WO2016177346A1 - 一种卡巴他赛脂肪乳注射剂及其制备方法和用途 - Google Patents

一种卡巴他赛脂肪乳注射剂及其制备方法和用途 Download PDF

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WO2016177346A1
WO2016177346A1 PCT/CN2016/081245 CN2016081245W WO2016177346A1 WO 2016177346 A1 WO2016177346 A1 WO 2016177346A1 CN 2016081245 W CN2016081245 W CN 2016081245W WO 2016177346 A1 WO2016177346 A1 WO 2016177346A1
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Prior art keywords
cabazitaxel
fat emulsion
injection
emulsion injection
prostate cancer
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PCT/CN2016/081245
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English (en)
French (fr)
Inventor
陈建明
高保安
周琴琴
王国成
杨国军
刘文丽
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江苏天士力帝益药业有限公司
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Application filed by 江苏天士力帝益药业有限公司 filed Critical 江苏天士力帝益药业有限公司
Priority to US15/571,596 priority Critical patent/US20180153848A1/en
Priority to CA2982625A priority patent/CA2982625A1/en
Priority to CN201680025365.7A priority patent/CN107530281A/zh
Priority to EP16789340.3A priority patent/EP3292860B1/en
Priority to RU2017138067A priority patent/RU2716218C2/ru
Priority to KR1020177031808A priority patent/KR20180006902A/ko
Priority to JP2017557193A priority patent/JP2018515484A/ja
Priority to AU2016258642A priority patent/AU2016258642B2/en
Publication of WO2016177346A1 publication Critical patent/WO2016177346A1/zh

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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
    • A61K31/335—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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • 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 the technical field of medicine, in particular to a cabazitaxel fat emulsion injection, a preparation method thereof and use thereof.
  • Cabazitaxel is a drug developed by Sanofi-aventis for the treatment of prostate cancer. It is a chemical semi-synthetic taxane small molecule compound with the chemical name 4-acetoxy-2 ⁇ -benzoyloxy- 5 ⁇ ,20-epoxy-1-hydroxy-7 ⁇ ,10 ⁇ -dimethoxy-9-oxo-taxol-11-ene-13 ⁇ -yl(2R,3S)-3-tert-butoxycarbonylamino- 2-Hydroxy-3-phenylpropionate, the structural formula is represented by the following formula (I). This product is white or off-white powder, almost insoluble in water, soluble in organic solvents such as ethanol.
  • cabazitaxel can bind to tubulin, promote microtubule dimer assembly into microtubules, prevent it from depolymerization, inhibit microtubule decomposition, and arrest cells in G 2 and M phases. Thereby inhibiting mitosis and proliferation of cancer cells.
  • cabazitaxel not only exhibits broad-spectrum anti-tumor activity similar to the first-generation taxanes (such as paclitaxel or docetaxel), but also has its unique advantages: 1) Overcoming drug resistance, showing significantly greater pharmacological activity against taxane-tolerant cells; (2) improving ability to cross the blood-brain barrier, showing better pharmacology to central nervous system tumors Activity (Patricia v rignaud, Dorothée Semiond, veronique Benning, et al. Preclinical profile of cabazitaxel [J]. Drug Des Devel Ther, 2014, 8:1851–1867.).
  • cabazitaxel preparation is cabazitaxel injection, trade name: Jevtana, the specification is 60mg/1.5ml, contains 60mg cabazitaxel and 1.5ml Tween-80, and the dilution is 5.7ml 13% (w /w) Aqueous ethanol solution.
  • the preparation was developed by Sanofi-Aventis and was approved by the US FDA on June 17, 2010 for the treatment of prostate cancer.
  • Tween-80 Poor safety: its composition solvent is Tween-80.
  • Tween-80 intravenous injection of 0.3% or 0.35% Tween-80 can cause allergic reactions in Grade 3 or above in Beagle dogs, such as blood pressure drop and heart rate slowdown.
  • Abnormal reactions such as skin erythema, salivation, vomiting, convulsions and convulsions (He Yongliang, Yi Yong, Wang Hongxing, et al. Study on allergic reactions in dogs with Tween-80 Chinese medicine injection [J].
  • Chinese Pharmacology and Clinical Medicine, 2005, 21 (1) 55-56.;Feng Wenning, Xiao Shunhan, Liu Minghua, et al.
  • Lipid Emulsion has long been a concern as a poorly soluble drug carrier.
  • a large number of drug-loaded fat emulsion injections have been widely used in clinical applications, such as alprostadil injection, propofol medium long-chain fat emulsion, dexamethasone palmitate injection, flurbiprofen ester injection, etc.
  • Significant advantages are shown in clinical applications. It can be seen that fat emulsions have unique advantages as poorly soluble drug carriers.
  • Chinese patent application CN201210484494.6 discloses a Cabazitaxel lipid microsphere injection and a preparation method thereof, wherein in order to solve the solubility problem of cabazitaxel, the literature first prepares cabazitaxel as a cabazitaxel phospholipid complex. The water solubility and fat solubility are increased, and then it is prepared into a lipid microsphere injection.
  • the biggest problem with this approach is that in the preparation of the cabazitaxel phospholipid complex, a large amount of toxic organic solvents such as chloroform, ethyl acetate, diethyl ether, etc. need to be introduced, and after the reaction, the organic solvent needs to be removed.
  • the oil for injection in this document uses long-chain triglycerides and medium-chain triglycerides, and specifically discloses soybean oil, safflower oil, sea buckthorn oil, evening primrose oil, corn oil, brucea javanica oil, coconut oil, Perilla oil, grape seed oil, olive oil, castor oil, tea oil, cottonseed oil, palm oil, and no further matching studies.
  • cabazitaxel fat emulsion injection in combination with the physical and chemical properties of cabazitaxel, so that the water solubility problem of cabazitaxel can be properly solved, and the use of spit is eliminated.
  • the adverse effects of Wen-80 the applicant found that cabazitaxel has the highest solubility in medium chain triglycerides (about 50 mg/g), while in long-chain oils such as soybean oil, olive oil, castor oil, and palm oil.
  • the solubility in the lower is lower (all less than 10mg / g).
  • the present invention specifically selects medium chain triglyceride as an injection oil, thereby preparing a stable, high drug-loading amount of cabazitaxel fat emulsion injection.
  • the present invention provides a cabazitaxel fat emulsion injection comprising cabazitaxel, medium chain triglyceride for injection, and lecithin.
  • the present invention also provides a method of preparing a cabazitaxel fat emulsion injection, the method comprising:
  • the obtained cabazitaxel fat emulsion injection is freeze-dried to prepare a cabazitaxel lyophilized milk.
  • the present invention also relates to the use of the cabazitaxel fat emulsion injection of the present invention for the preparation of a medicament for treating prostate cancer.
  • the present invention also relates to the use of the cabazitaxel fat emulsion injection of the present invention for treating prostate cancer.
  • the present invention also relates to a method of treating prostate cancer, which comprises administering a cabazitaxel fat emulsion injection of the present invention to a patient in need thereof.
  • the present invention also relates to a cabazitaxel fat emulsion injection for treating prostate cancer, which comprises cabazitaxel, medium chain triglyceride for injection, and lecithin.
  • the invention includes any of the following paragraphs:
  • a cabazitaxel fat emulsion injection comprising cabazitaxel, medium chain triglyceride for injection, and lecithin.
  • cabazitaxel fat emulsion injection characterized in that the cabazitaxel fat emulsion injection comprises the following components: cabazitaxel, medium chain triglyceride for injection, lecithin, co-emulsification Agent, stabilizer, isotonicity regulator, pH adjuster and water for injection.
  • cabazitaxel fat emulsion injection according to paragraph 3 or 4, wherein the cabazitaxel fat emulsion injection, in weight percent (w/v), comprises the following components:
  • cabazitaxel fat emulsion injection according to paragraph 3 or 4, wherein the cabazitaxel fat emulsion injection, in weight percent (w/v), comprises the following components:
  • the cabazitaxel fat emulsion injection can be further freeze-dried to prepare a cabazitaxel freeze-dried milk, so the formula can also contain a lyophilized proppant.
  • the appearance of the sample after lyophilization is improved to ensure good resolubility.
  • the Cabazitaxel lyophilized milk of the present invention is prepared by adding a lyophilized proppant in the form of an injection.
  • cabazitaxel fat emulsion injection according to paragraph 7, wherein the cabazitaxel lyophilized milk is formulated from a formulation comprising the following components: cabazitaxel, medium chain triglyceride for injection, Lecithin, co-emulsifier, stabilizer, isotonicity regulator, lyophilized proppant, pH adjuster and water for injection.
  • lecithin is lecithin for injection and is one or both selected from the group consisting of egg yolk lecithin and soybean lecithin.
  • the pH adjusting agent is selected from the group consisting of citric acid, hydrochloric acid, acetic acid, phosphoric acid, lactic acid, sodium citrate, dipotassium hydrogen phosphate, and phosphoric acid.
  • the pH adjusting agent is selected from the group consisting of citric acid, hydrochloric acid, acetic acid, phosphoric acid, lactic acid, sodium citrate, dipotassium hydrogen phosphate, and phosphoric acid.
  • the pH adjusting agent is selected from the group consisting of citric acid, hydrochloric acid, acetic acid, phosphoric acid, lactic acid, sodium citrate, dipotassium hydrogen phosphate, and phosphoric acid.
  • disodium hydrogenhydride potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium acetate, and sodium hydroxide.
  • lyophilized proppant is selected from the group consisting of lactose, sucrose, mannitol, dextran 20, dextran 40, dextran 70, One or more of xylitol, sorbitol, and trehalose.
  • cabazitaxel fat emulsion injection according to any one of the preceding paragraphs, wherein the lyophilized proppant is lactose, sucrose and/or mannitol.
  • cabazitaxel fat emulsion injection according to any of the preceding paragraphs, wherein the cabazitaxel fat emulsion injection has an average particle diameter of 60 to 250 nm, preferably 90 to 200 nm.
  • colostrum in a high-pressure homogenizer, further emulsification at a homogenization pressure of 5,000 to 20,000 psi, preferably 7,000 to 18,000 psi, adjusting the pH to 3.0 to 7.0 with a pH adjuster, filtering, dispensing, and sealing. , sterilized, that is, get the capsaicin fat emulsion injection; or
  • the cabazitaxel fat emulsion injection obtained in the step (4) is freeze-dried to prepare a cabazitaxel freeze-dried milk.
  • the sterilization in the step (4) is carried out by high-pressure steam, wherein the sterilization temperature is 100 to 121 ° C, and the sterilization time is 10 to 45 minutes.
  • a method of treating prostate cancer comprising administering to a patient in need thereof a cabazitaxel fat emulsion injection of any of paragraphs 1-18.
  • a cabazitaxel fat emulsion injection for treating prostate cancer wherein the cabazitaxel fat emulsion injection for treating prostate cancer comprises cabazitaxel, medium chain triglyceride for injection, and lecithin.
  • cabazitaxel fat emulsion injection for treating prostate cancer according to paragraph 27, wherein the cabazitaxel fat emulsion injection comprises the following components: cabazitaxel, medium chain triglyceride for injection , lecithin, co-emulsifier, stabilizer, isotonicity regulator, pH adjuster and water for injection.
  • the cabazitaxel fat emulsion injection for treating prostate cancer according to paragraph 25 or 26, wherein the cabazitaxel fat emulsion injection for treating prostate cancer is cabazitaxel lyophilized milk.
  • cabazitaxel fat emulsion injection for treating prostate cancer according to paragraph 31, wherein the cabazitaxel lyophilized milk is formulated from a formulation comprising the following components: cabazitaxel, for injection Medium chain triglycerides, lecithin, co-emulsifiers, stabilizers, isotonicity regulators, lyophilized proppants, pH adjusters, and water for injection.
  • the cabazitaxel fat emulsion injection for treating prostate cancer according to any one of paragraphs 25 to 34, wherein the lecithin is one or two selected from the group consisting of egg yolk lecithin and soybean lecithin.
  • the lecithin is one or two selected from the group consisting of egg yolk lecithin and soybean lecithin.
  • the cabazitaxel fat emulsion injection for treating prostate cancer according to any one of paragraphs 25 to 35, wherein the co-emulsifier is poloxamer 188.
  • the cabazitaxel fat emulsion injection for treating prostate cancer according to any one of paragraphs 25 to 36, wherein the isotonicity adjusting agent is glycerin.
  • the cabazitaxel fat emulsion injection for treating prostate cancer according to any of paragraphs 25-37, characterized in that The stabilizers are oleic acid and/or sodium oleate.
  • the cabazitaxel fat emulsion injection for treating prostate cancer according to any one of paragraphs 25 to 38, wherein the pH adjuster is selected from the group consisting of citric acid, hydrochloric acid, acetic acid, phosphoric acid, lactic acid, One or more of sodium citrate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium acetate, and sodium hydroxide.
  • the pH adjuster is selected from the group consisting of citric acid, hydrochloric acid, acetic acid, phosphoric acid, lactic acid, One or more of sodium citrate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium acetate, and sodium hydroxide.
  • lyophilized proppant is selected from the group consisting of lactose, sucrose, mannitol, dextran 20, One or more of dextran 40, dextran 70, xylitol, sorbitol, and trehalose.
  • the cabazitaxel fat emulsion injection for treating prostate cancer according to any one of paragraphs 32 to 40, wherein the lyophilized proppant is lactose, sucrose and/or mannitol.
  • the cabazitaxel fat emulsion injection provided by the present invention does not contain any solubilizing agent having toxic side effects such as Tween-80, which is of great clinical significance.
  • the preparation method of the invention omits the process of preparing the phospholipid complex, avoiding the need to add a large amount of toxic organic solvents such as chloroform and ethyl acetate in the preparation process of the cabazitaxel phospholipid complex.
  • the cabazitaxel fat emulsion injection of the present invention and the preparation method thereof can increase the safety of administration of the product and the safety of the production process, and at the same time, simplify the production process of the preparation.
  • the cabazitaxel fat emulsion preparation prepared by the method of the invention has simple preparation process, does not use toxic and harmful organic solvent, and has good stability and safety, and has good prospects in social and economic benefits.
  • cabazitaxel has a high solubility in injection medium chain triglycerides and has good stability (see Example 1), so the solubility problem of cabazitaxel can be solved without preparing a phospholipid complex. .
  • This avoids: (a) in the preparation of the cabazitaxel phospholipid complex, it is necessary to add a large amount of toxic organic solvents such as chloroform, ethyl acetate, diethyl ether, etc.; and, (b) after the reaction, the organic solvent is required. Removal, the process is cumbersome and complicated, difficult to control, and the problem of residual organic solvents will inevitably occur. At the same time, the production process of the preparation is also simplified.
  • the preparation of the drug-loaded fat emulsion is premised on the fact that the main drug should have a certain solubility in the oil for injection, otherwise a stable drug-loaded fat emulsion cannot be prepared.
  • the cabazitaxel fat emulsion injection of the present invention is desirably a long-term storage drug-loaded fat emulsion which should be stable for at least 2 years. Therefore, it must be ensured that the selected injection oil has sufficient solubility for cabazitaxel.
  • the colostrum was placed in a high-pressure homogenizer, further emulsified 3 times under a homogenizing pressure of 15000 psi, and the pH was adjusted to 5.0 with hydrochloric acid.
  • the 0.45 ⁇ m, 0.22 ⁇ m filter membrane was sterilized by filtration, aliquoted, freeze-dried, and sealed to obtain Cabazitaxel lyophilized milk.
  • Example 4 Cabazitaxel fat emulsion injection
  • the colostrum was placed in a high-pressure homogenizer, further emulsified 3 times under a homogenizing pressure of 16,000 psi, and disodium hydrogen phosphate was used.
  • the sodium dihydrogen phosphate was adjusted to a pH of 7.0, filtered through a 0.8 ⁇ m, 0.45 ⁇ m filter, dispensed, sealed, and sterilized at 115 ° C for 30 minutes to obtain a Cabazitaxel fat emulsion injection.
  • Example 6 Cabazitaxel freeze-dried milk
  • the colostrum was placed in a high-pressure homogenizer and further emulsified 5 times under 7000 psi homogenization pressure with citric acid and strontium.
  • Sodium citrate was adjusted to pH 4.0, and sterilized by filtration through 0.8 ⁇ m, 0.45 ⁇ m, and 0.22 ⁇ m filters, and the mixture was lyophilized and sealed to obtain Cabazitaxel lyophilized milk.
  • the colostrum was placed in a high-pressure homogenizer, further emulsified twice under a homogenous pressure of 20,000 psi, and the pH was adjusted with phosphoric acid. 3.0, respectively, sterilized by 0.45 ⁇ m, 0.22 ⁇ m filter, sub-packaged, freeze-dried, sealed, to obtain Cabazitaxel freeze-dried milk.
  • the colostrum was placed in a high-pressure homogenizer, further emulsified 3 times under a homogenizing pressure of 15000 psi, and the pH was adjusted with phosphoric acid and sodium hydroxide. To 5.5, the cells were sterilized by filtration through a 1.2 ⁇ m, 0.45 ⁇ m, and 0.22 ⁇ m filter, subpacked, lyophilized, and sealed to obtain Cabazitaxel lyophilized milk.
  • the colostrum was placed in a high-pressure homogenizer, further emulsified 3 times under a homogenizing pressure of 18000 psi, and the pH was adjusted with lactic acid to 5.0, respectively, sterilized by 0.45 ⁇ m, 0.22 ⁇ m filter membrane, sub-packaged, freeze-dried, sealed, to obtain Cabazitaxel freeze-dried milk.
  • Example 12 Cabazitaxel freeze-dried milk
  • the colostrum was placed in a high-pressure homogenizer and further emulsified 3 times under a homogenizing pressure of 17,000 psi.
  • the pH was adjusted to 5.0 with phosphoric acid and dipotassium hydrogen phosphate, respectively, filtered through a 0.8 ⁇ m, 0.22 ⁇ m filter, dispensed, sealed, and sterilized at 100 ° C for 45 minutes to obtain a Cabazitaxel fat emulsion injection.
  • Example 14 Cabazitaxel freeze-dried milk
  • the colostrum was placed in a high-pressure homogenizer and further emulsified at a homogenizing pressure of 15,000 psi. Then, the pH was adjusted to 6.0 with acetic acid and sodium acetate, and the cells were sterilized by filtration through a 0.8 ⁇ m, 0.22 ⁇ m filter, subpacked, freeze-dried, and sealed to obtain a freeze-dried milk of cabazitaxel.
  • the colostrum was placed in a high-pressure homogenizer and further emulsified at a homogenizing pressure of 16,000 psi. Then, the pH was adjusted to 6.0 with citric acid and sodium hydroxide, and the cells were sterilized by filtration through a 0.88 ⁇ m, 0.22 ⁇ m filter, and the mixture was lyophilized and sealed to obtain a Cabernet lyophilized milk.
  • Test Example 2 Stability test of cabazitaxel fat emulsion injection
  • Example 2 Samples prepared in Example 2, Example 3, Example 4, Example 6, Example 8, and Example 14 were taken. Placed at 25 °C ⁇ 2 ° C, humidity of 60% ⁇ 10% for 6 months, samples were taken at 0 months, 1 month, 2 months, 3 months, 6 months, respectively. Reconstitute with water to the concentration of the solution before lyophilization. The kapparita fat emulsion injection and the complex solution of the freeze-dried milk were taken separately, and the changes of pH value, particle size and percentage of labeling were mainly investigated. The results are shown in Table 2, Table 3 and Table 4, respectively.
  • the particle size in each of the examples is a particle diameter measured by using a British Malvern particle size analyzer (model: Nano-S type) after diluting the cabazitaxel fat emulsion injection with water 200 times.
  • the percentage of labeling in each example refers to the determination of the drug content by high performance liquid chromatography.
  • the injection volume is 10 ⁇ l.
  • the detection process includes: accurately weighing the appropriate amount of the product of the example, adding acetonitrile to dissolve and diluting to prepare a solution containing about 0.1 mg of cabazitaxel per 1 ml, and accurately measuring 10 ⁇ l of the injected liquid chromatograph (instrument model: Agilent 1100 series) Record the chromatogram; take the reference substance of cabazitaxel, accurately weigh and measure according to the same measurement method, and finally calculate the percentage of labeling of cabazitaxel according to the area of the external standard peak.
  • the Cabazitaxel fat emulsion injection of the present invention is placed at 25 ° C ⁇ 2 ° C, humidity of 60% ⁇ 10% for 6 months, pH value, particle size and marking percentage There was no significant change in the content, indicating that the Cabazitaxel fat emulsion injection of the present invention can be stored for a long period of time with stable quality.
  • the freeze-dried cabazitaxel lyophilized fat emulsion (Examples 2, 3, 6, 14) is more specific to the unlyophilized cabazitaxel fat emulsion injection (Examples 4 and 8). stable.

Abstract

本发明提供了一种卡巴他赛脂肪乳注射剂，所述卡巴他赛脂肪乳注射剂包含卡巴他赛、注射用中链甘油三酯、卵磷脂。本发明还提供了该卡巴他赛脂肪乳注射剂的制备方法和其在制备用于治疗前列腺癌的药物中的用途。

Description

一种卡巴他赛脂肪乳注射剂及其制备方法和用途 技术领域
本发明涉及医药技术领域，具体涉及一种卡巴他赛脂肪乳注射剂及其制备方法和用途。
背景技术
卡巴他赛(Cabazitaxel)是Sanofi-aventis公司研发的治疗前列腺癌的药物，是一种化学半合成紫杉烷类小分子化合物，化学名称为4-乙酰氧基-2α-苯甲酰氧基-5β,20-环氧基-1-羟基-7β,10β-二甲氧基-9-氧代紫杉-11-烯-13α-基(2R,3S)-3-叔丁氧基羰基氨基-2-羟基-3-苯基丙酸酯，结构式如下式(I)所示。本品为白色或类白色粉末，几乎不溶于水，溶于乙醇等有机溶剂。
Figure PCTCN2016081245-appb-000001
卡巴他赛作为微管抑制剂，能与微管蛋白结合，促使微管双聚体装配成微管，阻止其去多聚化过程，抑制微管分解，使细胞阻滞于G2和M期，从而抑制癌细胞的有丝分裂和增殖。而且卡巴他赛作为新型的第二代紫杉烷类药物，不仅与第一代紫杉烷(如紫杉醇、多西紫杉醇)显示出相似的广谱抗肿瘤活性，更具有其独特的优势：(1)克服了耐药性，对紫杉烷类耐受的细胞显示出明显更大的药理活性；(2)提高了透过血脑屏障的能力，对中枢神经系统肿瘤显示出较好的药理活性(Patricia v rignaud,Dorothée Semiond,veronique Benning,et al.Preclinical profile of cabazitaxel[J].Drug Des Devel Ther,2014，8:1851–1867.)。
目前，临床应用的卡巴他赛制剂为卡巴他赛注射液，商品名：Jevtana，规格为60mg/1.5ml，包含60mg卡巴他赛和1.5ml吐温-80，稀释液为5.7ml 13％(w/w)乙醇水溶液。该制剂由赛诺菲-安万特(Sanofi-Aventis)公司研发，于2010年6月17日获美国FDA批准上市，用于治疗前列腺癌。
然而，该卡巴他赛注射液存在以下主要缺点：
(1)安全性差：其组成溶剂为吐温-80，根据文献报道，静脉注射0.3％或0.35％吐温-80即可使Beagle犬出现3级以上过敏反应，如血压下降、心率减慢、皮肤红斑、流涎呕吐、痉挛抽搐等异常反应(何永亮，易勇，王红星，等.含吐温-80中药注射液对犬致过敏的研究[J].中药药理与临床，2005，21(1):55-56.；冯文宁，肖顺汉，刘明华，等.含吐温-80中药注射剂对不同动物的过敏反应[J].泸州医学院学报，2007，30(2):92-94.)。例如，已上市的多西紫杉醇注射液(含有吐温-80)在临床使用中出现多种不良反应，正是由于处方中含有吐温-80，导致出现如过敏反应、骨髓抑制、神经毒性、液体潴留、消化系统异常等不良反应，甚至因不良反应致死(史筱倩.多西他赛不良反应及分析[J].中国医药导报，2009，6(6):90-91.)。在临床使用时，患者需提前给予皮质激素、H2拮抗剂、抗组织胺类药物加以预防，同时密切监测整个用药过程；
(2)稳定性差：该卡巴他赛注射液在稀释用药时稳定性较差，需在30分钟内使用，存在极大的安全隐患；
(3)使用不便：该卡巴他赛注射液的使用要求在配制方面对医护人员进行严格的培训，且在输注时需要经过0.22μm滤膜同步过滤，不可使用聚氯乙烯和聚氨酯输注容器，且输注时需医护人员实时监控。
针对现有技术中的卡巴他赛注射液存在的安全性及稳定性等方面的不足，有必要对现有的卡巴他赛注射液进行改进，使得既能妥善解决卡巴他赛的水溶性问题，又能免除使用吐温-80带来的不利影响。
脂肪乳剂(Lipid Emulsion)作为难溶性药物载体早已备受人们关注。目前，已有大量载药脂肪乳剂注射液广泛应用于临床，如前列地尔注射液、丙泊酚中长链脂肪乳、地塞米松棕榈酸酯注射液、氟比洛芬酯注射液等，在临床应用中均显示出明显的优势。可见，脂肪乳剂作为难溶性药物载体具有其独特的优势。
中国专利申请CN201210484494.6公开了一种Cabazitaxel脂质微球注射液及其制备方法，其中，为了解决卡巴他赛的溶解性问题，该文献先将卡巴他赛制备为卡巴他赛磷脂复合物，增加其水溶性和脂溶性，再将其制备成脂质微球注射液。然而，这一做法的最大问题在于，在卡巴他赛磷脂复合物的制备过程中，需要引入大量有毒的有机溶剂，如氯仿、乙酸乙酯、乙醚等，且反应结束后，需再除去有机溶剂，其过程繁琐复杂，不易控制，且不可避免地会出现有机溶剂残留的问题，给临床用药带来安全隐患。其次，该文献中的注射用油选用长链甘油三酯、中链甘油三酯，具体公开了大豆油、红花油、沙棘油、月见草油、玉米油、鸦胆子油、椰子油、紫苏油、葡萄籽油、橄榄油、蓖麻油、茶油、棉籽油、棕榈油，且未进一步进行匹配性研究。事实上，该专利申请所选择的注射用油绝大多数属长链油，而卡巴他赛在绝大多数长链油中的溶解度是很低的，甚至完全不溶，如此，事实上，难以制备出高载药量的、稳定的载药乳剂。
尽管载药脂肪乳剂的制备技术较为成熟，然而仍需根据活性成分固有的理化性质，优选出与之相匹配的处方工艺，才能制备获得稳定、安全的载药脂肪乳剂。
发明内容
针对现有卡巴他赛注射制剂的不足，申请人结合卡巴他赛的理化性质，开发了一种卡巴他赛脂肪乳注射剂，使得既能妥善解决卡巴他赛的水溶性问题，又能免除使用吐温-80带来的不利影响。进一步地，经过潜心研究，申请人发现，卡巴他赛仅在中链甘油三酯中的溶解度相对最高(约50mg/g)，而在大豆油、橄榄油、蓖麻油、棕榈油等长链油中的溶解度较低(均小于10mg/g)。因此，针对卡巴他赛的上述溶解特性，本发明特别选用中链甘油三酯作为注射用油，从而制备出稳定的、高载药量的卡巴他赛脂肪乳注射剂。
因此，本发明的目的在于开发一种可静脉注射的、安全、稳定的卡巴他赛脂肪乳注射剂。
作为本发明的第一方面，本发明提供了一种卡巴他赛脂肪乳注射剂，该注射剂包含卡巴他赛、注射用中链甘油三酯、卵磷脂。
作为本发明的第二方面，本发明还提供了一种制备卡巴他赛脂肪乳注射剂的方法，所述方法包括：
(1)按配方量称取注射用中链甘油三酯、稳定剂，混匀，加热至50～80℃，然后加入卡巴他赛，在50～80℃下搅拌或剪切使其溶解，获得油相；
(2)将助乳化剂和等渗调节剂(在目标产品为卡巴他赛冻干乳的情况下，还另外包括冻干支撑剂)分散到适量注射用水中，加热至50～80℃，搅拌或剪切使其溶解，再加入卵磷脂，剪切使其分散，获得水相；
(3)将所述油相和所述水相在50～80℃下混合，同时用剪切乳化机乳化5～15分钟，获得初乳，随后用注射用水定容；以及
(4)将所述初乳置于高压均质机中，在5000～20000psi、优选7000-18000均质压力下进一步乳化，用pH调节剂调节pH至3.0-7.0，过滤，分装，封口，灭菌，即得卡巴他赛脂肪乳注射液；或者
(5)任选进一步地，将获得的卡巴他赛脂肪乳注射液经冷冻干燥，制备成卡巴他赛冻干乳。
作为本发明的第三方面，本发明还涉及本发明的卡巴他赛脂肪乳注射剂在制备用于治疗前列腺癌的药物中的用途。
作为本发明的第四方面，本发明还涉及本发明的卡巴他赛脂肪乳注射剂在治疗前列腺癌中的用途。
作为本发明的第五方面，本发明还涉及治疗前列腺癌的方法，所述方法包括向有需要的患者给予本发明的卡巴他赛脂肪乳注射剂。
作为本发明的第六方面，本发明还涉及用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，该注射剂包含卡巴他赛、注射用中链甘油三酯、卵磷脂。
具体而言，本发明包含如下段落所述的任一项：
1.一种卡巴他赛脂肪乳注射剂，所述卡巴他赛脂肪乳注射剂包含卡巴他赛、注射用中链甘油三酯、卵磷脂。
2.如段落1所述的卡巴他赛脂肪乳注射剂，其特征在于，所述卡巴他赛、所述注射用中链甘油三酯以及所述卵磷脂的重量比为(0.05-0.5):(2-10):(1-8)；优选为(0.1-0.3):(3-8):(3-6)。
3.如段落1或2所述的卡巴他赛脂肪乳注射剂，其特征在于，所述卡巴他赛脂肪乳注射剂是卡巴他赛脂肪乳注射液。
4.如段落3所述的卡巴他赛脂肪乳注射剂，其特征在于，所述卡巴他赛脂肪乳注射液包含以下组分：卡巴他赛、注射用中链甘油三酯、卵磷脂、助乳化剂、稳定剂、等渗调节剂、pH调节剂和注射用水。
其中，为了进一步保证卡巴他赛脂肪乳注射剂的长期储存稳定性，需加入适当的稳定剂和pH调节剂。
5.如段落3或4所述的卡巴他赛脂肪乳注射剂，其特征在于，所述卡巴他赛脂肪乳注射液，以重量百分比(w/v)计，包含以下组分：
Figure PCTCN2016081245-appb-000002
Figure PCTCN2016081245-appb-000003
6.如段落3或4所述的卡巴他赛脂肪乳注射剂，其特征在于，所述卡巴他赛脂肪乳注射液，以重量百分比(w/v)计，包含以下组分：
Figure PCTCN2016081245-appb-000004
7.如段落1或2所述的卡巴他赛脂肪乳注射剂，其特征在于，所述卡巴他赛脂肪乳注射剂是卡巴他赛冻干乳。
为了更进一步提高卡巴他赛脂肪乳注射剂的长期储存稳定性，可将卡巴他赛脂肪乳注射液进一步经冷冻干燥，制备成卡巴他赛冻干乳，故配方中也可含有冻干支撑剂，予以改善冻干后样品的外观，保证良好的复溶性。从而，本发明的卡巴他赛冻干乳是在注射液形式的基础上加入冻干支撑剂制成。
8.如段落7所述的卡巴他赛脂肪乳注射剂，其特征在于，所述卡巴他赛冻干乳由包含以下组分的配方配制而成：卡巴他赛、注射用中链甘油三酯、卵磷脂、助乳化剂、稳定剂、等渗调节剂、冻干支撑剂、pH调节剂和注射用水。
9.如段落7或8所述的卡巴他赛脂肪乳注射剂，其特征在于，所述卡巴他赛冻干乳，按重量百分比(w/v)计，由以下组分配制而成：
Figure PCTCN2016081245-appb-000005
10.如段落7或8所述的卡巴他赛脂肪乳注射剂，其特征在于，所述卡巴他赛冻干乳，按重量百分比(w/v)计，由以下组分配制而成：
Figure PCTCN2016081245-appb-000006
Figure PCTCN2016081245-appb-000007
11.如前述任一段落所述的卡巴他赛脂肪乳注射剂，其特征在于，所述卵磷脂为注射用卵磷脂，且选自蛋黄卵磷脂、大豆卵磷脂中的一种或两种。
12.如前述任一段落所述的卡巴他赛脂肪乳注射剂，其特征在于，所述助乳化剂为泊洛沙姆188。
13.如前述任一段落所述的卡巴他赛脂肪乳注射剂，其特征在于，所述等渗调节剂为甘油。
14.如前述任一段落所述的卡巴他赛脂肪乳注射剂，其特征在于，所述稳定剂为油酸和/或油酸钠。
15.如前述任一段落所述的卡巴他赛脂肪乳注射剂，其特征在于，所述pH调节剂选自枸橼酸、盐酸、醋酸、磷酸、乳酸、枸橼酸钠、磷酸氢二钾、磷酸氢二钠、磷酸二氢钾、磷酸二氢钠、醋酸钠、氢氧化钠中的一种或多种。
16.如段落8-15中任一项所述的卡巴他赛脂肪乳注射剂，其特征在于，所述冻干支撑剂选自于乳糖、蔗糖、甘露醇、右旋糖酐20、右旋糖酐40、右旋糖酐70、木糖醇、山梨醇、海藻糖中的一种或多种。
17.如段落8-16中任一项所述的卡巴他赛脂肪乳注射剂，其特征在于，所述冻干支撑剂为乳糖、蔗糖和/或甘露醇。
18.如前述任一段落所述的卡巴他赛脂肪乳注射剂，其特征在于，所述卡巴他赛脂肪乳注射剂的平均粒径为60-250nm，优选90-200nm。
19.段落1-18中任一项所述的卡巴他赛脂肪乳注射剂的制备方法，其特征在于，包括如下步骤：
(1)按配方量称取注射用中链甘油三酯、稳定剂，混匀，加热至50～80℃，加入卡巴他赛，在50～80℃下搅拌或剪切使其溶解，获得油相；
(2)将助乳化剂、等渗调节剂(在目标产品为卡巴他赛冻干乳的情况下，还另外包括冻干支撑剂)分散到适量注射用水中，加热至50～80℃，搅拌或剪切使溶解，再加入卵磷脂，剪切使其分散，获得水相；
(3)将所述油相和所述水相在50～80℃下混合，同时用剪切乳化机乳化5～15分钟，获得初乳，随后用注射用水定容；以及
(4)将所述初乳置于高压均质机中，在5000～20000psi、优选7000～18000psi的均质压力下进一步乳化，用pH调节剂调节pH至3.0～7.0，过滤，分装，封口，灭菌，即得卡巴他赛脂肪乳注射液；或者
(5)任选进一步地，将步骤(4)获得的卡巴他赛脂肪乳注射液经冷冻干燥，制备成卡巴他赛冻干乳。
20.如段落19所述的制备方法，其特征在于，将步骤(1)中所述的稳定剂溶解于步骤(2)的 水相中，和/或将步骤(2)所述的卵磷脂溶解于步骤(1)的油相中。
21.如段落19或20所述的制备方法，其特征在于，步骤(4)中的所述过滤是以孔径为0.22μm、0.45μm、0.8μm或1.2μm的囊式过滤器进行过滤；
步骤(4)中的所述灭菌是通过高压蒸汽进行灭菌，其中，灭菌温度为100～121℃，灭菌时间为10～45分钟。
22.段落1-18中任一项所述的卡巴他赛脂肪乳注射剂在制备用于治疗前列腺癌的药物中的用途。
23.段落1-18中任一项所述的卡巴他赛脂肪乳注射剂在治疗前列腺癌中的用途。
24.一种治疗前列腺癌的方法，所述方法包括向有需要的患者给予段落1-18中任一项所述的卡巴他赛脂肪乳注射剂。
25.一种用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，所述用于治疗前列腺癌的卡巴他赛脂肪乳注射剂包含卡巴他赛、注射用中链甘油三酯、卵磷脂。
26.如段落25所述的用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，其特征在于，所述卡巴他赛、所述注射用中链甘油三酯以及所述卵磷脂的重量比为(0.05-0.5):(2-10):(1-8)；优选为(0.1-0.3):(3-8):(3-6)。
27.如段落25或26所述的用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，其特征在于，所述用于治疗前列腺癌的卡巴他赛脂肪乳注射剂是卡巴他赛脂肪乳注射液。
28.如段落27所述的用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，其特征在于，所述卡巴他赛脂肪乳注射液包含以下组分：卡巴他赛、注射用中链甘油三酯、卵磷脂、助乳化剂、稳定剂、等渗调节剂、pH调节剂和注射用水。
29.如段落27或28所述的用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，其特征在于，所述卡巴他赛脂肪乳注射液，以重量百分比(w/v)计，包含以下组分：
Figure PCTCN2016081245-appb-000008
30.如段落27或28所述的用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，其特征在于，所述卡巴他赛脂肪乳注射液，以重量百分比(w/v)计，包含以下组分：
Figure PCTCN2016081245-appb-000009
Figure PCTCN2016081245-appb-000010
31.如段落25或26所述的用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，其特征在于，所述用于治疗前列腺癌的卡巴他赛脂肪乳注射剂是卡巴他赛冻干乳。
32.如段落31所述的用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，其特征在于，所述卡巴他赛冻干乳由包含以下组分的配方配制而成：卡巴他赛、注射用中链甘油三酯、卵磷脂、助乳化剂、稳定剂、等渗调节剂、冻干支撑剂、pH调节剂和注射用水。
33.如段落31或32所述的用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，其特征在于，所述卡巴他赛冻干乳，按重量百分比(w/v)计，由以下组分配制而成：
Figure PCTCN2016081245-appb-000011
34.如段落31或32所述的用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，其特征在于，所述卡巴他赛冻干乳，按重量百分比(w/v)计，由以下组分配制而成：
Figure PCTCN2016081245-appb-000012
35.如段落25-34中任一项所述的用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，其特征在于，所述卵磷脂选自蛋黄卵磷脂、大豆卵磷脂中的一种或两种。
36.如段落25-35中任一项所述的用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，其特征在于，所述助乳化剂为泊洛沙姆188。
37.如段落25-36中任一项所述的用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，其特征在于，所述等渗调节剂为甘油。
38.如段落25-37中任一项所述的用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，其特征在于，所 述稳定剂为油酸和/或油酸钠。
39.如段落25-38中任一项所述的用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，其特征在于，所述pH调节剂选自枸橼酸、盐酸、醋酸、磷酸、乳酸、枸橼酸钠、磷酸氢二钾、磷酸氢二钠、磷酸二氢钾、磷酸二氢钠、醋酸钠、氢氧化钠中的一种或多种。
40.如段落32-39中任一项所述的用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，其特征在于，所述冻干支撑剂选自于乳糖、蔗糖、甘露醇、右旋糖酐20、右旋糖酐40、右旋糖酐70、木糖醇、山梨醇、海藻糖中的一种或多种。
41.如段落32-40中任一项所述的用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，其特征在于，所述冻干支撑剂为乳糖、蔗糖和/或甘露醇。
42.如段落25-41所述的用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，其特征在于，所述用于治疗前列腺癌的卡巴他赛脂肪乳注射剂的平均粒径为60-250nm，优选90-200nm。
与市售卡巴他赛注射剂相比，本发明提供的卡巴他赛脂肪乳注射剂不含吐温-80等任何具有毒副作用的增溶剂，这在临床上具有极其重要的意义。与现有技术相比，本发明的制备方法省略了制备成磷脂复合物的过程，避免了卡巴他赛磷脂复合物的制备过程中所需要的加入大量有毒的有机溶剂，如氯仿、乙酸乙酯、乙醚等的步骤、以及反应结束后，需要除去有机溶剂的步骤。这些过程繁琐复杂，不易控制，且必然会出现有机溶剂残留的问题。因此，本发明的卡巴他赛脂肪乳注射剂及其制备方法可增加产品的用药安全性及生产过程的安全性，同时，也简化了制剂的生产工艺。本发明的方法制备的卡巴他赛脂肪乳制剂，制备工艺简单，不使用有毒有害的有机溶剂，并且稳定性和安全性俱佳，在社会效益和经济效益方面具有良好前景。
发明人发现，卡巴他赛在注射用中链甘油三酯中溶解度较大，且稳定性较好(参见实施例1)，故无需制备成磷脂复合物，即可解决卡巴他赛的溶解性问题。这样避免了：(a)在卡巴他赛磷脂复合物的制备过程中，需要加入大量有毒的有机溶剂，如氯仿、乙酸乙酯、乙醚等；而且，(b)反应结束后，需要将有机溶剂除去，过程繁琐复杂，不易控制，且必然会出现的有机溶剂残留的问题。同时，也简化了制剂的生产工艺。
具体实施方式
以下以具体的实施例说明本发明的技术方案，但本发明的保护范围不限于所述实施例的范围。所采用的试剂均为市售产品。实施例中，除非特殊说明，“％”是指重量体积百分含量(w/v)。
试验例1：卡巴他赛在注射用油中的溶解度考察
制备载药的脂肪乳剂，前提条件是主药应在注射用油中具有一定的溶解度，否则无法制备出稳定的载药脂肪乳剂。本发明的卡巴他赛脂肪乳注射剂希望是一种长期储存的载药脂肪乳剂，至少应在2年内稳定。故一定要保证所选的注射用油对卡巴他赛有足够的溶解度。
针对卡巴他赛的理化性质，发明人对多种注射用油(中链甘油三酯、大豆油、橄榄油、蓖麻油、棕榈油)中的溶解度进行了考察。
本试验例中，分别称取卡巴他赛适量，将其置于70℃的注射用中链甘油三酯、大豆油、橄榄油、蓖麻油、棕榈油中，加热搅拌，观察溶解状态。将溶解的药物溶液在4-6℃条件下储存72小时，进行低温挑战性试验，观察低温储存72小时时溶液的外观变化，如溶液出现浑浊，说明用该浓度的油溶 液所制备脂肪乳剂长期储存存在药物析出的风险。结果见表1。
表1卡巴他赛在注射用油中的溶解度结果
Figure PCTCN2016081245-appb-000013
“—”：完全不溶
由上述表1的结果可知，卡巴他赛在注射用大豆油、橄榄油、蓖麻油及棕榈油中的溶解度很低，浓度为10mg/g时，即使在70℃下搅拌1h也不能完全溶解；而在注射用中链甘油三酯中的溶解度相对较大，70℃条件下，浓度达60mg/g也能较快完全溶解，在低温(4-6℃)下储存72h后，其溶解度约为50mg/g。
实施例1卡巴他赛冻干乳
称取注射用中链甘油三酯50g、油酸0.3g，混匀，加热至70℃，加入卡巴他赛1.5g，在70℃下搅拌、剪切使溶解，得油相；称取乳糖150g分散到700ml注射用水中，加热至70℃，搅拌、剪切使溶解，再加入蛋黄卵磷脂50g，剪切使分散，得水相；将油相和水相在70℃下混合，同时用剪切乳化机乳化8分钟，得初乳，用注射用水定容至1000ml；将初乳置于高压均质机中，在15000psi均质压力下进一步乳化3次，用盐酸调节pH至5.0，分别经0.45μm、0.22μm滤膜过滤除菌，分装，冷冻干燥，封口，即得到卡巴他赛冻干乳。
实施例2卡巴他赛冻干乳
称取注射用中链甘油三酯50g、油酸0.3g，混匀，加热至70℃，加入卡巴他赛1.5g，在70℃下搅拌、剪切使溶解，得油相；称取2g泊洛沙姆188、乳糖150g分散到700ml注射用水中，加热至70℃，搅拌、剪切使溶解，再加入蛋黄卵磷脂50g，剪切使分散，得水相；将油相和水相在70℃下混合，同时用剪切乳化机乳化8分钟，得初乳，用注射用水定容至1000ml；将初乳置于高压均质机中，在10000psi均质压力下进一步乳化3次，用盐酸调节pH至5.0，分别经0.45μm、0.22μm滤膜过滤除菌，分装，冷冻干燥，封口，即得到卡巴他赛冻干乳。
实施例3卡巴他赛冻干乳
称取注射用中链甘油三酯20g、油酸0.3g，混匀，加热至50℃，加入卡巴他赛0.5g，在50℃下搅拌、剪切使溶解，得油相；称取2g泊洛沙姆188、乳糖100g分散到800ml注射用水中，加热至50℃，搅拌、剪切使溶解，再加入蛋黄卵磷脂10g，剪切使分散，得水相；将油相和水相在50℃下 混合，同时用剪切乳化机乳化15分钟，得初乳，用注射用水定容至1000ml；将初乳置于高压均质机中，在5000psi均质压力下进一步乳化6次，用枸橼酸调节pH至4.0，分别经0.8μm、0.22μm滤膜过滤除菌，分装，冷冻干燥，即得到卡巴他赛冻干乳。
实施例4卡巴他赛脂肪乳注射液
称取注射用中链甘油三酯100g，加热至70℃，加入卡巴他赛5g，在70℃下搅拌、剪切使溶解，得油相；称取油酸钠0.3g、5g泊洛沙姆188、甘油22g分散到750ml注射用水中，加热至70℃，搅拌、剪切使溶解，再加入蛋黄卵磷脂80g，剪切使分散，得水相；将油相和水相在70℃下混合，同时用剪切乳化机乳化10分钟，得初乳，用注射用水定容至1000ml；将初乳置于高压均质机中，在16000psi均质压力下进一步乳化3次，用磷酸氢二钠、磷酸二氢钠调节pH至7.0，分别经0.8μm、0.45μm滤膜过滤，分装，封口，115℃下灭菌30分钟，即得到卡巴他赛脂肪乳注射液。
实施例5卡巴他赛冻干乳
称取注射用中链甘油三酯30g、油酸0.3g，混匀，加热至80℃，加入大豆卵磷脂10g，在80℃下搅拌、剪切使溶解，加入卡巴他赛1.0g，在80℃下搅拌、剪切使溶解，得油相；称取5g泊洛沙姆188、乳糖100g、50g右旋糖酐40分散到750ml注射用水中，加热至80℃，搅拌、剪切使溶解，得水相；将油相和水相在80℃下混合，同时用剪切乳化机乳化5分钟，得初乳，用注射用水定容至1000ml；将初乳置于高压均质机中，在15000psi均质压力下进一步乳化3次，用醋酸、醋酸钠调节pH至6.0，分别经1.2μm、0.45μm、0.22μm滤膜过滤除菌，分装，冷冻干燥，封口，即得到卡巴他赛冻干乳。
实施例6卡巴他赛冻干乳
称取注射用中链甘油三酯30g、油酸0.1g，混匀，加热至70℃，加入卡巴他赛1.0g，在70℃下搅拌、剪切使溶解，得油相；称取乳糖100g、蔗糖50g分散到750ml注射用水中，加热至70℃，搅拌、剪切使溶解，再加入大豆卵磷脂30g，剪切使分散，得水相；将油相和水相在70℃下混合，同时用剪切乳化机乳化5分钟，得初乳，用注射用水定容至1000ml；将初乳置于高压均质机中，在7000psi均质压力下进一步乳化5次，用枸橼酸、枸橼酸钠调节pH至4.0，分别经0.8μm、0.45μm、0.22μm滤膜过滤除菌，分装，冷冻干燥，封口，即得到卡巴他赛冻干乳。
实施例7卡巴他赛冻干乳
称取注射用中链甘油三酯60g、油酸0.3g，混匀，加热至60℃，加入卡巴他赛1.5g，在60℃下搅拌、剪切使溶解，得油相；称取乳糖100g、甘露醇50g分散到700ml注射用水中，加热至60℃，搅拌、剪切使溶解，再加入蛋黄卵磷脂60g，剪切使分散，得水相；将油相和水相在60℃下混合，同时用剪切乳化机乳化10分钟，得初乳，用注射用水定容至1000ml；将初乳置于高压均质机中，在20000psi均质压力下进一步乳化2次，用磷酸调节pH至3.0，分别经0.45μm、0.22μm滤膜过滤除菌，分装，冷冻干燥，封口，即得到卡巴他赛冻干乳。
实施例8卡巴他赛脂肪乳注射液
称取注射用中链甘油三酯50g，加热至60℃，加入卡巴他赛1.5g，在60℃下搅拌、剪切使溶解，得油相；称取油酸钠0.2g、3g泊洛沙姆188、甘油22g分散到850ml注射用水中，加热至60℃，搅 拌、剪切使溶解，再加入蛋黄卵磷脂40g，剪切使分散，得水相；将油相和水相在60℃下混合，同时用剪切乳化机乳化8分钟，得初乳，用注射用水定容至1000ml；将初乳置于高压均质机中，在15000psi均质压力下进一步乳化4次，用磷酸调节pH至3.0，分别经0.8μm、0.22μm滤膜过滤，分装，封口，121℃下灭菌15分钟，即得到卡巴他赛脂肪乳注射液。
实施例9卡巴他赛冻干乳
称取注射用中链甘油三酯40g，加热至70℃，加入卡巴他赛1.5g，在70℃下搅拌、剪切使溶解，得油相；称取乳糖130g、甘露醇20g分散到700ml注射用水中，加热至70℃，搅拌、剪切使溶解，再加入蛋黄卵磷脂20g、大豆卵磷脂20g，剪切使分散，得水相；将油相和水相在70℃下混合，同时用剪切乳化机乳化7分钟，得初乳，用注射用水定容至1000ml；将初乳置于高压均质机中，在15000psi均质压力下进一步乳化3次，用磷酸、氢氧化钠调节pH至5.5，分别经1.2μm、0.45μm、0.22μm滤膜过滤除菌，分装，冷冻干燥，封口，即得到卡巴他赛冻干乳。
实施例10卡巴他赛冻干乳
称取注射用中链甘油三酯50g，加热至80℃，加入卡巴他赛1.5g，在80℃下搅拌、剪切使溶解，得油相；称取油酸钠0.3g、山梨醇75g、木糖醇75g分散到700ml注射用水中，加热至80℃，搅拌、剪切使溶解，再加入大豆卵磷脂50g，剪切使分散，得水相；将油相和水相在80℃下混合，同时用剪切乳化机乳化5分钟，得初乳，用注射用水定容至1000ml；将初乳置于高压均质机中，在18000psi均质压力下进一步乳化3次，用乳酸调节pH至5.0，分别经0.45μm、0.22μm滤膜过滤除菌，分装，冷冻干燥，封口，即得到卡巴他赛冻干乳。
实施例11卡巴他赛冻干乳
称取注射用中链甘油三酯50g，加热至70℃，加入卡巴他赛1.5g，在70℃下搅拌、剪切使溶解，得油相；称取油酸钠0.3g、1g泊洛沙姆188、乳糖100g、30g右旋糖酐20、甘露醇20g分散到700ml注射用水中，加热至70℃，搅拌、剪切使溶解，再加入蛋黄卵磷脂20g、大豆卵磷脂20g，剪切使分散，得水相；将油相和水相在70℃下混合，同时用剪切乳化机乳化8分钟，得初乳，用注射用水定容至1000ml；将初乳置于高压均质机中，在15000psi均质压力下进一步乳化3次，用磷酸氢二钾、磷酸二氢钾调节pH至6.0，分别经1.2μm、0.45μm、0.22μm滤膜过滤除菌，分装，冷冻干燥，封口，即得到卡巴他赛冻干乳。
实施例12卡巴他赛冻干乳
称取注射用中链甘油三酯50g，加热至60℃，加入卡巴他赛1.5g，在60℃下搅拌、剪切使溶解，得油相；称取乳糖120g、30g右旋糖酐70分散到700ml注射用水中，加热至60℃，搅拌、剪切使溶解，再加入蛋黄卵磷脂50g，剪切使分散，得水相；将油相和水相在60℃下混合，同时用剪切乳化机乳化10分钟，得初乳，用注射用水定容至1000ml；将初乳置于高压均质机中，在16000psi均质压力下进一步乳化3次，用盐酸调节pH至4.0，分别经0.45μm、0.22μm滤膜过滤除菌，分装，冷冻干燥，封口，即得到卡巴他赛冻干乳。
实施例13卡巴他赛脂肪乳注射液
称取注射用中链甘油三酯50g、油酸0.3g，混匀，加热至70℃，加入卡巴他赛2.0g，在70℃下 搅拌、剪切使溶解，得油相；称取甘油2.2g分散到800ml注射用水中，加热至70℃，再加入蛋黄卵磷脂60g，剪切使分散，得水相；将油相和水相在70℃下混合，同时用剪切乳化机乳化6分钟，得初乳，用注射用水定容至1000ml；将初乳置于高压均质机中，在17000psi均质压力下进一步乳化3次，用磷酸、磷酸氢二钾调节pH至5.0，分别经0.8μm、0.22μm滤膜过滤，分装，封口，100℃下灭菌45分钟，即得到卡巴他赛脂肪乳注射液。
实施例14卡巴他赛冻干乳
称取注射用中链甘油三酯60g、油酸0.3g，混匀，加热至70℃，加入卡巴他赛2.0g，在70℃下搅拌、剪切使溶解，得油相；称取2g泊洛沙姆188、乳糖150g、甘露醇30g分散到700ml注射用水中，加热至70℃，搅拌、剪切使溶解，再加入蛋黄卵磷脂50g，剪切使分散，得水相；将油相和水相在70℃下混合，同时用剪切乳化机乳化5分钟，得初乳，用注射用水定容至1000ml；将初乳置于高压均质机中，在15000psi均质压力下进一步乳化3次，用醋酸、醋酸钠调节pH至6.0，分别经0.8μm、0.22μm滤膜过滤除菌，分装，冷冻干燥，封口，即得到卡巴他赛冻干乳。
实施例15卡巴他赛冻干乳
称取注射用中链甘油三酯50g，加热至70℃，加入卡巴他赛2.0g，在70℃下搅拌、剪切使溶解，得油相；称取油酸钠0.3g、乳糖150g分散到700ml注射用水中，加热至70℃，搅拌、剪切使溶解，再加入大豆卵磷脂50g，剪切使分散，得水相；将油相和水相在70℃下混合，同时用剪切乳化机乳化8分钟，得初乳，用注射用水定容至1000ml；将初乳置于高压均质机中，在16000psi均质压力下进一步乳化3次，用枸橼酸、氢氧化钠调节pH至6.0，分别经0.45μm、0.22μm滤膜过滤除菌，分装，冷冻干燥，封口，即得到卡巴他赛冻干乳。
实施例16卡巴他赛冻干乳
称取注射用中链甘油三酯60g、油酸0.2g，混匀，加热至65℃，加入卡巴他赛2.0g，在65℃下搅拌、剪切使溶解，得油相；称取乳糖150g、蔗糖20g分散到700ml注射用水中，加热至65℃，搅拌、剪切使溶解，再加入蛋黄卵磷脂30g、大豆卵磷脂30g，剪切使分散，得水相；将油相和水相在65℃下混合，同时用剪切乳化机乳化10分钟，得初乳，用注射用水定容至1000ml；将初乳置于高压均质机中，在16000psi均质压力下进一步乳化4次，用乳酸调节pH至4.5，分别经1.2μm、0.45μm、0.22μm滤膜过滤除菌，分装，冷冻干燥，封口，即得到卡巴他赛冻干乳。
实施例17卡巴他赛冻干乳
称取注射用中链甘油三酯80g、油酸0.3g，混匀，加热至70℃，加入卡巴他赛3.0g，在70℃下搅拌、剪切使溶解，得油相；称取4g泊洛沙姆188、乳糖150g、蔗糖20g、甘露醇30g分散到600ml注射用水中，加热至70℃，搅拌、剪切使溶解，再加入蛋黄卵磷脂60g，剪切使分散，得水相；将油相和水相在70℃下混合，同时用剪切乳化机乳化8分钟，得初乳，用注射用水定容至1000ml；将初乳置于高压均质机中，在15000psi均质压力下进一步乳化，用醋酸、醋酸钠调节pH至5.5，分别经0.45μm、0.22μm滤膜过滤除菌，分装，冷冻干燥，封口，即得到卡巴他赛冻干乳。
实施例18卡巴他赛冻干乳
称取注射用中链甘油三酯60g，加热至70℃，加入卡巴他赛3.0g，在70℃下搅拌、剪切使溶解， 得油相；称取3g泊洛沙姆188、乳糖100g、山梨醇40g、木糖醇40g分散到650ml注射用水中，加热至70℃，搅拌、剪切使溶解，再加入蛋黄卵磷脂60g，剪切使分散，得水相；将油相和水相在70℃下混合，同时用剪切乳化机乳化7分钟，得初乳，用注射用水定容至1000ml；将初乳置于高压均质机中，在17000psi均质压力下进一步乳化3次，用磷酸氢二钠、磷酸二氢钠调节pH至6.5，分别经0.8μm、0.22μm滤膜过滤除菌，分装，冷冻干燥，封口，即得到卡巴他赛冻干乳。
实施例19卡巴他赛脂肪乳注射液
称取注射用中链甘油三酯90g、油酸0.3g，混匀，加热至70℃，加入卡巴他赛4.0g，在70℃下搅拌、剪切使溶解，得油相；称取5g泊洛沙姆188、甘油22g分散到800ml注射用水中，加热至70℃，搅拌、剪切使溶解，再加入蛋黄卵磷脂60g，剪切使分散，得水相；将油相和水相在70℃下混合，同时用剪切乳化机乳化8分钟，得初乳，用注射用水定容至1000ml；将初乳置于高压均质机中，在15000psi均质压力下进一步乳化4次，用枸橼酸调节pH至5.0，分别经0.8μm、0.22μm滤膜过滤，分装，封口，121℃下灭菌10分钟，即得到卡巴他赛脂肪乳注射液。
实施例20卡巴他赛冻干乳
称取注射用中链甘油三酯80g、油酸0.3g，混匀，加热至70℃，加入卡巴他赛4.0g，在70℃下搅拌、剪切使溶解，得油相；称取4g泊洛沙姆188、乳糖200g、海藻糖100g分散到800ml注射用水中，加热至70℃，搅拌、剪切使溶解，再加入蛋黄卵磷脂70g，剪切使分散，得水相；将油相和水相在70℃下混合，同时用剪切乳化机乳化10分钟，得初乳，用注射用水定容至1000ml；将初乳置于高压均质机中，在16000psi均质压力下进一步乳化3次，用枸橼酸、氢氧化钠调节pH至6.0，分别经0.88μm、0.22μm滤膜过滤除菌，分装，冷冻干燥，封口，即得到卡巴他赛冻干乳。
试验例2卡巴他赛脂肪乳注射剂的稳定性试验
分别取实施例2、实施例3、实施例4、实施例6、实施例8、实施例14所制备的样品。在25℃±2℃，湿度为60％±10％下放置6个月，分别于0个月、1个月、2个月、3个月、6个月时取样，其中冻干乳用注射用水复溶成冻干前溶液的浓度。分别取卡巴他赛脂肪乳注射液以及冻干乳的复溶液，重点考察pH值、粒径以及标示百分含量的变化，结果分别见表2、表3、表4。
表2卡巴他赛脂肪乳注射剂pH值随时间变化
Figure PCTCN2016081245-appb-000014
表3卡巴他赛脂肪乳注射剂粒径随时间变化
Figure PCTCN2016081245-appb-000015
注：各实施例中的粒径是将卡巴他赛脂肪乳注射剂用水稀释200倍后，使用英国马尔文粒径测定仪(型号：Nano-S型)测定的粒径。
表4卡巴他赛脂肪乳注射剂标示百分含量随时间变化
Figure PCTCN2016081245-appb-000016
注：各实施例中的标示百分含量是指采用高效液相色谱法测定的药物含量色谱测定条件为：采用C18硅胶柱，流动相为：乙腈/水＝30/70，检测波长为232nm，进样量为10μl。检测过程包括：精密称取实施例的产品适量，加乙腈溶解并稀释制成每1ml中约含卡巴他赛0.1mg的溶液，精密量取10μl注入液相色谱仪(仪器型号：Agilent 1100系列)，记录色谱图；另取卡巴他赛对照品，精密称取并按照同样的测定方法测定，最后按照外标峰的面积计算卡巴他赛的标示百分含量。
由上述表2-表4可以看出，本发明的卡巴他赛脂肪乳注射剂，在25℃±2℃，湿度为60％±10％下放置6个月，pH值、粒径以及标示百分含量未见明显变化，说明本发明的卡巴他赛脂肪乳注射剂可长期储存，质量稳定。特别是经冷冻干燥后的卡巴他赛冻干脂肪乳(实施例2、3、6、14)，相对于未冻干的卡巴他赛脂肪乳注射液(实施例4、8)而言更为稳定。

Claims (42)

  1. 一种卡巴他赛脂肪乳注射剂，所述卡巴他赛脂肪乳注射剂包含卡巴他赛、注射用中链甘油三酯、卵磷脂。
  2. 如权利要求1所述的卡巴他赛脂肪乳注射剂，其特征在于，所述卡巴他赛、所述注射用中链甘油三酯以及所述卵磷脂的重量比为(0.05-0.5):(2-10):(1-8)；优选为(0.1-0.3):(3-8):(3-6)。
  3. 如权利要求1或2所述的卡巴他赛脂肪乳注射剂，其特征在于，所述卡巴他赛脂肪乳注射剂是卡巴他赛脂肪乳注射液。
  4. 如权利要求3所述的卡巴他赛脂肪乳注射剂，其特征在于，所述卡巴他赛脂肪乳注射液包含以下组分：卡巴他赛、注射用中链甘油三酯、卵磷脂、助乳化剂、稳定剂、等渗调节剂、pH调节剂和注射用水。
  5. 如权利要求3或4所述的卡巴他赛脂肪乳注射剂，其特征在于，所述卡巴他赛脂肪乳注射液，以重量百分比(w/v)计，包含以下组分：
    Figure PCTCN2016081245-appb-100001
  6. 如权利要求3或4所述的卡巴他赛脂肪乳注射剂，其特征在于，所述卡巴他赛脂肪乳注射液，以重量百分比(w/v)计，包含以下组分：
    Figure PCTCN2016081245-appb-100002
  7. 如权利要求1或2所述的卡巴他赛脂肪乳注射剂，其特征在于，所述卡巴他赛脂肪乳注射剂是卡巴他赛冻干乳。
  8. 如权利要求7所述的卡巴他赛脂肪乳注射剂，其特征在于，所述卡巴他赛冻干乳由包含以下组分的配方配制而成：卡巴他赛、注射用中链甘油三酯、卵磷脂、助乳化剂、稳定剂、等渗调节剂、冻干支撑剂、pH调节剂和注射用水。
  9. 如权利要求7或8所述的卡巴他赛脂肪乳注射剂，其特征在于，所述卡巴他赛冻干乳，按 重量百分比(w/v)计，由以下组分配制而成：
    Figure PCTCN2016081245-appb-100003
  10. 如权利要求7或8所述的卡巴他赛脂肪乳注射剂，其特征在于，所述卡巴他赛冻干乳，按重量百分比(w/v)计，由以下组分配制而成：
    Figure PCTCN2016081245-appb-100004
  11. 如前述任一项权利要求所述的卡巴他赛脂肪乳注射剂，其特征在于，所述卵磷脂为注射用卵磷脂，且选自蛋黄卵磷脂、大豆卵磷脂中的一种或两种。
  12. 如前述任一项权利要求所述的卡巴他赛脂肪乳注射剂，其特征在于，所述助乳化剂为泊洛沙姆188。
  13. 如前述任一项权利要求所述的卡巴他赛脂肪乳注射剂，其特征在于，所述等渗调节剂为甘油。
  14. 如前述任一项权利要求所述的卡巴他赛脂肪乳注射剂，其特征在于，所述稳定剂为油酸和/或油酸钠。
  15. 如前述任一项权利要求所述的卡巴他赛脂肪乳注射剂，其特征在于，所述pH调节剂选自枸橼酸、盐酸、醋酸、磷酸、乳酸、枸橼酸钠、磷酸氢二钾、磷酸氢二钠、磷酸二氢钾、磷酸二氢钠、醋酸钠、氢氧化钠中的一种或多种。
  16. 如权利要求8-15中任一项所述的卡巴他赛脂肪乳注射剂，其特征在于，所述冻干支撑剂选自于乳糖、蔗糖、甘露醇、右旋糖酐20、右旋糖酐40、右旋糖酐70、木糖醇、山梨醇、海藻糖中的一种或多种。
  17. 如权利要求8-16中任一项所述的卡巴他赛脂肪乳注射剂，其特征在于，所述冻干支撑剂为乳糖、蔗糖和/或甘露醇。
  18. 如前述任一项权利要求所述的卡巴他赛脂肪乳注射剂，其特征在于，所述卡巴他赛脂肪乳注射剂的平均粒径为60-250nm，优选90-200nm。
  19. 权利要求1-18中任一项所述的卡巴他赛脂肪乳注射剂的制备方法，其特征在于，包括如下步骤：
    (1)按配方量称取注射用中链甘油三酯、稳定剂，混匀，加热至50～80℃，加入卡巴他赛，在50～80℃下搅拌或剪切使其溶解，获得油相；
    (2)将助乳化剂、等渗调节剂(在目标产品为卡巴他赛冻干乳的情况下，还另外包括冻干支撑剂)分散到适量注射用水中，加热至50～80℃，搅拌或剪切使溶解，再加入卵磷脂，剪切使其分散，获得水相；
    (3)将所述油相和所述水相在50～80℃下混合，同时用剪切乳化机乳化5～15分钟，获得初乳，随后用注射用水定容；以及
    (4)将所述初乳置于高压均质机中，在5000～20000psi、优选7000～18000psi的均质压力下进一步乳化，用pH调节剂调节pH至3.0～7.0，过滤，分装，封口，灭菌，即得卡巴他赛脂肪乳注射液；或者
    (5)任选进一步地，将步骤(4)获得的卡巴他赛脂肪乳注射液经冷冻干燥，制备成卡巴他赛冻干乳。
  20. 如权利要求19所述的制备方法，其特征在于，将步骤(1)中所述的稳定剂溶解于步骤(2)的水相中，和/或将步骤(2)所述的卵磷脂溶解于步骤(1)的油相中。
  21. 如权利要求19或20所述的制备方法，其特征在于，步骤(4)中的所述过滤是以孔径为0.22μm、0.45μm、0.8μm或1.2μm的囊式过滤器进行过滤；和/或
    步骤(4)中的所述灭菌是通过高压蒸汽进行灭菌，其中，灭菌温度为100～121℃，灭菌时间为10～45分钟。
  22. 权利要求1-18中任一项所述的卡巴他赛脂肪乳注射剂在制备用于治疗前列腺癌的药物中的用途。
  23. 权利要求1-18中任一项所述的卡巴他赛脂肪乳注射剂在治疗前列腺癌中的用途。
  24. 一种治疗前列腺癌的方法，所述方法包括向有需要的患者给予权利要求1-18中任一项所述的卡巴他赛脂肪乳注射剂。
  25. 一种用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，所述用于治疗前列腺癌的卡巴他赛脂肪乳注射剂包含卡巴他赛、注射用中链甘油三酯、卵磷脂。
  26. 如权利要求25所述的用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，其特征在于，所述卡巴他赛、所述注射用中链甘油三酯以及所述卵磷脂的重量比为(0.05-0.5):(2-10):(1-8)；优选为(0.1-0.3):(3-8):(3-6)。
  27. 如权利要求25或26所述的用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，其特征在于，所述用于治疗前列腺癌的卡巴他赛脂肪乳注射剂是卡巴他赛脂肪乳注射液。
  28. 如权利要求27所述的用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，其特征在于，所述卡巴他赛脂肪乳注射液包含以下组分：卡巴他赛、注射用中链甘油三酯、卵磷脂、助乳化剂、稳定剂、等渗调节剂、pH调节剂和注射用水。
  29. 如权利要求27或28所述的用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，其特征在于，所述卡巴他赛脂肪乳注射液，以重量百分比(w/v)计，包含以下组分：
    Figure PCTCN2016081245-appb-100005
  30. 如权利要求27或28所述的用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，其特征在于，所述卡巴他赛脂肪乳注射液，以重量百分比(w/v)计，包含以下组分：
    Figure PCTCN2016081245-appb-100006
  31. 如权利要求25或26所述的用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，其特征在于，所述用于治疗前列腺癌的卡巴他赛脂肪乳注射剂是卡巴他赛冻干乳。
  32. 如权利要求31所述的用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，其特征在于，所述卡巴他赛冻干乳由包含以下组分的配方配制而成：卡巴他赛、注射用中链甘油三酯、卵磷脂、助乳化剂、稳定剂、等渗调节剂、冻干支撑剂、pH调节剂和注射用水。
  33. 如权利要求31或32所述的用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，其特征在于，所述卡巴他赛冻干乳，按重量百分比(w/v)计，由以下组分配制而成：
    Figure PCTCN2016081245-appb-100007
  34. 如权利要求31或32所述的用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，其特征在于，所述卡巴他赛冻干乳，按重量百分比(w/v)计，由以下组分配制而成：
    Figure PCTCN2016081245-appb-100008
  35. 如权利要求25-34中任一项所述的用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，其特征在于，所述卵磷脂选自蛋黄卵磷脂、大豆卵磷脂中的一种或两种。
  36. 如权利要求25-35中任一项所述的用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，其特征在于，所述助乳化剂为泊洛沙姆188。
  37. 如权利要求25-36中任一项所述的用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，其特征在于，所述等渗调节剂为甘油。
  38. 如权利要求25-37中任一项所述的用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，其特征在于，所述稳定剂为油酸和/或油酸钠。
  39. 如权利要求25-38中任一项所述的用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，其特征在于，所述pH调节剂选自枸橼酸、盐酸、醋酸、磷酸、乳酸、枸橼酸钠、磷酸氢二钾、磷酸氢二钠、磷酸二氢钾、磷酸二氢钠、醋酸钠、氢氧化钠中的一种或多种。
  40. 如权利要求32-39中任一项所述的用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，其特征在于，所述冻干支撑剂选自于乳糖、蔗糖、甘露醇、右旋糖酐20、右旋糖酐40、右旋糖酐70、木糖醇、山梨醇、海藻糖中的一种或多种。
  41. 如权利要求32-40中任一项所述的用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，其特征在于，所述冻干支撑剂为乳糖、蔗糖和/或甘露醇。
  42. 如权利要求25-41所述的用于治疗前列腺癌的卡巴他赛脂肪乳注射剂，其特征在于，所述用于治疗前列腺癌的卡巴他赛脂肪乳注射剂的平均粒径为60-250nm，优选90-200nm。
PCT/CN2016/081245 2015-05-06 2016-05-06 一种卡巴他赛脂肪乳注射剂及其制备方法和用途 WO2016177346A1 (zh)

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