WO2009118754A2 - Procédé pour préparer une composition lyophilisée stable - Google Patents

Procédé pour préparer une composition lyophilisée stable Download PDF

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Publication number
WO2009118754A2
WO2009118754A2 PCT/IN2009/000171 IN2009000171W WO2009118754A2 WO 2009118754 A2 WO2009118754 A2 WO 2009118754A2 IN 2009000171 W IN2009000171 W IN 2009000171W WO 2009118754 A2 WO2009118754 A2 WO 2009118754A2
Authority
WO
WIPO (PCT)
Prior art keywords
solution
carbon dioxide
doxorubicin
sparge
lyophilized composition
Prior art date
Application number
PCT/IN2009/000171
Other languages
English (en)
Other versions
WO2009118754A3 (fr
Inventor
Ashish Sehgal
Bhavesh Vallabhbhai Patel
Aditya Patel
Jayanta Kumar Mandal
Original Assignee
Astron Research Limited
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 Astron Research Limited filed Critical Astron Research Limited
Publication of WO2009118754A2 publication Critical patent/WO2009118754A2/fr
Publication of WO2009118754A3 publication Critical patent/WO2009118754A3/fr

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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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin

Definitions

  • This invention relates to a process to obtain a stable lyophilized composition by lowering the pH during solution phase before lyophilization without addition of an acid or buffer during preparation of composition.
  • Anthracycline glycoside is an antineoplastic antibiotic, which is obtained from the fermentation of streptomyces paucities.
  • Anthracycline glycosides are DNA interacting drugs that are widely used in chemotherapy for treatment of various types of cancer including breast, ovarian, bladder and lung cancer as well as non-Hodgkin's lymphoma, Hodgkin's disease and sarcoma. These drugs bind up the DNA of the cancer cells and stop the growth and multiplication of the cells.
  • Anthracycline glycosides bind to nucleic acids, presumably by specific intercalation of the planar anthracycline nucleus with the DNA double helix.
  • the anthracycline ring is lipophilic, but the saturated end of the ring system contains abundant hydroxyl groups adjacent to the amino sugar, producing a hydrophilic center.
  • the molecule is amphoteric, containing acidic functions in the ring phenolic groups and a basic function in the sugar amino group. It binds to cell membranes as well as plasma proteins.
  • Anthracycline glycosides have been used successfully to produce regression in disseminated neoplastic conditions such as acute lymphoblastic leukemia, acute myeloblasts leukemia, Wilms' tumor, neuroblastoma, soft tissue and bone sarcomas, breast carcinoma, ovarian carcinoma, transitional cell bladder carcinoma, thyroid carcinoma, gastric carcinoma, Hodgkin's disease, malignant lymphoma and bronchogenic carcinoma in which the small cell histologic type is the most responsive compared to other cell types.
  • WO 2006122309 disclose stable iyophilized composition of anthracycline glycoside salt and process of preparations where in one of the process is for inhibition of the generation of aglycon and bis anhydro impurities and thereby stability of the composition is achieved by using a buffer and appropriate solvent and in another process the same is achieved by using resin and a solvent.
  • US 20070004653 disclose stable lyophilized composition of anthracycline glycoside salt, wherein anthracycline glycoside is combined with a solvent between 50-70° C followed by an addition of an acid to adjust pH between 3.2 to 3.8.
  • the inert gas is used to inhibit the generation of aglycon and bis anhydro impurities in the composition.
  • the inventive step in this patent specifically relates to adjustment of pH of the solution with physiologically acceptable use of inert gas wherein the said composition is for ready to use.
  • Anthracycline glycosides are their tendency to get hydrolyzed in aqueous solution when pH reaches above 4. This critical characteristic originate during the preparation of lyophilized composition when pH of the solution reaches above 4, being responsible for generation of hydrolysis impurities and thereby inhibit long-term stability of composition as impurities resides in the lyophilized cake. Using either organic or inorganic acid or buffer that maintain the pH of the solution less than 4 solves this critical characteristic.
  • Anthracycline glycosides above and hereinafter refers to as "Anthracycline glycosides or its pharmaceutically acceptable salts".
  • the preferred anthracycline glycosides of the present invention are doxorubicin or its pharmaceutically acceptable salts.
  • the present invention is a step forward in the direction to provide a stable, lyophilized pharmaceutical composition Object of the Invention
  • the main object of the present invention is to maintain an acidic pH of solution during the preparation of composition without addition of acid or buffer and hence preclude the generation of undesired impurities.
  • Another object of the invention is to prevent hydrolysis of ingredient(s) in aqueous solution to inhibit generation of impurities during preparation.
  • Another object of the invention is to obtain lyophilized cake having the pH range 4.5-6.5 that is acceptable range under pharmacopeias specifications.
  • Another object of the invention is to provide a process that maintain the pH of the anthracycline glycoside solution less than 4 to produce stable, readily soluble, lyophilized composition of anthracycline glycosides preferably doxorubicin.
  • One more object of the invention is to inhibit the development of hydrolysis impurities by maintaining the pH less than 4 during the process of preparation of lyophilized formulation doxorubicin.
  • This invention relates to process to obtain stable lyophilized composition of an active ingredient showing stability at acidic pH by maintaining pH of solution wherein the process does not include addition of acid or buffer during the preparation. This process is useful to obtain stable lyophilized composition without addition of acid or buffer.
  • the present invention relates to a process for preparing stable, readily soluble, lyophilized composition of anthracycline glycosides in which pH of solution containing anthracycline glycoside and co-solublizing agent is maintained less than 4 by continuous sparge of carbon dioxide till the lyophilisation process commences.
  • This process of the present invention prevents hydrolysis of ingredient(s) by keeping the pH of the composition below 4 and thereby generation of impurities in the composition / solution wherein the process includes continuous sparging of carbon dioxide.
  • the term “sparging” refers to a technique, which involves bubbling a chemically inert gas through a liquid with connotation to remove dissolved gases (e.g. oxygen) from the liquid and thereby prevent the oxidation or hydrolysis of active ingredient in a composition.
  • dissolved gases e.g. oxygen
  • the term “sparging” involves bubbling of a carbon dioxide gas through a solution not only remove dissolved gases but also to maintain an acidic pH.
  • This invention relates to process of maintaining acidic pH of solution for stabilizing the active ingredient without addition of an acid or buffer. Therefore, to maintain pH of the solution and by that means inhibit the generation of impurities, this process includes continuous sparge of carbon dioxide till lyophilisation commences. Further sparged carbon dioxide gas is removed during lyophilization by applying vacuum and hence lyophilized cake attains pH between 4.5-6.5 that is acceptable as per pharmacopeial specification.
  • An active ingredient showing pH dependency are selected from the group comprising of anthracycline glycoside derivatives and the like.
  • the present invention provides a stable, readily soluble, lvophilized composition of anthracycline glycosides by a process involving sparge of carbon dioxide wherein carbon dioxide is sparged till lyophilization process commences.
  • the present invention describes the process related to an improvement in stability of lyophilized composition including dissolution of co-solublizer and one or more inert excipients in water followed by sparge of carbon dioxide to maintain pH less than 4.
  • Now anthracycline glycoside is dissolved in the solution with continuous stirring during which sparging of carbon dioxide also continues until clear solution is obtained.
  • Now carbon dioxide sparged water is added to the solution to achieve the desired volume wherein pH of the solution is maintained less than 4.
  • the resulting solution is clarified and filtered with the help of carbon dioxide gas and distributed in sterile vials with partial stoppering.
  • Partially stoppered vials are placed in lyophilizer wherein lyophilization is carried out in a conventional way.
  • the conventional way of lyophilisation includes freezing of the solution at -40 to -50° C followed with primary drying below eutectic point and secondary drying at final temperature of 35-40° C and the vials are sealed under sterile conditions by conventional procedure.
  • the content of dry unopened vials are completely stable for at least 6 months at 40° C.
  • the reconstitution of lyophilized composition is made by conventional way. In one of the method physiological saline is used wherein volume of saline may vary and it depends on the kind and amount of active ingredient present in lyophilized composition.
  • the main components of lyophilized composition prepared by the above process are anthracycline glycoside as active drug substance, pharmaceutically acceptable co- solublizers to enhance solubility during reconstitution and optionally inert excipient(s).
  • the said anthracycline glycoside can be doxorubicin, epirubicin, esorubicin, daunorubicin, idarubicin or its pharmaceutically acceptable salts, wherein the active drug substance is in the range from 1 to 100 mg/mL.
  • the co-solublising agent is in the range of 0.1-10 mg/ml.
  • the co-solubilizing agent used to enhance solubility during reconstitution of lyophilized composition is selected from the group comprising of p-hydroxybenzoic acid and the methyl ester thereof, p-amino benzoic acid and the methyl ester thereof-, o-hydroxy-benzoic acid and the methyl ester thereof 3-methyl-4-chlorophenol and the 3,5-dimethyl-4-chlorophenol, or a combination of two or more of said compounds.
  • a particularly preferred co-solubiliser in the present invention is p-hydroxy-benzoic acid methyl ester.
  • the inert excipient is in the range of 5 - 50 mg/ml, can be selected from but not limited to lactose, mannitol, sorbitol, or maltose, preferably lactose monohydrate in suitable amount.
  • step 3 Mix the solution of step 1 & step 2 and add Doxorubicin hydrochloride in resulting solution with constant stirring.
  • Example 1 8. Lyophilize the solution in conventional way
  • the present invention can be illustrated by but not limited to following example(s).
  • Example 1
  • step 3 Mix the solution of step 1 & step 2 and add Doxorubicin hydrochloride in resulting solution with constant stirring.
  • Tablel Stability study data for carbon dioxide sparged formulation according to example 1.
  • Example 2 is carried out following the process according to Example 1, omitting the steps wherein sparging with carbon dioxide is performed.
  • Table2 Stability study data for carbon dioxide sparged formulation according to example 2.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne un procédé pour obtenir une composition lyophilisée stable en abaissant le pH pendant la phase en solution avant lyophilisation sans ajout d’un acide ou d’un tampon pendant la préparation de composition.
PCT/IN2009/000171 2008-03-28 2009-03-13 Procédé pour préparer une composition lyophilisée stable WO2009118754A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN667MU2008 2008-03-28
IN667/MUM/2008 2008-03-28

Publications (2)

Publication Number Publication Date
WO2009118754A2 true WO2009118754A2 (fr) 2009-10-01
WO2009118754A3 WO2009118754A3 (fr) 2009-12-10

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017122114A1 (fr) * 2016-01-12 2017-07-20 Intron Biotechnology, Inc. Formulations lyophilisées de protéine antibactérienne
US9907910B2 (en) 2013-03-15 2018-03-06 Windgap Medical, Inc. Portable drug mixing and delivery device and associated methods
US9907911B2 (en) 2014-08-18 2018-03-06 Windgap Medical, Inc. Portable drug mixing and delivery device and associated methods
US10195361B2 (en) 2013-03-15 2019-02-05 Windgap Medical, Inc. Portable drug mixing and delivery system and method
US10220147B2 (en) 2015-08-13 2019-03-05 Windgap Medical, Inc. Mixing and injection device with sterility features
US10350364B2 (en) 2009-11-11 2019-07-16 Windgap Medical, Inc. Portable Drug Mixing and Delivery Device and Associated Methods
US10391262B2 (en) 2014-03-18 2019-08-27 Windgap Medical, Inc. Removable actuating cap for use with an auto-injector assembly
US10569017B2 (en) 2013-03-15 2020-02-25 Windgap Medical, Inc. Portable drug mixing and delivery device and associated methods
US11116903B2 (en) 2014-08-18 2021-09-14 Windgap Medical, Inc Compression seal for use with a liquid component storage vial of an auto-injector
CN115192721A (zh) * 2021-12-09 2022-10-18 苏州百迈生物医药有限公司 一种膀胱灌注药物复方制剂及其制备方法和应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2034707A (en) * 1978-10-25 1980-06-11 Erba Farmitalia Anthracycline glycosides
WO1993013804A1 (fr) * 1992-01-07 1993-07-22 Farmitalia Carlo Erba Srl Compositions pharmaceutiques contenant des glycosides d'anthracycline lies a des derives polymeres, et leur procede de preparation
WO2006122309A2 (fr) * 2005-05-11 2006-11-16 Sicor, Inc. Glycosides d'anthracycline lyophylises stables
US20070116729A1 (en) * 2005-11-18 2007-05-24 Palepu Nageswara R Lyophilization process and products obtained thereby

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2034707A (en) * 1978-10-25 1980-06-11 Erba Farmitalia Anthracycline glycosides
WO1993013804A1 (fr) * 1992-01-07 1993-07-22 Farmitalia Carlo Erba Srl Compositions pharmaceutiques contenant des glycosides d'anthracycline lies a des derives polymeres, et leur procede de preparation
WO2006122309A2 (fr) * 2005-05-11 2006-11-16 Sicor, Inc. Glycosides d'anthracycline lyophylises stables
US20070116729A1 (en) * 2005-11-18 2007-05-24 Palepu Nageswara R Lyophilization process and products obtained thereby

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PERLOVICH G L ET AL: "Thermodynamics of solubility, sublimation and solvation processes of parabens" EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, ELSEVIER, AMSTERDAM, NL, vol. 24, no. 1, 1 January 2005 (2005-01-01), pages 25-33, XP025316207 ISSN: 0928-0987 [retrieved on 2005-01-01] *

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10350364B2 (en) 2009-11-11 2019-07-16 Windgap Medical, Inc. Portable Drug Mixing and Delivery Device and Associated Methods
US10195361B2 (en) 2013-03-15 2019-02-05 Windgap Medical, Inc. Portable drug mixing and delivery system and method
US9907910B2 (en) 2013-03-15 2018-03-06 Windgap Medical, Inc. Portable drug mixing and delivery device and associated methods
US10569017B2 (en) 2013-03-15 2020-02-25 Windgap Medical, Inc. Portable drug mixing and delivery device and associated methods
US10391262B2 (en) 2014-03-18 2019-08-27 Windgap Medical, Inc. Removable actuating cap for use with an auto-injector assembly
US10300199B2 (en) 2014-08-18 2019-05-28 Windgap Medical, Inc. Portable drug mixing and delivery device and associated methods
US10537680B2 (en) 2014-08-18 2020-01-21 Windgap Medical, Inc. Portable drug mixing and delivery device and associated methods
US10300198B2 (en) 2014-08-18 2019-05-28 Windgap Medical, Inc. Portable drug mixing and delivery device and associated methods
US11116903B2 (en) 2014-08-18 2021-09-14 Windgap Medical, Inc Compression seal for use with a liquid component storage vial of an auto-injector
US9950115B2 (en) 2014-08-18 2018-04-24 Windgap Medical, Inc. Portable drug mixing and delivery device and associated methods
US9925335B2 (en) 2014-08-18 2018-03-27 Windgap Medical, Inc Portable drug mixing and delivery device and associated methods
US11007320B2 (en) 2014-08-18 2021-05-18 Windgap Medical, Inc. Portable drug mixing and delivery device and associated methods
US9907911B2 (en) 2014-08-18 2018-03-06 Windgap Medical, Inc. Portable drug mixing and delivery device and associated methods
US10220147B2 (en) 2015-08-13 2019-03-05 Windgap Medical, Inc. Mixing and injection device with sterility features
RU2734308C2 (ru) * 2016-01-12 2020-10-15 Интрон Байотекнолоджи, Инк. Лиофилизированные композиции антибактериального белка
RU2708393C1 (ru) * 2016-01-12 2019-12-06 Интрон Байотекнолоджи, Инк. Лиофилизированные композиции антибактериального белка
WO2017122114A1 (fr) * 2016-01-12 2017-07-20 Intron Biotechnology, Inc. Formulations lyophilisées de protéine antibactérienne
CN115192721A (zh) * 2021-12-09 2022-10-18 苏州百迈生物医药有限公司 一种膀胱灌注药物复方制剂及其制备方法和应用
CN115192721B (zh) * 2021-12-09 2023-11-07 苏州百迈生物医药有限公司 一种膀胱灌注药物复方制剂及其制备方法和应用

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