WO2008031285A1 - Pharmaceutical composition containing docetaxel-cyclodextrin inclusion complex and its preparing process - Google Patents

Pharmaceutical composition containing docetaxel-cyclodextrin inclusion complex and its preparing process Download PDF

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Publication number
WO2008031285A1
WO2008031285A1 PCT/CN2006/002692 CN2006002692W WO2008031285A1 WO 2008031285 A1 WO2008031285 A1 WO 2008031285A1 CN 2006002692 W CN2006002692 W CN 2006002692W WO 2008031285 A1 WO2008031285 A1 WO 2008031285A1
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Prior art keywords
cyclodextrin
docetaxel
sulfobutyl
ethanol
hydroxypropyl
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PCT/CN2006/002692
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English (en)
French (fr)
Inventor
Yong Ren
Jianfeng Gao
Shuqin Yu
Ling Wu
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Nanjing Normal University
Nanjing Huge-Ring Medicine Technology Development Co., Ltd
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Application filed by Nanjing Normal University, Nanjing Huge-Ring Medicine Technology Development Co., Ltd filed Critical Nanjing Normal University
Priority to EP06804920A priority Critical patent/EP2080524A4/en
Priority to JP2009526995A priority patent/JP5103476B2/ja
Priority to US12/440,942 priority patent/US8481511B2/en
Publication of WO2008031285A1 publication Critical patent/WO2008031285A1/zh
Priority to US13/932,434 priority patent/US8765716B2/en
Priority to US14/284,152 priority patent/US20140336149A1/en

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    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • composition containing cyclodextrin/dene paclitaxel inclusion compound and preparation method thereof containing cyclodextrin/dene paclitaxel inclusion compound and preparation method thereof
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin or sulfobutyl- ⁇ -cyclodextrin and docetaxel inclusion complex and preparation method of the same .
  • Docetaxd Docetaxd or docetaxel, docetaxel (trade name: Taxotere) is a compound prepared by structural modification of the needle extract of Taxus baccata (European yew). Is a white or off-white powdery solid, the molecular formula C 43 H 53 N0 14 , chemical name [2aR-(2aa, 4p, 4aP, 6p, 9a, (aR*, pS*), l la, 12a, 12aa, 12ba) ]-P-[[(l,l-dimethylethoxy)carbonyl]amino]- ⁇ -hydroxyphenylpropionic acid [12b-acetoxy-12-benzoyloxy-2a,3,4,4a, 5,6,9,10,ll,12,12a,12b-dodecyl-4,6,11-trihydroxy-4a,8,13,13-tetradecyl-5-oxo-7,11- Indolyl-1H-cyclopentapent
  • the molecular weight is 807.19.
  • This product is a new anti-tumor drug of taxane. It is a fat-soluble compound and hardly soluble in water ( 2.903 g/mi). Due to the structural substitution of benzoyl group in paclitaxel with tert-butyloxycarbonyl, polyene Paclitaxel is slightly more water soluble than paclitaxel (0.25 ⁇ 0.60 ⁇ ⁇ /ml).
  • the anti-tumor mechanism of this product is the same as that of paclitaxel. It also exerts its anti-tumor activity by inhibiting the depolymerization of tubulin.
  • the depolymerization inhibitory activity of tubulin polymerization is about twice that of paclitaxel, and it is effective for advanced breast cancer. Better than other single-agent treatments (25% - 53%), and stronger than anthracyclines, 49% effective in treating advanced breast cancer, advanced non-alpha-cell lung cancer, advanced ovarian cancer, pancreatic cancer, head and neck cancer And gastric cancer have a good effect.
  • Docetaxel is poorly soluble in water and commonly used pharmaceutically acceptable organic solvents.
  • Clinical application for injection, confirmation The injection is prepared from docetaxel Tween solution (injection size: 1 ml, 20 mg/ml) plus 13% ethanol and physiological saline or glucose.
  • the Tween solution has low stability and needs to be stored at 2 ⁇ 8 °C at low temperature and protected from light.
  • the clinically used injection is prone to precipitation.
  • This product has similar side effects as paclitaxel. It can cause severe allergic reactions after injection. The incidence of moderate to severe allergies is as high as 25.9% (Onconlogy, 1997, 11 (7): 11 ), 75 mg / m 2 and 100 mg / m.
  • Inclusion preparations prepared using acetyl- ⁇ -cyclodextrin or hydroxypropyl- ⁇ -cyclodextrin can significantly reduce the cardiovascular and respiratory toxic side effects of the formulation, but the preferred disclosure of this patent
  • the protocol is to prepare a composition with docetaxel/hydroxypropyl- ⁇ -cyclodextrin 1: 133 mass ratio, docetaxel solubility of 0.75 mg/ml; mass ratio 1:50 docetaxel / acetyl- ⁇ -
  • the cyclodextrin composition, the paclitaxel has a solubility of up to 1.00 mg/ml.
  • docetaxel per dose (20 mg) prepared by this technique still needs to be used. Less than 1 ml of ethanol is solubilized. If the docetaxel in the prior art is used for the inclusion of cyclodextrin, the clinical drug requirements cannot be met.
  • the main problem is: the solubility of docetaxel in the preparation after cyclodextrin inclusion is still low, and the clinical use is inconvenient (required) A large amount of solvent), it is difficult to reach the dosage requirements suitable for the application; the use of a large amount of cyclodextrin seriously affects the practical application effect; the inclusion compound is solubilized with a high-dose organic solvent, which is not conducive to the solubilization of cyclodextrin, and also increases the preparation
  • the irritancy reduces patient compliance.
  • the current technology only focuses on the pharmaceutically stable stability of the formulation (whether the solution is clarified/precipitated), while ignoring/ignoring the chemical stability of the drug in the formulation, especially in the solution.
  • cyclodextrin has the property of catalyzing ester compounds (Organic Chemistry, 2002; 22(11): 827-834), docetaxel containing ester-based side chains may tend to be in solution due to inclusion of cyclodextrin. Stabilization may also accelerate decomposition due to the catalysis of cyclodextrin (resulting in reduced stability), and the effect of inclusion on stability is directly related to the cyclodextrin structural shield (cyclodextrin). These factors make it difficult to promote the application of the prior art. Therefore, use less cyclodextrin, use as little or no organic solvent as possible to increase the solubility of docetaxel to meet the requirements for clinical application, and must maintain sufficient medicinal and chemical stability of the drug. At present, cyclodextrin inclusion technology is applied to the technical difficulties of docetaxel.
  • cyclodextrin and cyclodextrin derivatives currently available for injection are only (X-cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin and sulfobutyl- ⁇ -cyclodextrin (Expert Opin Drug Deliv, 2005). Mar; 2(2): 335 - 51 ), wherein hydroxypropyl- ⁇ -cyclodextrin is a non-ionized neutral derivative, and sulfobutyl- ⁇ -cyclodextrin is an ionized derivative.
  • sulfobutyl- ⁇ -cyclodextrin has a more significant improvement in safety, stability, drug solubilization and production preparation techniques.
  • CN 1800221A novel cyclodextrin derivative hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin
  • the present invention employs hydroxypropyl- Sulfobutyl- ⁇ -cyclodextrin or sulfobutyl- ⁇ -cyclodextrin improves docetaxel, and low ratio (mass ratio 1:17) inclusion complex can make docetaxel solubility up to 15 mg/ml Above, the prepared injection has good pharmacy, chemical stability, strong activity and low irritation, and the clathrate solid is diluted 500 times. Stable for several days, has important clinical application value.
  • the object of the present invention is to overcome the defects of low solubility of docetaxel in the preparation of the prior art; the chemical stability of pharmacy; the high proportion of cyclodextrin; the defects of residual organic solvents, and the realization of technical breakthroughs in the field, providing a A cyclodextrin docetaxel-stable inclusion complex with high solubility and pharmaceutical stability of docetaxel, a low cyclodextrin ratio, and little residual organic solvent for clinical use.
  • the present invention also provides a process for the preparation of such a clathrate.
  • the pharmaceutical composition containing the cyclodextrin/polyene paclitaxel inclusion compound means a composition obtained by the following preparation method:
  • the filtrate is decompressed to remove ethanol to obtain a liquid clathrate
  • the water is removed under reduced pressure and dried to obtain a solid clathrate.
  • the resulting clathrate contains a small amount or a trace amount of ethanol.
  • small or trace amount of ethanol means: the solid inclusion compound has an ethanol content of less than 2%.
  • the invention adopts hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin or sulfobutyl- ⁇ -cyclodextrin to be mixed with the docetaxel raw material solution with an appropriate amount of ethanol under the condition of aqueous solution, and the added ethanol can promote the cooperation of the package.
  • the ethanol is removed to obtain a stable docetaxel/cyclodextrin inclusion compound, and the inclusion compound is compounded with a common medicinal auxiliary material to prepare a packaged pharmaceutical composition for clinical use.
  • the solubility of docetaxel is increased, stability is increased, side effects are reduced, and a docetaxel product having clinical application value is obtained.
  • the preparation of clathrates is the key to the technology of the present invention.
  • the sulfobutyl- ⁇ -cyclodextrin used in the present invention is an ionized cyclodextrin derivative, and its pharmaceutically acceptable sulfobutyl- ⁇ -cyclodextrin is a 6 to 7 substituted product (SBEH3-CD, trade name Captisol ); we develop Hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin (HP-SBE-P-CD) is a novel cyclo-purified derivative (CN 1800221A) substituted with a mixture of hydroxypropyl and sulfobutyl groups. Low, inclusion performance is better than sulfobutyl- ⁇ -cyclodextrin, more suitable for non-oral preparations.
  • Docetaxel is formulated with as little ethanol as possible in hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin, or sulfobutyl- ⁇ -cyclodextrin, or sulfobutyl- ⁇ -cyclodextrin a pure aqueous solution of a mixture of hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin, and a solution of docetaxel in ethanol is added dropwise with stirring;
  • the filtrate is depressurized to remove ethanol, to obtain a liquid clathrate, or to remove ethanol under reduced pressure, and then to remove water under reduced pressure, and dry to obtain a solid docetaxel inclusion compound having a content of not more than 2% ethanol.
  • the specific steps of the method for preparing a pharmaceutical composition containing a cyclodextrin/dene paclitaxel inclusion complex of the present invention are:
  • cyclodextrin mass ratio of 1:17 which means: hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin, or sulfobutyl- ⁇ -ring Dextrin, or a mixture of sulfobutyl- ⁇ -cyclodextrin and hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin mixed with 2-10 times of pure water, slowly added to the mixture under stirring a solution prepared from cedarol and ethanol (the amount of ethanol is the amount required to dissolve docetaxel), and when docetaxel is added, it can be heated and stirred at room temperature or at 25 to 65 ° C, and stirred to form an inclusion compound.
  • the mixture was filtered through a 0.2 to 0.4 ⁇ m microporous membrane filter, and then an aqueous solution of docetaxel containing a small amount or a trace amount of ethanol obtained by ethanol was removed as much as possible under reduced pressure.
  • the solid inclusion compound prepared by the invention has high water solubility and is easy to dissolve without adding other auxiliary solvents, and the prepared aqueous solution has small side effects of hemolysis and is suitable for clinical use.
  • the solid inclusion compound containing the clinically administered dose of 20 mg of docetaxel and the physiological saline solution for injection can be kept stable for several days after being formulated into a solution.
  • the other isotonic doses of the medicinal excipients do not substantially affect the solution. Stability.
  • the solid clathrate is diluted with a conventional injectable pharmaceutical excipient solution to a suitable concentration and sterilized, and the resulting composition solution is ready for injection.
  • Ultraviolet absorption in the determination system is an effective method for judging the cooperation of the package ("cyclodextrin chemistry", Science Press, 2001, P135).
  • Ultraviolet spectroscopy experiments showed that the UV absorption of docetaxel in aqueous solution changed with the concentration of cyclodextrin (non-absorption of cyclodextrin itself) (Fig. 1).
  • concentration of cyclodextrin increased, the UV absorption of docetaxel was significantly enhanced, indicating that docetaxel has a distinct and strong inclusion complex with the cyclodextrin used in the present invention.
  • Inclusion stability constant Ka is a measure of the degree of inclusion.
  • UV spectrophotometry is a common method for determining Ka. Changing the concentration of cyclodextrin makes the UV absorption of docetaxel (constant concentration) solution change regularly, so as to obtain the relationship between cyclodextrin concentration (C) and UV absorbance (A). The relationship between 1/C and 1/A can be obtained.
  • the cyclodextrin used in the present invention not only has a large inclusion constant Ka, but also related experiments of the present invention have found that the presence of ethanol can significantly increase the Ka value and enhance the inclusion ability of the cyclodextrin, thereby promoting the inclusion. Ethanol is not only used as a co-solvent during the inclusion process.
  • Peak change about 360 °C melting endothermic decomposition.
  • the physical mixture maintains the endothermic peak characteristics of cyclodextrin and docetaxel.
  • the dehydrated endothermic bees and phase transition peaks disappeared, and a new phase transition peak appeared at about 180 °C, 360 °.
  • the exothermic decomposition of C has a significant change in the position (temperature) and shape (thermal effect) of each peak, thus indicating that the inclusion compound has formed.
  • the residual amount (%) of ethanol in the preparation of the inclusion compound was obtained in multiple batches. The results are shown in Table 2.
  • the stability of the drug composition includes the chemical stability of the drug and the pharmaceutically stable stability of the composition. Solid inclusion stability
  • HPLC chromatographic conditions column 008 (: 18 (25011111 ⁇ 4.6 ⁇ ); mobile phase, water: B Nitrile (53: 47); flow t lO ml/min; detection wavelength 230 nm; measurement time: 30,00 minutes; detection sensitivity 1.0000 AUFS.
  • Sample docetaxel starting material; docetaxel/sulfobutyl- ⁇ -cyclodextrin inclusion complex (a, mass ratio 1:17); docetaxel/hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin Inclusion complex (b, mass ratio 1:17). Take docetaxel raw materials and inclusion complexes, and divide 3 parts into test samples, respectively, for light, high temperature and high humidity force P speed test:
  • Inclusion complex a 99.684 96.478 94.235 95.331 Inclusion compound b 99.645 97.985 95.407 95.310
  • the color of docetaxel raw material is slightly deeper and the content is more obvious; the color of the inclusion compound is unchanged, the content is reduced little, and the impurities are basically No change.
  • the results showed that the docetaxel in the solid inclusion compound was chemically stable, and the inclusion technique was effective in improving the stability of docetaxel.
  • Solution stability shield ratio 1:17 Solid inclusion compound is dissolved in a solution containing docetaxel 15 mg/ml with physiological saline or isotonic glucose solution, and diluted 1-1000 times after sterilization to prepare different concentrations of injection. The liquid was observed continuously for 5 hours to 10 days, and the stability test results of the physiological saline dilution system of the docetaxel/hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin inclusion compound are shown in Table 5, Table 5 Dextrin inclusion docetaxel injection solution state drug concentration solution state*
  • the hemolytic activity of the solution prepared with the inclusion compound physiological saline was significantly different from that of the existing docetaxel preparation.
  • the sulfobutyl- ⁇ -cyclodextrin inclusion complex diluting solution (a) has only a slight hemolysis, and the hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin inclusion compound (b) has a lower hemolytic effect and is clinically administered.
  • the concentration range (docetaxel content of about 0.08 mg/ml) is substantially free of hemolysis, while the existing docetaxel preparation has a hemolysis of more than 20%. The results are shown in Figure 4.
  • the inclusion compound significantly improves the solubility of docetaxel (up to 15mg/ml), and the solution can be kept clear and stable for a long time after dilution, and has low hemolysis, small toxic and side effects, and good drug activity.
  • the solid and liquid samples are stable, and the drug/cyclodextrin ratio In small cases, the dosage of cyclodextrin in the preparation is low, which is suitable for clinical use.
  • the clathrate of the present invention has less residual organic solvent, which is advantageous for improving the safety of administration.
  • the preparation method is simple, the operation is simple, the cost is low, and there is no environmental pollution.
  • the inclusion complex is stable in nature and has good compatibility with other pharmaceutical excipients, and is convenient for preparation of the preparation.
  • the injection prepared by the inclusion compound has no corrosive components and is non-toxic, and is convenient for clinical use and practical.
  • Figure 1 Ultraviolet absorption scan of docetaxel at different concentrations of hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin in 7J solution (220 nm ⁇ 245 nm);
  • Figure 3 HPLC chromatogram of the high temperature test (5 days) of the docetaxel starting material
  • Figure 4 Commercially available docetaxel formulation, docetaxel/hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin inclusion complex, docetaxel/tradoxy- ⁇ -cyclodextrin inclusion complex diluted with physiological saline Solution, docetaxel concentration - hemolysis curve.
  • Example 1 1.70 g of hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin was mixed with 5.0 ml of pure water, and a solution of 100.0 mg of paclitaxel and 1.0 ml of ethanol was slowly added dropwise with stirring, and the mixture was thoroughly mixed and stirred until the system was stirred. Completely dissolved, 'filtered with 0.2 ⁇ 0.4 ⁇ pore filter, the filtrate was evaporated under reduced pressure at 55 ° C. After sterilization, the water was evaporated to dryness under reduced pressure. The solid was dried under reduced pressure for 48 hours to give a white solid. Inclusion compound.
  • Example 2 Basically the same as Example 1, but wherein hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin is
  • Example 3 Basically the same as Example 1, but the docetaxel therein was 170 mg.
  • Example 4 Basically the same as Example 1, except that the cyclodextrin was sulfobutyl- ⁇ -cyclodextrin.
  • Example 5 Basically the same as Example 2, but the cyclodextrin therein was sulfobutyl- ⁇ -cyclodextrin.
  • Example 6 Basically the same as Example 3, except that the cyclodextrin was sulfobutyl- ⁇ -cyclodextrin.
  • Example 7 Basically the same as Example 1, except that the cyclodextrin was a mixture of sulfobutyl- ⁇ -cyclodextrin and hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin in a mass ratio of 1:1.
  • Example 8 Basically the same as Example 2, except that the cyclodextrin was a mixture of sulfobutyl- ⁇ -cyclodextrin and hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin in a mass ratio of 1:50.
  • Example 9 Basically the same as Example 3, except that the cyclodextrin was a mixture of sulfobutyl- ⁇ -cyclodextrin and hydroxypropyl-t-butyl- ⁇ -cyclodextrin in a ratio of 50:1.
  • Example 10 Basically the same as Example 1, except that cyclodextrin, docetaxel and pure water were first mixed, and ethanol was slowly added dropwise with stirring until the system was completely dissolved.
  • Example 11 Basically the same as Example 1, except that the obtained powdery clathrate was diluted with an isotonic concentration of glucose injection.
  • Example 12 Basically the same as in Example 1, except that the obtained powdery clathrate was diluted with an isotonic concentration of fructose injection.

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Description

含有环糊精 /多烯紫杉醇包合物的药物组合物及其制备方法
技术领域
本发明涉及的是一种含有羟丙基-磺丁基 -β-环糊精或磺丁基 -β-环糊精与 多烯紫杉醇包合物的药物组合物以及该药物組合物的制备方法。
背景技术
多烯紫杉醇 （Docetaxd )或称多西紫杉醇、 多西他赛（商品名： 泰索 帝 Taxotere)是由浆果紫杉（ Taxus baccata , European yew )针叶提取物经结 构修饰而合成制备的化合物，为白色或类白色粉状固体，分子式 C43H53N014, 化学名 [2aR-(2aa，4p,4aP,6p,9a,(aR*，pS*),l la,12a,12aa,12ba)]-P-[[(l，l-二甲 基乙氧基）羰基]氨基] -α-羟基苯丙酸 [12b-乙酰氧 -12-苯曱酰氧 -2a，3,4,4a,5,6,9,10,l l,12，12a，12b-十二氢 -4，6，11-三羟基 -4a，8,13,13-四曱基 -5- 氧代 -7,11-亚曱基 -1H-环癸五烯并 [3,4]苯并 [1,2-b]氧杂丁环 -9-基]^旨三水合 物。 分子量 807.19, 本品属紫杉类新型抗肿瘤药物， 为脂溶性化合物， 难溶 于水（ 2.903 g/mi ), 由于结构上以特丁氧羰基取代了紫杉醇中的苯曱酰基， 因而多烯紫杉醇水溶性略大于紫杉醇（ 0.25 ~ 0.60μβ /ml )。
本品抗肿瘤机制与紫杉醇相同，也是通过抑制微管蛋白解聚来发挥其抗 肿瘤活性， 但在微管蛋白聚合的解聚抑制活性约为紫杉醇的 2倍， 对晚期 乳腺癌效果较好 ，优于其它单种药治疗 (25 % - 53 %)的结果,也强于蒽环类 药物， 治疗晚期乳癌有效率达 49%, 对晚期非 α细胞肺癌、 晚期卵巢癌、 胰 腺癌、 头颈癌及胃癌皆有较好疗效。
多烯紫杉醇难溶于水， 及常用的药用有机溶剂。 临床应用为注射剂， 确 认 本 其注射液由多烯紫杉醇吐温溶液（注射剂规格： 1ml, 20mg/ml )加 13%乙 醇及生理盐水或葡萄糖配制而成。 其吐温溶液稳定性较低， 需置于 2 ~ 8°C低 温避光保存， 临床使用的注射液容易析出沉淀。 本品有与紫杉醇相似的毒副 作用， 注射后容易引起较严重的过敏反应， 中重度过敏发生率高达 25.9% ( Onconlogy, 1997,11(7):11 ), 75 mg/ m2和 100mg/ m2剂量使用时， 中度以上 过敏发生率分别为 31%和 41.3%, 注射部位反应率也较高达 13.3% ( Cancer, 1995,754:968 )。 故使用多烯紫杉醇时需要作防过敏反应处理， 从使用多烯 紫杉醇治疗前 1 天晚 8 点开始服用大剂量激素， 一般口服地塞米松 4.5 mg 每曰早晚各一次， 连服 3 ~ 5 天， 注射多烯紫杉醇前 30 ~ 60分肿肌注苯海 拉明 40mg、 静注西咪替丁 300mg, 以预防超敏反应。 为防止胃肠道反应， 常规于化疗开始前 30 min静注恩丹西酮或奈西雅。 另外， 临床使用多烯紫 杉醇也颇为烦瑣，输液过程中需严密观察输液部位有无渗漏，如有渗漏必须立 即更换注射部位，并行局部封闭，并且外用喜疗妥软膏（每天 3 次治疗数天）。 同时， 用药期间需常规心电监护， 密切观察呼吸、 心率、 血压变化， 高度警 惕过敏反应的发生， 务必做好严重过敏反应的医护抢救准备。 目前， 改进多 烯紫杉醇制剂稳定性， 降低毒副作用是人们广泛关注的技术难点。
近年来对紫杉烷类剂型研究主要以脂质体、纳米粒、白蛋白交联前体物、 环糊精包合物等为研究热点， 其技术关键集中在选用材料的生物相容性、体 内耐受性、紫杉綻化合物增溶效果及剂型稳定性等问题方面。与紫杉醇一样， 多烯紫杉醇的制剂改进中环糊精包合技术应用日益增多， 乙酰 -环糊精、 羟丙基 -β-环糊精及 2,6-二甲基 -β-环糊精已有用于多烯紫杉醇的改进研究的 报道。 目前的研究显示，应用环糊精包合技术不仅能增强多烯紫杉醇稳定性、 提高溶解度， 而且可以大幅度提高药物活性， 降低毒副作用， 使用甲基 -β- 环糊精包合多烯紫杉醇等多种药物， 测定其对多种肿瘤细胞活性 IC50的影 响 （European Journal of Cancer, 1998, 34: 168-174 )发现， 加入甲基 -β-环 糊精后， 多烯紫杉醇 IC50 CD降低最显著， 不同细胞的 IC5。/IC5。CD 比值变化 在 4.7 ~ 14.3之间， 证明： 环糊精包合能够显著增强多烯紫杉醇活性。 采用乙 酰 -β-环糊精或羟丙基 -β-环糊精（WO9924073; CN1222321/ ZL 98811010.5 ) 制备的包合制剂可显著降低制剂的心血管和呼吸系统毒副作用，但是该专利 公开的优选方案是以多烯紫杉醇 /羟丙基 -β-环糊精 1: 133 质量比制备组合 物， 多烯紫杉醇溶解度为 0.75mg/ml; 质量比 1: 50的多烯紫杉醇 /乙酰基 -γ-环 糊精組合物， 多婦紫杉醇的溶解度可达 1.00mg/ml, 尽管多烯紫杉醇的溶解 度有所提高， 但是该技术制备的每剂量规格 ( 20 mg ) 的多烯紫杉醇注射液 仍然需要使用不少于 1 ml的乙醇助溶。 如果采用现有技术对的多烯紫杉醇 进行环糊精的包合， 无法达到临床的药物要求， 主要问题是： 环糊精包合后 制剂的多烯紫杉醇溶解度仍然偏低， 临床使用不便（需大量溶剂）， 难以达 到适合应用的剂量要求； 使用大量环糊精， 严重影响实际应用效果； 包合物 配合高剂量有机溶剂增溶， 即不利于环糊精的增溶作用， 也增加了制剂的刺 激性， 降低了患者使用顺应性。 技术方法方面， 目前的技术仅仅注重制剂的 药剂学稳定性（溶液是否澄清 /沉淀）， 而无视 /忽视制剂中尤其是溶液中药物 的化学稳定性。 由于环糊精具有催化酯类化合物的特性 （有机化学， 2002;22(11)： 827-834 ),含酯基侧链的多烯紫杉醇在溶液中即可能由于环糊精 的包合而趋向稳定化， 也可能因为环糊精的催化而加速分解（导致稳定性降 低）， 包合作用对稳定性的影响与环糊精结构性盾（环糊精品种）直接相关。 这些因素导致现有技术难以推广应用。 因此， 使用较少的环糊精、 尽可能不 使用或少使用有机溶剂提高多烯紫杉醇溶解度，使之达到适合临床应用剂量 的要求， 同时必须保持药物具有足够的药剂学和化学稳定性， 是目前环糊精 包合技术应用于多烯紫杉醇的技术难点。
目前能 用于注射的环糊精及环糊精衍生物仅有 （X-环糊精、 羟丙基 -β- 环糊精和磺丁基 -β-环糊精 ( Expert Opin Drug Deliv, 2005 Mar;2(2): 335 - 51 ), 其中羟丙基 -β-环糊精是非离子化的中性衍生物， 磺丁基 -β-环糊精是离子化 的衍生物。 研究表明 （药学前沿， 中国医药科技出版社， 2001: 46-59 )， 磺 丁基 -β-环糊精在安全性，稳定性， 药物增溶作用及生产制备技术等方面都具 有更为显著的提高。 近来我们研制开发了新型环糊精衍生物羟丙基-磺丁基 -β-环糊精（ CN 1800221A )， 该新型衍生物具有优良的性能和良好的安全性。 本发明采用羟丙基-磺丁基 -β-环糊精或磺丁基 -β-环糊精改进多烯紫杉醇， 低 配比的 （质量比 1: 17 ) 包合物即可使多烯紫杉醇溶解度达 15 mg/ml 以上， 其制备的注射液药剂学、 化学稳定性好、 活性强且刺激性小， 包合物固体稀 释 500倍可稳定保存数天， 具有重要临床实际应用价值。
发明内容
本发明的目的是： 克服现有技术制剂中多烯紫杉醇溶解度低； 药剂学化 学稳定性较 ; 环糊精比例过高； 残留有机溶剂多等缺陷， 实现了该领域内 的技术突破， 提供一种多烯紫杉醇溶解度和药剂学稳定性高、 环糊精比例较 低、 有机溶剂残留少的环糊精多烯紫杉醇稳定包合物， 以实现临床使用。 本 发明还将提供这种包合物的制备方法。
完成本发明的技术方案是： 含有环糊精 /多烯紫杉醇包合物的药物组合 物， 由多烯紫杉醇、 环糊精与药用辅料组成， 其中多烯紫杉醇与环糊精的质 量比为 1 ： 10 ~ 150， 所述的环糊精是： 羟丙基-磺丁基 -β-环糊精， 或磺丁基 -β-环糊精， 或磧丁基 -β-环糊精与羟丙基-磺丁基 -β-环糊精任意比例的混合 物； 环糊精包合多烯紫杉醇的稳定常数 Ka = 2056M -1〜 13051Μ·1 。
对该包合态药物组合物的进一步限定，所述的含有环糊精 /多烯紫杉醇包 合物的药物组合物， 是指用以下制备方法得到的组合物:
在羟丙基-磺丁基 -β-环糊精， 或磺丁基 -β-环糊精， 或磺丁基 -β-环糊精与 羟丙基-磺丁基爷环糊精混合物的純水溶液中， 搅拌下滴加多烯紫杉醇的乙 醇溶液；
体系溶解后以 0.2 ~ 0.4μιη微孔滤膜过滤；
滤液减压除乙醇， 得到的液体包合物；
或减压除乙醇后再减压除水， 干燥， 得到的固体包合物。 所得的包合物 含有少量或微量乙醇。 所说的 "少量或微量乙醇" 是指： 固体包合物中乙醇 含量小于 2% 。
本发明采用羟丙基-磺丁基 -β-环糊精或磺丁基 -β-环糊精在水溶液条件下 与加有适量乙醇的多烯紫杉醇原料溶液混合， 加入的乙醇可促进包合作用， 生成包合物后除去乙醇，制得稳定的多烯紫杉醇 /环糊精包合物，其包合物与 常用药用辅料复合， 制备成为可供临床使用的包合态药物组合物， 从而提高 多烯紫杉醇的溶解度、 增加稳定性、 降低副作用， 获得具有临床应用价值的 多烯紫杉醇产品。 制备包合物是本发明的技术关键。
本发明使用的磺丁基 -β-环糊精是离子化的环糊精衍生物，其药用的磺丁 基 -β-环糊精是 6〜7取代的产物（SBEH3-CD， 商品名 Captisol ); 我们研制开 发的羟丙基-磺丁基 -β-环糊精 ( HP-SBE-P-CD )是以羟丙基和磺丁基混合取 代的新型环 ^精衍生物（CN 1800221A ), 该产品毒性低， 包合性能优于磺 丁基 -β-环糊精， 更适合用于非口服制剂。
上述方案实现的关键、 也是本发明的第二发明任务的技术方案是： 含有 环糊精 /多烯紫杉醇包合物的药物組合物的制备方法， 步骤如下，
多烯紫杉醇与尽可能少的乙醇配制成溶液，在羟丙基-磺丁基 -β-环糊精， 或磺丁基 -β-环糊精， 或磺丁基 -β-环糊精与羟丙基-磺丁基 -β-环糊精的混合物 的纯水溶液中， 搅拌下滴加多烯紫杉醇的乙醇溶液；
体系溶解后以 0.2 ~ 0.4μιη 孔滤膜过滤；
滤液减压除乙醇， 得到液体包合物 、 或减压除乙醇后再减压除水， 千燥， 得到含量不高于 2% 乙醇的固体多 烯紫杉醇包合物。
更优化和更具体地说，本发明的含有环糊精 /多烯紫杉醇包合物的药物组 合物的制备方法的具体步骤是：
用多烯紫杉醇 ： 环糊精质量比 1 ： 17的比例配制环糊精的纯水溶液， 该溶液是指： 羟丙基-磺丁基 -β-环糊精， 或磺丁基 -β-环糊精， 或磺丁基 -β-环 糊精与羟丙基-磺丁基 -β-环糊精的混合物与 2 ~ 10倍质量的纯水混合制成的 溶液， 搅拌下緩慢加入比例多烯紫杉醇与乙醇配制的溶液（乙醇用量是以能 够溶解多烯紫杉醇为度所需要的量）， 加入多烯紫杉醇时可室温也可在 25 ~ 65°C间加热搅拌， 搅拌加热生成包合物后， 以 0.2 ~ 0.4μιη微孔滤膜过滤， 然后减压尽量除去乙醇得到的含有少量或微量乙醇的多烯紫杉醇水溶液。
将上述多烯紫杉醇水溶液减压除水至尽，再减压真空干燥后即得多浠紫 杉醇的固体包合物。
本发明制备的固体包合物水溶性高， 易于溶解而不需加入其他助溶剂， 配制的水溶液溶血副作用小， 适宜临床使用。 含有临床给药剂量 20mg多烯 紫杉醇的固体包合物加注射用生理盐水稀鋒 10~1000倍配制成溶液后数天内 皆能够保持稳定， 加入的其他等渗剂量的药用辅料基本不影响溶液的稳定 性。
该固体包合物与常用的含有可注射的药用辅料溶液稀释到适当浓度经 灭菌处理后， 所得的组合物溶液可供注射使用。
包合作用的驺 ^正：
测定体系紫外吸收是判断包合作用的有效方法（《环糊精化学》， 科学出 版社 2001 , P135 )。 紫外光谱实验发现， 水溶液中， 多烯紫杉醇的紫外吸收 随环糊精（环糊精自身无吸收）浓度的变化而发生改变（附图 1 )。 随环糊精 浓度的增大， 多烯紫杉醇紫外吸收明显增强， 说明多烯紫杉醇与本发明使用 的环糊精存在明显而强的包合作用。
包合稳定常数的测定：
包合稳定常数 Ka是包合作用程度的量度， 紫外分光光度法是测定 Ka 的常用方法。 改变环糊精浓度使多烯紫杉醇（浓度恒定）溶液紫外吸收呈现 规律性变化， 从而获得环糊精浓度 ( C )与紫外吸光度 ( A )的关系， 由 1/C 与 1/A关系曲线可定量计算出环糊精 /多烯紫杉醇的表观一级包合稳定常数 Ka, 同时实验测定了加入乙醇对 Ka的影响变化， 各种环糊精的 Ka见表 1 :
表 1 多烯紫杉醇 /环糊精的表观一级包合稳定常数 Ka (Μ'1; 231nm) a
环糊 精
¾0 60% EtOH
磺丁基 -β-if糊精 2056 6968 羟丙基-磺丁基 -β-环糊精 13051 30117
羟丙基 -β-环糊精 582 2694
β-环糊精 379
结果显示多烯紫杉醇的包合中， β-环糊精和羟丙基 -β-环糊精包合常数小 于本发明使用的环糊精，这可能是使用该两种环糊精的现有技术效果较差的 重要原因。 本发明使用的环糊精不仅具有较大的包合常数 Ka, 而且本发明 的相关实验发现， 乙醇的存在能够显箸提高 Ka值， 增强环糊精的包合能力 因而具有促进包合的作用， 包合过程中乙醇不仅仅是作为助溶剂。 一般情况 下， 有机溶剂与药物竟争包合， 乙醇通常表现为降低药物 Ka的效应 （中国 药科大学学报， 2005, 36 ( 1 ): 13-17 )。 与羟丙基 -β-环糊精不同， 本发明使 用的环糊精在蒸除乙醇后的纯水条件下仍然具有较大的 Ka , 足以生成稳定 的包合物， 因而本发明在包合物形成后将乙醇尽量去除， 以获得较纯净的药 物包合物， 尽可能降低乙醇对药物产生的影响。 利用乙醇对多烯紫杉醇包合 作用的影响制备包合物是本发明成功的技术基础。
包合物制备及验证：
采用加入适量乙醇使包合充分作用后， 再减压除去乙醇， 经干燥制备了 多种比例的多烯紫杉醇 /环糊精包合物， DTA 实脸证实固体物为包合物而非 简单的物理混合物。 以盾量比 1: 17的多烯紫杉醇 /磺丁基 -β-环糊精包合物 为例分析说明：
称取多烯紫杉醇、 磺丁基 -β-环糊精、 多烯紫杉醇与磺丁基 -β-环糊精物 理混合物、 包合物共四种样品各约 5.0mg, 进行差示扫描热分析： A1203参 比， 量程士 50μν， 升温范围 30°C ~ 400°C， 升温速率 10°C/min, 得 DTA图 谱。 结果表明： 多烯紫杉醇在 230°C有一熔融峰、 约 350°C吸热分解； 磺丁 基-环糊精在 70-90°C和 250-270°C处分别为脱水吸热峰和相变峰，约 360 °C熔 融吸热分解。 物理混合物保持了环糊精和多烯紫杉醇的吸热峰特征， 而包合 物图谱上， 脱水吸热蜂和相变峰基本消失， 约 180°C处出现一新的相变峰， 360°C放热分解， 其各峰的位置（温度）和形状（热效应）都发生了明显变 化， 因此说明包合物已形成。
包合物中的残留乙醇：
包合物1 HNMR显示微弱的乙醇甲基峰，由乙醇甲基峰 ( ί ,δ= 1.10912 ) 与环糊精特征峰（H-1峰， d,5= 5.18257-5.05401 )的积分面积比计算出多批 制备包合物中的乙醇残留量（％)， 结果见表 2，
表 2 多烯紫杉醇 /环糊精固体包合物中乙醇残留量
：&合物批号 环糊精 药物 /环糊精比 乙醇残留量（％)
20060111 a 1 17 0.17
20060121 b 1 ： 17 0.13
20060221 a 1 : 30 0.32
20060302 b 1 . 30 0.27
20060513 b 1 50 0.30
20060511 a 1 50 0.44
20060408 a + b 0.36
20060623 b 1： 100 1.15
*: a =磺丁基 -β-环糊精； b =羟丙基-磺丁基 -β-环糊精
实验 明， 本发明技术制备过程中虽然使用较多乙醇， 但经纯化处理后 乙醇残留很少， 低比例环糊精（1 ： 50以下）制备的包合物中乙醇残留一般 低于 1.0%; 较大比例环糊精制备包合物也仅有不足 2.0% 的乙醇残留。低残 留的乙醇为提高多烯紫杉醇制剂稳定性、 降低刺激等副作用提供了有利保 障。
包合增溶试验：
标准曲线： 以乙醇溶解多烯紫杉醇配制得 0.67mg/ml的多烯紫杉醇溶液， 以 純净水稀释成 3.35 g/ml - 20.^g/ml系列溶液， 228nm下测定紫外吸收 A, 以 A对浓度 C (mg/ml)作图绘制标准曲线， 得 A = 13.881C+0.3577 (r =0.9998 )。
纯净水中过量多烯紫杉醇原料， 或包合物， 25。C±1°C振荡 72h, 过滤， 静置， 移取适量的滤液， 纯净水稀释， 分别于 228nm处测定光吸收强度， 依 标准曲线得多烯紫杉醇和包合物 25°C下溶解度， 见表 3 表 3 多烯紫杉醇在环糊精溶液中的溶解度
环糊精 * (药物比） 溶解度 （mg/ml) 增溶倍数
0 0.002903 1 a ( 1:17) 15.007 5169 b ( 1:17) 15.547 5355
*:a=磺丁基 -β-环糊精; b=羟丙基-磺丁基 -β-环糊精 结果显示， 本发明使用的环糊精对多烯紫杉醇有极强的增溶作用， 两 种环糊精对多烯紫杉醇的增溶作用相差不大。 多烯紫杉醇溶解度的大幅提高 有利于制备稳定的非口服制剂。
样品稳定性试验：
药物组 物的稳定性包括药物的化学稳定性及組合物的药剂学稳定性。 固体包合物稳定性
HPLC法色谱条件： 色谱柱008(：18(25011111^4.6匪)； 流动相， 水:乙 腈 (53： 47); 流t l.O ml/min; 检测波长 230nm; 测定时间： 30,00分钟； 检 测灵敏度 1.0000AUFS。 样品： 多烯紫杉醇原料； 多烯紫杉醇 /磺丁基 -β-环糊精包合物 （a，质量 比 1:17 ) ； 多烯紫杉醇 /羟丙基-磺丁基 -β-环糊精包合物 （b,质量比 1:17 ) 。 取多烯紫杉醇原料和包合物若干， 均分 3份为试验样品， 分别进行光照、 高 温和高湿度力 P速试猃：
1 ) 光照试验 样品置于透明密封容器中， 放在装有日光灯的光照箱内， 在 4500 ±500LX光照度的条件下放置 5天，取样检查分析， 结果与 0天样品 比较。
2 ) 高温试验 样品分别置于密封洁净容器中， 在 60 °C的温度下放置 5天， 取样检查分析， 结果与 0天样品比较。
3 ) 高湿度试验 样品分别置于恒湿密闭器 中于 25°C、 相对湿度 90±5% 条件下放置 5天， 取样检查分析， 结果与 0天样品比较。
HPLC测定图例见附图 2， 附图 3, 各试^结果见表 4,
表 4 5天加速试验的样品含量测定结果
样 品 含 量（％)
0天 光照 |¾温 高湿 多烯紫杉醇原料 99.675 90.176 87.859 83.877
包合物 a 99.684 96.478 94.235 95.331 包合物 b 99.645 97.985 95.407 95.310 加速试验条件下， 多烯紫杉醇原料颜色略变深， 含量下降较明显； 包合物外 观颜色无改 , 含量降低很少， 杂质基本无变化。 结果显示， 固体包合物中 多烯紫杉醇化学性庸稳定， 包合技术对提高多烯紫杉醇稳定性效果明显。 包合物溶液及药物稳定性
(1) 溶液稳定性 盾量比 1:17 固体包合物用生理盐水或等渗葡糖液 溶解成含多烯紫杉醇 15mg/ml溶液， 灭菌处理后稀释 1-1000倍制成不同浓 度注射液、 连续观察 5 小时 ~ 10 天， 其中对多烯紫杉醇 /羟丙基-磺丁基 -β- 环糊精包合物的生理盐水稀释体系的稳定性观察试验结果见表 5, 表 5 环糊精包合多烯紫杉醇注射液的溶液状态 药物浓度 溶液状态 *
稀释倍数
mg/ml 0小时 5小时 10小时 15小时 20小时 2天 4天 6天 10天
1 7.50 + + + + + - - - -
10 1.50 + + + + + + + + +
20 0.75 + + + + + + + + +
50 0.30 + + + + + + + + +
100 0.15 + + + + + + + + +
500 0.03 + + + + + + + + +
1000 0.015 + + + + + + + + +
* + ： 澄清无沉淀 ； - ： 产生沉淀或浑浊
( 2 ) 溶液中的多烯紫杉醇稳定性试验（含量测定）
采用上述相同的 HPLC 色谱条件， 取样品： 多烯紫杉醇原料； 多烯紫杉 醇 /磺丁基 -β-环糊精质量比 1:17包合物（a )； 多烯紫杉醇 /羟丙基-磺丁基 -β- 环糊精质量比 1:17包合物（b )若干， 生理盐水溶解， 超声 30分钟后用生理 盐水稀释 100倍， 静置， 分别于 0、 2、 4、 6、 8 小时取样测定 HPLC谱， 得 溶液中多烯紫杉醇含量， 结果见表 6 表 6 含水溶液中样品含量随时间的变化 含 量（％)
样 品
0小时 5小时 10小时 24小时 96小时 多烯紫杉醇原料 99.675 99.025 97.381 93.433 86.384 包合物 a 99.684 99.239 98.359 98.035 95.812 包合物 b 99.645 99.554 99.002 97.459 96.386 多烯紫杉醇分解明显， 包合物样品在含水溶液中， 化学性质稳定， 含量 10小 时内基本不变。 溶液中样品分解的半衰期分别为： 多烯紫杉醇 362.413小时、 包合物 a 1341.035 小时、 包合物 b 1502.927小时， 包合技术使多烯紫杉醇 稳定性分别增强了 3.7和 4.15 倍。
溶血作用试验：
(参考 献： 国家食品药品监督管理局 《化学药物刺激性、 过敏性和溶 血性研究技术指导原则》， 2005, 3, 18; 国家药品监督管理局 《中药注射剂 研究的技术要求》， 1999， 11 , 12 )
包合物生理盐水配制的溶液的溶血性与现有多烯紫杉醇制剂对比具显 著差异。 磺丁基 -β-环糊精包合物稀释溶液（a )仅具轻微溶血作用， 羟丙基- 磺丁基 -β-环糊精包合物（b )溶血作用更低， 临床给药浓度范围 （多烯紫杉 醇含量约 0.08mg/ml )基本无溶血作用 , 而现有多烯紫杉醇制剂溶血达 20% 以上。 结果见附图 4 。
本发明的优点：
包合物显著提高了多烯紫杉醇溶解度（达 15mg/ml以上）， 溶液稀释后 能够长时间保持清澈稳定， 且溶血作用低、 毒副作用小， 药物活性好。
多烯紫杉醇与环糊精包合后， 固态、液态样品含量稳定， 药物 /环糊精比 例小、 制剂中环糊精用量低， 适宜用于临床。
本发明的包合物有机溶剂残留少， 有利于提高用药安全性。
制备方法简单、 操作简便、 成本低且无环境污染。 包合物性质稳定、 与 其他药用辅料相容性好， 便于制剂的制备。
包合物制备的注射液无腐蚀性成分、无毒害，临床使用方便、实用性强。 附图说明
图 1: 7J溶液中不同羟丙基-磺丁基 -β-环糊精浓度下的多烯紫杉醇紫外吸 收扫描图 （220nm ~ 245nm );
图 2: 多烯紫杉醇 /羟丙基-磺丁基 -β-环糊精包合物高温试验（5 天）的
HPLC色谱图；
图 3: 多,烯紫杉醇原料高温试验（ 5天）的 HPLC色谱图；
图 4: 市售多烯紫杉醇制剂、 多烯紫杉醇 /羟丙基-磺丁基 -β-环糊精包合 物、 多烯紫杉醇 /蹟丁基 -β-环糊精包合物生理盐水稀释的溶液， 多烯紫杉醇 浓度 -溶血作用曲线图。
具体实施方式
实施例 1 : 将 1.70g羟丙基-磺丁基 -β-环糊精与 5.0ml纯水混合， 搅拌下 緩慢滴加 100.0 mg多晞紫杉醇与 1.0ml乙醇配制的溶液，充分混合搅拌至体 系完全溶解， '以 0.2 ~ 0.4μηι 孔滤膜过滤， 滤液 55°C下减压蒸除乙醇， 灭 菌处理后减压蒸除水分至干， 固体物继续减压干燥 48小时， 即得白色固体 包合物。
上述粉状包合物 360 mg (含多烯紫杉醇 20mg )与 250 ml 注射用生理 盐水混合即溶解成为液态包合组合物， 该溶液可方便用于注射。 实施例 2: 与实施例 1基本相同， 但其中的羟丙基-磺丁基 -β-环糊精为
3.0g与 15ml纯水混合， 多烯紫杉醇为 20 mg。
实施例 3: 与实施例 1基本相同， 但其中的多烯紫杉醇为 170 mg。
实施例 4:与实施例 1基本相同，但其中的环糊精采用磺丁基 -β-环糊精。 实施例 5:与实施例 2基本相同，但其中的环糊精采用磺丁基 -β-环糊精。 实施例 6:与实施例 3基本相同，但其中的环糊精采用磺丁基 -β-环糊精。 实施例 7: 与实施例 1基本相同， 但其中的环糊精采用磺丁基 -β-环糊精 与羟丙基-磺丁基 -β-环糊精质量比 1 ： 1的混合物。
实施例 8: 与实施例 2基本相同， 但其中的环糊精采用磺丁基 -β-环糊精 与羟丙基-磺丁基 -β-环糊精质量比 1 ： 50的混合物。
实施例 9: 与实施例 3基本相同， 但其中的环糊精釆用磺丁基 -β-环糊精 与羟丙基-横丁基 -β-环糊精廣量比 50 ： 1的混合物。
实施例 10: 与实施例 1基本相同，但先将环糊精、 多烯紫杉醇与纯水混 合， 搅拌下緩慢滴加乙醇至体系完全溶解。
实施例 11 : 与实施例 1基本相同，但得到的粉状包合物用等渗浓度的葡 萄糖注射液稀释。
实施例 12: 与实施例 1基本相同，但得到的粉状包合物用等渗浓度的果 糖注射液稀释。

Claims

权 利 要 求 书
1、 一种含有环糊精 /多烯紫杉醇包合物的药物组合物， 由多烯紫杉醇、 环糊^ "与药用辅料组成，其中多烯紫杉醇与环糊精的盾量比为 1 ： 10 ~ 150, 所述的环糊精是：羟丙基-磺丁基 -β-环糊精，或磺丁基 -β-环糊精，或磺丁基 -β- 环糊精与羟丙基-磺丁基 -β-环糊精的混合物； 环糊精包合多烯紫杉醇的稳定 常数 Ka = 2056M-1 - 13051M-1 。
2、按照权利要求 1所述的含有环糊精 /多烯紫杉醇包合物的药物组合物， 其特征在于，所述的含有环糊精 /多烯紫杉醇包合物的药物组合物，是指用以 下制备方法得到的组合物： 在羟丙基-磺丁基 -β-环糊精，或磺丁基 -β-环糊精， 或磺丁基 -β-环糊精与羟丙基-磺丁基 -β-环糊精的混合物的純水溶液中 , 搅拌 下滴加多烯紫杉醇的乙醇溶液， 体系溶解后以 0.2 ~ 0.4μιη微孔滤膜过滤， 滤液减压除 醇， 然后再减压除水， 干燥， 得到的固体包合物， 或减压除乙 醇后得到的液体包合物。
3、 一种权利要求 1所述的含有环糊精 /多烯紫杉醇包合物的药物组合物 的制备方法， 步骤如下， 在羟丙基-磺丁基 -β-环糊精， 或磺丁基 -β-环糊精， 或磺丁基 -β-环糊精与羟丙基-磺丁基 -β-环糊精的混合物的纯水溶液中 , 搅拌 下滴加多烯紫杉醇的乙醇溶液；
体系溶解后以 0.2 ~ 0.4μπι ^啟孔滤膜过滤， 滤液减压除乙醇， 得到液体 包合物， 或减压除乙醇后再减压除水， 干燥， 得到的固体包合物。
4、 按照权利要求 3所述的含有环糊精 /多烯紫杉醇包合物的药物组合物 的制备方法， 其特征在于， 具体步驟是： 用 1 ： 17质量比的多烯紫杉醇 ： 环糊精配制环糊精的纯水溶液， 该溶 液是指： 羟丙基-碓丁基 -β-环糊精， 或磺丁基 -β-环糊精， 或磺丁基 -β-环糊精 与羟丙基-磺丁基 -β-环糊精的混合物与 2 ~ 10倍质量的纯水混合制成的溶液， 搅拌下緩慢加入比例多烯紫杉醇与可溶解多烯紫杉醇的适量乙醇配制的溶 液，加入多烯紫杉醇时在室温或在 25 ~ 65°C间加热搅拌，搅拌加热生成包合 物后， 以 0.2 ~ 0.4μιη微孔滤膜过滤， 然后减压尽量除去乙醇， 再继续减压 除水至尽， 减压真空干燥后得固体包合物。
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CN1931369A (zh) 2007-03-21
EP2080524A1 (en) 2009-07-22
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JP5103476B2 (ja) 2012-12-19
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