WO2014173205A1 - Composition pharmaceutique contenant de la micafungine ou un sel de celle-ci - Google Patents

Composition pharmaceutique contenant de la micafungine ou un sel de celle-ci Download PDF

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Publication number
WO2014173205A1
WO2014173205A1 PCT/CN2014/072688 CN2014072688W WO2014173205A1 WO 2014173205 A1 WO2014173205 A1 WO 2014173205A1 CN 2014072688 W CN2014072688 W CN 2014072688W WO 2014173205 A1 WO2014173205 A1 WO 2014173205A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
micafungin
dextran
sodium
solution
Prior art date
Application number
PCT/CN2014/072688
Other languages
English (en)
Chinese (zh)
Inventor
项文娟
孙长安
王小雷
孙运栋
Original Assignee
江苏豪森药业股份有限公司
江苏豪森医药集团连云港宏创医药有限公司
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Publication date
Application filed by 江苏豪森药业股份有限公司, 江苏豪森医药集团连云港宏创医药有限公司 filed Critical 江苏豪森药业股份有限公司
Publication of WO2014173205A1 publication Critical patent/WO2014173205A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics

Definitions

  • the present invention relates to a pharmaceutical composition of the cyclic polypeptide compound micafungin.
  • 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. Background technique
  • Micafungin is the second echinocandin antifungal drug approved by the FDA following caspofungin.
  • Mikafen sodium for injection, trade name 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 a stronger antibacterial activity, a lower minimum effective concentration, and a lower incidence of adverse reactions than caspofungin.
  • Patent CN1179748C is a micafungin sodium preparation patent in which a pharmaceutical composition in the form of lyophilized form of micafungin sodium is prepared using lactose as an excipient.
  • lactose is produced from the residual liquid from the milk and the casein and casein.
  • Most Chinese people are intolerant to lactose, which can cause symptoms such as abdominal cramps, diarrhea, and flatulence. And the protein in lactose may cause a serious allergic reaction and cause life-threatening. Therefore, the use of lactose as an excipient in lyophilized powder injections, especially in non-antitumor drugs, is relatively more risky.
  • Patent CN100352495C is also a micafungin sodium preparation patent, which is a pharmaceutical composition for preparing lyophilized form of micafungin sodium using maltose as an excipient.
  • Maltose is commonly used in solid preparations and as a sweetener and tablet filler. It has been reported that patients with impaired renal function cause hyponatremia after the application of immunoglobulin 10% maltose intravenous infusion. It is currently believed to be caused by the accumulation of maltose and other highly permeable active metabolites, indicating that maltose is not suitable for intravenous infusion, that is, there is a risk that maltose is used as an excipient for lyophilized powder.
  • Patent CN102614491A is also a micafungin sodium formulation patent in which a pharmaceutical 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 national 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.
  • the high osmotic activity of trehalose in the organs of the organs can cause adverse reactions such as gastrointestinal discomfort in patients. Therefore, seaweed Sugar as an excipient for micafungin sodium freeze-dried powder needle has a major safety hazard.
  • the present invention provides a safe, effective and stable pharmaceutical composition for antifungal comprising:
  • composition further comprises a pH adjuster; wherein
  • the polysaccharide is dextran, starch, cellulose or high fructose, preferably dextran;
  • the disaccharide is sucrose, cellobiose or sucrose, preferably sucrose; preferably, the pharmaceutically acceptable salt is micafungin sodium;
  • the weight ratio of the micafungin to the excipient is 1:2 to 1:15; preferably, the pharmaceutical composition is a lyophilized powder injection, and more preferably, the moisture content is not more than 3.6%.
  • the excipient is a mixture of dextran and sucrose, more preferably, the weight ratio of the glucan to sucrose is 2:1 to 1:3, more preferably the weight ratio of dextran to sucrose is 2
  • the pH adjusting agent is capric acid, hydrochloric acid, acetic acid, sodium dihydrogen phosphate or hydrogen hydroxide. Sodium, 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 an infection caused by Aspergillus and Candida. Sexual disease.
  • micafungin pharmaceutical composition of 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 process for the preparation of a micafungin pharmaceutical composition, the method comprising the steps of:
  • step (3) (4) Add pure water, and make the solution prepared in step (3) to a predetermined volume. After filtration and filling, freeze it by conventional methods.
  • the micafungin or a pharmaceutically acceptable salt thereof pharmaceutical composition provided by the present invention is more stable than the existing preparation.
  • the lyophilized product prepared in the examples of the present invention was stable in appearance at 40 ° C for 30 days and at 60 ° C for 10 days, and the active ingredient was not significantly degraded. It is indicated that the micafungin pharmaceutical composition prepared by the present invention can be stored at room temperature for a long period of time. In addition, under the same freeze-drying process conditions, the micafungin pharmaceutical composition prepared in the examples of the present invention has much lower moisture than the existing preparation. It indicates that the lyophilization process of the present invention requires low drying process and more energy saving, which can significantly reduce production costs.
  • dextran, sucrose or the like which is safer is used as an excipient.
  • the excipients 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%.
  • Example 1 The embodiments of the present invention will be described in detail below with reference to the 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 is dissolved in pure water (750 ml) at room temperature, and dickafen sodium is added, and the mixture is allowed to stand or gently stirred until the drug substance is dissolved.
  • 0.1 mol/L citric acid aqueous solution and/or O.lmol/L sodium hydroxide aqueous solution was added, 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.
  • an appropriate amount of 0.1 mol/L hydrochloric acid solution and/or 0.1 mol/L sodium hydroxide aqueous solution was added, 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. Lyophilization was carried out by a conventional method to obtain a lyophilized composition each containing 50 mg of micafungin.
  • the dextran 40 and sucrose are dissolved in 750 ml of pure water at room temperature, and then micafung sodium is added, and the mixture is allowed to stand or gently stirred until the drug substance is dissolved.
  • an appropriate amount of a 0.1 mol/L aqueous solution of citric acid and/or a 0.1 mol/L aqueous sodium hydroxide solution was added, 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 controlled 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.
  • the dextran 40 and sucrose are dissolved in 750 ml of 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.
  • 0.1 mol/L acetic acid solution and/or 0.1 mol/L sodium hydroxide aqueous solution was added, 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. Lyophilization was carried out by a conventional method to obtain a lyophilized composition each containing 50 mg of micafungin.
  • the dextran 20 and sucrose are dissolved in 750 ml of pure water at room temperature, and then micafung sodium is added, and the mixture is allowed to stand or gently stirred until the drug substance is dissolved.
  • a 0.1 mol/L sodium dihydrogen phosphate solution and/or an O.lmol/L sodium hydroxide aqueous solution was added thereto, 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 tube 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.
  • the dextran 70 and sucrose are dissolved in 750 ml of pure water at room temperature, and then micafung sodium is added, and the mixture is allowed to stand or gently stirred until the drug substance is dissolved.
  • an appropriate amount of O.lmol/L aqueous citric acid solution and/or O.lmol/L sodium hydroxide aqueous solution was added, 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 controlled 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.
  • 2% aqueous citric acid solution 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 sucrose is dissolved in 2000 ml of pure water (water bath below 50 ° C), cooled to 20 ° C or lower, and micafung sodium is added to the sucrose solution, and gently stirred to dissolve, thereby avoiding generation of bubbles.
  • 2% aqueous citric acid solution 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 2500 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 4 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 0.4% aqueous sodium hydroxide, 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 lyophilized compositions each containing 50 mg of micafungin. Comparison of the stability of micafungin
  • the micafungin pharmaceutical composition prepared in the examples of the present invention was significantly more stable than the four comparative examples under high temperature conditions.
  • the micapifen detergent composition prepared in the four comparative examples showed a significant increase in total impurities at 40 ° C and 60 ° C, which was inferior in stability and 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 pharmaceutical composition prepared by the present invention can be stored at room temperature for a long period of time, and the storage cost is low.
  • Example 3 the micafungin pharmaceutical composition prepared by using a mixture of dextran 40 and sucrose 2:3 as an excipient has the best stability.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Communicable Diseases (AREA)
  • Organic Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Oncology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne une composition pharmaceutique contenant de la micafungine ou un sel de celle-ci. Dans la composition, un polysaccharide ou un monosaccharide ou un mélange de polysaccharide et de monosaccharide est utilisé en tant qu'excipient, et la composition peut contenir une quantité appropriée d'agent de régulation de pH.
PCT/CN2014/072688 2013-04-26 2014-02-28 Composition pharmaceutique contenant de la micafungine ou un sel de celle-ci WO2014173205A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201310151783.9 2013-04-26
CN201310151783.9A CN103330933B (zh) 2013-04-26 2013-04-26 含有米卡芬净或其盐的药物组合物

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WO2014173205A1 true WO2014173205A1 (fr) 2014-10-30

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017060923A1 (fr) * 2015-10-10 2017-04-13 Gufic Biosciences Limited Formulation parentérale lyophilisée de micafungine sodique et son procédé

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105106933A (zh) * 2015-09-06 2015-12-02 江苏奥赛康药业股份有限公司 含米卡芬净的冻干组合物及其制备方法
CN106860856B (zh) * 2015-12-14 2019-05-31 山东新时代药业有限公司 一种含有阿尼芬净的冻干粉及制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009140162A1 (fr) * 2008-05-15 2009-11-19 Baxter International Inc. Formulations pharmaceutiques stables
CN102614492A (zh) * 2011-01-31 2012-08-01 上海天伟生物制药有限公司 一种含有棘白菌素类抗真菌剂米卡芬净的液体药用组合物

Family Cites Families (2)

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Publication number Priority date Publication date Assignee Title
TWI233805B (en) * 1999-07-01 2005-06-11 Fujisawa Pharmaceutical Co Stabilized pharmaceutical composition in lyophilized form as antifungal agent
AU2009240389A1 (en) * 2008-04-25 2009-10-29 Nanobio Corporation Nanoemulsions for treating fungal, yeast and mold infections

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009140162A1 (fr) * 2008-05-15 2009-11-19 Baxter International Inc. Formulations pharmaceutiques stables
CN102614492A (zh) * 2011-01-31 2012-08-01 上海天伟生物制药有限公司 一种含有棘白菌素类抗真菌剂米卡芬净的液体药用组合物

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017060923A1 (fr) * 2015-10-10 2017-04-13 Gufic Biosciences Limited Formulation parentérale lyophilisée de micafungine sodique et son procédé

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TWI650133B (zh) 2019-02-11
TW201440783A (zh) 2014-11-01
CN103330933B (zh) 2015-08-05
CN103330933A (zh) 2013-10-02

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