WO2016110870A1 - Composition pharmaceutique de bortézomid - Google Patents

Composition pharmaceutique de bortézomid Download PDF

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Publication number
WO2016110870A1
WO2016110870A1 PCT/IN2016/000006 IN2016000006W WO2016110870A1 WO 2016110870 A1 WO2016110870 A1 WO 2016110870A1 IN 2016000006 W IN2016000006 W IN 2016000006W WO 2016110870 A1 WO2016110870 A1 WO 2016110870A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical formulation
stable ready
bortezomib
liquid pharmaceutical
use liquid
Prior art date
Application number
PCT/IN2016/000006
Other languages
English (en)
Inventor
Pragjibhai Gondaliya Deepak
Keshav Gurjar Mukund
Satish Mehta Samit
Pravinbhai Patel Hiren
Ishwarbhai Patel Haresh
Manubhai Patel Neha
Original Assignee
Emcure Pharmaceuticals 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 Emcure Pharmaceuticals Limited filed Critical Emcure Pharmaceuticals Limited
Publication of WO2016110870A1 publication Critical patent/WO2016110870A1/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
    • A61K31/69—Boron compounds
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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

  • the present invention relates to a stable ready-to-use injectable pharmaceutical formulation of bortezomib or pharmaceutically acceptable salts thereof. Methods of preparing such formulations are also provided.
  • Bortezomib [N-(2-pyrazine) carbonyl-L-phenylalanine-L-leucine boronic acid] is an antineoplastic agent.
  • the solubility of bortezomib, as the monomeric boronic acid, in water is 3.3 to 3.8 mg/mL over a pH range of 2 to 6.5.
  • Bortezomib has the following chemical structure.
  • VELCADE 3.5 mg sterile lyophilized powder for intravenous infusion in single-dose vials.
  • Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells.
  • the 26S proteasome is a large protein complex that degrades ubiquitinated proteins.
  • the ubiquitin-proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis, which can affect multiple signaling cascades within the cell. This disruption of normal homeostatic mechanisms can lead to cell death.
  • alkylboronic acids undergo a spontaneous 1,3- rearrangement to give the homologous amines, owing to the instability of free a- amino groups. These compounds yield boric acids and alcohols by degradation and undergo oxidative reactions that easily destroy the C— B bond. These alkylboronic acid compounds readily form boroxines (anhydrides) under dehydrating conditions. Both, alkylboronic acid and their boroxines are often air- sensitive. Peroxides or molecular oxygen and its radicals, light, metal ions, and alkaline conditions that normally facilitate oxidation found to be unfavorable to the stability of bortezomib or any other alkyl boronic acid derivative.
  • US5780454 discloses bortezomib and its pharmaceutically acceptable salts or boronate ester thereof.
  • US6713446 and US6958319 disclose novel boronate ester compounds. These patents also disclose stable lyophilized compositions comprising boric acid compound and a compound having at least two hydroxyl groups that readily release the boronic acid compound upon dissolutions in aqueous media. However, such reconstituted aqueous solution is stable only for 43 hours when stored at ambient temperature (23°C). Further, VELCADE® pack insert discloses that such reconstituted aqueous solution should be administered within 8 hours of preparation.
  • WO2010039762 discloses ready-to-use formulations of bortezomib with a variety of solvents such as WFI, Propylene glycol monocaprylate, dimethylsulfoxide. It also discloses ready-to-use formulation comprising amino acid, vitamin, carboxylic acid, sodium chloride or EDTA in WFI.
  • IN3324/Del/2012 discloses stable parenteral composition comprising bortezomib with stabilizing agents selected from the group of water soluble polymers and amino acids.
  • WO2010089768 discloses solution of bortezomib with tromethamine and bulking agent in water; wherein the solution has pH from 6.6 to 7.2.
  • the present specification relates to a stable ready-to-use injectable pharmaceutical formulation of bortezomib or pharmaceutically acceptable salts thereof.
  • the present specification relates to a stable ready-to-use injectable pharmaceutical formulation
  • a stable ready-to-use injectable pharmaceutical formulation comprising bortezomib or pharmaceutically acceptable salts thereof, a substantially non-aqueous solvent system comprising propylene glycol as a predominant component and optionally a buffer.
  • the present specification relates to a stable ready-to-use injectable pharmaceutical formulation of bortezomib or pharmaceutically acceptable salts thereof.
  • the present specification relates to a stable ready-to-use injectable pharmaceutical formulation comprising bortezomib or pharmaceutically acceptable salts thereof, a substantially non-aqueous solvent system comprising propylene glycol as a predominant component and optionally a buffer.
  • the suitable non-aqueous solvent system comprises non-aqueous solvents selected from the group comprising propylene glycol, one or more short chain alcohols (C1-C6) e.g. ethanol, dimethyl acetamide, N-methyl pyrrolidone, dimethyl sulphoxide, glycerol and mixtures thereof.
  • the amount of non-aqueous solvents is at least 60 %w/v, at least 75 %w/v, at least 85 %w/v, at least 95 %w/v, e.g. 90%w/v.
  • the formulations may further comprise water in an amount of equal or less than 25 %w/v, equal or less than 20 %w/v, equal or less than 10 %w/v, equal or less than 5 %w/v, equal or less than 2 %w/v, e.g. 10%w/v. ⁇ '
  • the buffer if used in the formulation of present invention is selected from the group comprising of phosphate buffer, benzoate buffer, citrate buffer, tartrate buffer, lactate buffer, succinate buffer, maleate buffer, bicarbonate buffer, TRIS buffer, glycine buffer, histidine buffer and the like.
  • the formulations of present invention may additionally comprise pH adjusting agents e.g. acids, bases or mixtures thereof.
  • acids include hydrochloric acid, sulfuric acid, and the like.
  • bases include sodium hydroxide, potassium hydroxide, and the like.
  • the amount of pH adjusting agents and optional buffer employed in the formulations of the present invention is suitable to adjust the pH of the formulation to above 5, e.g. 6, e.g. 6.5, e.g. 7, e.g. 7.5, e.g. 8, e.g. 8.5, e.g. 9.
  • the pharmaceutical formulations of the present specification may be prepared by suitable conventional process. For example, dissolving bortezomib in substantially non-aqueous solvent either alone or in combination water, and adjusting the pH of the solution above 5 with buffers or pH adjusting agents. The formulation is then filtered through sterile grade filter. Filtered solution then filled in final package which is clear glass vials with 20mm bromobutyl rubber stoppers. Entire manufacturing process is carried out under continuous nitrogen purging and under sodium vapor lamp.
  • the following experiments are provided to exemplarily illustrate various aspects of the inventive subject matter presented herein. However, it should be apparent to those skilled in the art that many more modifications besides those already described are possible without departing from the inventive concepts herein.
  • test formulations of the present invention were prepared by dissolving bortezorhib in substantially non-aqueous solvent either alone or in combination water, and adjusting the pH of the solution above 5 with buffers or pH adjusting agents. The formulation is then filtered through sterile grade filter. Filtered solution then filled in final package which is clear glass vials with 20mm bromobutyl rubber stoppers. Entire manufacturing process is carried out under continuous nitrogen purging and under sodiuni vapor lamp. (Examples la, lb, Stability data is

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une formulation pharmaceutique injectable, stable et prête à l'emploi, de bortézomib ou de sels pharmaceutiquement acceptables de celui-ci. La présente invention concerne également des procédés de préparation de telles formulations.
PCT/IN2016/000006 2015-01-07 2016-01-05 Composition pharmaceutique de bortézomid WO2016110870A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN58/MUM/2015 2015-01-07
IN58MU2015 2015-01-07

Publications (1)

Publication Number Publication Date
WO2016110870A1 true WO2016110870A1 (fr) 2016-07-14

Family

ID=55795017

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2016/000006 WO2016110870A1 (fr) 2015-01-07 2016-01-05 Composition pharmaceutique de bortézomid

Country Status (1)

Country Link
WO (1) WO2016110870A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4134083A1 (fr) 2021-08-12 2023-02-15 Extrovis AG Compositions pharmaceutiques de bortézomib

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5780454A (en) 1994-10-28 1998-07-14 Proscript, Inc. Boronic ester and acid compounds
US6713446B2 (en) 2001-01-25 2004-03-30 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Formulation of boronic acid compounds
WO2010039762A2 (fr) 2008-10-01 2010-04-08 Dr. Reddy's Laboratories Ltd. Compositions pharmaceutiques comprenant des composés d’acide boronique
WO2010089768A2 (fr) 2009-01-09 2010-08-12 Sun Pharma Advanced Research Company Limited Composition pharmaceutique
US20110230441A1 (en) 2010-03-18 2011-09-22 Innopharma, Llc Stable bortezomib formulations
US20120172808A1 (en) * 2010-03-18 2012-07-05 Innopharma, Llc Stable Bortezomib Formulations
US20140073583A1 (en) * 2012-09-11 2014-03-13 Innopharma, Inc. Stable compositions of peptide epoxy ketones

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5780454A (en) 1994-10-28 1998-07-14 Proscript, Inc. Boronic ester and acid compounds
US6713446B2 (en) 2001-01-25 2004-03-30 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Formulation of boronic acid compounds
US6958319B2 (en) 2001-01-25 2005-10-25 The United States Of America As Represented By The Department Of Health And Human Services Formulation of boronic acid compounds
WO2010039762A2 (fr) 2008-10-01 2010-04-08 Dr. Reddy's Laboratories Ltd. Compositions pharmaceutiques comprenant des composés d’acide boronique
WO2010089768A2 (fr) 2009-01-09 2010-08-12 Sun Pharma Advanced Research Company Limited Composition pharmaceutique
US20110230441A1 (en) 2010-03-18 2011-09-22 Innopharma, Llc Stable bortezomib formulations
WO2011116286A2 (fr) * 2010-03-18 2011-09-22 Innopharma, Llc Formulations stables à base de bortézomib
US20120172808A1 (en) * 2010-03-18 2012-07-05 Innopharma, Llc Stable Bortezomib Formulations
US8263578B2 (en) 2010-03-18 2012-09-11 Innopharma, Inc. Stable bortezomib formulations
US20120322763A1 (en) 2010-03-18 2012-12-20 Innopharma, Inc. Stable Bortezomib Formulations
US20120322762A1 (en) 2010-03-18 2012-12-20 Innopharma, Inc. Stable Bortezomib Formulations
US20140073583A1 (en) * 2012-09-11 2014-03-13 Innopharma, Inc. Stable compositions of peptide epoxy ketones

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4134083A1 (fr) 2021-08-12 2023-02-15 Extrovis AG Compositions pharmaceutiques de bortézomib

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