obtain a clear transparent solution, using a 0.22 ⁇ m microporous membrane to filter the solution while hot, and lyophilizing in vacuum; For parts by weight.
  • the VP-16-TPGS micelle prepared by the method has a small particle size, has a high drug loading amount and an encapsulation efficiency, and has economic value.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
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  • General Chemical & Material Sciences (AREA)
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Abstract

提供了一种依托泊苷胶束的制备方法，步骤如下：将3-5份VP-16和6-12份TPGS溶于20-30份甲醇中，混合均匀，30-40℃下抽真空旋蒸除去溶剂，制得均一的含VP-16和TPGS的混合薄膜；加入80-90份超纯水，90-100℃水浴中振摇，制得澄清透明溶液，用微孔滤膜趁热过滤溶液，真空冷冻干燥即得；各原料均为重量份。制得的VP-16-TPGS胶束具有较小的粒径，具有较高的载药量和包封率，具有经济价值。

Description

一种依托泊苷胶束的制备方法 技术领域
本发明具体涉及一种依托泊苷胶束的制备方法。
背景技术
依托泊苷(etoposide，VP-16)，化学名为4-去甲基表鬼臼毒素-9-(4,6-O-(R)亚乙基)-β-D-吡喃葡糖苷，鬼臼毒素的糖代谢产物，是一种半合成的抗肿瘤药物。VP-16对小细胞肺癌具有良好的疗效，有效缓解率达40％～85％；对其他多种肿瘤，如急性白血病、卵巢癌、睾丸肿瘤、恶性淋巴瘤等也有效。目前临床上常用为VP-16注射液，由于VP-16难溶于水，该注射液含有大量的无水乙醇、吐温80、聚乙二醇400作为药用辅料，易引起超敏反应、胃肠道刺激、高血压等不良反应，使得该注射液难以被患者耐受。因而亟需开发一种安全、有效的VP-16注射液，以降低VP-16注射液的不良反应。
D-α-生育酚-聚乙二醇琥珀酸酯(TPGS)是一种水溶性的天然维生素E衍生物，由疏水性的维生素E链段和亲水性的聚乙二醇链段组成，可以自组装形成胶束，已被用作疏水性抗肿瘤药物紫杉醇、多烯紫杉醇、多柔比星等的传递载体。维生素E是人体必需的一种维生素，而聚乙二醇已被美国FDA批准可用人体，因而TPGS是一种安全的材料；作为药物载体时，可避免其他辅料所引起的不良反应。
目前，纳米技术已被广泛应用到药物的传递和肿瘤治疗中。胶束制备方法简单且不使用有毒溶剂，可提高制剂的安全性；同时其特殊的“亲水-疏水”链段构成的“核-壳”结构，使其具有优异的装载疏水性药物的性能；而其纳米级别的尺寸(<100nm)及亲水的外壳，使其具有长循环的特性，并被动靶向于肿瘤组织部位，进而提高疗效。胶束已成为目前研究的热点。
发明内容
本发明的目的在于提供一种依托泊苷胶束的制备方法。
本发明通过下面技术方案实现：
一种依托泊苷胶束的制备方法，包括如下步骤：将3-5份VP-16和6-12份TPGS溶于20-30份甲醇中，混合均匀，30-40℃下抽真空旋蒸除去溶剂，制得均一的含VP-16和TPGS的混合薄膜；加入80-90份超纯水，90-100℃水浴中振摇，制得澄清透明溶液，用微孔滤膜趁热过滤溶液，真空冷冻干燥即得；各原料均为重量份。
优选地，所述的制备方法，将4份VP-16和9份TPGS溶于25份甲醇中。
优选地，所述的制备方法，35℃下抽真空旋蒸除去溶剂。
优选地，所述的制备方法，95℃水浴中振摇。
优选地，所述的制备方法，所述微孔滤膜的孔径为0.22μm。
本发明技术效果：
本方法制得的VP-16-TPGS胶束具有较小的粒径，具有较高的载药量和包封率，具有经济价值。
具体实施方式
下面结合实施例具体介绍本发明的实质性内容。
实施例1
一种依托泊苷胶束的制备方法，包括如下步骤：将4份VP-16和9份TPGS溶于25份甲醇中，混合均匀，35℃下抽真空旋蒸除去溶剂，制得均一的含VP-16和TPGS的混合薄膜；加入85份超纯水，95℃水浴中振摇，制得澄清透明溶液，用0.22μm微孔滤膜趁热过滤溶液，真空冷冻干燥即得；各原料均为重量份。
实施例2
一种依托泊苷胶束的制备方法，包括如下步骤：将3份VP-16和6份TPGS溶于20份甲醇中，混合均匀，30℃下抽真空旋蒸除去溶剂，制得均一的含VP-16和TPGS的混合薄膜；加入80份超纯水，90℃水浴中振摇，制得澄清透明溶液，用0.22μm微孔滤膜趁热过滤溶液，真空冷冻干燥即得；各原料均为重量份。
实施例3
一种依托泊苷胶束的制备方法，包括如下步骤：将5份VP-16和12份TPGS溶于30份甲醇中，混合均匀，40℃下抽真空旋蒸除去溶剂，制得均一的含VP-16和TPGS的混合薄膜；加入90份超纯水，100℃水浴中振摇，制得澄清透明溶液，用0.22μm微孔滤膜趁热过滤溶液，真空冷冻干燥即得；各原料均为重量份。
本方法制得的VP-16-TPGS胶束具有较小的粒径，具有较高的载药量和包封率，具有经济价值。

Claims (5)

  1. 一种依托泊苷胶束的制备方法，其特征在于包括如下步骤：将3-5份VP-16和6-12份TPGS溶于20-30份甲醇中，混合均匀，30-40℃下抽真空旋蒸除去溶剂，制得均一的含VP-16和TPGS的混合薄膜；加入80-90份超纯水，90-100℃水浴中振摇，制得澄清透明溶液，用微孔滤膜趁热过滤溶液，真空冷冻干燥即得；各原料均为重量份。
  2. 根据权利要求1所述的制备方法，其特征在于：将4份VP-16和9份TPGS溶于25份甲醇中。
  3. 根据权利要求1所述的制备方法，其特征在于：35℃下抽真空旋蒸除去溶剂。
  4. 根据权利要求1所述的制备方法，其特征在于：95℃水浴中振摇。
  5. 根据权利要求1所述的制备方法，其特征在于：所述微孔滤膜的孔径为0.22μm。
PCT/CN2017/101790 2017-09-14 2017-09-15 一种依托泊苷胶束的制备方法 WO2019051733A1 (zh)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112545988A (zh) * 2020-04-03 2021-03-26 南京农业大学 氢溴酸常山酮-tpgs聚合物胶束及其制备方法

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CN103142479A (zh) * 2013-03-29 2013-06-12 中国药科大学 一种磷脂-维生素e琥珀酸聚乙二醇酯胶束的应用
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* Cited by examiner, † Cited by third party
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CN112545988A (zh) * 2020-04-03 2021-03-26 南京农业大学 氢溴酸常山酮-tpgs聚合物胶束及其制备方法

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