Novel paclitaxel emulsion for intravenous injection and its preparation method

Abstract

Disclosed is a novel paclitaxel emulsion for intravenous injection and its preparation method which consists of, dissolving yew alcohol with an oil for injection and preparing emulsion from medicinal adjuvant such as right amount of emulsifying agent, mixing yew alcohol, oil for injection, emulsifying agent and anti-oxidant so as to obtain the oil phase, mixing water for injection and isotonic conditioning agent to obtain aqueous phase, mixing the oil phase with the aqueous phase for emulsifying, carrying out further emulsifying, stirring, high-pressure homogenizing to prepare yew emulsion meeting venous injection.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a paclitaxel emulsion for intravenous injection prepared by dissolving an anticancer drug paclitaxel with an injection oil and using a suitable emulsifier and other pharmaceutical auxiliary materials and a preparation method thereof. Background technique [0002] Paclitaxel (trade name Taxol) is a highly effective anticancer drug extracted from Taxus brevidolia, Pacific yew. It is a complex diterpenoid compound with a molecular formula of C 47 h 51 NO 14 , the relative molecular mass is 853.9. Paclitaxel has good anticancer activity, and has good curative effect for treating ovarian cancer, breast cancer, colon cancer, non-small cell lung cancer, neck cancer and melanoma. [0003] The solubility of paclitaxel in water is very small, almost insoluble in water (<0.004mg / ml), and the bioavailability of oral administration is poor, so it can only be ...

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Problems solved by technology

[0003] The solubility of paclitaxel in water is very small, almost insoluble in water (<0.004mg / ml), and the bioavailability of oral administration is poor, so it can only be administered by intravenous injection

The solubility of paclitaxel in commonly used injection oils is also very small, and the current clinical commonly used paclitaxel preparation is an oil preparation (Cremophor® EL) made by mixing polyoxyethylene castor oil and absolute ethanol 1:1, that is, paclitaxel Cremophor preparation. Before the medicine is diluted to the administration concentration with normal saline or 5% glucose solution, ethanol has greater irritation during injection, and polyoxyethylene castor oil has side effects, which can cause severe allergic reactions, and patients need antiallergic precautions before injection. The whole process is extremely inconvenient. In addition, Cremophor preparations tend to form precipitates after dilution, which affects the absorption and utilization of paclitaxel.

A variety of new formulations of paclitaxel have been reported. For example, Bissery et al. used ethanol, Tween-80, polypropylene glycol, etc. as paclitaxel co-solubilizers, diluted with glucose solution before administration, and used for intravenous infusion of paclitaxel (Bissery MC , et al., Cancer Res, 1991,51:4845), but the ethanol and Tween-80 and other irritating substances are contained in the co-solubilized substance, and Tween-80 has a certain hemolytic effect and has a relatively large adverse reaction, and After this dilution, it is extremely unstable, and paclitaxel is easy to separate out; Pan Linlin et al. adopt mixed surfactant and mixed solvent to solubilize paclitaxel, and have prepared paclitaxel injection (Pan Linlin et al., Journal of Shenyang Pharmaceutical University, 2004, 21 (2): 101-104), the injection needs to be diluted with normal saline or glucose injection before injection, and sometimes flocculation and particle precipitation will occur. Clinical outlook unknown

Shama A, Zhang Jingqing, Wei Fengying, Zhang Changying, etc. have done research on paclitaxel liposomes (Sharma A, et al.Int JCancer, 1997, 71 (1): 103; Zhang Jingqing, West China Pharmaceutical Journal, 2001, 16 (1) : 23; etc.), the stability of liposomes is greatly affected by temperature, and the storage time is short. Due to the large particle size of liposomes, its main target sites are liver and spleen, and the distribution of other parts is very low. The efficacy of some tumors can not meet the requirements; Csethati prepared a variety of paclitaxel coatings with various cyclodextrins (Cserhati T, et al., J PharmBiomed Anal, 1995, 13: 533-541.), but cyclodextrins have relatively Large allergic reactions and hemolysis, large adverse reactions limit the wide application of paclitaxel cyclodextrin coating; Kan et al. prepared paclitaxel O / w emulsion with non-ionic surfactant and phospholipid (Kan P, et al. , Controlled Release, 1999, 58:271-278), but the emulsion contains Tween-80, and the patient has hemolysis after intravenous injection, which has a relatively large adverse reaction; Zhang Yuru et al. dissolve paclitaxel, phospholipids and bile salts in In an organic solvent, the needle powder is made by freeze-drying (Zhang Hairu et al., CN1148957, 1997). When in use, directly add 5% glucose or 0.9% sodium chloride injection to dissolve and inject it intravenously, but paclitaxel is easy to separate out when diluted

In short, including other preparations such as microemulsions, proliposomes, topical administration, etc., because there are certain problems in terms of encapsulation efficiency, stability, side effects, bioavailability or convenience of administration, and paclitaxel As with Cremophor preparations, satisfactory results cannot be obtained