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WO2014071743A1 - Composition contenant un médicament antifongique et un tampon lactate - Google Patents

Composition contenant un médicament antifongique et un tampon lactate Download PDF

Info

Publication number
WO2014071743A1
WO2014071743A1 PCT/CN2013/078643 CN2013078643W WO2014071743A1 WO 2014071743 A1 WO2014071743 A1 WO 2014071743A1 CN 2013078643 W CN2013078643 W CN 2013078643W WO 2014071743 A1 WO2014071743 A1 WO 2014071743A1
Authority
WO
WIPO (PCT)
Prior art keywords
caspofungin
pharmaceutical composition
pharmaceutically acceptable
composition according
acceptable salt
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/CN2013/078643
Other languages
English (en)
Chinese (zh)
Inventor
张辉
孙飘扬
吴玉霞
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 Hengrui Medicine Co Ltd
Original Assignee
Jiangsu Hengrui Medicine 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 Hengrui Medicine Co Ltd filed Critical Jiangsu Hengrui Medicine Co Ltd
Publication of WO2014071743A1 publication Critical patent/WO2014071743A1/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
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K9/08—Solutions
    • 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 for the treatment and/or prevention of fungal infections comprising caspofungin or a pharmaceutically acceptable salt thereof and a lactate buffer.
  • Caspofungin has the following structural formula,
  • Caspofungin inhibits the synthesis of ⁇ -(1,3 ⁇ glucan, which is an essential component of many filamentous fungi and yeast cell walls, whereas ⁇ -(1,3 ⁇ Portuguese) is absent in mammalian cells.
  • Glycosamps Caspofungin has antibacterial activity against a wide variety of pathogenic Aspergillus and Candida fungi and is effective against amphotericin and fluconazole-resistant fungi.
  • the caspofungin compound itself is highly unstable and can be degraded in a variety of ways including, but not limited to, hydrolysis, dimerization, and oxidation. Due to the instability of caspofungin, in order to ensure the long-term stability and drug stability of caspofungin, it is necessary to develop a technical solution and a preparation thereof which can ensure the stability of caspofungin, so as to minimize the unnecessary The production of degradants.
  • a pharmaceutical composition of caspofungin containing an acetate buffer is disclosed in the patent ZL97195514.X or US Pat. No.
  • WO2009002481A1 discloses the preparation of a lyophilized composition using a non-reducing sugar such as trehalose, and it is considered that the use of non-reducing sugars can increase the glass transition temperature (Tg) of the lyophilized powder and increase the stability of the lyophilized composition to heat.
  • Tg glass transition temperature
  • the acetate composition is still used for stabilizing or acetate buffer.
  • the entire invention does not deviate from the scope of the invention of ZL97195514.X or US6136783, and the pharmaceutical composition is not stable enough.
  • Patent application CN101516397A or WO2008012310A1 discloses that a very stable caspofungin pharmaceutical composition can be prepared using a very small amount of acetic acid as a pH adjuster, and an acetate buffer system is still used, and the invention is still in the patent ZL97195514.X or The scope of the invention of US 6,136,783, and the pharmaceutical composition is more unstable than the pharmaceutical composition disclosed in the patents ZL97195514.X or US6136783, and cannot be employed in practice.
  • CN102166186A claims to have made a caspofungin composition containing sulfate, citrate, phosphate, or lactate, but after investigation, the experimental data in this literature is far from the actual situation, caspofungin
  • the net is extremely unstable, the lyophilized powder needs to be stored at 2-8 ° C, and the re-dissolved contact with water will quickly produce a large amount of impurities. According to the application, it is placed at 40 ° C, and the commercially available caspofungin is in the market. It also has good stability after reconstitution, which contradicts the actual situation. Therefore, those skilled in the art, after reading the application specification, do not think that the application is completing the preparation of the caspofungin composition.
  • the inventors have unexpectedly discovered a pharmaceutical composition having better stability than the caspofungin pharmaceutical composition containing an acetate buffer, which is entirely due to the expectations of the prior art and known techniques. outer.
  • composition of the present invention can improve the chemistry of caspofungin or a pharmaceutically acceptable salt thereof Stability, and improved stability, can guarantee its commercialization as a medicinal product and extend its shelf life as a medicinal product.
  • the pharmaceutical composition of the present invention contains caspofungin or a pharmaceutically acceptable salt thereof, and further contains a pharmaceutically acceptable amount of a lactate buffer.
  • the inventors have surprisingly found that the addition of a lactate buffer greatly reduces the degradation of caspofungin or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition may be an injectable parenteral pharmaceutical preparation, preferably the pharmaceutical composition is in the form of a lyophilized powder.
  • the amount of the lactate buffer in the pharmaceutical composition of the present invention is such that the pharmaceutical composition is effective to obtain a pH between 4 and 8, preferably 5 to 7, more preferably pH value of 5.5-6.5.
  • the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable amount of an excipient selected from the group consisting of sodium chloride, mannitol, sucrose, fructose, xylitol, and dextrorotatory One or more of sugar, trehalose, and glycine, preferably a mixture of glycine and sucrose.
  • the weight ratio of said sucrose to caspofungin or a pharmaceutically acceptable salt thereof is from 1.5:1 to 0.2:1, preferably from 1:1 to 0.5:1.
  • the weight of the caspofungin, when using caspofungin pharmaceutically acceptable salt, is based on the caspofungin contained therein.
  • sucrose is a key factor in the stability of the preparation, and the amount thereof is not arbitrarily selected, and the more it is not, the better.
  • the amount of sucrose is increased to a certain amount, the stability of the preparation is decreased, and the sucrose is Increased dosage is less economical. Therefore, it is very important to choose a suitable amount.
  • sucrose in the above dosage range can achieve the best stabilizing effect.
  • the weight ratio of glycine to caspofungin or a pharmaceutically acceptable salt thereof is from 1:10 to 10:1, more preferably from 1:4 to 4:1.
  • the pharmaceutical composition of the present invention contains 30-50 mg/mL of caspofungin or a pharmaceutically acceptable salt thereof, based on caspofungin, 10-60 mM lactate Buffer, 30-70 mg/mL of excipient and water.
  • the pharmaceutical composition of the invention comprises 42 mg/mL of caspofungin or a pharmaceutically acceptable salt thereof, 25 mM to 50 mM lactate, based on caspofungin Buffer, 30mg/mL sucrose, 20mg/mL glycine And water. More preferably, the pharmaceutical composition of the present invention consists of the above components.
  • the amount of the lactate buffer agent also has a significant effect on the stability of the composition.
  • the amount of the lactate buffer is too large or too small to have a negative effect on stability. Selecting the right amount of dosage can greatly improve the stability and reduce the production of related substances.
  • the lactate buffer is used in an amount of 10-60 mM, preferably 25-60 mM, more preferably 25-50 mM.
  • the pharmaceutically acceptable salt of caspofungin in the pharmaceutical composition of the invention is caspofungin diacetate (or caspofungin acetate).
  • Another aspect of the invention provides the use of a pharmaceutical composition as described above for the manufacture of a medicament for the treatment or prevention of a fungal infection in a mammal.
  • the present invention also provides a method for preparing the above pharmaceutical composition, which comprises the steps of: a) dissolving an excipient and lactic acid in water; adding and dissolving caspofungin or a pharmaceutically acceptable salt thereof, and using The base is adjusted to the desired pH; in a preferred embodiment, the step of lyophilizing the pharmaceutical composition is also included.
  • the caspofungin composition 1 was prepared according to the following table:
  • Component dosage (mg/mL)
  • compositions 2, 3, and 4 having a pH of 5.0, 7.0, and 8.0 were separately prepared in the same manner as in Example 1.
  • the prepared lyophilized powder was sampled at 30 ° C for investigation, and samples were taken at 5 days and 10 days respectively. Samples were taken at 25 ° C for sampling, samples were taken at 6 months, and samples were subjected to HPLC. Analytical determination, comparison of impurities L-747969 and total impurity changes, wherein the impurity L-747969 is the main hydrolysis and thermal degradation impurities of caspofungin acetate. The results are as follows:
  • compositions 5, 6, 7, 8, 9, 10 were prepared according to the method of Example 1.
  • the components and amounts of the compositions are shown in the following table, wherein the pH of the composition was adjusted with NaOH, and the components were all in mg. /ml
  • compositions 5, 6, 7, 8, and 9 prepared in Example 3 were each sampled at 30 ° C for sampling, and samples were taken at 5 days and 10 days, respectively, and samples were taken at 25 ° C for investigation.
  • the sample was sampled at 6 M, and the sample was analyzed by HPLC to compare the change of impurity L-747969 and total impurities.
  • the impurity L-747969 was the main hydrolysis and thermal degradation impurity of caspofungin acetate.
  • compositions 11, 12, 13, and 14 were prepared in the same manner as in Example 1.
  • the compositions and amounts of the compositions are shown in the following table, wherein the pH of the compositions was adjusted with NaOH, and the amount of each component was mg/mlo.
  • Component Composition 11 Component Composition 12 Composition 13 Composition 14 Caspofungin 46.6 46.6 46.6 46.6
  • compositions 11, 12, 13, and 14 prepared in Example 3 were each sampled at 30 ° C for sampling, and samples were taken at 5 days and 10 days, respectively, and samples were taken at 25 ° C for investigation.
  • the sample was sampled by 6M, and the sample was analyzed by HPLC to compare the change of impurity L-747969 and total impurities.
  • the impurity L-747969 was the main hydrolysis and thermal degradation impurity of caspofungin acetate.
  • compositions 15, 16, 17, 18, 19 were prepared as in Example 1, and these combinations were prepared. Except for the different amounts of lactate buffer, the other components and content are the same, wherein the pH value of the composition is adjusted by NaOH, and the dosage of each component is mg/ml. After conversion, the lactate buffer in each composition is converted. The amounts were 5 mM, 20 mM, 50 mM, 60 mM, 70 mM, respectively.
  • compositions 15, 16, 17, 18, 19 prepared in Example 3 were sampled at 30 ° C, respectively, and sampled at 5 days and 10 days, respectively, and samples were taken at 25 ° C for investigation. Samples were taken at 6 M, and the samples were analyzed by HPLC to compare the changes of impurity L-747969 and total impurities.
  • the impurity L-747969 was the main hydrolysis and thermal degradation impurity of caspofungin acetate.

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

Abstract

La présente invention concerne une composition pharmaceutique contenant de la caspofungine ou un sel pharmaceutiquement acceptable de celle-ci et une quantité pharmaceutiquement acceptable d'un tampon lactate.
PCT/CN2013/078643 2012-11-09 2013-07-02 Composition contenant un médicament antifongique et un tampon lactate Ceased WO2014071743A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201210447151.2 2012-11-09
CN2012104471512A CN103212058A (zh) 2012-01-18 2012-11-09 含有抗真菌药物和乳酸盐缓冲剂的组合物

Publications (1)

Publication Number Publication Date
WO2014071743A1 true WO2014071743A1 (fr) 2014-05-15

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2013/078643 Ceased WO2014071743A1 (fr) 2012-11-09 2013-07-02 Composition contenant un médicament antifongique et un tampon lactate

Country Status (3)

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CN (1) CN103212058A (fr)
TW (1) TW201417825A (fr)
WO (1) WO2014071743A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GR1008818B (el) * 2015-05-22 2016-08-01 Φαρματεν Ανωνυμος Βιομηχανικη Και Εμπορικη Εταιρεια Φαρμακευτικων Ιατρικων Και Καλλυντικων Προϊοντων Φαρμακευτικο σκευασμα περιεχον εναν αντιμυκητιασικο παραγοντα εχινοκανδινης και μεθοδος παρασκευης αυτου
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
CN107158359A (zh) * 2017-05-26 2017-09-15 江苏恒瑞医药股份有限公司 一种稳定的卡泊芬净冻干组合物及其制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101516387A (zh) * 2006-07-26 2009-08-26 桑多斯股份公司 卡泊芬净制剂
CN102166186A (zh) * 2011-04-18 2011-08-31 深圳市健元医药科技有限公司 一种更加稳定的氮杂环己肽类制剂
WO2012038371A1 (fr) * 2010-09-20 2012-03-29 Xellia Pharmaceuticals Aps Composition à base de caspofongine
CN102488886A (zh) * 2011-09-26 2012-06-13 上海天伟生物制药有限公司 一种低杂质含量的卡泊芬净制剂及其制备方法和用途
CN103212059A (zh) * 2012-01-18 2013-07-24 江苏恒瑞医药股份有限公司 含有抗真菌药物和乳酸盐缓冲液的组合物

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102488889B (zh) * 2011-09-26 2014-01-22 上海天伟生物制药有限公司 一种低杂质含量的卡泊芬净制剂及其制备方法和用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101516387A (zh) * 2006-07-26 2009-08-26 桑多斯股份公司 卡泊芬净制剂
WO2012038371A1 (fr) * 2010-09-20 2012-03-29 Xellia Pharmaceuticals Aps Composition à base de caspofongine
CN102166186A (zh) * 2011-04-18 2011-08-31 深圳市健元医药科技有限公司 一种更加稳定的氮杂环己肽类制剂
CN102488886A (zh) * 2011-09-26 2012-06-13 上海天伟生物制药有限公司 一种低杂质含量的卡泊芬净制剂及其制备方法和用途
CN103212059A (zh) * 2012-01-18 2013-07-24 江苏恒瑞医药股份有限公司 含有抗真菌药物和乳酸盐缓冲液的组合物

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CN103212058A (zh) 2013-07-24
TW201417825A (zh) 2014-05-16

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