TW201440783A - Pharmaceutical composition comprising micafungin or the salts thereof - Google Patents

Abstract

The present invention relates to a pharmaceutical composition comprising Micafungin or the salts thereof which uses polysaccharide or disaccharide or the mixture of them as excipient and may contain appropriate pH adjusting agent. The pharmaceutical composition according to the present invention has superior stability and potential safety than the formulations in the art.

Description

Medicinal composition containing micafungin or a salt thereof

The present invention relates to a pharmaceutical composition of the cyclic polypeptide compound micafungin. In particular, the present invention relates to a stable pharmaceutical composition comprising micafungin and a pharmaceutically acceptable salt thereof as an active ingredient, a polysaccharide or a disaccharide or a mixture thereof as an excipient.

Micafungin is the second echinocandin antifungal drug approved by the FDA following caspofungin. Mikafenjing sodium for injection, marketed as Mi Kaimin, was developed by Japan Astellas Pharmaceutical Co., Ltd., first listed in Japan in 2002, approved by the FDA in 2005, and entered China in 2006. Its clinical trials have shown that micafungin has stronger antibacterial activity, lower minimum effective concentration and lower incidence of adverse reactions than caspofungin.

Patent CN1179748C is a micafene sodium preparation patent, in which lactose is used as an excipient to prepare a medicinal composition in the form of lyophilized form of micafungin sodium. Commercially available lactose is produced from the residual liquid of cheese and casein extracted from milk. Most Chinese are intolerant to lactose, which can cause symptoms such as abdominal cramps, diarrhea, and flatulence. And the protein in lactose may cause serious allergic reactions and cause life-threatening. Therefore in lyophilized powder injection The use of lactose as an excipient, especially in non-anti-tumor drugs, is relatively more risky.

Patent CN100352495C is also a patent for micafungin sodium preparation, which is a pharmaceutical composition for preparing lyophilized form of micafungin sodium using maltose as an excipient. Maltose is commonly used in solid formulations and as a sweetener and tablet filler. It has been reported that patients with impaired renal function cause hyponatremia after the application of 10% immunoglobulin intravenous infusion of maltose. It is currently believed to be caused by the accumulation of maltose and other highly osmotic active metabolites, indicating that maltose is not suitable for intravenous infusion, that is, there is a certain risk of using maltose as an excipient for lyophilized powder.

Patent CN102614491A is also a patent for micafungin sodium preparation, in which medicinal composition in the form of lyophilized form of micafungin sodium is prepared using trehalose as an excipient. Trehalose is commonly used in cosmetics and foods and is not currently included in any country's pharmacopoeia or excipient database. It can be seen that trehalose is not approved by any country and can be used in medicines, and it is not suitable for use as a pharmaceutical excipient, and can not be used as an excipient for lyophilized powder for intravenous infusion. In addition, the high osmotic activity of trehalose in the organs of the organs can cause adverse reactions such as gastrointestinal discomfort in patients. Therefore, the use of trehalose as an excipient for micafungin sodium lyophilized powder needle has a major safety hazard.

Because of the remarkable efficacy of micafungin sodium, it is currently the first line of drugs for the treatment of Candida and Aspergillus infection. Therefore, there is an urgent need to develop an effective and safe micafungin sodium composition.

The present invention provides a safe, effective and stable pharmaceutical composition for antifungal comprising: 1) micafungin or its pharmaceutically acceptable salt of formula (I); and 2) pharmaceutically acceptable Polysaccharide or disaccharide or a mixture thereof as an excipient,

Optionally, the composition further comprises a pH adjusting agent; wherein, preferably, the polysaccharide is dextran, starch, cellulose or high fructose, preferably dextran; preferably, the disaccharide is sucrose, fiber Disaccharide or pine disaccharide, preferably sucrose; preferably, the pharmaceutically acceptable salt is micafungin sodium; preferably, the weight ratio of micafungin to excipient is 1:2~ Preferably, the pharmaceutical composition is a lyophilized powder injection, more preferably, wherein the moisture content is not more than 3.6%.

Further, the above scheme comprises the following preferred embodiment: wherein the excipient is a mixture of dextran and sucrose, more preferably, the The weight ratio of dextran to sucrose is 2:1~1:3, and the weight ratio of dextran to sucrose is 2:3; wherein the pH adjuster is citric acid, hydrochloric acid, acetic acid, dihydrogen phosphate Sodium or sodium hydroxide, preferably citric acid and/or sodium hydroxide.

Another object of the present invention is to provide a use of a pharmaceutical composition for antifungal in the preparation of a medicament for preventing or treating an infectious disease, preferably the infectious disease is selected from the group consisting of an infection caused by Aspergillus and Candida. Sexual disease.

Further, the micafungin medicinal composition provided by the present invention can be reconstituted by pharmaceutically acceptable sodium chloride or glucose injection, diluted, and administered by intravenous infusion.

The invention also provides a preparation method of micafungin medicinal composition, the method comprising the following steps:

(1) dissolving the excipient or excipient composition in an appropriate amount of pure water; (2) dissolving micafungin in the aqueous solution of the excipient prepared in the step (1); (3) using 0.1 mol/L The pH of the solution prepared in the step (2) was adjusted to 5.5 with an aqueous solution of citric acid and/or a 0.1 mol/L aqueous sodium hydroxide solution.

(4) Adding pure water, the solution prepared in the step (3) is made up to a predetermined volume, and after filtration and filling, it is lyophilized by a conventional method.

The medicinal composition of micafungin or a pharmaceutically acceptable salt thereof provided by the present invention has better stability than the existing preparation. The lyophilized product prepared in the examples of the present invention has a stable appearance and no significant degradation of the active ingredient at 30 °C for 30 days and at 60 °C for 10 days. Mika prepared by the present invention Fenjing pharmaceutical composition can be stored at room temperature for a long time. In addition, under the same lyophilization process conditions, the micafungin medicinal composition prepared by the embodiment of the invention has much lower moisture than the existing preparation. It shows that the lyophilization process of the invention has low requirements on the drying process, more energy saving, and can significantly reduce the production cost.

In the micafungin sodium lyophilized powder composition provided by the present invention, dextran, sucrose or the like having higher safety is used as an excipient. The adjuvants used in the present invention are commonly used in intravenously administered injections and are used in amounts much less than the maximum amount specified by the FDA Inactive Ingredient Database. The maximum amount of dextran specified in the FDA Inactive Ingredients Database is 30% (http://www.accessdata.fda.gov/scripts/cder/iig/getiigWEB.cfm); sucrose in the FDA Inactive Ingredient Database The maximum amount specified is 19.5% (http://www.accessdata.fda.gov/scripts/cder/iig/getiigWEB.cfm). It can be seen that the excipients used in the present invention are safer and have fewer adverse reactions, and are more suitable for the physical fitness of the people of our country. Moreover, the medicinal composition of micafungin sodium prepared by the present invention is equivalent to the existing preparation, and has better stability and safety than the existing preparation.

Embodiments of the present invention will be described in detail below with reference to specific embodiments. The following examples are merely illustrative of the invention and are not to be considered as limiting the scope of the invention.

Example 1

The dextran 70 was dissolved in pure water (750 ml) at room temperature, and dickafen sodium was added, and the mixture was allowed to stand or gently stirred until the drug substance was dissolved. To the solution, a 0.1 mol/L aqueous solution of the turmeric acid and/or a 0.1 mol/L aqueous sodium hydroxide solution was added in an appropriate amount, and the pH of the solution was adjusted to 5.5. It was then diluted to 1250 ml with pure water. The resulting solution was dispensed into 500 10 ml control antibiotic bottles, 2.5 ml per vial. It was lyophilized by a conventional method to obtain a lyophilized composition each containing 50 mg of micafungin.

Example 2

The dextran 20 and sucrose are dissolved in 750 ml of pure water at room temperature, and then micafungin sodium is added, and the mixture is allowed to stand or gently stirred until the drug substance is dissolved. To the solution, 0.1 mol/L hydrochloric acid solution and/or 0.1 mol/L sodium hydroxide aqueous solution was added in an appropriate amount, and the pH of the solution was adjusted to 5.5. It was then diluted to 1250 ml with pure water. The resulting solution was dispensed into 500 10 ml control antibiotic bottles, 2.5 ml per vial. Freeze by conventional methods to obtain Each of the lyophilized compositions containing 50 mg of micafungin.

Example 3

Dissolve dextran 40 and sucrose in 750 ml of pure water at room temperature, then add micafungin sodium, and let stand or gently stir until the drug substance is dissolved. To the solution, 0.1 mol/L aqueous solution of citric acid and/or 0.1 mol/L aqueous sodium hydroxide solution was added in an appropriate amount, and the pH of the solution was adjusted to 5.5. It was then diluted to 1250 ml with pure water. The resulting solution was dispensed into 500 10 ml control antibiotic bottles, 2.5 ml per vial. It was lyophilized by a conventional method to obtain a lyophilized composition each containing 50 mg of micafungin.

Example 4

Dissolve dextran 40 and sucrose in 750ml of pure water at room temperature, then add micafungin sodium, stand or gently stir. After the dissolution of the drug substance is completed. To the solution, 0.1 mol/L acetic acid solution and/or 0.1 mol/L sodium hydroxide aqueous solution was added in an appropriate amount, and the pH of the solution was adjusted to 5.5. It was then diluted to 1250 ml with pure water. The resulting solution was dispensed into 500 10 ml control antibiotic bottles, 2.5 ml per vial. It was lyophilized by a conventional method to obtain a lyophilized composition each containing 50 mg of micafungin.

Example 5

The dextran 20 and sucrose are dissolved in 750 ml of pure water at room temperature, and then micafungin sodium is added, and the mixture is allowed to stand or gently stirred until the drug substance is dissolved. To the solution, 0.1 mol/L sodium dihydrogen phosphate solution and/or 0.1 mol/L sodium hydroxide aqueous solution was added in an appropriate amount, and the pH of the solution was adjusted to 5.5. It was then diluted to 1250 ml with pure water. The resulting solution was dispensed into 500 10 ml control antibiotic bottles, 2.5 ml per vial. It was lyophilized by a conventional method to obtain a lyophilized composition each containing 50 mg of micafungin.

Example 6

The dextran 70 and sucrose are dissolved in 750 ml of pure water at room temperature, and then micafungin sodium is added, and the mixture is allowed to stand or gently stirred until the drug substance is dissolved. To the solution, 0.1 mol/L aqueous solution of citric acid and/or 0.1 mol/L aqueous sodium hydroxide solution was added in an appropriate amount, and the pH of the solution was adjusted to 5.5. It was then diluted to 1250 ml with pure water. The resulting solution was dispensed into 500 10 ml control antibiotic bottles, 2.5 ml per vial. It was lyophilized by a conventional method to obtain a lyophilized composition each containing 50 mg of micafungin.

Comparative Example 1:

The lactose is dissolved in 2000 ml of pure water (water bath below 50 ° C), and it is cooled to below 20 ° C, and micafungin sodium is added to the lactose solution, and the mixture is gently stirred to dissolve, and bubbles are prevented during the process. After adding a 2% aqueous solution of citric acid (9.5 ml), a 0.4% aqueous sodium hydroxide solution (about 24 ml) was added to the solution to adjust the pH of the chemical solution to 5.5, and then diluted with pure water to a volume of 2500 ml. The resulting solution was dispensed into 1000 10 ml control antibiotic bottles, 2.5 ml each. It was lyophilized by a conventional method to obtain a lyophilized composition each containing 50 mg of micafungin.

Comparative Example 2:

The dextran was dissolved in 2000 ml of pure water (water bath below 50 ° C), and it was cooled to below 20 ° C. Mikafen sodium was added to the dextran solution, and the mixture was gently stirred to dissolve, and bubbles were prevented during the process. After further adding a 2% aqueous solution of citric acid (9.5 ml), a 0.4% aqueous sodium hydroxide solution (about 24 ml) was added to the solution to adjust pH 5.5, and then diluted with pure water to a volume of 2,500 ml. The resulting solution was dispensed into 1000 10 ml control antibiotic bottles, 2.5 ml per vial. It was lyophilized by a conventional method to obtain a lyophilized composition each containing 50 mg of micafungin.

Comparative Example 3:

The sucrose was dissolved in 2000 ml of pure water (water bath below 50 ° C), and it was cooled to below 20 ° C, and micafungin sodium was added to the sucrose solution, and the mixture was gently stirred to dissolve, and bubbles were prevented during the process. After adding 2% aqueous solution of citric acid (9.5 ml), a 0.4% aqueous sodium hydroxide solution (about 24 ml) was added to the solution to adjust the pH 5.5, and then diluted with pure water to make a volume. To a volume of 2500ml. The resulting solution was dispensed into 1000 10 ml control antibiotic bottles, 2.5 ml per vial. It was lyophilized by a conventional method to obtain a lyophilized composition each containing 50 mg of micafungin.

Comparative Example 4:

The trehalose is dissolved in 2000 ml of pure water (water bath below 50 ° C), and it is cooled to below 20 ° C, and micafungin sodium is added to the trehalose solution, and the mixture is gently stirred to dissolve, and bubbles are prevented during the process. The pH was adjusted to 5.5 using a 2% aqueous solution of citric acid or a 0.4% aqueous sodium hydroxide solution, and then diluted with pure water to a volume of 2,500 ml. The resulting solution was dispensed into 1000 10 ml control antibiotic bottles, 2.5 ml per vial. It was lyophilized by a conventional method to obtain a lyophilized composition each containing 50 mg of micafungin.

Comparison of the stability of micafungin

The samples of the above six examples and four comparative examples were examined, and the stability at 40 ° C and 60 ° C was examined. The active material was analyzed by HPLC using an analytical column ODS C18 column, specification: 250 C18 analysis, S-5 μm. Column temperature: 25 ° C, 210 nm detection, mobile phase: A: 0.5% sodium dihydrogen phosphate solution; B: acetonitrile. Gradient: B 0'(3%)~5'(8%)~15'(40%)~25'(50%)~35'(50%)~36'(3%)~43'(3% ). The content of micafungin was calculated according to the external standard method. The results of the investigation are shown in Tables 1~2.

It can be seen from the data in Tables 1 and 2:

(1) Under high temperature conditions, the micafungin medicinal composition prepared in the examples of the present invention has significantly better stability than the four comparative examples. The micafungin medicinal composition prepared in the four comparative examples showed a significant increase in total impurities at 40 ° C and 60 ° C, and the stability was poor, which was not suitable for medicinal development. The pharmaceutical composition is prepared according to the embodiment of the invention, and the appearance of the finished product is stable under high temperature conditions, and the active ingredient has no obvious degradation. It is indicated that the micafungin medicinal composition prepared by the invention can be stored at room temperature for a long time, and the storage cost is low.

(2) In the examples of the present invention, the medicinal composition of micafungin was prepared by using the mixture of dextran 40 and sucrose 2:3 as an excipient, and the stability was the best.

(3) It can be seen from the moisture data in the two tables that under the same lyophilization process conditions, the micafungin medicinal composition prepared in the examples of the present invention has much lower moisture than the comparative examples. It shows that the lyophilization process of the invention has low requirements on the drying process, more energy saving, and can significantly reduce the production cost.

Claims (17)

A pharmaceutical composition for antifungal, characterized in that the composition comprises: 1) micafungin or a pharmaceutically acceptable salt thereof of the formula (I); and 2) a pharmaceutically acceptable polysaccharide or disaccharide or The mixture is used as an excipient, Optionally, the composition further comprises a pH adjusting agent. The anti-fungal pharmaceutical composition according to claim 1, wherein the polysaccharide is glucan. The anti-fungal pharmaceutical composition according to claim 2, wherein the glucan is dextran. The anti-fungal pharmaceutical composition according to claim 3, wherein the dextran is dextran 20, dextran 40 or dextran 70. The anti-fungal pharmaceutical composition according to claim 1, wherein the disaccharide is sucrose. The anti-fungal pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt is micafungin sodium. The anti-fungal pharmaceutical composition according to claim 1, wherein the weight ratio of the micafungin to the excipient is 1:2 to 1:15. A pharmaceutical composition for antifungal according to claim 1, which is a lyophilized powder injection. The anti-fungal pharmaceutical composition according to claim 8, wherein the moisture content is not more than 3.6%. The anti-fungal pharmaceutical composition according to claim 9, wherein the moisture content is not more than 2%. The anti-fungal pharmaceutical composition according to any one of claims 1 to 10, wherein the excipient is a mixture of dextran and sucrose. The anti-fungal pharmaceutical composition according to claim 11, wherein the weight ratio of the glucan to sucrose is from 2:1 to 1:3. The anti-fungal pharmaceutical composition according to claim 12, wherein the weight ratio of the glucan to sucrose is 2:3. The antifungal pharmaceutical composition according to any one of claims 1 to 10, wherein the pH adjusting agent is selected from the group consisting of citric acid, hydrochloric acid, acetic acid, sodium dihydrogen phosphate, and/or sodium hydroxide. . The anti-fungal pharmaceutical composition according to claim 14, wherein the pH adjusting agent is selected from the group consisting of citric acid and/or sodium hydroxide. A pharmaceutical composition for antifungal use according to any one of claims 1 to 15 for the preparation of a prophylactic or therapeutic infectious disease Use of the drug. The use of claim 16, wherein the infectious disease is selected from an infectious disease caused by Aspergillus and Candida.