WO2016166653A1 - Compositions pharmaceutiques liquides stables de bortézomib - Google Patents

Compositions pharmaceutiques liquides stables de bortézomib Download PDF

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Publication number
WO2016166653A1
WO2016166653A1 PCT/IB2016/052057 IB2016052057W WO2016166653A1 WO 2016166653 A1 WO2016166653 A1 WO 2016166653A1 IB 2016052057 W IB2016052057 W IB 2016052057W WO 2016166653 A1 WO2016166653 A1 WO 2016166653A1
Authority
WO
WIPO (PCT)
Prior art keywords
bortezomib
ready
formulation
use liquid
solvents
Prior art date
Application number
PCT/IB2016/052057
Other languages
English (en)
Inventor
Kocherlakota Chandrashekhar
Banda Nagaraju
Original Assignee
Leiutis Pharmaceuticals Pvt 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 Leiutis Pharmaceuticals Pvt Ltd filed Critical Leiutis Pharmaceuticals Pvt Ltd
Priority to GB1718468.0A priority Critical patent/GB2554008A/en
Priority to US15/565,617 priority patent/US20180110822A1/en
Priority to DE112016001715.4T priority patent/DE112016001715T5/de
Publication of WO2016166653A1 publication Critical patent/WO2016166653A1/fr

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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
    • A61K38/05—Dipeptides
    • 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

  • Bortezomib is a modified di-peptidyl boronic acid.
  • the chemical name for bortezomib, the monomeric boronic acid is [(lR)-3-methyl-l-[[(2S)-l-oxo-3-phenyl-2-[(pyrazinyl carbonyl)amino]propyl]amino]butyl] boronic acid.
  • 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.
  • the chemical structure of Bortezomib is shown below:
  • 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 maintaining homeostasis within cells by regulating the intracellular concentration of specific proteins. 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.
  • Bortezomib is provided commercially as a mannitol boronic ester, which in reconstituted form consists of the mannitol ester in equilibrium with its hydrolysis product, the monomeric boronic acid.
  • the drug substance exists in its cyclic anhydride form as a trimeric boroxine in solid state.
  • Bortezomib is sold as mannitol ester under the brand name Velcade ® which is supplied as a sterile lyophilized powder for intravenous infusion and available in single-dose vials containing 3.5 mg of Bortezomib.
  • the inactive ingredient is 35 mg mannitol, USP per vial.
  • Velcade ® when reconstituted forms a solution consisting of mannitol ester in equilibrium with Bortezomib. Velcade ® is reconstituted with 0.9% sodium chloride to a final concentration of 1 mg/ml of Bortezomib.
  • U.S. Patent Nos. 6,713,446 and 6,958,319 to Gupta Shanker et al. describe pharmaceutical compositions of boronic acid compounds prepared by lyophilizing an aqueous mixture comprising a boronic acid compound and a sugar that readily releases the boronic acid compound upon dissolution in aqueous media.
  • U.S Patent No. 6,617,317 to Adams Julian et al. discloses a method for reducing the rate of degradation of proteins in an animal comprising contacting cells of the animal with certain boronic ester and acid compounds. Also disclosed are novel boronic ester and acid compounds, their synthesis and uses.
  • PCT Publication WO2010/089768 to Namdeo Alok et al. discloses pharmaceutical composition comprising Bortezomib and tromethamine in lyophilized form which is stable at room temperature and upon reconstitution forms aqueous solutions that are stable for at least 12 hours.
  • propylene glycol has limited use in pediatric population. Even though propylene glycol is considered to be harmless, in high concentrations, adverse effects such as lactic acidosis and hyperosmolarity, hemolysis, renal toxicity including tubular dysfunction and acute tubular necrosis are reported. When propylene glycol is present in high doses in intravenous formulations, it increases the formulation osmolality. (EMA/CHMP/704195/2013) Hence its use in patients of diminished renal function should be monitored by determining plasmatic osmolality daily.
  • the present invention relates to ready to use glycol free liquid formulations of Bortezomib intended for parenteral administration.
  • One aspect of the invention is to provide stable ready to use liquid pharmaceutical formulation comprising Bortezomib dissolved in suitable solvent or mixture of solvents, wherein the formulation is free of glycols.
  • Another aspect of the present invention is to provide stable ready to use liquid formulation comprising Bortezomib, chelating agents, suitable solvent or mixture of solvents and other pharmaceutically acceptable excipients thereof.
  • Yet another aspect of the present invention is to provide stable ready to use liquid formulation comprising of Bortezomib, chelating agents, stabilizers, suitable solvent or mixture of solvents and other pharmaceutically acceptable excipients thereof.
  • Bossezomib includes its pharmaceutically acceptable salts, solvates and hydrates thereof.
  • glycol means class of organic chemicals characterized by having two hydroxyl (-OH) groups attached to separate carbon atoms; which may include dihydric alcohols such as ethylene glycol, propylene glycol, butylene glycol and polyalkylene glycols such as polyethylene glycol, polypropylene glycol, polybutylene glycol and the like.
  • glycol free as used herein generally means that the described composition comprises glycols less than about 10% by weight, based on the total weight of the formulation.
  • Bortezomib formulations refers to formulations that contain Bortezomib in dissolved or solubilized form and are to be intended to be used as such or upon further dilution in intravenous diluents.
  • compositions of the present invention are intended for parenteral administration.
  • the pharmaceutical formulation of the present invention is a stable ready to use liquid formulation that is free of glycols.
  • the inventors have surprisingly found that it is possible to develop stable liquid formulations of Bortezomib overcoming the disadvantages associated with prior art.
  • Chelating agents selected from the group comprising DOTA, DTPA and EDTA iii.
  • Anti-oxidants selected from the group comprising monothioglycerol, sodium metabisulfite and L-cysteine
  • v. Optionally stabilizers such as sugars and aminoacids.
  • One or more solvents such as ethanol, glycerine and water
  • v Optionally stabilizers such as mannitol, sorbitol, arginine, glycine and lysine.
  • Suitable solvents can be selected from aqueous and non-aqueous solvents such as, but are not limited to, glycerine, ethanol, n-propanol, n-butanol, isopropanol, ethyl acetate, dimethyl carbonate, acetonitrile, dichloromethane, methyl ethyl ketone, methyl isobutyl ketone, cyclohexane, dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N- Methyl-2-pyrrolidone (NMP), l,3-dimethyl-2-imidazolidinone (DMI), acetone, tetrahydrofuran (THF), dimethylformamide (DMF), propylene carbonate (PC), dimethyl isosorbide, water and mixtures thereof.
  • Preferred solvents are ethanol, glycerine and water.
  • the formulation of the present invention comprises stabilizers such as sugars and amino acids.
  • Suitable stabilizers include glucose, trehalose, sucrose, mannitol, sorbitol, arginine, glycine, proline, methionine, lysine and the like.
  • Suitable chelating agents include, but not limited to DOTA (1,4,7,10- tetraazacyclododecane-l,4,7,10-tetraacetic acid), DTPA (diethylene triaminepentaacetic acid), EDTA (Ethylenediaminetetraacetic acid), ODDA (l,4,10,13-tetraoxa-7,16- diazacyclooctadecane-7) , TTT A (1,7,13 -triaza-4, 10,16-trioxacyclooctadecane-N,N',N" - triacetate), DOTRP (tetraethyleneglycol-l,5,9-triazacyclododecane-N,N',N",- tris(methylene phosphonic acid), EGTA (ethylene glycol-bis(P-aminoethyl ether)- tetraacetic acid) and the like.
  • DOTA 1,4,7,10- t
  • compositions of the present invention also contain one or more antioxidants.
  • Suitable anti-oxidants include, but are not limited to monothioglycerol, ascorbic acid, sodium bisulfite, sodium metabisulfite, L-cysteine, thioglycolic acid, citric acid, tartaric acid, phosphoric acid, gluconic acid, thiodipropionic acid and the like. Most preferred anti-oxidant is monothioglycerol.
  • compositions of the present invention optionally contain other pharmaceutically acceptable adjuvants such as buffering agents, pH adjusting agents, preservatives, tonicity modifiers and the like.
  • the invention further relates to a process of preparing ready to use liquid formulations of Bortezomib comprising
  • liquid formulations of Bortezomib can be prepared by the following process comprising
  • step (iii) Addition of solution of step (ii) to step (i) (iv) Filtering and filling of the solution in suitable container or vials followed by stoppering and sealing of the vials.
  • Bortezomib formulation prepared according to the invention was tested for stability at various conditions such as 2-8°C, 25°C/60%RH, 30°C/65%RH and 40°C/75%RH for 2 months.
  • the stability data of the invention formulation is summarized in Table 1.
  • Table 1 Stability Profile of the formulation prepared according to example 1 (3.5mg/ml).
  • Ethanol was taken into compounding vessel and monothioglycerol and Bortezomib were added and stirred.
  • DOTA, mannitol and L-arginine were added to the compounding vessel containing water for injection and stirred to form a uniform solution.
  • Water for injection solution was transferred to ethanol solution and stirred.
  • the solution was filtered and filled into suitable containers. The vials were stored at 2°-8°C.
  • Monothioglycerol, mannitol and DOTA were added to water followed by the addition of Bortezomib (Mixture I). Arginine was dissolved in water and heated. (Mixture II). The obtained Arginine solution was added to mixture I and stirred till a clear solution was obtained. The solution was filtered and filled into suitable containers.

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

Abstract

La présente invention concerne des compositions pharmaceutiques liquides stables de bortézomib ou un sel pharmaceutiquement acceptable de celui-ci. En outre, la présente invention concerne des formulations parentérales liquides de bortézomib comprenant du bortézomib, un ou plusieurs solvants et d'autres adjuvants pharmaceutiquement acceptables de celui-ci.
PCT/IB2016/052057 2015-04-13 2016-04-12 Compositions pharmaceutiques liquides stables de bortézomib WO2016166653A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
GB1718468.0A GB2554008A (en) 2015-04-13 2016-04-12 Stable liquid pharmaceutical compositions of bortezomib
US15/565,617 US20180110822A1 (en) 2015-04-13 2016-04-12 Stable liquid pharmaceutical compositions of bortezomib
DE112016001715.4T DE112016001715T5 (de) 2015-04-13 2016-04-12 Stabile flüssige pharmazeutische Zusammensetzungen von Bortezomib

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
IN1908CH2015 2015-04-13
IN1908/CHE/2015 2015-04-13
IN201641000573 2016-01-07

Publications (1)

Publication Number Publication Date
WO2016166653A1 true WO2016166653A1 (fr) 2016-10-20

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Family Applications (1)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101807462B1 (ko) * 2017-03-09 2017-12-08 씨제이헬스케어 주식회사 보르테조밉을 포함하는 안정한 제제 및 이의 제조방법
WO2021048417A1 (fr) 2019-09-11 2021-03-18 Seald As Polythérapies comprenant du dasatinib, destinées au traitement du cholangiocarcinome
WO2021048418A1 (fr) 2019-09-11 2021-03-18 Seald As Polythérapies comprenant du bortézomib pour le traitement du cholangiocarcinome
WO2021048412A1 (fr) 2019-09-11 2021-03-18 Seald As Polythérapies comprenant du panobinostat pour le traitement du cholangiocarcinome
WO2021048419A1 (fr) 2019-09-11 2021-03-18 Seald As Polythérapies comprenant du tramétinib pour le traitement du cholangiocarcinome
WO2023220641A2 (fr) 2022-05-11 2023-11-16 Juno Therapeutics, Inc. Méthodes et utilisations associées à une thérapie par lymphocytes t et leur production
WO2023220655A1 (fr) 2022-05-11 2023-11-16 Celgene Corporation Méthodes pour surmonter la résistance aux médicaments par ré-sensibilisation de cellules cancéreuses à un traitement avec une thérapie antérieure par l'intermédiaire d'un traitement avec une thérapie par lymphocytes t
WO2024097905A1 (fr) 2022-11-02 2024-05-10 Celgene Corporation Méthodes de traitement au moyen d'une thérapie par lymphocytes t et d'une thérapie d'entretien par agent immunomodulateur

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2344165A2 (fr) * 2008-10-01 2011-07-20 Dr. Reddy's Laboratories, Ltd. Compositions pharmaceutiques comprenant des composés d acide boronique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2344165A2 (fr) * 2008-10-01 2011-07-20 Dr. Reddy's Laboratories, Ltd. Compositions pharmaceutiques comprenant des composés d acide boronique

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101807462B1 (ko) * 2017-03-09 2017-12-08 씨제이헬스케어 주식회사 보르테조밉을 포함하는 안정한 제제 및 이의 제조방법
WO2018164513A1 (fr) * 2017-03-09 2018-09-13 씨제이헬스케어 주식회사 Préparation stable contenant du bortézomib et son procédé de préparation
TWI660727B (zh) * 2017-03-09 2019-06-01 韓商Ｃｊ醫藥健康股份有限公司 包含硼替佐米（bortezomib）之穩定調配物及其製備方法
WO2021048417A1 (fr) 2019-09-11 2021-03-18 Seald As Polythérapies comprenant du dasatinib, destinées au traitement du cholangiocarcinome
WO2021048418A1 (fr) 2019-09-11 2021-03-18 Seald As Polythérapies comprenant du bortézomib pour le traitement du cholangiocarcinome
WO2021048412A1 (fr) 2019-09-11 2021-03-18 Seald As Polythérapies comprenant du panobinostat pour le traitement du cholangiocarcinome
WO2021048419A1 (fr) 2019-09-11 2021-03-18 Seald As Polythérapies comprenant du tramétinib pour le traitement du cholangiocarcinome
WO2023220641A2 (fr) 2022-05-11 2023-11-16 Juno Therapeutics, Inc. Méthodes et utilisations associées à une thérapie par lymphocytes t et leur production
WO2023220655A1 (fr) 2022-05-11 2023-11-16 Celgene Corporation Méthodes pour surmonter la résistance aux médicaments par ré-sensibilisation de cellules cancéreuses à un traitement avec une thérapie antérieure par l'intermédiaire d'un traitement avec une thérapie par lymphocytes t
WO2024097905A1 (fr) 2022-11-02 2024-05-10 Celgene Corporation Méthodes de traitement au moyen d'une thérapie par lymphocytes t et d'une thérapie d'entretien par agent immunomodulateur

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