WO2007062564A1 - Composition lyophilisee de taxane-liposome et son procede preparation - Google Patents

Composition lyophilisee de taxane-liposome et son procede preparation Download PDF

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Publication number
WO2007062564A1
WO2007062564A1 PCT/CN2006/002433 CN2006002433W WO2007062564A1 WO 2007062564 A1 WO2007062564 A1 WO 2007062564A1 CN 2006002433 W CN2006002433 W CN 2006002433W WO 2007062564 A1 WO2007062564 A1 WO 2007062564A1
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Prior art keywords
liposome
taxane
lyophilized composition
docetaxel
cyclodextrin
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PCT/CN2006/002433
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English (en)
French (fr)
Inventor
Guoqin Niu
Kepan Gao
Suzhao Hu
Yong Gan
Hong Miao
Xingmei Han
Rong Shen
Li Ying
Yahong Zhao
Jiansheng Han
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Shanghai Pharmaceutical (Group) Co., Ltd.
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Publication of WO2007062564A1 publication Critical patent/WO2007062564A1/zh

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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
    • A61K9/127—Liposomes
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to pharmaceutical preparation technology, in particular to a taxane liposome lyophilized composition and a preparation method thereof.
  • Paclitaxel was launched in 1992 and was initially used as a second-line treatment for breast cancer and uterine cancer. In 1998, it was combined with cisplatin as a first-line treatment for non-small cell lung cancer and uterine cancer.
  • the dosage form of commercially available products is alcohol and Cremophore EL (polyoxyethylene castor oil glyceryl ether) delivery system, which is highly toxic, especially allergic reaction.
  • the instructions indicate that in order to prevent serious allergic reactions, all patients receiving this drug should Corticosteroids (such as dexamethasone), diphenhydramine, and H2 receptor antagonists (such as cimetidine, ranitidine) are pre-administered.
  • Docetaxel In the process of structural modification of paclitaxel, a new paclitaxel derivative, Docetaxel, was synthesized, which has better bioavailability and anticancer activity than paclitaxel, and has less toxic side effects. Approved by the US FDA in 1998 for the treatment of breast cancer and non-small cell lung cancer. At the same time, docetaxel also showed activity against ovarian cancer, Kaposi's sarcoma, leukemia, colon cancer, melanoma. Docetaxel was first marketed by AVENTIS of France in the form of TAXOTERE injection. The preparation contains a large amount of TweenSO (polysorbate 80, nonionic surfactant). The allergic reaction is serious, and it needs to be used three days before the administration. Dexamethasone was given to prevent the occurrence of allergic reactions.
  • TweenSO polysorbate 80, nonionic surfactant
  • US Patent No. 5,670,536 discloses a liposome preparation of docetaxel and a derivative thereof, which is characterized by a combination of an unsaturated phospholipid and a small amount of a negatively charged phospholipid, and a drug/phospholipid mass ratio of 3- At 20%, liposome preparations which were clarified at 20 ⁇ for 8 weeks were obtained.
  • the stability evaluation index was that the drug did not crystallize or precipitate, but there was no particle size and encapsulation stability data.
  • negative charge Phospholipid PG is extremely high in lecithin Less, not easy to get, foreign only reagent specifications, expensive.
  • US Patent Nos. 5,424,073 (1995) and 5,648,090 disclose a paclitaxel liposome formulation in which a special phospholipid, cardiolipid, is added to the main component PC.
  • This phospholipid is more specific and its molecular structure It has a large hydrophilic group and 4 aliphatic carbon chains, which can increase the ratio of encapsulated paclitaxel to total phospholipids to 9 mol%, but it is stored under 4 ,, its stability is only about one month, and cardiolipin It is also difficult to obtain, and currently only the reagent specifications are expensive.
  • Chinese patent CN1291474A discloses a paclitaxel liposome lyophilized composition and a preparation method thereof.
  • the composition of the composition is paclitaxel, phospholipid, cholesterol, mannitol or glucose, and special amino acid (such as lysine, threonine or Methionine)
  • the liposome lyophilized composition is a white-like loose mass, and its stability is as follows: storage at low temperature (2-10 degrees Celsius) 0-12 months after re-dissolution, the solution No crystals were precipitated or aggregated, but no data were reported on the change in particle size and encapsulation efficiency of the liposome composition in solution.
  • the anti-tumor drug liposome composition if the particle size in the solution is greater than 200 nm due to aggregation and fusion of the liposome, the rate of removal in the body is greatly accelerated, and the drug is not When it reaches the tumor site, it is cleared, and it does not achieve a good anti-tumor effect.
  • the technical problem to be solved by the present invention is to design a docetaxel drug liposome lyophilized composition which is low in cost and which is stable after reconstituted liposome traits.
  • the solution of the present invention is to add a cyclodextrin component to a formulation of a lyophilized composition of a docewood liposome.
  • the technique has not been reported, and it cannot be predicted based on traditional knowledge. of.
  • the present invention provides a taxane pharmaceutical liposome lyophilized composition
  • a taxane pharmaceutical liposome lyophilized composition comprising one or more phosphatidylcholines (PC), cholesterol or a derivative thereof, cyclodextrin, docetaxel and lyophilized
  • the protective agent has a taxane concentration of 3-6 mg/ml in the composition, and the composition exists in the form of a lyophilized product to facilitate storage stability, and a clear and stable liposome solution can be obtained after reconstitution and reconstruction.
  • the taxane liposome lyophilized composition of the present invention has a weight percentage of each component of: docetaxel 0.4%-1.9%, phospholipid 9.5%-25%, cholesterol 1.5%-2.3%, cyclodextrin 4.5%- 1.6%, dry excipients 84.1% - 70.2%.
  • the taxane liposome lyophilized composition of the present invention preferably has a weight percentage of each component: taxane 0.6%-1.2%, phospholipid 14.5%-22.7%, cholesterol 1.3%-2.1%, cyclodextrin 3.1 %-4.7%, lyophilized vehicle 71.6%-78.1%.
  • the docetaxel liposome composition of the present invention more preferably the weight percentage of each component is: taxane 0.7%-1.0%> phospholipid 17.0%-20.4%, cholesterol 1.7%-2.1%, cyclodextrin Fine 3.3%-3.7%, lyophilized excipients 73.5%-76.4%.
  • the taxane liposome lyophilized composition of the present invention is paclitaxel or docetaxel; and the phospholipid may be egg yolk lecithin for injection, soy lecithin and/or hydrogenated soybean lecithin;
  • the cyclodextrin may be alpha-cyclodextrin, beta-cyclodextrin or a respective derivative thereof;
  • the lyophilized excipient is sucrose, trehalose, maltose.
  • Another object of the present invention is to provide a method for preparing a lyophilized composition of a docetaxel liposome, which comprises stirring the docetaxel, rock fat, cholesterol, and cyclodextrin in the proportions of the components.
  • a method for preparing a lyophilized composition of a docetaxel liposome which comprises stirring the docetaxel, rock fat, cholesterol, and cyclodextrin in the proportions of the components.
  • anhydrous ethanol or isopropanol the solution is made into a clear solution, and then placed in a constant temperature water bath at a temperature of 30-50 ° C, the solvent is removed under reduced pressure in a rotary evaporator, and then dissolved in a pH of 6.
  • the lyophilized product prepared according to the technical scheme of the present invention has an encapsulation efficiency of more than 90% and an average particle diameter of 60-150 nm; in particular, encapsulation at 8 hours after reconstitution and dilution by 5 times with 5% glucose infusion solution The rate is still above 90%, and the average particle size is 60-150 nm.
  • the lyophilized composition of the present invention is stable in quality after storage for 12 months at a low temperature (2 ⁇ 10 ° C), and particularly has a high drug liposome encapsulation rate and 8 h (hours) after reconstitution dilution.
  • the smaller liposome size can not only meet the safety requirements of intravenous injection, but also improve the therapeutic effect of docetaxel.
  • the pharmaceutical composition of the present invention since the present invention does not contain a surfactant, the pharmaceutical composition of the present invention is not subjected to anti-allergy treatment before use, and the body does not cause an allergic reaction.
  • the present invention achieves the goal of improving the stability of the taxane liposome delivery system, and in particular, maintaining a better liposome trait maintenance for a period of time after reconstitution dilution of the liposome lyophilized composition.
  • the taxane liposome lyophilized composition prepared according to the technical scheme of the present invention is reconstituted and diluted 5 times with 5% glucose infusion solution. After that, the liposome morphology was more stable, and the average particle size was 80 nm when stored at room temperature for 8 hours, and the encapsulation efficiency was basically unchanged; and the cyclodextrin-free (CD) formulation was used (the remaining components and preparation methods are the same as the present invention,
  • the paclitaxel liposome prepared by sample No.1 was a paclitaxel liposome lyophilized composition, and the encapsulation efficiency decreased to 59.6% ⁇ 1.77% when stored at room temperature for 8 hours .
  • Table 1 'Table 1. Effect of CD on encapsulation efficiency after reconstitution of taxane liposome lyophilized product
  • the lyophilized composition of the taxol liposome prepared according to the technical scheme of the present invention is diluted 5-160 times by reconstitution (the concentration of docetaxel can be diluted to 0.01 mg/mD, and stored at room temperature for more than 20 hours, no precipitate is precipitated yet. .
  • the lyophilized composition of the docetaxel liposome prepared according to the technical scheme of the present invention is also preferable in terms of stability at low temperature (2 ° C - 10 ° C).
  • the results of the experiment showed that the encapsulation efficiency and particle size of the liposome were basically stable within 12 months of investigation.
  • the data are shown in Table 2 and Table 3: Table 2. Freeze-dried of taxane-containing liposomes Product low temperature storage encapsulation rate change. (%) Time (month) Example 3 Example 4 Example 9 Example 12 Example 13 Example 14
  • the main advantage of the yew lyophilized composition of the present invention is that
  • Freeze-drying, vacuum plugging or sealing with an inert gas yields a white block-like docetaxel liposome formulation.
  • the lyophilized product was shaken and dissolved in the same volume of water for injection to obtain a stable liposome suspension having an average particle diameter of 80 nm.
  • Freeze-drying, vacuum plugging or sealing with an inert gas yields a white block-like docetaxel liposome formulation.
  • the lyophilized product was shaken and dissolved in the same volume of water for injection to obtain a clarified stable liposome suspension having an average particle diameter of 90.
  • the liposome preparation procedure was the same as in Example 5 except that the components were as follows: 5 g egg yolk lecithin, 450 mg cholesterol, 170 mg paclitaxel, 870 mg HP-p-CD.
  • the lyophilized product was shaken and dissolved in the same volume of water for injection to obtain a clarified stable liposome suspension having an average particle diameter of 120 nm.
  • the liposome preparation procedure was the same as in Example 5 except that the components were as follows: 4 g egg yolk lecithin, 450 mg cholesterol, 170 mg docetaxel, 850 mg sulfobutyl ether-p-CD.
  • the lyophilized product was shaken and dissolved in the same volume of water for injection to obtain a clarified stable liposome suspension having an average particle diameter of 90 nm.
  • the liposome preparation procedure was the same as in Example 5 except that the components were as follows: 4 g egg yolk lecithin, 450 mg cholesterol, 170 mg docetaxel, 600 m g p-CD.
  • the lyophilized product was shaken and dissolved in the same volume of water for injection to obtain a clarified stable liposome suspension having an average particle diameter of 95 nm.
  • the liposome preparation procedure was the same as in Example 5 except that the components were as follows: 4 g egg yolk lecithin, 400 mg cholesterol, 170 mg paclitaxel, 850 mg light ethyl-P-CD.
  • the lyophilized product was shaken and dissolved in the same volume of water for injection to obtain a clarified stable liposome suspension having an average particle diameter of 125 nm.
  • the liposome preparation procedure was the same as in Example 5 except that the components were as follows: 4 g egg yolk lecithin, 450 mg cholesterol, 170 mg docetaxel, 850 mg glucosyl-p-CD.
  • the lyophilized product was shaken and dissolved in the same volume of water for injection to obtain a clarified stable liposome suspension having an average particle diameter of 90 nm.
  • the liposome preparation procedure was the same as in Example 5 except that the components were as follows: 4 g egg yolk lecithin, 500 mg cholesterol, 170 mg docetaxel, 850 mg methyl-P-CD.
  • the lyophilized product was shaken and dissolved in the same volume of water for injection to obtain a clarified stable liposome suspension having an average particle diameter of 100 nm.
  • the liposome preparation procedure was the same as in Example 5 except that the components were as follows: 5 g egg yolk lecithin, 450 mg cholesterol, 170 mg paclitaxel, 705 mg cc-CD.
  • the lyophilized product was shaken and dissolved in the same volume of water for injection to obtain a clarified stable liposome suspension having an average particle diameter of 130 nm.
  • the liposome preparation procedure was the same as in Example 5 except that the components were as follows: 4 g egg yolk lecithin, 450 mg cholesterol, 170 mg docetaxel, 826 mg methyl-a-CD.
  • the lyophilized product was shaken and dissolved in the same volume of water for injection to obtain a clarified stable liposome suspension having an average particle diameter of 120 nm.
  • the liposome preparation procedure was the same as in Example 5 except that the components were as follows: 4 g egg yolk lecithin, 450 mg cholesterol, 170 mg docetaxel, 881 mg hydroxypropyl-a-CD.
  • the lyophilized product was shaken and dissolved in the same volume of water for injection to obtain a clarified stable liposome suspension having an average particle diameter of 79 nm.

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Description

一种紫杉垸脂质体冻干组合物及其制备方法 技术领域
本发明涉及药物制剂技术， 尤其涉及一种紫杉垸脂质体冻干组合物及其制备方法。 技术背景
紫杉醇于 1992年上市， 初期用于乳腺癌与子宫癌的二线治疗， 于 1998年开始与顺 氯氨铂合用作为非小细胞型肺癌与子宫癌的一线治疗。 市售产品的剂型釆用酒精和 Cremophore EL (聚氧乙烯蓖麻油甘油醚）给药系统， 毒性大、 尤其是过敏反应， 其说明 书中指出 "为防止出现严重过敏反应， 所有接受该药病人应预先给予皮质类固醇（如地 塞米松)、 苯海拉明和 H2受体拮抗剂（如西米替丁、 雷尼替丁）"。
在对紫杉醇结构改造过程中，又新合成了紫杉醇衍生物- -- ---多烯紫杉醇（Docetaxel), 其生物利用度和抗癌活性均优于紫杉醇、而毒副作用小。 1998年经美国 FDA批准，用于 治疗乳腺癌和非小细胞肺癌。 同时多烯紫杉醇还表现出抗卵巢癌、 卡波西肉瘤、 白血病、 结肠癌、黑色素瘤的活性。多烯紫杉醇最早是由法国 AVENTIS公司以 TAXOTERE (泰素 帝)注射剂形式上市， 制剂中含有大量的 TweenSO (聚山梨酯 80， 非离子型表面活性剂）， 过敏反应严重， 其用药前三天需给予地塞米松以预防过敏反应的发生。
因紫杉垸类药物难溶于水， 脂质体剂型的紫杉垸药物研究已成为热门研究课题。 然 而， 电中性的脂质体有聚集趋势， 而疏水性的紫杉烷所具有的膜活性作用又促进了脂质 体聚集， 因此普通紫杉烷脂质体制剂的脂质体形态很不稳定， 如包封率降低、 因聚集而 形成的大颗粒和紫杉烷晶体的析出， 使得该种制剂远达不到人体静脉注射用药的安全性 要求。
曾有一些专利公开了加入某种磷脂组份， 可提高脂质体的稳定性的报道， 如： 美国专利 US 5415869 ( 1995) 揭示当加入荷负电性的磯脂， 如磷脂酰甘油酯（PG) 与磷脂酰胆碱（PC)组合成脂质体膜材， 紫杉醇约占磷脂的 3mol%左右时， 其储存稳定 性约为一周， 而载药达 4mol%时， 则只能稳定 2天。
美国专利 US 5670536(1997)公开了一种多烯紫杉醇及其衍生物的脂质体制剂，该专 利指出以不饱和磷脂和少量荷负电性磷脂为组合膜材， 药物 /磷脂质量比为 3-20%时， 可 得到于 20Ό储存维持 8周澄清的脂质体制剂， 其稳定性评价指标为药物无结晶析出或不 产生沉淀， 但没有粒径和包封率稳定性数据； 另外， 负电性磷脂 PG在卵磷脂中含量极 少， 不易得到， 国外也只有试剂规格， 价格昂贵。
美国专利 US 5424073(1995)和 US5648090(1997)公开了一种紫杉醇脂质体配方，在 主成份 PC外添加一种特别的磷脂——心磷脂（cardiolipid), 这种磷脂较为特殊， 其分 子结构具有一个较大的亲水基与 4个脂肪碳链所组成， 可使包封的紫杉醇占总磷脂比例 提升至 9mol%， 但在 4Ό以下储存， 其稳定性也仅一个月左右， 且心磷脂同样不易得到， 目前也仅有试剂规格， 价格昂贵。
由于这些用于提高稳定性的磷脂组份价格昂贵， 它们都在一定程度上限制了紫杉垸 类脂质体药物的市场化实施。
中国专利 CN1291474A揭示了一种紫杉醇脂质体冻干组合物及其制备方法， 组合物 配方组成为紫杉醇、 磷脂、 胆固醇、 甘露醇或葡萄糖， 特别添加了氨基酸 （如赖氨酸、 苏氨酸或蛋氨酸） 作为稳定剂， 所述脂质体冻干组合物为类白色疏松块状物， 其稳定性 表现为： 在低温储存（摄氏 2-10度） 0-12个月后复溶解， 其溶液中无结晶析出、不聚集， 但没有报道脂质体组合物在溶液中的粒径和包封率变化的数据。
然而， 对于抗肿瘤药物脂质体组合物来讲， 如果由于脂质体的聚集、 融合使其在溶 液中的粒径大于 200nm以上， 则其在体内的被清除速度会大大加快， 药物在未到达肿瘤 部位时即被清除， 达不到较好的抗肿瘤效果。
因此， 低成本地提高紫杉烷类脂质体药物组合物、 尤其是复溶稀释后组合物脂质体 性状的稳定性， 是本领域技术人员长期以来一直希望予以克服的技术难题。 发明内容
本发明所要解决的技术问题在于设计一种具有低成本性的、 复溶后脂质体性状仍然 稳定的紫杉垸药物脂质体冻干组合物。
本发明为了解决上述技术问题， 本发明的方案是在紫杉垸脂质体冻干组合物配方中 加入环糊精成份， 该项技术未见有相关报道， 同时也是无法根据传统见解来加以预测的。
本发明提供了一种紫杉烷药物脂质体冻干组合物， 它包括一种或多种磷脂酰胆碱 (PC),胆 醇或其衍生物、环糊精、紫杉垸和冻干保护剂， 组合物中紫杉烷药物浓度为 3-6mg/ml， 组合物以冻干品形式存在有利于其储存稳定性， 复溶重建后仍可得澄清稳定 的脂质体溶液。
本发明紫杉烷脂质体冻干组合物，其各组份重量百分比为： 紫杉垸 0.4%-1.9%、磷脂 9.5%-25%、 胆固醇 1.5%-2.3%、 环糊精 4.5%-1.6%、 干赋形剂 84.1%-70.2%。 本发明紫杉烷脂质体冻干组合物，其优选的各组份重量百分比为：紫杉烷 0.6%-1.2%、 磷脂 14.5%-22.7%、 胆固醇 1.3%-2.1%、 环糊精 3.1%-4.7%、 冻干赋形剂 71.6%-78.1%。
本发明紫杉垸脂质体冻千组合物， 其更为优选的各组份重量百分比为： 紫杉烷 0.7%-1.0%> 磷脂 17.0%-20.4%、 胆固醇 1.7%-2.1%、 环糊精 3.3%-3.7%、 冻干赋形剂 73.5%-76.4%。
本发明紫杉烷脂质体冻干组合物中， 所述的紫杉烷为紫杉醇或多烯紫杉醇； 所述的 磷脂可以是注射用蛋黄卵磷脂、 大豆卵磷脂和 /或氢化大豆卵磷脂； 所述的环糊精可以是 α-环糊精、 β-环糊精或其各自的衍生物； 所述的冻干赋形剂为蔗糖、 海藻糖、 麦芽糖。
本发明的另一目的是提供了紫杉垸脂质体冻干组合物的制备方法， 该方法是将紫杉 垸、 磯脂、 胆固醇、 环糊精按上各组份配比比例先后搅拌溶于无水乙醇或异丙醇中， 使 溶液成澄明溶液，然后放入温度为 30-50°C的恒温水浴中，在旋转蒸发器中减压除去溶剂 后成膜， 再加入溶于 pH6.8的 10mM PBS (磷酸缓冲液） 的冻干赋形剂， 水化、 超声或 均质至粒径为 0.1 μηι左右， 除菌过滤， 分装入西林瓶内， 冷冻干燥， 即得白色块状的紫 杉烷脂质体， 真空压塞或通氮气、 氦气、 氩气后压塞， 密封。
按本发明技术方案所制备的冻干品，其包封率在 90%以上，平均粒径在 60-150纳米； 尤其是在用 5%葡萄糖输液复溶稀释 5倍后 8小时时的包封率仍在 90%以上，平均粒径在 60-150纳米。
本发明的冻干组合物在低温（2Ό— 10°C )储存 12个月后仍质量稳定， 特别是在复 溶稀释后 8h (小时） 时仍具有较高的药物脂质体包封率和较小的脂质体粒径， 从而既达 到人体静脉注射用药的安全性要求、 也有利于提高紫杉垸的治疗效果。 同时， 由于本发 明不含有表面活性剂， 故本发明药物组合物在使用前不予患者抗过敏治疗， 其机体也不 会产生过敏反应。
本发明达到了提高紫杉烷脂质体给药系统的稳定性、 特别是使脂质体冻干组合物在 复溶稀释后的一段时间内仍具有较好的脂质体性状维持之目的。
经比较研究发现， 本发明紫杉垸脂质体冻干组合物与不含环糊精处方的紫杉垸脂质 体冻干组合物相比， 在相同制备方法条件下， 前者在用 5%葡萄糖输液复溶稀释 5倍后 8 小时时的脂质体包封率基本没有变化， 而后者的包封率则有非常显著的降低， 且本发明 产品在室温存放 20h时仍无沉淀析出， 显示出优越的质量稳定性。
紫杉垸脂质体冻干组合物复溶后的稳定性比较
按本发明技术方案制备的紫杉烷脂质体冻干组合物用 5%葡萄糖输液复溶稀释 5倍 后， 其脂质体形态更稳定， 在室温存放 8h时平均粒径 80纳米、 包封率基本无变化； 而 按不含环糊精（CD) 处方 （其余组份和制备方法同本发明、 其中样品 No.l 为紫杉醇脂 质体冻干组合物）制备的紫杉垸脂质体， 在室温存放 8h时的包封率降为 59.6%±1.77%; 数据见表 1 : ' 表 1. CD对紫杉烷脂质体冻干品复溶后包封率的影响 配方 样品 冻千复溶后包封率％
Oh 8h
No.l 89.9 58
不含 CD No.2 91.2 59.3
No.3 93.4 61.5
实施例 3 91.3 92.8
含 -CD 实施例 4 96.1 96.6
实施例 9 95.3 96.3
实施例 12 90 94.7
含 a -CD 实施例 13 92.2 95.3
实施例 14 91.3 96
含和不含环糊精 （CD)对紫杉烷脂质体冻干品复溶稀释并室温放置 8h时包封率的 影响有极显著的统计学意义 （P<0.001 )。
另， 按本发明技术方案制备的紫杉垸脂质体冻干组合物， 经复溶稀释 5-160倍（多 烯紫杉醇浓度可稀释至 0.01mg/mD， 室温存放 20h以上， 仍无沉淀析出。
本发明低温储存质量稳定性观察
按本发明技术方案制备的紫杉垸脂质体冻干组合物， 在低温 (2°C - 10°C )储存的稳 定性方面也较好。 实验结果表明： 在考察的 12个月内， 脂质体的包封率和粒径均基本稳 定， 数据见表 2、 表 3 : 表 2.含环糊精的紫杉烷脂质体冻干品低温储存包封率变化 .（％) 时间 （月） 实施例 3 实施例 4 实施例 9 实施例 12 实施例 13 实施例 14
0 91.3 93.1 95.3 93 92.2 92.5
1 91.8 93.5 95.1 93.6 91.8 91.3 3 91.6 93.4 94.5 93.6 92.5 92.3
6 91.9 93.6 94.8 93.3 92.1 91.8
12 91.1 93.5 94.5 92.5 91.5 91.2 含有环糊精的紫杉烷脂质体冻干组合物， 在低温条件下储存 12个月期间， 包封率变 化无显著性差异 （P>0.05)。 表 3.含环糊精的紫杉烷脂质体冻干品低温储存粒径变化 (nm) 时间 （月） 实施例 3 实施例 4 实施例 9 实施例 12 实施例 13 实施例 14
0 75.7 82.3 79.2 85.3 79.6 84.5
1 77.8 80.8 78.6 84.9 82.3 88.2
3 77.2 86.3 82.5 86.5 81.5 85.5
.6 75.3 83.9 81.6 89.1 80.9 86.2
12 76.8 89.7 90.3 99.4 95.6 89.9 含有环糊精的紫杉烷脂质体冻干组合物， 在低温条件下储存 12个月期间， 粒径变化 无显著性差异（P>0.05)。
由此， 本发明紫杉垸脂质体冻干组合物主要优点在于-
1.具有良好的储存质量稳定性， 特别是在复溶后的液态介质中具有优越的质量稳定 性， 可供临床静脉输注使用；
2.不含表面活性剂， 患者无须在用药前接受抗过敏药物治疗；
3.低成本性环糊精和低毒性溶媒的采用， 使本发明具有良好的市场化实施前景。 下面结合具体实施例， 进一步阐明本发明。 这些实施例仅用于说明本发明而不用于 限制本发明的范围。 下列实施例中未注明具体条件的方法， 通常按常规条件制备。 具体实施方式
实施例 1
紫杉垸脂质体冻干组合物制备
取 9.5g蛋黄卵磷脂， 1.5g胆固醇， 0.4g多烯紫杉醇， 4.5g HP-p-CD， 溶解于无水乙 醇， 置于圆底烧瓶中， 减压旋转蒸发成膜， 加入含 84.1g海藻糖的 pH6.8的 10mM PBS 溶液， 37°C水化 2h， 用超声波仪超声或高压均质机均质， 再用 0.22μπι滤膜过滤除菌， 分装于西林瓶内， 使每瓶含 20mg多烯紫杉醇。 进行冷冻干燥， 真空压塞或通惰性气体 封口即得白色块状多烯紫杉醇脂质体制剂。 冻干品加相同体积注射用水振摇溶解， 得澄 清稳定的脂质体悬液， 平均粒径 150nm。
实施例 2
紫杉垸脂质体冻干组合物制备
取 25g蛋黄卵磷脂， 1.3g胆固醇， 1.9g多烯紫杉醇， 1.6g HP-P-CD， 溶解于无水乙 醇， 置于圆底烧瓶中， 减压旋转蒸发成膜， 加入含 70.2g蔗糖的 pH6.8的 10mM PBS溶 液， 37°C水化 2h， 用超声波仪超声或髙压均质机均质， 再用 0.22μπι滤膜过滤除菌， 分 装于西林瓶内， 使每瓶含 20mg多烯紫杉醇。 进行冷冻干燥， 真空压塞或通惰性气体封 口即得白色块状多烯紫杉醇脂质体制剂。 冻千品加相同体积注射用水振摇溶解， 得澄清 稳定的脂质体悬液， 平均粒径 60nm。
实施例 3
紫杉垸脂质体冻干组合物制备
取 4g大豆卵磷脂， 450mg胆固醇， 170mg多烯紫杉醇， 725mg ΗΡ-β-CD, 溶解于无 水乙醇，置于圆底烧瓶中，减压旋转蒸发成膜,加入含 28.8g麦芽糖的 pH6.8的 lOmM PBS 溶液， 37°C水化 2h， 用超声波仪超声或高压均质机均质， 再用 0.22μπι滤膜过滤除菌， 分装于西林瓶内， 使每瓶含 20mg多烯紫杉醇。 进行冷冻干燥， 真空压塞或通惰性气体 封口即得白色块状多烯紫杉醇脂质体制剂。 冻干品加相同体积注射用水振摇溶解， 得澄 清稳定的脂质体悬液，平均粒径 80nm。
实施例 4 .
紫杉垸脂质体冻干组合物制备
取 3.2g蛋黄卵磷脂， 0.8g大豆卵磷脂， 405mg胆固醇， 170mg紫杉醇， 870mg ΗΡ-β-CD, 溶解于无水乙醇，置于圆底烧瓶中,减压旋转蒸发成膜，加入含 32g蔗糖的 pH6.8的 lOmM PBS溶液， 37°C水化 2h， 用超声波仪超声或高压均质机均质， 再用 0.22μπι滤膜过滤除 菌， 分装于西林瓶内， 使每瓶含 20mg多烯紫杉醇。 进行冷冻干燥， 真空压塞或通惰性 气体封口即得白色块状多烯紫杉醇脂质体制剂。 冻干品加相同体积注射用水振摇溶解， 得澄清稳定的脂质体悬液，平均粒径 145nm。
实施例 5
紫杉烷脂质体冻干组合物制备
取 3.6g蛋黄卵磷脂， 0.4g氢化大豆卵磷脂， 450mg胆固醇， 170mg多烯紫杉醇， 870mg ΗΡ-β-CD, 溶解于无水乙醇， 置于圆底烧瓶中， 减压旋转蒸发成膜， 加入含 32g蔗糖的 pH6.8的 lOmM PBS溶液， 37°C水化 2h,用超声波仪超声或高压均 机均质，再用 0.22μιη 滤膜过滤除菌， 分装于西林瓶内， 使每瓶含 20mg多烯紫杉醇。 进行冷冻干燥， 真空压 塞或通惰性气体封口即得白色块状多烯紫杉醇脂质体制剂。 冻干品加相同体积注射用水 振摇溶解， 得澄清稳定的脂质体悬液，平均粒径 90。
实施例 6
紫杉垸脂质体冻干组合物制备
脂质体制备步骤同实施例 5，只是各组分如下： 5g蛋黄卵磷脂， 450mg胆固醇， 170mg 紫杉醇， 870mg HP-p-CD。 冻干品加相同体积注射用水振摇溶解， 得澄清稳定的脂质体 悬液，平均粒径 120mn。
实施例 Ί
紫杉烷脂质体冻干组合物制备
脂质体制备步骤同实施例 5，只是各组分如下： 4g蛋黄卵磷脂， 450mg胆固醇， 170mg 多烯紫杉醇， 850mg磺丁基醚 -p-CD。 冻干品加相同体积注射用水振摇溶解， 得澄清稳 定的脂质体悬液，平均粒径 90nm。
实施例 8
紫杉烷脂质体冻干组合物制备
脂质体制备步骤同实施例 5，只是各组分如下： 4g蛋黄卵磷脂， 450mg胆固醇， 170mg 多烯紫杉醇， 600mg p-CD。 冻干品加相同体积注射用水振摇溶解， 得澄清稳定的脂质体 悬液，平均粒径 95nm。
实施例 9
紫杉垸脂质体冻干组合物制备
脂质体制备步骤同实施例 5，只是各组分如下： 4g蛋黄卵磷脂， 400mg胆固醇， 170mg 紫杉醇， 850mg轻乙基 -P-CD。 冻干品加相同体积注射用水振摇溶解， 得澄清稳定的脂 质体悬液，平均粒径 125nm。
实施例 10
紫杉垸脂质体冻干组合物制备
脂质体制备步骤同实施例 5,只是各组分如下： 4g蛋黄卵磷脂， 450mg胆固醇， 170mg 多烯紫杉醇， 850mg葡萄糖基 -p-CD。 冻干品加相同体积注射用水振摇溶解， 得澄清稳 定的脂质体悬液，平均粒径 90nm。
实施例 11 紫杉烷脂质体冻干组合物制备
脂质体制备步骤同实施例 5，只是各组分如下： 4g蛋黄卵磷脂， 500mg胆固醇， 170mg 多烯紫杉醇， 850mg 甲基 -P-CD。 冻干品加相同体积注射用水振摇溶解， 得澄清稳定的 脂质体悬液，平均粒径 100nm。
实施例 12
紫杉烷脂质体冻干组合物制备
脂质体制备步骤同实施例 5，只是各组分如下： 5g蛋黄卵磷脂， 450mg胆固醇， 170mg 紫杉醇， 705mg cc-CD。 冻干品加相同体积注射用水振摇溶解， 得澄清稳定的脂质体悬液, 平均粒径 130nm。
实施例 13
紫杉烷脂质体冻干组合物制备
脂质体制备步骤同实施例 5,只是各组分如下： 4g蛋黄卵磷脂， 450mg胆固醇， 170mg 多烯紫杉醇， 826mg 甲基 -a-CD。 冻干品加相同体积注射用水振摇溶解， 得澄清稳定的 脂质体悬液，平均粒径 120nm。
实施例 14
紫杉垸脂质体冻干组合物制备
脂质体制备步骤同实施例 5，只是各组分如下： 4g蛋黄卵磷脂， 450mg胆固醇， 170mg 多烯紫杉醇， 881mg羟丙基 -a-CD。 冻干品加相同体积注射用水振摇溶解， 得澄清稳定 的脂质体悬液，平均粒径 79nm。

Claims

权利要求
1、一种紫杉烷脂质体冻干组合物， 其特征在于该紫杉烷脂质体冻千组合物由下列重 量百分比组份组成： 紫杉烷 0.4%-1.9%、 磷脂 9.5%-25%、 胆固醇 1.5%-2.3%、 环糊精 1.6%-4.5%、 冻干赋形剂 70.2%-84.1%。
2、按权利要求 1所述的紫杉烷脂质体冻干组合物， 其特征在于该紫杉烷脂质体冻干 组合物由下列重量百分比组份组成： 紫杉垸 0.6%-1.2%、 磷脂 14.5%-22.7%、 胆固醇 1.3%-2.1%、 环糊精 3.1%-4.4%、 冻干赋形剂 71.6%-78.1% o
3、按权利要求 1所述的紫杉垸脂质体冻干组合物， 其特征在于该紫杉垸脂质体冻干 组合物由下列重量百分比组份组成： 紫杉烷 0.7%-1.0%、 磷脂 17.0%-20.4%、 胆固醇 1.7%-2.1%、 环糊精 3.3%-3.7%、 冻干赋形剂 73.5%-76.4%。
4、 按权利要求 1-3任一项所述的紫杉垸脂质体冻干组合物， 其特征在于所述的紫杉 垸脂质体冻干组合物复溶后的脂质体平均粒径为 60-150纳米。
5、 按权利要求 1-3任一项所述的紫杉烷脂质体冻干组合物， 其特征在于所述的紫杉 垸为紫杉醇、 多烯紫杉醇或其混合物。
6、 按权利要求 1-3任一项所述的紫杉垸脂质体冻干组合物， 其特征在于所述的磷脂 为蛋黄卵磷脂、 大豆卵磷脂和 /或氢化大豆磷脂。
7、 按权利要求 1-3任一项所述的紫杉烷脂质体冻干组合物， 其特征在于所述的环糊 精为 α-环糊精或其衍生物、 β-环糊精或其衍生物。
8、 按权利要求 1-3任一项所述的紫杉烷脂质体冻干组合物， 其特征在于所述的冻干 赋形剂为海藻糖、 麦芽糖或蔗糖。
9、 一种如权利要求 1-3任一项所述的紫杉烷脂质体冻干组合物的制备方法， 其特征 在于， 该方法为： 将紫杉烷与环糊精先溶解于无水乙醇或异丙醇， 再与相应配比的磷脂、 胆固醇共同溶解于无水乙醇或异丙醇中，于 30-50°C的水浴条件下减压旋转蒸发成膜，加 入冻干赋形剂 pH6.8的 10mM磷酸缓冲液， 水化， 再用高压乳勾或探头超声方法制得粒 径在 200nm以下的脂质体， 0.22μιη无菌过滤、 分装入西林瓶内， 冷冻干燥后通入氮气、 氦气或氩气， 即得紫杉烷脂质体冻干组合物。
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CN1163563A (zh) * 1994-10-24 1997-10-29 奇诺英药物化学工厂有限公司 含司来吉兰的脂质体组合物
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