TW201440782A - Pharmaceutical composition of micafungin or the salts thereof - Google Patents

Abstract

The present invention relates to a pharmaceutical composition of Micafungin or the salts thereof. The composition uses polysaccharide or monosaccharide 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 of micafungin or its salt

The present invention relates to a stable 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 monosaccharide 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 monosaccharide 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 monosaccharide is glucose, fructose Or rhamnose, preferably glucose; preferably, the pharmaceutically acceptable salt is micafungin sodium; preferably, the weight ratio of micafungin to excipient is 1:2~1: Preferably, the pharmaceutical composition is a lyophilized powder injection, 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 glucose, more preferably, The weight ratio of the glucan to glucose is 1:0.5~1:5, and the weight ratio of glucan to glucose is 1:1; wherein the pH adjuster is capric acid, hydrochloric acid, acetic acid, phosphoric acid Sodium hydrogen or sodium hydroxide, preferably tannic acid and/or sodium hydroxide.

Another object of the present invention is to provide a use of an antifungal pharmaceutical composition for the preparation of a medicament for preventing or treating an infectious disease. Preferably, the infectious disease is selected from the group consisting of Aspergillus and Candida. 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 steps of: (1) dissolving an excipient or an excipient composition in an appropriate amount of pure water; (2) micafungin Dissolving in the aqueous solution of the excipient prepared in the step (1); (3) adjusting the pH of the solution prepared in the step (2) to 0.1 mol/L aqueous solution of citric acid and/or 0.1 mol/L aqueous sodium hydroxide solution 5.5; (4) adding pure water, the solution prepared in step (3) is made up to a predetermined volume, after filtration, filling, and lyophilized by a conventional method.

The pharmaceutical 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 at 60 ° C for 10 days, indicating that the rice prepared by the present invention The carbendham medicinal composition can be stored at room temperature for a long period of 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, indicating that the lyophilization process of the invention has low requirements on the drying process and is more energy-saving. Significantly reduce production costs.

In the micafungin sodium lyophilized powder composition provided by the present invention, dextran, glucose, fructose or the like with higher safety is used as an excipient. These three excipients are commonly used in intravenous injections. Glucan is a plasma substitute and is mainly used for the treatment of various shocks; glucose and fructose are also commonly used in injections to supplement body nutrition. Also, in the present invention, the amount of the three is much smaller than the maximum amount prescribed by the FDA inactive ingredient database. The maximum amount of glucose specified in the FDA Inactive Ingredients Database is 45.5% (http://www.accessdata.fda.gov/scripts/cder/iig/getiigWEB.cfm); dextran is in the FDA Inactive Ingredient Database The maximum dosage is 30% (http://www.accessdata.fda.gov/scripts/cder/iig/getiigWEB.cfm); the maximum amount of fructose specified in the FDA Inactive Ingredients Database is 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.

The implementation of the present invention will be described below in conjunction with specific embodiments. The program is described in detail. 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 is 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 freeze-dried by a conventional method using a conventional lyophilizer to obtain a lyophilized composition each containing 50 mg of micafungin.

Example 2

Dissolve dextran 20 and glucose in 750ml of pure water at room temperature, then add micafungin sodium, let stand or gently stir until the original The drug 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. It was freeze-dried by a conventional method using a conventional lyophilizer to obtain a lyophilized composition each containing 50 mg of micafungin.

Example 3

The dextran 40 and glucose 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.

Example 4

The dextran 40 and fructose 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 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 70 and glucose are dissolved in 750 ml of pure water (750 ml) 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 20 and glucose 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 2% aqueous solution of citric acid (9.5 ml), a 0.4% aqueous solution of sodium hydroxide (about 24 ml) was added to the solution to adjust the pH of the solution to 5.5, and then diluted with pure water. Make up to 2500ml. 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:

Dissolve trehalose in 2000ml of pure water (water below 50°C) Bath), cool it to below 20 ° C, add micafungin sodium to the trehalose solution, gently stir to dissolve, avoiding bubbles 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 three 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: B0' (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) micafungin prepared by the embodiment of the present invention under high temperature conditions The drug composition was significantly better than the three comparative examples. The micafungin medicinal composition prepared by the three 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 prepared by the embodiment of the invention has stable appearance and high degradation of the active ingredient under high temperature conditions. 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 glucose 1:1 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 (18)

A pharmaceutical composition for antifungal, comprising: 1) micafungin represented by formula (I) or a pharmaceutically acceptable salt thereof; and 2) a pharmaceutically acceptable polysaccharide or Monosaccharide or a mixture thereof 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. Medicinal composition for antifungal as described in claim 1 And the monosaccharide is glucose or fructose. The anti-fungal pharmaceutical composition according to claim 5, wherein the monosaccharide is glucose. 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 9, wherein the moisture content is not more than 3.6%. The anti-fungal pharmaceutical composition according to claim 10, wherein the moisture content is not more than 2%. The anti-fungal pharmaceutical composition according to any one of claims 1 to 11, wherein the excipient is a mixture of dextran and glucose. The anti-fungal pharmaceutical composition according to claim 12, wherein the weight ratio of the glucan to glucose is 1:0.5 to 1:5. The anti-fungal pharmaceutical composition according to claim 13, wherein the weight ratio of the glucan to glucose is 1:1. The anti-fungal pharmaceutical composition according to any one of claims 1 to 11, 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. . Medicinal composition for antifungal as described in claim 15 And the pH adjusting agent is selected from the group consisting of citric acid and/or sodium hydroxide. Use of a pharmaceutical composition for antifungal according to any one of claims 1 to 16 for the preparation of a medicament for preventing or treating an infectious disease. The use of claim 17, wherein the infectious disease is selected from an infectious disease caused by Aspergillus and Candida.