WO2009043226A1

WO2009043226A1 - A stable liquid composition comprising taxan derivatives and its preparation method.

Info

Publication number: WO2009043226A1
Application number: PCT/CN2008/001426
Authority: WO
Inventors: Piaoyang Sun; Yuxia Wu; Yan Xu
Original assignee: Jiangsu Hengrui Medicine Co., Ltd.
Priority date: 2007-09-30
Filing date: 2008-08-05
Publication date: 2009-04-09
Also published as: CN101396354B; CN101396354A; TW201004656A; HK1126405A1

Abstract

A liquid composition and the preparation method thereof. Said composition comprises taxan derivatives and surfactant with a pH of less than 5.

Description

A stable taxane derivative liquid composition and a preparation method thereof. Technical field

The present invention relates to a liquid composition, and more particularly to a stable liquid composition of a triterpenoid compound, a process for its preparation and its use. Background technique

The taxane derivative is a biguanide compound which can be used in the field of medicine and has been used as a therapeutic agent for tumors such as ovarian cancer, breast cancer, and lung cancer. Taking docetaxel as an example (docetaxel/Taxotere), docetaxel is currently a clinically effective drug. It is also a semi-synthetic antitumor drug developed by Rone-Poulenc Rorer of France. It was first launched in 1995. It can promote the assembly of microtubules, prevent the dissociation of microtubules, inhibit the differentiation of tumor cells, and ultimately lead to the death of tumor cells. It has shown reliable efficacy against many common tumors and has become the most widely used anticancer drug in clinical application. Taxane derivatives such as docetaxel are generally used clinically in liquid dosage forms for concentrated infusion. For example, the conventional recommended dosing regimen for docetaxel is 1 time / 3 weeks, 1 hour intravenous infusion of 75 mg / m ² .

There have been many studies on intravenous dosage forms for taxane derivatives such as docetaxel. Such drugs are poorly water-soluble, and are generally prepared as a concentrated solution dissolved in a surfactant and an aqueous solution of ethanol, which is then dissolved in an infusion solution for clinical use. Rowinsky, Lorraine, Cazenave, and Doneyeer et al. published the following formulation method on August 1, 1990 (National Cancer Institute, Vol. 82, No. 15, 1247-1259). People first prepared the name "mother liquor". A solution, the "mother liquor" is a mixed solution of 50% by volume of ethanol and 50% by volume of polyoxyethylene castor oil, the mixed solution contains about 6 mg/ml of paclitaxel, and when injected, the solution is chlorine-containing. Mix the sodium or glucose perfusate.

An injectable composition containing a taxane derivative which dissolves the taxane compound docetaxel in a surfactant such as Tween 80, is described in Chinese Patent Application Nos. 93119653.1 and 02147245.9. A diluent solution such as ethanol is added, and the diluent solution may be separated or mixed with the surfactant solution, and the mixed liquid is used as a drug solution for preparing a clinical infusion.

Example 1 of U.S. Patent No. 5,403,858 A discloses a method for preparing docetaxel mother liquor, which is dissolved in anhydrous ethanol, followed by addition of Tween 80, and then ethanol is removed to obtain a mother liquor, and the mother liquor is 5%. When the glucose perfusate was diluted to concentrations of 0.1, 0.3, and 0.5 mg/ml, the stability of the resulting diluted solution was observed. On the basis of this, the applicant of the present invention has studied it and surprisingly found that by adjusting the production process of the mother liquor, the stability of the mother liquor is greatly improved, the degradation of the active ingredient or the related substances is significantly reduced, and the safety of the drug is markedly improved. Sex. Summary of the invention

The technical problem to be solved by the present invention is to provide a liquid composition of a triterpenoid derivative having high stability. The liquid composition of the present invention is particularly suitable for use in the preparation of an injection of a triterpenoid derivative, such as a liquid composition or an injection preparation (also known as an injection) of docetaxel, which is less susceptible to degradation during storage and is more safe and effective.

At present, when preparing an injection of a taxane such as docetaxel, the drug is dissolved in a surfactant to prepare a surfactant solution (also referred to as "mother liquor"), and is not required to be adjusted with an acid or a base. The pH of the mother liquor, after the mother liquor is diluted with a diluent (such as glucose solution or sodium chloride solution), the pH of the resulting injection is suitable for physiological needs. Since the product itself meets physiological needs, the skilled person does not need or adjust the acidity and alkalinity according to the preparation method of the general preparation.

After examining the various factors of the preparation, the applicant of the present invention unexpectedly found that when a certain amount of acidic reagent (also called an acidic regulator) is added to the surface active solution of the mother liquor to make it weakly acidic, the mother liquor Stability is greatly improved. According to the method of Example 1 (hereinafter referred to as the original formulation process) of US5403858A, the inventors prepared a mother liquor containing a surfactant having a pH of 6.0 to 8.0 when no acidity adjusting agent was added to adjust its acidity and alkalinity. The inventors have found through experiments that if the acid regulator is added to the solution and the acidity is adjusted to be weakly acidic, the solution is more stable. The mother liquor was prepared by the original prescription process, and placed at 40 ° C for 10 days, and the content of the relevant substance was 11.7%. The mother liquor was prepared according to the formulation process of the present invention, and placed at 40 ° C for 10 days, and the content of the relevant substance was found to be 0.84%. It can be seen that the transportation and storage conditions of the products prepared by the original prescription process are more severe, and the products of the invention can be placed under normal temperature conditions for a long time, which is beneficial to the transportation and storage of the products. The above results are expected by those skilled in the art. In particular, when the pH of the mother liquor is 3.0 to 5.0, the obtained mother liquor not only improves the stability, but also the pH of the obtained injection is suitable for physiological needs after being diluted by a diluent such as a glucose solution or a sodium chloride solution. In other words, whether the acid regulator is added to the mother liquor and the solution obtained by dilution with the diluent are clinically acceptable physiological pH, such as pH 4-4.5.

Accordingly, it is an object of the present invention to provide a liquid composition which is a surfactant solution in which a taxane derivative is dissolved, characterized in that the pH of the surfactant solution is 5 or less, preferably pH. It is 3-5, more preferably 3.5-4.5.

The taxane derivative described herein is preferably a compound of the formula: or a pharmaceutically acceptable ester thereof:

Wherein R represents a hydrogen atom or an acetyl group, and R _t represents a tert-butoxycarbonylamino or benzoylamino group, preferably docetaxel or an ester thereof.

In order to impart a desired weak acidity to the liquid composition, an acidic regulator may be added to the composition, and the most suitable composition for clinical use may consist of only a taxane derivative, a surfactant, and an acid regulator, but not Other substances, preferably the taxane derivative is docetaxel or an ester thereof.

The acidity adjusting agent may be any one of an organic acid or an inorganic acid conventionally adjusted in the art, or a combination thereof. For ease of handling, the acidic modifier used is preferably in the form of a solution, which can be prepared as a suitable solution for solid organic or inorganic acids, preferably using ethanol to prepare an acidic modifier. The organic acid or inorganic acid to be used may be an acid commonly used in the art, such as citric acid, fumaric acid, maleic acid, malic acid, hydrochloric acid, sulfuric acid, tartaric acid, etc., preferably citric acid, more preferably ruthenium. Acidic ethanol solution. The content of the acidic regulator in the composition is generally from 0.01 to 20 mg/ml, preferably from 0.05 to 10 mg/ml, more preferably from 0.1 to 5 mg/ml, and most preferably from 0.1 to 2.8 mg/ml.

The surfactant for dissolving a drug of the present invention is a surfactant conventionally used in the art, in particular, a surfactant used in the prior art for a taxane, such as polyoxyethyl ether, ethylene oxide, glycerin. Any one or combination of ester, hydrogenated castor oil, polyoxyethylene castor oil, castor oil, preferably polyoxyethyl ether, especially Tween 80.

It has been found that the liquid content of the liquid for injection of the taxanes in the surfactant solution should be reduced as much as possible to facilitate the stability of the solution of the triterpenoids. Accordingly, the content of ethanol in the liquid composition is preferably not more than 10%, preferably not more than 5%, more preferably not more than 3%, particularly preferably not more than 1.5%.

The concentration in the surfactant can be selected according to the needs of use and the solubility of the triterpenoid derivative in the surfactant. Currently, the concentration of the injectable preparation for clinical use is generally 1 - 10 g per 100 ml of the surfactant solution, and the usual concentration of docetaxel injection is 4 g / 100 ml.

The invention specifically provides a liquid composition, in particular a liquid composition for injection, consisting of docetaxel, citric acid and Tween 80, wherein the ethanol content is 1.5%, docetaxel The content can be 4g/100ml.

In another aspect, the present invention provides the use of the above liquid composition for the preparation of a medicament for treating a tumor. Another aspect of the present invention provides a method of preparing a taxane derivative injection preparation, particularly a method of preparing a docetaxel injection preparation. When preparing the injection preparation of the present invention, a surfactant solution for obtaining a taxane compound is prepared according to a conventional method, and an acidic regulator is added to the surfactant solution to adjust the pH to 3-5, preferably a triterpenoid derivative. It is docetaxel or its ester.

The invention specifically provides a method for preparing docetaxel injection, which is dissolved in docetaxel plus absolute ethanol, then added to Tween 80, stirred evenly, and adjusted to pH value by using citric acid anhydrous ethanol solution to 3- 5. Remove ethanol to 1.5% ethanol.

The method of preparing a surfactant solution of a taxane compound can be carried out by a method disclosed in the prior art. E.g:

1) preparing a solution having a lower ethanol content, first dissolving the triterpene derivative in ethanol, and then adding a surfactant, which can form a micelle of a surfactant-encapsulated taxane derivative after dilution in an aqueous medium, by vacuum Drying or other suitable means to remove ethanol from the solution, at least partially;

2) The triterpene derivative is directly dissolved in the surfactant. The preferred method is to prepare a surfactant solution containing 1-2% ethanol, then continuously add the taxane derivative, and pulverize it by using a screw mixer or centrifugally. The machine is constantly stirring.

As used herein, "mother liquor" means a surfactant solution in which a taxane compound is dissolved. The method for determining the pH value of the mother liquor is as follows: Take appropriate amount of the liquid, add 13% (V/V) ethanol solution, dilute it to about 10 mg/ml of the taxane compound solution, and measure the pH value, preferably the taxane. The derivative is docetaxel or an ester thereof.

Unless stated otherwise, the percentages stated herein are by weight.

detailed description

The present invention will be specifically described with reference to the embodiments, which are intended to illustrate the technical scope of the invention and not to limit the nature of the invention.

Example 1 Preparation of docetaxel mother liquor

Docetaxel 20g

Tween 80 500ml

Method of preparation: Docetaxel mother liquor was prepared according to the method disclosed in Example 1 of US 5,403,858 A. Example 2 Preparation of docetaxel mother liquor

Docetaxel An appropriate amount of citric acid ethanol solution

Tween 80 500ml

Preparation method: Weigh 20g of docetaxel, add 1000ml of absolute ethanol, stir to dissolve, then add the prescription amount of Tween-80 (polysorbate-80), stir evenly, with citric acid (formed with anhydrous ethanol) Appropriate amount, adjust the pH value, filter through 0.22μιη microporous membrane, disperse in the vial, remove the ethanol under vacuum and reduce the ethanol content. When the ethanol content is 1.5%, add the plug and roll the outer cover. Example 3-10 Study on the effect of pH on the stability of docetaxel preparations

According to the preparation methods of Examples 1 and 2, mother liquids containing an acid regulator (Examples 3-9) and no acid regulator (Example 10) were separately prepared and placed at 30 ° C and 2 to 8 ° C, respectively. 30 days, determine the relevant assessment items. Example 10 The pH of the mother liquor was adjusted without adding a rubber acid solution, and the pH was 6.0 to 8.0. The results are shown in Table 1:

Study on the effect of pH on the stability of docetaxel preparation

Example 3 4 5 6 7 8 9 10 Amount of citric acid (mg/ml) 14 8 4.8 3.6 3 2 1 0 Starting 3.01 3.50 3.96 4.26 4.56 4.88 5.67 6.26 Determination 30 ° C 30 days 3.05 3.52 4.00 4.21 4.60 4.90 5.66 6.20 pH 2~8°C

3.00 3.48 3.95 4.22 4.62 4.86 5.67 6.26 30 days

Starting 0.51 0.53 0.56 052 0.52 0.54 0.53 0.52 About 30°C30 days 0.53 0.56 0.55 0.58 0.61 0.76 0.83 1.22 Substance % 2~8°C

0.52 0.53 0.52 0.55 0.53 0.53 0.53 0.64 30 days

Starting 100.5 99.8 101.0 100.1 99.4 99.8 100.2 100.7

30 30 days 99.5 99.2 100.4 100.5 100.4 100.2 99.7 99.4 Content%

2 to 8. C

100.1 100.3 99.9 99.7 100.0 100.7 99.5 99.7

30 days Light yellow yellow yellow yellow yellow yellow yellow yellow yellow yellow yellow color start color sticky color sticky color sticky color sticky color sticky color sticky thick liquid thick liquid thick liquid thick liquid thick liquid thick liquid thick liquid thick liquid Light yellow yellowish yellowish yellowish yellowish yellowish yellowish yellowish yellowish appearance

30. C30 Day Color Sticky Sticky Sticky Sticky Sticky Sticky Sticky Sticky Sticky

Thick liquid thick liquid thick liquid thick liquid thick liquid thick liquid thick liquid thick liquid

2~8°C Light yellow Light yellow Light yellow Light yellow Light yellow Light yellow Light yellow Light yellow Color Sticky Sticky Sticky Sticky Sticky Sticky Sticky Sticky Sticky Sticky Sticky

30 days

Thick liquid thick liquid thick liquid thick liquid thick liquid thick liquid thick liquid thick liquid results show: When the pH value of the mother liquid is less than 5.0, placed under 30 Ό conditions for one month, the content of related substances is significantly smaller than the mother liquor with pH greater than 5.0; When the pH is 3.5 to 4.5, it is left at a temperature of 30 Torr for one month, and the contents of the substances are basically the same. In Example 10, the pH of the rubber was adjusted without adding barium, and the pH was determined to be 6.26. The substrate was placed at 30 ° C for one month, and the related substance was significantly higher than the mother liquid having a pH of less than 5.0. It is concluded that when the pH of the mother liquor is weakly acidic, the liquid is more stable, especially when the pH is 3.0 to 5.0. Example 11 Study on Stability of Liquid Compositions of the Invention

Under high temperature conditions (40 ° C, 60 ° C, light 45001ux), placed for 10 days, the liquid composition of the present invention and the stability test of Example 1, were sampled at 0, 5, 10 days, respectively, using high-performance liquid phase The relevant substances and contents were determined by chromatography, and the results are shown in Tables 2 and 3. Stability test results of the liquid composition of the present invention

0 light yellow viscous liquid 3.78 qualified 0.52 99.4

60 °C 5 Light yellow viscous liquid 3.83 Qualified 2.05 98.9

10 light yellow viscous liquid 3.92 qualified 3.76 98.1

0 light yellow viscous liquid 3.78 qualified 0.52 99.4

4500

5 light yellow viscous liquid 3.80 qualified 0.58 99.7 lux

10 light yellow viscous liquid 3.81 qualified 0.52 99.4

Stability test results of Example 1

It follows that the liquid composition of the present invention contains an acid regulator which is more stable than the tadazine derivative mother liquor known in the prior art and can be placed at a normal temperature for a long period of time, facilitating transportation and storage.

Claims

Rights request

A liquid composition, which is a surfactant solution in which a taxane derivative is dissolved, characterized in that the pH of the surfactant solution is 5 or less, preferably 3-5. 5-4. 5。 More preferably 3. 5-4. 5.

2. The liquid composition according to claim 1, wherein the taxane derivative is a compound of the formula: or a pharmaceutically acceptable ester thereof:

Wherein R represents a hydrogen atom or an acetyl group, and represents a tert-butoxycarbonylamino or a benzoylamino group.

The liquid composition according to claim 2, wherein the taxane derivative is docetaxel or an ester thereof.

The liquid composition according to claim 1, wherein the pH is measured by adding a 13% aqueous solution of ethanol to the surfactant solution and diluting it into a solution of 10 mg/mr of the taxane derivative. The measured value is preferably a taxane derivative such as docetaxel or a salt thereof or an ester thereof.

The liquid composition according to any one of claims 1 to 4, wherein the composition contains an acidic regulator.

6. The liquid composition according to claim 5, which composition consists of a taxane derivative, a surfactant, and an acid regulator.

The liquid composition according to claim 5 or 6, wherein the acidic regulator is selected from the group consisting of an organic acid, an inorganic acid, or a combination thereof.

The liquid composition according to claim 7, wherein the acidic regulator is selected from the group consisting of a solution of an organic acid, an inorganic acid, or a combination thereof, preferably an ethanol solution.

The liquid composition according to claim 7, wherein the organic acid or inorganic acid is selected from the group consisting of citric acid, fumaric acid, maleic acid, malic acid, oxalic acid, acetic acid, and hydrochloric acid, or a combination thereof.

10. The liquid composition according to claim 9, wherein the acid regulator is citric acid or a solution thereof. It is preferably a solution of citric acid in ethanol.

The liquid composition according to any one of claims 1 to 10, wherein the surfactant is selected from the group consisting of polyoxyethyl ether, ethylene oxide, glycerin, hydrogenated castor oil, castor oil or combination.

12. The liquid composition according to claim 11, wherein the surfactant is polyoxyethyl ether.

13. The liquid composition according to claim 12, wherein the surfactant is Tween 80.

The content of the organic acid and the inorganic acid in the composition is from 0.01 to 20 mg/ml.

The content of the organic acid and the inorganic acid is 0.05-10 mg/ml c.

16. The liquid composition according to claim 15, wherein the content of the organic acid and the inorganic acid is

0. 1 to 5nig/ml.

The content of the organic acid and the inorganic acid is 0.1 to 2. 8 mg / ral.

The liquid composition according to any one of claims 1 to 17, wherein the content of ethanol is not more than 10%.

19. The liquid composition according to claim 18, wherein the amount of ethanol does not exceed 5%.

20. The liquid composition according to claim 19, wherein the content of ethanol is not more than 3%.

21. The liquid composition according to claim 20, wherein the content of ethanol does not exceed 1.5%.

The liquid composition according to claim 1, wherein the concentration of the taxane derivative is from 1 to 10 g/100 ml, and preferably the taxane derivative is docetaxel or a salt thereof or an ester thereof.

23. The liquid composition according to claim 22, wherein the concentration of the taxane derivative is

4 g / 100 ml, preferably the Tara's derivative is docetaxel or a salt thereof or an ester thereof.

24. The liquid composition of claim 1 having a composition of docetaxel, ruthenium acid and Tween 80, wherein the ethanol content is 1.5%.

25. The liquid composition according to claim 24, wherein the composition has a docetaxel content of 4 g/100 ml.

The liquid composition according to any one of claims 1 to 25, wherein the liquid composition is an injection.

27. Use of a liquid composition according to any one of claims 1 to 26 in the manufacture of a medicament for the treatment of tumors.

The method for preparing a liquid composition according to any one of claims 1 to 26, wherein an acidic regulator is added to the surfactant solution of the obtained taxane derivative to adjust the pH to 5 the following, Preferably, the pH is 3-5, more preferably 3. 5-4. 5, Preferably, the taxane derivative is docetaxel or an ester thereof.

The preparation method according to claim 28, comprising the steps of: taking a taxane derivative, dissolving with anhydrous ethanol, adding Tween 80, stirring uniformly, and adjusting with a solution of citric acid anhydrous ethanol The pH value, the ethanol is removed, and the ethanol content is 1.5%. Preferably, the taxane derivative is docetaxel or an ester thereof.