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WO2014173204A1 - Composition pharmaceutique de micafungine ou un sel de celle-ci - Google Patents

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

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Publication number
WO2014173204A1
WO2014173204A1 PCT/CN2014/072683 CN2014072683W WO2014173204A1 WO 2014173204 A1 WO2014173204 A1 WO 2014173204A1 CN 2014072683 W CN2014072683 W CN 2014072683W WO 2014173204 A1 WO2014173204 A1 WO 2014173204A1
Authority
WO
WIPO (PCT)
Prior art keywords
micafungin
pharmaceutical composition
dextran
sodium
glucose
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2014/072683
Other languages
English (en)
Chinese (zh)
Inventor
项文娟
孙长安
王小雷
孙运栋
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jiangsu Hansoh Pharmaceutical Group Co Ltd
Original Assignee
Jiangsu Hansoh Pharmaceutical Group Co Ltd
Jiangsu Hansoh Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jiangsu Hansoh Pharmaceutical Group Co Ltd, Jiangsu Hansoh Pharmaceutical Co Ltd filed Critical Jiangsu Hansoh Pharmaceutical Group Co Ltd
Publication of WO2014173204A1 publication Critical patent/WO2014173204A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin

Definitions

  • the present invention relates to a stable 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 monosaccharide 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 monosaccharide is glucose, fructose or rhamnose, preferably glucose; 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, preferably, wherein the moisture content is not more than 3.6%.
  • the excipient is a mixture of dextran and glucose, more preferably, the weight ratio of the glucan to glucose is 1:0.5 to 1:5, more preferably the weight ratio of dextran to glucose is 1 :1 ;
  • the pH adjusting agent is citric acid, hydrochloric acid, acetic acid, sodium dihydrogen phosphate or sodium hydroxide, preferably citric 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) using a 0.1 mol / L aqueous solution of citric acid and / or 0.1 mol / L aqueous sodium hydroxide solution, the pH of the solution prepared in step (2) is adjusted to 5.5;
  • 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 pharmaceutical composition of micafungin or a pharmaceutically acceptable salt thereof provided by the present invention is more stable 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 40 ° C for 10 days, indicating that the micafungin pharmaceutical composition prepared by the present invention can be used for a long period of time. Store at room temperature.
  • the micafungin pharmaceutical composition prepared by the embodiment of the invention has much lower water content than the existing preparation, indicating that the lyophilization process of the invention has low requirements on the drying process and is more energy-saving. Can significantly reduce production costs.
  • the micafungin sodium lyophilized powder composition provided by the present invention, dextran, glucose, fructose or the like having 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, the amount of the three in the present invention 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); Glucan is specified in the FDA Inactive Ingredients Database The maximum amount is 30% (http://www.accessdata.fda.gov/scripts/cder/iig/getiigWEB.cfm); fructose at
  • the excipients used in the present invention are safer, have fewer adverse reactions, and are more suitable for the physical fitness of our people.
  • the micafungin sodium pharmaceutical composition prepared by the present invention is equivalent in effectiveness to the existing preparation, and has better stability and safety than the existing preparation.
  • 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.
  • an appropriate amount of an aqueous solution of O.lmol/L citric acid and/or an aqueous solution of 0.1 mol/L of sodium hydroxide 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.
  • a conventional lyophilizer it was lyophilized by a conventional method to obtain a lyophilized composition each containing 50 mg of micafungin.
  • the dextran 20 and glucose are dissolved in 750 ml of pure water under warm conditions, and then micafungin sodium is added, and the mixture is allowed to stand or gently stirred until the drug substance is dissolved.
  • Add to solution A suitable amount of 0.1 mol/L hydrochloric acid solution and/or 0.1 mol/L sodium hydroxide aqueous solution was adjusted to pH 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 using a conventional lyophilizer to obtain a lyophilized composition each containing 50 mg of micafungin.
  • 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.
  • an appropriate amount of 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 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.
  • an appropriate amount of O.lmol/L sodium dihydrogen phosphate 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. Lyophilization was carried out by a conventional method to obtain a lyophilized composition each containing 50 mg of micafungin.
  • 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.
  • 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 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. Comparative Example 1 :
  • Anhydrous citric acid 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
  • the resulting solution was dispensed into 1000 10 ml control antibiotic bottles, 2.5 ml each. Freeze-dried by conventional methods to obtain a lyophilized combination of 50 mg of micafungin
  • 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. Freeze by conventional methods to obtain Each lyophilized composition 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 superior in stability to the three comparative examples under high temperature conditions.
  • the micapifen detergent composition prepared in 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 in the examples of the present invention has stable appearance and high degradation of the active ingredient under high temperature conditions. It is indicated that the micafungin pharmaceutical composition prepared by the invention can be stored at room temperature for a long time, and the storage cost is low.
  • Example 3 the micafungin pharmaceutical composition prepared by using a mixture of dextran 40 and glucose 1:1 as an excipient has the best stability.

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

Abstract

La présente invention concerne une composition pharmaceutique de 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. La stabilité et la sécurité potentielle de la composition pharmaceutique de la présente invention sont supérieures à celles d'une préparation existante.
PCT/CN2014/072683 2013-04-26 2014-02-28 Composition pharmaceutique de micafungine ou un sel de celle-ci Ceased WO2014173204A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201310150069.8 2013-04-26
CN201310150069.8A CN103330932B (zh) 2013-04-26 2013-04-26 一种米卡芬净或其盐的药物组合物

Publications (1)

Publication Number Publication Date
WO2014173204A1 true WO2014173204A1 (fr) 2014-10-30

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PCT/CN2014/072683 Ceased WO2014173204A1 (fr) 2013-04-26 2014-02-28 Composition pharmaceutique de micafungine ou un sel de celle-ci

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CN (1) CN103330932B (fr)
TW (1) TWI634897B (fr)
WO (1) WO2014173204A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103330932B (zh) * 2013-04-26 2015-12-23 江苏豪森药业股份有限公司 一种米卡芬净或其盐的药物组合物

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000051567A1 (fr) * 1999-03-03 2000-09-08 Eli Lilly And Company Procedes permettant de preparer des compositions et des formulations pharmaceutiques orales d'echinocandine b
CN1636591A (zh) * 1999-07-01 2005-07-13 藤泽药品工业株式会社 冻干形式的稳定的药用组合物
CN102512659A (zh) * 2011-01-31 2012-06-27 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的药用组合物及其制备方法和用途
CN102614491A (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药用组合物及其制备方法和用途
CN103330932A (zh) * 2013-04-26 2013-10-02 江苏豪森药业股份有限公司 一种米卡芬净或其盐的药物组合物

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000051567A1 (fr) * 1999-03-03 2000-09-08 Eli Lilly And Company Procedes permettant de preparer des compositions et des formulations pharmaceutiques orales d'echinocandine b
CN1636591A (zh) * 1999-07-01 2005-07-13 藤泽药品工业株式会社 冻干形式的稳定的药用组合物
CN102512659A (zh) * 2011-01-31 2012-06-27 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的药用组合物及其制备方法和用途
CN102614491A (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药用组合物及其制备方法和用途
CN103330932A (zh) * 2013-04-26 2013-10-02 江苏豪森药业股份有限公司 一种米卡芬净或其盐的药物组合物

Also Published As

Publication number Publication date
CN103330932B (zh) 2015-12-23
CN103330932A (zh) 2013-10-02
TWI634897B (zh) 2018-09-11
TW201440782A (zh) 2014-11-01

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