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WO2016188625A1 - Composition pharmaceutique contenant un agent antifongique à base de type échinocandine et son procédé de préparation - Google Patents

Composition pharmaceutique contenant un agent antifongique à base de type échinocandine et son procédé de préparation Download PDF

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Publication number
WO2016188625A1
WO2016188625A1 PCT/EP2016/000840 EP2016000840W WO2016188625A1 WO 2016188625 A1 WO2016188625 A1 WO 2016188625A1 EP 2016000840 W EP2016000840 W EP 2016000840W WO 2016188625 A1 WO2016188625 A1 WO 2016188625A1
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WO
WIPO (PCT)
Prior art keywords
aqueous solution
solution
lyophilization
agent
caspofungin
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/EP2016/000840
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English (en)
Other versions
WO2016188625A9 (fr
Inventor
Evangelos Karavas
Efthymios Koutris
Vasiliki SAMARA
Ioanna Koutri
Christina KIZIRIDI
Anastasia Kalaskani
Andreas KAKOURIS
George GOTZAMANIS
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.)
Pharmathen SA
Original Assignee
Pharmathen SA
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 Pharmathen SA filed Critical Pharmathen SA
Priority to EP16728831.5A priority Critical patent/EP3298026A1/fr
Publication of WO2016188625A1 publication Critical patent/WO2016188625A1/fr
Publication of WO2016188625A9 publication Critical patent/WO2016188625A9/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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

Definitions

  • the present invention relates to a stable pharmaceutical composition for intravenous administration comprising an echinocandin antifungal agent such as Caspofungin or pharmaceutical acceptable salt thereof and a method for the preparation thereof.
  • Caspofungin acetate belongs to a new class of antifungals referred to as the echinocandins. Echinocandins work by inhibiting fungal cell wall synthesis. Specifically, they disrupt cell wall glucan formation through non-competitive inhibition of the enzyme complex 1,3-D-glucan synthase, which is present in most pathogenic fungi and is essential for fungal cell wall formation.
  • Echinocandins are considered fungicidal and their effects appear to depend on fungal growth and metabolism. Like previous antifungals, the echinocandins exhibit a postantifungal effect against Candida spp. that lasts longer than 12 hours at concentrations above the minimum inhibitory concentration (MIC) and up to 2 hours when concentrations are below the MIC. They are also used to treat infections caused by Aspergillus spp.
  • the chemical name of Caspofungin acetate is
  • the molecular formula is C 52 H 88 NioOi 5 .2C 2 H 4 0 2 , corresponding to a molecular weight of 1213.42. It is a white to almost white powder freely soluble in water and methanol and slightly soluble in ethanol.
  • US 6245349 B discloses a drug delivery composition in concentrate form that contains an antifungal agent dilutable with an aqueous liquid to form an oil-in-water microemulsion containing the antifungal agent in dissolved form.
  • EP 1582204 B discloses pharmaceutical formulations comprising an echinocandin compound or echinocandin/carbohydrate complex and a pharmaceutically acceptable micelle-forming surfactant in a non-toxic aqueous solvent such that the solubilization of the echinocandin compound is optimized and the ability to freeze-dry the solution is maintained.
  • an object of the present invention to provide an improved stable solid dosage formulation, suitable for intravenous administration after reconstitution in a sterile solvent, containing an echinocandin antifugal agent and in particular Caspofungin or pharmaceutical acceptable salt thereof, as an active ingredient, which overcomes the deficiencies of the prior art and avoids the degradation of the active pharmaceutical ingredient resulting in longer shelf-life of the product. It is another object of the present invention to provide a safe injectable preparation containing Caspofungin or pharmaceutical acceptable salt thereof.
  • the solution of the present invention is subjected to sterilization process (filtration) according to the Pharmacopoeia requirements (European Pharmacopoeia 5.0; 01/2005:50101), before being subjected to lyophilization.
  • Another aspect of the present invention is to provide a solid composition prepared by a process which comprises lyophilization of an aqueous solution comprising Caspofungin or pharmaceutical acceptable salt thereof, a buffering agent, diluents/bulking agents and optionally other excipients to form a readily reconstitutable powder.
  • a further approach of the present invention is to provide a process for preparing a drug delivery system for echinocandin antifungal agents and in particular Caspofungin or pharmaceutical acceptable salt thereof, which comprises reconstituting a unit dosage of the composition in a physiologically acceptable volume of a parenterally acceptable solvent, to form an injectable solution.
  • the main objective of the present invention is to provide a proper qualitative and quantitative composition of Caspofungin or pharmaceutical acceptable salt thereof, prepared by a suitable manufacturing process in order to obtain a stable and efficacious composition.
  • a process for the preparation of a stable, solid dosage form suitable for parenteral administration after ex tempore reconstitution in a sterile solvent, containing an echinocandin antifungal agent and in particular Caspofungin or pharmaceutical acceptable salt thereof, as an active ingredient, an effective amount of a buffering agent and pharmaceutically acceptable diluents/bulking agents which comprises:
  • a pharmaceutical composition comprising an active ingredient is considered to be “stable” if said ingredient degrades less or more slowly than it does on its own and/or in known pharmaceutical compositions.
  • the main object of the present invention is to prepare an aqueous solution comprising an echinocandin antifungal agent and in particular Caspofungin or pharmaceutical acceptable salt thereof, as an active ingredient, and suitable inactive ingredients, such as buffering agents and diluents/bulking agents aimed to be subjected to lyophilization.
  • Buffering agents maximize the stability of pharmaceutical formulations in order to achieve predictable pH control. Buffering agents may be selected from glacial acetic acid, citric acid, tartaric acid, boric acid, lactic acid. Most preferably the buffering agent is glacial acetic acid or lactic acid.
  • the formulations of the present invention comprise from 0.1% to 0.4% (w/v) of buffering agent, most preferably 0.15% (w/v) of buffering agent.
  • Diluents may be selected from lactose, sorbitol, maltodextrin, sucrose, sorbitol, and mannitol.
  • Preferable diluents/bulking agents are sucrose and mannitol.
  • the formulations of the present invention comprise from 3% to 7% (w/v) of diluent/bulking agent, most preferably 5% (w/v) of diluent/bulking agent.
  • Sterilization is necessary for the complete destruction or removal of all microorganisms (including spore-forming and non-spore-forming bacteria, viruses, fungi, and protozoa) that could contaminate pharmaceuticals and thereby constitute a health hazard. Due to thermal instability of Caspofungin sterilization of the solution was performed through aseptic filtration.
  • Filters can be made of several different materials such as nitrocellulose, polyvinylidene fluoride, polyethersulfone.
  • the filtration equipment and the filters themselves may be purchased as pre-sterilized disposable units in sealed packaging, or must be sterilized by the user, generally by autoclaving at a temperature that does not damage the fragile filter membranes.
  • the filter membranes need testing for punctures made during or prior to use.
  • pharmaceutical sterile filtration is performed in a room with highly filtered air.
  • freeze-drying and “lyophilization” are used interchangeably unless otherwise stated.
  • Lyophilization is a dehydration process typically used to preserve a perishable material or make the material more convenient for transport. It works by freezing the material and then reducing the surrounding pressure to allow the frozen water in the material to sublimate directly from the solid phase to the gas phase.
  • Freeze-drying is usually used to increase the shelf life of products, such as vaccines and other injectables. By removing the water from the material and sealing the material in a vial, the material can be easily stored, shipped, and later reconstituted to its original form for injection.
  • a freeze-dried substance is sealed to prevent the re-absorption of moisture, the substance may be stored at room temperature without refrigeration, and be protected against spoilage for many years. Preservation is possible because the greatly reduced water content inhibits the action of microorganisms and enzymes that would normally spoil or degrade the substance. Freeze-drying also causes less damage to the substance than other dehydration methods using higher temperatures. Moreover, it does not usually cause shrinkage or toughening of the material being dried. Freeze-dried products can be rehydrated (reconstituted) much more quickly and easily because the process leaves microscopic pores. The pores are created by the ice crystals that sublimate, leaving gaps or pores in their place. This is especially important when it comes to pharmaceutical uses.
  • the following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope or spirt of the invention.
  • Table 1 Compositions 1 to 5 of example 1
  • Glacial Acetic Acid 1.50 - - - - -
  • compositions 1 to 5 were prepared using different buffering agents and their physicochemical properties were studied in order to select the most suitable one according to the target characteristics as well as proper chemical stability.
  • compositions 1 to 5 The process followed for the preparation of Compositions 1 to 5 comprises the following stages:
  • compositions 1 to 5 were also analyzed for their assay and related substances at zero time (Table 4) and after 3 months storage at 5°C ⁇ 3°C (Table 5).
  • compositions 1 to 5 performed with different buffering agent it was noted that the pH of the lyophilized product after reconstitution is slightly increased (approximately 0.5 units); thus, the target pH value of the solution before lyophilization is set to 5.0-7.0.
  • compositions 1 and 5 exhibited the best physical properties. In terms of chemical stability both compositions have similar impurities profile. Thus, it was decided that either acetic acid or lactic acid are suitable buffering agents for the present invention. Further trials were performed with Composition 1 and 5 in which the pH of the solution was adjusted near the low (5.3) and high limit (6.7) in order to study its influence on the stability of the final product.
  • Table 8 Stability data at zero time and after 3 months storage at 5 C
  • the average % Assay for Caspofungin is not decreased when the solution is in intimate contact with the filter for 8 hours, indicating that no adsorption from the filter occurs. Also, it was not observed any significant increment at the impurities, thus the filter is inert for this product and can be safely used for the manufacturing of the product.
  • compositions 1 & 5 were prepared at low temperature (10°C-15°C) and the solubility of the inactive ingredients and Caspofungin was tested in terms of processing. Dissolution time in cooled water of all the ingredients was approximately the same as in water at 20-25°C, which is attributed to their high solubility in water.
  • Table 15 Stability data at zero time, 8 & 10 hours
  • the bulk solution remains stable for 8 hours stored at 5 C, whereas after this time the total impurities level is increased. This leads to the conclusion that the time in which the active ingredient remains in solution is a critical parameter for the final drug product's quality.
  • Lyophilization cycle development The lyophilization process took place in a lab lyophilizator and the following cycle was applied to formulation trials already presented:
  • precooling is applied where the chamber shelves are kept cold to 0°C.
  • the main objective of this step is to convert the liquid solution into solid through freezing. This step is of paramount importance since it is the first process step and determines the final properties of the product.
  • the shelves were cooled from 0°C to - 50°C and -40°C respectively. When the lowest temperature of -50°C or -40°C is reached we obtain the maximum solidification of the whole solution. In order to minimize the heterogeneity and produce a uniform batch we keep the temperature stable for 1 h and 30 min.
  • the primary drying or sublimation phase starts with the reduction of the chamber pressure and the shelf temperature is raised to supply the heat removed by ice sublimation.
  • the frozen material is placed under 0.1 mbar vacuum which is well below the vapour pressure of ice.
  • the temperature rises to -30°C in ramp duration of 30 min and remains for 15min.
  • the same is applied raising the temperature 10°C stepwise in order to achieve the sublimation of ice and to avoid the structural collapse of the cake which results in a melt back of ice in the solution.
  • the vapour composition in the chamber changes drastically from water vapor to air so the vacuum is reduced to the value of 0.06 mbar.
  • the product temperature increases to the shelf temperature (10°C) and remains for 45 min in order to achieve the equilibrium between the product and the shelves where ice sublimation ends and therefore no heat is removed out of the product.
  • the secondary drying or desorption phase starts when ice is being distilled away by raising the temperature. At this step is being allowed the progressive extraction of bound water in order to reach the appropriate moisture for the final product. Complete drying of the product is achieved at the final temperature with a higher vacuum (0.06 mbar) in order to remove of that water (moisture), which has such a close interaction with the residual product that could not be crystallized during the freezing phase as pure ice.
  • This water "unfrozen water” has to be reduced to a level optimal for stability, to less than 1.5%.
  • Two different temperatures were applied (15°C and 20°C respectively) and it was found that higher temperature (20°C) is better since the reduction of moisture to less than 1.5% is achieved in less time, as shown in the following table:
  • compositions 1 & 5 are the preferred compositions of the present invention since all tests demonstrated that their physical properties and chemical stability were the appropriate.
  • compositions of the present invention were prepared with the following manufacturing process:

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une solution aqueuse comprenant un agent antifongique de type échinocandine tel que l'acétate de Caspofungine, comme principe actif, un agent tampon et au moins un diluant/agent d'étoffement. L'invention concerne également la lyophilisation de ladite solution dans le but de récupérer une poudre sèche pour sa reconstitution avant utilisation.
PCT/EP2016/000840 2015-05-22 2016-05-20 Composition pharmaceutique contenant un agent antifongique à base de type échinocandine et son procédé de préparation Ceased WO2016188625A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP16728831.5A EP3298026A1 (fr) 2015-05-22 2016-05-20 Composition pharmaceutique contenant un agent antifongique à base de type échinocandine et son procédé de préparation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GR20150100238A GR1008818B (el) 2015-05-22 2015-05-22 Φαρμακευτικο σκευασμα περιεχον εναν αντιμυκητιασικο παραγοντα εχινοκανδινης και μεθοδος παρασκευης αυτου
GRGR20150100238 2015-05-22

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WO2016188625A1 true WO2016188625A1 (fr) 2016-12-01
WO2016188625A9 WO2016188625A9 (fr) 2017-04-27

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EP (1) EP3298026A1 (fr)
GR (1) GR1008818B (fr)
WO (1) WO2016188625A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210085751A1 (en) * 2017-12-22 2021-03-25 Arecor Limted Novel composition

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6245349B1 (en) 1996-02-23 2001-06-12 éLAN CORPORATION PLC Drug delivery compositions suitable for intravenous injection
WO2009002481A1 (fr) * 2007-06-26 2008-12-31 Merck & Co., Inc. Composition antifongique lyophilisée
CN103212058A (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剂的组合物
EP2618814A1 (fr) * 2010-09-20 2013-07-31 Xellia Pharmaceuticals ApS Composition à base de caspofongine
EP1582204B1 (fr) 1999-03-03 2013-09-25 Eli Lilly & Company Formulations pharmaceutiques d'échinocandine contenant des tensioactifs formant des micelles
CN103315966A (zh) * 2013-06-18 2013-09-25 江苏奥赛康药业股份有限公司 一种注射用醋酸卡泊芬净药物组合物及其制备方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6245349B1 (en) 1996-02-23 2001-06-12 éLAN CORPORATION PLC Drug delivery compositions suitable for intravenous injection
EP1582204B1 (fr) 1999-03-03 2013-09-25 Eli Lilly & Company Formulations pharmaceutiques d'échinocandine contenant des tensioactifs formant des micelles
WO2009002481A1 (fr) * 2007-06-26 2008-12-31 Merck & Co., Inc. Composition antifongique lyophilisée
EP2618814A1 (fr) * 2010-09-20 2013-07-31 Xellia Pharmaceuticals ApS Composition à base de caspofongine
CN103212058A (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剂的组合物
CN103315966A (zh) * 2013-06-18 2013-09-25 江苏奥赛康药业股份有限公司 一种注射用醋酸卡泊芬净药物组合物及其制备方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CARPENTER J F ET AL: "Rational design of stable lyophilized protein formulations: Some practical advice", PHARMACEUTICAL RESEARCH, SPRINGER NEW YORK LLC, US, vol. 14, no. 8, 1 January 1997 (1997-01-01), pages 969 - 975, XP002303280, ISSN: 0724-8741, DOI: 10.1023/A:1012180707283 *
JOHNSON R E ET AL: "Mannitol-sucrose mixtures- Versatile formulations for protein lyophilization", JOURNAL OF PHARMACEUTICAL SCIENCES, AMERICAN PHARMACEUTICAL ASSOCIATION, WASHINGTON, US, vol. 91, no. 4, 1 January 2002 (2002-01-01), pages 914 - 922, XP002502335, ISSN: 0022-3549, DOI: 10.1002/JPS.10094 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210085751A1 (en) * 2017-12-22 2021-03-25 Arecor Limted Novel composition

Also Published As

Publication number Publication date
EP3298026A1 (fr) 2018-03-28
GR1008818B (el) 2016-08-01
WO2016188625A9 (fr) 2017-04-27

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