WO2013102920A1 - Formulation lyophilisée stable de bendamustine - Google Patents

Formulation lyophilisée stable de bendamustine Download PDF

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Publication number
WO2013102920A1
WO2013102920A1 PCT/IN2012/000744 IN2012000744W WO2013102920A1 WO 2013102920 A1 WO2013102920 A1 WO 2013102920A1 IN 2012000744 W IN2012000744 W IN 2012000744W WO 2013102920 A1 WO2013102920 A1 WO 2013102920A1
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WO
WIPO (PCT)
Prior art keywords
bendamustine
lyophilized
solution
composition
powder
Prior art date
Application number
PCT/IN2012/000744
Other languages
English (en)
Inventor
Rajput HARSH
Mehta SANDIP
Patel PANKAL
Patel Bhavesh
Sehgal Ashish
Kumar Mandal Jayanta
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 WO2013102920A1 publication Critical patent/WO2013102920A1/fr

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Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • 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

Definitions

  • This invention relates to a stable lyophilized Bendamustine composition having better impurity profile and process for its preparation.
  • Bendamustine chemically known as 4-[5-[Bis(2-chloroethyl)amino]- l - methylbenziniidazol-2-yl]butanoic acid is a nitrogen mustard used in the treatment of chronic lymphocytic leukemia and lymphomas. It belongs to the family of drugs called alkylating agents.
  • Bendamustine is marketed under the trade names Ribomustin® and Treanda®. Bendamustine degrade in aqueous solutions (like other nitrogen mustards) and hence it is supplied as a lyophilized product.
  • the current lyophilized formulation of Bendamustine contains Bendamustine hydrochloride and mannitol in a sterile lyophilized form as a white powder for intravenous use following reconstitution.
  • the finished lyophilizate is unstable when exposed to light. Therefore, the product is stored in brown or amber-colored glass bottles.
  • the current lyophilized formulation of Bendamustine contains degradation products that may occur during manufacturing of the drug substance and/or during the lyophilization process to make the finished drug product.
  • Various impurities are found in the finished formulation like dimmer form (Impurity B) and other unknown impurities such as impurity A, impurity C etc.
  • German Patent DE 80967 discloses an injectable preparation of .gamma.-[ l -methyl- 5-bis-(.beta.-chloroethyl)-amino-benzimaidazolyl-(2)- ]-butric acid hydrochloride.
  • German Patent DE 159289 discloses an injectable solution of Bendamustine in anhydrous monovalent or polyvalent alcohol (polyol).
  • US200601 59713 discloses methods of producing lyophilized Bendamustine having lower impurity profile.
  • the main objective of the present invention is to obtain stable lyophilized Bendamustine composition having better impurity profile.
  • Another object of the invention is to develop a process for the preparation of stable lyophilized Bendamustine composition having better impurity profile.
  • Another object of the present invention is to develop a process for the preparation of stable lyophilized Bendamustine composition by controlled lyophilization.
  • Another object of the present invention is to develop a process for the preparation of stable lyophilized Bendamustine composition having better impurity profile by controlling moisture content of the end product at optimum level in order to reduce impurity.
  • Another object of the present invention is to develop a process for the preparation of stable lyophilized Bendamustine comprising annealing step followed by controlled lyophilization to obtain porous uniform cake which is easy to reconstitute at the time of administration.
  • Invention relates to stable lyophi iized ' Bendamustine composition having better impurity profile. Further invention relates to stable lyophiiized Bendamustine composition having optimum moisture content and better impurity profile.
  • Further invention relates to stable lyophiiized Bendamustine composition having better impurity profile and easy to reconstitute.
  • Further invention relates to process for preparing stable lyophiiized Bendamustine composition having optimum moisture content and better impurity profile.
  • Further invention relates to process for preparing stable lyophiiized Bendamustine composition which is easy to reconstitute by performing annealing step prior to lyophilization.
  • Further invention relates to process for preparing stable lyophiiized Bendamustine composition having optimum moisture content and better impurity profile and easy to reconstitute at the time of administration.
  • stable pharmaceutical composition is meant any pharmaceutical composition having sufficient stability to have utility as a pharmaceutical product.
  • a stable pharmaceutical composition has sufficient stability to allow storage at a convenient temperature, preferably between -20 °C and 40 °C, more preferably about 2 °C to about 8 °C, for a reasonable period of time, e.g., the shelf-life of the product which can be as short as one month but is typically six months or longer, more preferably one year or two year.
  • stable pharmaceutical composition includes reference to pharmaceutical compositions with specific ranges of impurities as described herein.
  • a stable pharmaceutical composition is one which has minimal degradation of the active ingredient, e.g., it retains at least about 80% of un-degraded active, preferably at least about 90%, and more preferably at least about 95%, after storage at 2-30 °C for a 1 to 3 year period of time.
  • Controlled lyophilization means controlling different parameters of lyophilization like lyophilization cycle time/duration, temperature, vacuum, etc.
  • Lyophilization is the technique used for the drug product may be susceptible to physical and chemical degrade in solution phase. Lyophilization also known as freeze-drying technique is a technique used to remove water from a solution to leave a dry 'cake' as an end product. In lyophilization or freeze-drying process water is removed from a product after it is frozen and placed under a vacuum, allowing the ice to change directly from a solid to a vapor, without passing through a liquid phase.
  • the process consists of three separate, unique, and interdependent processes; a freezing phase, a primary drying phase (sublimation), and a secondary drying phase (desorption).
  • “Annealing” is generally a thermal treatment process wherein product temperature is cycled, for example freezing the drug solution to -40 °C and holding at this temperature for specific time period followed by raising temperature up to - 10 °C and holding at this temperature for specific time period and repeating the same steps in cyclic manner to get desired results.
  • Bendamustine refers to Bendamustine or its pharmaceutically acceptable salts thereof, preferably Bendamustine hydrochloride salt.
  • Bendamustine degrade in aqueous solutions (like other nitrogen mustards) and hence it is supplied as a lyophilized product to avoid exposure to water.
  • the inventors of the present invention have surprisingly found that reducing moisture below certain level the stability of the lyophilized product found to be less as amount of impurity B increases upon storage for 2-3 months. So, lyophil ized Bendamustine product having optimum moisture level shows better stability upon storage for 2-3 months.
  • Such optimum moisture level in lyophilized product found to be 1 - 1 0 % preferably 1 -5% and more preferably 1 -4%.
  • the moisture content of the final formulation can be controlled in many ways. Such as controlling different parameters of the lyophilization cycle like process time, vacuum, etc. Further person skilled in the art can also achieve the desired moisture content into final formulation by humidifying the lyophilizate by exposing it to water vapor. Further, inventors of the present invention have also found that performing annealing during lyophilization gives more uniform porous cake as end product which takes less time to reconstitute as compare the product prepared without performing annealing step during lyophilization.
  • the lyophilized formulations of the present invention may be reconstituted with water, preferably Sterile Water for Injection, or other sterile fluid such as co- solvents, with shaking for appropriate time duration to obtain appropriate solution of Bendamustine for administration, as through parenteral injection following further dilution into an appropriate intravenous admixture container, for example, normal saline.
  • water preferably Sterile Water for Injection, or other sterile fluid such as co- solvents
  • Example-1
  • the lyophilized compositions of Bendamustine were prepared using procedure explained in Example- 1 with controlling different parameters of the process to obtain final product having different initial moisture contents eg. 0.2% and around 3.0% and kept them for stability testing.
  • the impurity profile of these lyophilized compositions obtained at different time interval and temperature conditions are disclosed below in respective Tables.
  • step-6 The solution of the step-6 was then lyophilized in suitable container under controlled conditions.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition de Bendamustine lyophilisée stable présentant un meilleur profil d'impuretés. La présente invention concerne en outre un procédé de préparation d'une telle composition de Bendamustine lyophilisée stable facile à reconstituer.
PCT/IN2012/000744 2011-11-18 2012-11-12 Formulation lyophilisée stable de bendamustine WO2013102920A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN3253MU2011 2011-11-18
IN3253/MUM/2011 2011-11-18

Publications (1)

Publication Number Publication Date
WO2013102920A1 true WO2013102920A1 (fr) 2013-07-11

Family

ID=48048105

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2012/000744 WO2013102920A1 (fr) 2011-11-18 2012-11-12 Formulation lyophilisée stable de bendamustine

Country Status (1)

Country Link
WO (1) WO2013102920A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015138199A1 (fr) * 2014-03-13 2015-09-17 Voudouris Vasilios Dispersions solides de bendamustine et perfusion continue
US9849115B2 (en) 2013-08-27 2017-12-26 Vasilios Voudouris Bendamustine pharmaceutical compositions
EA037673B1 (ru) * 2018-07-04 2021-04-29 Тютор С.А.С.И.Ф.И.А. Способ получения фармацевтической композиции, содержащей бендамустин, фармацевтическая композиция бендамустина

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DD159289A1 (de) 1981-06-01 1983-03-02 Uwe Olthoff Verfahren zur herstellung stabiler injektionsloesungen von n-lostverbindungen
US20060159713A1 (en) 2005-01-14 2006-07-20 Cephalon, Inc. Bendamustine pharmaceutical compositions
WO2011103150A2 (fr) * 2010-02-18 2011-08-25 Cephalon, Inc. Préparations lyophilisées de bendamustine
WO2012103226A2 (fr) * 2011-01-25 2012-08-02 Dr. Reddy's Laboratories Ltd. Formulations de bendamustine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DD159289A1 (de) 1981-06-01 1983-03-02 Uwe Olthoff Verfahren zur herstellung stabiler injektionsloesungen von n-lostverbindungen
US20060159713A1 (en) 2005-01-14 2006-07-20 Cephalon, Inc. Bendamustine pharmaceutical compositions
WO2011103150A2 (fr) * 2010-02-18 2011-08-25 Cephalon, Inc. Préparations lyophilisées de bendamustine
WO2012103226A2 (fr) * 2011-01-25 2012-08-02 Dr. Reddy's Laboratories Ltd. Formulations de bendamustine

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9849115B2 (en) 2013-08-27 2017-12-26 Vasilios Voudouris Bendamustine pharmaceutical compositions
US10786486B2 (en) 2013-08-27 2020-09-29 Vasilios Voudouris Bendamustine pharmaceutical compositions
US11701344B2 (en) 2013-08-27 2023-07-18 Vasilios Voudouris Bendamustine pharmaceutical compositions
WO2015138199A1 (fr) * 2014-03-13 2015-09-17 Voudouris Vasilios Dispersions solides de bendamustine et perfusion continue
US9320730B2 (en) 2014-03-13 2016-04-26 Vasilios Voudouris Bendamustine solid dispersions and continuous infusion
CN106102722A (zh) * 2014-03-13 2016-11-09 V·沃道里斯 苯达莫司汀固体分散体和连续输液
US9907752B2 (en) 2014-03-13 2018-03-06 Vasilios Voudouris Bendamustine solid dispersions and continuous infusion
AU2015229842B2 (en) * 2014-03-13 2020-06-25 Vasilios VOUDOURIS Bendamustine solid dispersions and continuous infusion
EA037673B1 (ru) * 2018-07-04 2021-04-29 Тютор С.А.С.И.Ф.И.А. Способ получения фармацевтической композиции, содержащей бендамустин, фармацевтическая композиция бендамустина

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