WO2007009355A1

WO2007009355A1 - Paclitaxel injection and preparation method thereof

Info

Publication number: WO2007009355A1
Application number: PCT/CN2006/001665
Authority: WO
Inventors: Jianming Chen; Baoan Gao; Zundong Huang; Haisheng Chen; Qin Xiao; Chengan Huang
Original assignee: Holley Pharmaceuticals Co. Ltd.
Priority date: 2005-07-20
Filing date: 2006-07-13
Publication date: 2007-01-25
Also published as: CN1723887A

Abstract

A paclitaxel injection and the preparation method thereof. The said paclitaxel injection consists of paclitaxel 0.01-2%(w/v), stabilizer 1-70%(w/v), and the remainder is solvent for injection, wherein stabilizer is one or more agents selected from soybean phospholipid, yolk phospholipid, Tween-80, cholesterol, sodium cholate, Poloxamer 188, monoolein. It is prepared as follows: dissolving the stabilizer in said solvent by thermal stirring or ultrasonic stirring, adding paclitaxel, stirring, filtering, loading it in containers and sterilizing. It has low toxic by-effect and stable property.

Description

Paclitaxel injection and preparation method thereof

The present invention relates to the field of medical technology, and in particular to a novel formulation and a preparation method for preparing a paclitaxel injection by using an injection solvent to dissolve the anticancer drug paclitaxel and using a suitable stabilizer. Background technique

Paclitaxel (trade name Taxol) is a potent anticancer drug extracted from Taxus brevidolia (Pacific yew), a complex diterpenoid with a molecular formula of C _47. H ₅₁ N0 ₁₄ , relative molecular mass is 853.9. Paclitaxel has good anticancer activity and is effective for treating ovarian cancer, breast cancer, colon cancer, non-small cell lung cancer, cervical cancer, melanoma, and the like.

Paclitaxel has a low solubility in water and is almost insoluble in water (<0. 004 mg / ml). Oral administration has poor bioavailability and can only be administered by intravenous injection. The currently used paclitaxel preparation is a mixture of polyoxyethylene castor oil and absolute ethanol 1:1 (Cremophor® EL), which is a paclitaxel Cremophor preparation. When the polyoxyethylene castor oil in the composite solvent is degraded in vivo, It releases histamine, causing a severe allergic reaction. Paclitaxel injection registered in China (trade name is Taxol), the specification states that "to prevent serious allergic reactions, all patients receiving this drug should be given corticosteroids (such as dexamethasone), benzene. Hellamin and H2 receptor antagonists (such as cimetidine, ranitidine), and the administration process requires strict monitoring, the whole process is extremely inconvenient. In addition, the Cremophor preparation has poor stability after dilution, and is easy to precipitate, which reduces the safety of clinical medication and affects the absorption and utilization of paclitaxel. Shama A and Zhang Jingqi studied paclitaxel liposomes (Sharma A, et al., Int J Cancer, 1997, 71 (1): 103; Zhang Jingwei, West China Pharmaceutical Journal, 2001, 16 (1): 23), lipid The stability of the plastid is greatly affected by temperature, and the storage time is short. Due to the large particle size of the liposome, the main target sites are liver and spleen, and other parts are distributed very low, and the curative effect on some tumors cannot meet the requirements. . . . Csethati has prepared a variety of paclitaxel wraps with various cyclodextrins

(Cserhati T, et al., J Pharm Biomed Anal, 1995, 13 : 533-541. ) , but cyclodextrin has a large allergic reaction and hemolysis, and large adverse reactions limit the inclusion of paclitaxel cyclodextrin. widely used. Zhang Yuru et al. dissolved paclitaxel, phospholipids and bile salts in an organic solvent and made a powder injection by freeze-drying method.

(CN1148957, 1997.), when added directly by adding 5% glucose or 0.9% sodium chloride injection after intravenous infusion, but it is easy to have paclitaxel when diluted. In summary, including other preparations such as microemulsions, precursor liposomes, Local administration or the like has a certain group of problems in terms of encapsulation efficiency, stability, side effects, bioavailability or ease of administration, and cannot completely replace the paclitaxel Cremophor preparation. Minute

Summary of the invention

The invention provides a novel paclitaxel injection and a preparation method thereof. That is, an injection preparation is prepared by dissolving the paclitaxel with a solvent for injection and using a suitable stabilizer. The injection is diluted with 5%, 10% glucose or 0.9% sodium chloride solution into an injection solution, and has good stability and small side effects, ensuring the safety of the drug, and there is no appearance of precipitation after other dosage forms are diluted, further ensuring The effective use of paclitaxel.

The paclitaxel injection of the present invention is composed of the following components: w/v% content

Paclitaxel 0.01-2

Stabilizer 1-70

Injection solvent

The stabilizers include, but are not limited to, soybean phospholipid for injection, egg yolk phospholipid, Tween 80, cholesterol, sodium cholate, poloxamer 188 (F68) or glycerol monooleate, and one or more selected ones. mixture.

The solvent for injection includes, but is not limited to, anhydrous ethanol, glycerin, propylene glycol, polyethylene glycol and the like, and one or more kinds of mixtures are used.

The preparation method of the paclitaxel injection of the present invention is as follows:

Weigh the stabilizer into the solvent for injection according to the formula amount, dissolve the stabilizer at room temperature or with heating or ultrasonication, heat at 40-90 ° C, add paclitaxel, stir or ultrasonically dissolve paclitaxel completely, filter, dispense , disinfection, get paclitaxel injection.

In the preparation method, the stabilizer is first dissolved in the solvent for injection, and then paclitaxel is added in order to avoid decomposition of paclitaxel by heat when the dissolution stabilizer is heated.

The filtering device in the preparation method includes, but is not limited to, a microporous membrane, a sand filter rod, a leaching funnel, a plate and frame filter press, and the like, and may be used alone or in combination of one or more.

The disinfection in the preparation method refers to sterilization including methods including, but not limited to, circulating steam, high pressure steam, etc., temperature 100-121 ° C, time 5 - 120 minutes. The novel paclitaxel injection prepared by the invention is a colorless or light yellow transparent liquid. The drug loading is 0.1-20 mg paclitaxel/ml. The injection of the invention can be directly dissolved in 5%, 10% glucose or 0.9% sodium chloride solution into an injection solution.

The present invention provides a novel paclitaxel injection containing no polyoxyethylene castor oil, which has good stability and water solubility, and has a large drug loading amount, and can be directly dissolved in 5%, 10% glucose or 0.9% sodium chloride. The solution is intravenously instilled after injection, which is convenient to use. After 72 hours, the content of the injection was 98% - 102% of the labeled amount, indicating that the stability was greatly improved. Moreover, no desensitization and strict monitoring are required before administration, which makes the patient easy to accept, improves the safety of clinical medication, and reduces the burden on the patient. The injection also has a certain targeting effect. The toxic side effects of the paclitaxel injection of the present invention are much lower than that of the paclitaxel cremophor preparation. The paclitaxel injection of the invention overcomes a series of problems in the prior art various dosage forms in terms of encapsulation efficiency, stability, side effects, bioavailability and ease of administration, and is an ideal dosage form pursued by medical personnel and patients. . The preparation method of the paclitaxel injection of the invention is simple and feasible, and is suitable for mass preparation and industrial production. detailed description

Example 1 Preparation of a novel paclitaxel injection

Measure 30 ml of absolute ethanol, add 15 g of soy lecithin for injection, 1.66 g of cholesterol, 50 g of Tween-80, dissolve with 45 Ό heating, add 600 mg of paclitaxel, stir until dissolved, add absolute ethanol to 100 ml, Filter with a microporous membrane (0.22 um), dispense, and routinely sterilize.

Example 2 Preparation of a novel paclitaxel injection

20 ml of absolute ethanol, 10 g of soy lecithin for injection, 0.1 g of sodium cholate, 0.1 g of Tween, 80 g of Tween, 60 Ό heating and stirring to dissolve, add 500 mg of paclitaxel, stir until dissolved, add anhydrous ethanol to 100 ML, filtered with a medium sand filter rod, dispensed, and routinely disinfected.

Example 3 Preparation of a novel paclitaxel injection

Measure 5 ml of absolute ethanol, 5 ml of polyethylene glycol, mix, add 12 g of soy lecithin for injection, 1.5 g of poloxamer (F68), 0.1 g of sodium cholate, dissolve by ultrasound, and add paclitaxel 400 mg. Stir until dissolved, add absolute ethanol to 100 ml, filter with immersion funnel (No. 6), dispense, and routinely disinfect. Example 4 Preparation of a novel paclitaxel injection

Measure 20 ml of absolute ethanol, 10 ml of glycerin, mix, add 5 g of Tween-80, stir to dissolve, add 300 mg of paclitaxel, sonicate to dissolve, add absolute ethanol to 100 ml, filter with plate and plate filter. Dispensing, routine disinfection can be.

Example 5 Preparation of a novel paclitaxel injection

Measure 15 ml of absolute ethanol and 15 ml of propylene glycol, mix, add 15 g of soy lecithin for injection, 1.5 g of cholesterol, 10 g of Tween-80, dissolve at 75 ° C with stirring, add 1500 mg of paclitaxel, and dissolve to dissolve. Add anhydrous ethanol to 100 ml, first coarsely filter with a plate and frame filter, then finely filter with a microporous membrane (0.22 um), dispense, and routinely disinfect.

Example 6 Preparation of a novel paclitaxel injection

Measure 30 ml of propylene glycol, add 10 g of soy lecithin for injection, 1.5 g of cholesterol, and 805 g of Tween. Dissolve by stirring at 85 °C, add 20 mg of paclitaxel, stir until dissolved, add propylene glycol to 100 ml, first use The sand filter is coarsely filtered, then finely filtered with a microporous membrane (0.22 um), subpacked, and routinely sterilized. Example 7 A novel paclitaxel injection (injected with the formulation of Example 1) and a paclitaxel Crcmophor injection prepared with polyoxyethylene castor oil were apparently compared in a 5% glucose diluent, as shown in Table 1.

Table 1

Example 8 Content stability test of novel paclitaxel injection in 5% glucose dilution (taking Example 1 injection as an example)

HPLC was used to determine the content of the new paclitaxel injection in 5% glucose dilution at different times. In order to avoid possible drug precipitation, the measurement results could not reflect the actual drug content. Therefore, when preparing the test solution, the test sample should be used first. After filtering the 0.22 um microporous membrane, it was then configured into a test solution. The result of this measurement is the true drug content. The test results are shown in Table 2.

Table 2

Time (h) 0 2 4 8 12 18 24 36 48 60 72 Paclitaxel

0.3620 0.3620 0.3628 0.3622 0.3618 0.3619 0.3616 0.3612 0.3588 0.3556 0.3540 degrees mg/ml

Marking amount

100.00 100.00 100.22 100.05 99.94 99.97 99.89 99.78 99.12 98.23 97.79 ( )

Claims

Rights request

A paclitaxel injection characterized in that it consists of the following components:

Component w/v <3⁄4 content

Paclitaxel 0.01-2

Stabilizer 1 - 70

Solvent for injection.

The paclitaxel injection according to claim 1, wherein the stabilizer is selected from the group consisting of soybean phospholipid, egg yolk phospholipid, Tween 80, cholesterol, sodium cholate, poloxamer 188 or glycerol monooleate. One or more mixtures.

The paclitaxel injection according to claim 1, wherein the solvent for injection is one or more selected from the group consisting of anhydrous ethanol, glycerin, propylene glycol or polyethylene glycol.

A method for preparing a paclitaxel injection, which comprises the formulation according to claim 1, adding a stabilizer to a solvent for injection, stirring at room temperature or heating at 40-9 CTC or sonicating the stabilizer, then adding paclitaxel, stirring or ultrasonication Dissolve paclitaxel, filter, dispense, and disinfect.

The preparation method according to claim 4, wherein in the preparation method, the stabilizer is selected from the group consisting of soybean phospholipid, egg yolk phospholipid, Tween 80, cholesterol, sodium cholate, poloxamer 188 or glycerol single. One or more mixtures of oleates.

The process according to claim 4, wherein the solvent for injection is selected from the group consisting of one or more of anhydrous ethanol, glycerin, propylene glycol or polyethylene glycol.

The preparation method according to claim 4, wherein in the preparation method, the filtering device is used alone or in a microfiltration membrane, a sand filter rod, a leaching funnel or a plate and frame filter press. More than one type is used together.