WO2014102755A1 - Formulations de bortézomib - Google Patents

Formulations de bortézomib Download PDF

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Publication number
WO2014102755A1
WO2014102755A1 PCT/IB2013/061430 IB2013061430W WO2014102755A1 WO 2014102755 A1 WO2014102755 A1 WO 2014102755A1 IB 2013061430 W IB2013061430 W IB 2013061430W WO 2014102755 A1 WO2014102755 A1 WO 2014102755A1
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WO
WIPO (PCT)
Prior art keywords
bortezomib
solution
pharmaceutical composition
lactic acid
lyophilized
Prior art date
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PCT/IB2013/061430
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English (en)
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WO2014102755A4 (fr
Inventor
Pradeep SHIVAKUMAR
Shivamurthy RAMAKRISHNAIAH
Badrinath ALAMPALLI
Akshaykant CHATURVEDI
Original Assignee
Shilpa Medicare 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.)
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Publication date
Application filed by Shilpa Medicare Limited filed Critical Shilpa Medicare Limited
Priority claimed from IN5769CH2013 external-priority patent/IN2013CH05769A/en
Publication of WO2014102755A1 publication Critical patent/WO2014102755A1/fr
Publication of WO2014102755A4 publication Critical patent/WO2014102755A4/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
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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 bortezomib pharmaceutical compositions and processes for preparing the same.
  • alkyl boronic acids are relatively difficult to obtain in analytically pure form.
  • Snyderet al. in J. Am. Chern. Soc, 3611(1958) demonstrates that alkyl boronic acid compounds readily form boroxines (anhydrides) under dehydrating conditions.
  • alkyl boronic acids and their boroxines are often air-sensitive.
  • Korcek et al., J. Chern. Soc, Perkin Trans. 2242 (1972) teaches that butyl boronic acid is readily oxidized by air to generate I-butanol and boric acid.
  • the ubiquitin-proteasome pathway (UBP) modulates intracellular protein degradation.
  • the 26S proteasome is a multi-enzyme protease that degrades misfolded or redundant proteins; conversely, blockade of the proteasomal degradation pathways results in accumulation of unwanted proteins and cell death.
  • Cancer cells are more highly proliferative than normal cells and their rate of protein translation and degradation is also faster. This typical behavior led to the development of various proteasome inhibitors as useful therapeutics in cancer.
  • Bortezomib chemically known as ((N-(2-pyrazine) carbonyl-L-phenylalanine-L-leucine boronic acid) is a 26S proteasome inhibitor that is approved for use in treatment of relapsed multiple myeloma and mantle cell lymphoma. It is believed that the boron atom in bortezomib binds to the catalytic site of the proteasome, ultimately leading to proteasome inhibition and reduced degradation of pro-apoptotic factors, which in turn triggers apoptosis in treated cells.
  • bortezomib was reported to be susceptible to oxidative degradation under a number of experimental conditions, and that the oxidation of alkyl boranes (which yields the ester of boric acid) can also be due to reaction with alkyl peracids, alkyl peroxides, or oxygen radical species.
  • alkyl peracids alkyl peroxides
  • oxygen radical species oxygen radical species
  • WO 2009/154737 Attempts to form the ester of boronic acid with alpha-hydroxy and beta-carboxylic acids like citric acid and with buffers were disclosed in WO 2009/154737.
  • Namdeo et al in WO2010089768 discloses parenteral pharmaceutical composition comprising therapeutically effective amounts of N-(2-pyrazine) carbonyl-L-phenylalanine-L-leucine boronic acid or its salts or its derivatives and tromethamine wherein the composition is stable.
  • Kocherlakota et al in WO2010039762 disclose pharmaceutical compositions comprising bortezomib for oral or parenteral administration. Specific aspects relate to stable, sugar free pharmaceutical compositions of bortezomib, including its pharmaceutically acceptable salts or solvates, in the form of ready-to-use solutions, lyophilized forms, or physical admixtures, and the preparation thereof.
  • Bricout et al in WO2010114982 disclose a lyophilized cake comprising bortezomib or a pharmaceutically acceptable salt or ester thereof, a cyclodextrin and atleast one member selected from the group of bulking agents and surfactants.
  • Soppimath et al in US8263578 disclose a storage- stable liquid pharmaceutical composition that includes bortezomib in a therapeutically effective amount, the composition comprising: a single-phase liquid formulation comprising a substantially non-aqueous solvent system suitable for injection, an aqueous acetate buffer, and bortezomib, wherein the bortezomib is present in the formulation at a therapeutically effective concentration; wherein the solvent system comprises as a predominant component propylene glycol, and wherein the buffer has a pH of 3; and wherein the solvent system, the buffer, and the pH are selected such as to be effective to suppress formation of at least one of an amide degradation product, a first carbinolamide degradation product, and a second carbinolamide degradation product when the liquid formulation is stored under storage conditions.
  • Soppimath et al describes degradation of bortezomib in solution as a well-known phenomenon and an exemplary degradation scheme is depicted in Scheme I below.
  • compound II is a first carbinolamide degradation product
  • compound III is a second carbinolamide degradation product (which is a stereo isomer of II). Hydrolysis of II or III will lead to the formation of the corresponding amide IV, which can be further hydrolyzed to the carboxylic acid product V.
  • Usayapant et al in WO2012047845 disclose a bortezomib composition includes bortezomib and boric acid in a mass ratio of boric acid to bortezomib is from 1: 1 to 10: 1.
  • Anderson et al in WO2012148799 disclose a non-aqueous, homogeneous solution comprising a solubilized lipophilic pharmaceutical agent and an amphiphilic liquid polymeric solvent, the formulation being essentially free of non-polymeric organic solvents, water and non- solubilized particles, wherein the solubilized lipophilic pharmaceutical agent has a concentration of at least about 0.5 mg/niL, and further wherein the solution remains stable and essentially free of non-solubilized particles for at least 40 days when stored at room temperature.
  • Navin et al in WO2013128419 disclose a pharmaceutical composition
  • a pharmaceutical composition comprising Bortezomib or pharmaceutically acceptable salt or solvate thereof, tromethamine and an organic carboxylic acid, wherein the pH of the composition is from about 3.0 to 6.0.
  • Bortezomib includes- WO2008075376, WO2011099018, WO2011107912 and WO2012131707.
  • compositions comprising bortezomib Form-SB, devoid of any pharmaceutically acceptable excipient; or with components particularly polyvinylpyrrolidone, lactic acid and an antioxidant with improved properties.
  • the pharmaceutical compositions of the present invention are obtained by lyophilization of a mixture comprising neat Bortezomib monohydrate- Form-SB, or bortezomib or pharmaceutically acceptable salt or solvate thereof, with components particularly, polyvinylpyrrolidone, lactic acid and an antioxidant.
  • the composition comprises either neat Bortezomib or with additional components particularly- polyvinylpyrrolidone, lactic acid and sodium metabisulphite.
  • pre-lyophilized solutions of the present invention remains much convenient and acceptable, having well controlled levels of specified impurities during the product manufacturing stage, and the lyophilized compositions also have controlled levels of specified impurities and good reconstitution time.
  • composition devoid of any pharmaceutically acceptable excipient, wherein said composition is having moisture content in the range of 3.5%-6.5 %w/w.
  • aspects of the present invention also relate to a pharmaceutical composition
  • a pharmaceutical composition comprising Bortezomib or pharmaceutically acceptable salt or solvate, with components particularly polyvinylpyrrolidone, lactic acid, and an antioxidant.
  • aspects of the present invention further relate to a pharmaceutical composition
  • a pharmaceutical composition comprising Bortezomib or pharmaceutically acceptable salt or solvate , polyvinylpyrrolidone, lactic acid, and an antioxidant; wherein the antioxidant is selected from sodium metabisulphite, butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, DL-tocopherol, tocopherol acetate, tocopherol polyethylene glycol Succinate, L-cysteine, or mixtures thereof.
  • a pharmaceutical composition comprising Bortezomib, polyvinylpyrrolidone, lactic acid and sodium metabisulphite.
  • aspects of the present invention also relate to a process of preparing pharmaceutical composition
  • a process of preparing pharmaceutical composition comprising Bortezomib, polyvinylpyrrolidone, lactic acid and sodium metabisulphite.
  • aspects of the present invention relate to a pharmaceutical composition
  • a pharmaceutical composition comprising Bortezomib, polyvinylpyrrolidone, lactic acid and sodium metabisulphite, wherein impurity 2 is not more than 0.5% and the said compositions are useful in the treatment of cancer.
  • Fig.l is Illustration of X-ray powder diffraction (XRPD) pattern of Bortezomib (I) as monohydrate Form-SB.
  • Fig.2 is Illustration of DSC thermogram of Bortezomib (I) as monohydrate Form-SB.
  • Fig.3 is Illustration of IR spectra of Bortezomib (I) as monohydrate Form-SB. DETAILED DESCRIPTION OF THE INVENTION
  • composition devoid of any pharmaceutically acceptable excipient, wherein said composition is having moisture content in the range of 3.5%-6.5 %w/w.
  • composition devoid of any pharmaceutically acceptable excipient, wherein said composition is having moisture content in the range of 4%-5%w/w.
  • a pharmaceutical composition comprising Bortezomib (I) as monohydrate Form-SB
  • step (iii) Filtering the solution obtained in step (iii) to obtain a filtered solution;
  • step (iv) Lyophilizing the filtered solution of step (iv), wherein the lyophilized composition is having moisture content of 3.5%-6.5 %w/w.
  • a pharmaceutical composition comprising Bortezomib or pharmaceutically acceptable salt or solvate, optionally comprising polyvinylpyrrolidone, lactic acid, and an antioxidant.
  • a pharmaceutical composition comprising Bortezomib or pharmaceutically acceptable salt or solvate, polyvinylpyrrolidone, lactic acid, and an antioxidant selected from sodium metabisulphite, butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, DL-tocopherol, tocopherol acetate, tocopherol polyethylene glycol Succinate, L-cysteine, or mixtures thereof.
  • a pharmaceutical composition comprising Bortezomib, polyvinylpyrrolidone, lactic acid and sodium metabisulphite.
  • a lyophilized composition comprising Bortezomib Form-SB, polyvinylpyrrolidone, lactic acid and sodium metabisulphite.
  • a process of preparing a pharmaceutical composition comprising:
  • Step (b) solution is made upto final volume with water for injection.
  • step (c) Lyophilizing the solution of step (c).
  • a process of preparing a pharmaceutical composition comprising:
  • Step (b) solution is made upto final volume with water for injection.
  • step (c) Lyophilizing the solution of step (c).
  • a pharmaceutical composition comprising Bortezomib, polyvinylpyrrolidone, lactic acid and sodium metabisulphite; wherein the Bortezomib is in the range of 1 to 3.5mg.
  • pre-lyophilized solution comprising Bortezomib Form-SB, polyvinylpyrrolidone, lactic acid and sodium metabisulphite, where in the pH of pre-lyophilized solution is between 3.5 to 5.5.
  • pre-lyophilized solution comprising Bortezomib Form-SB, polyvinylpyrrolidone, lactic acid and sodium metabisulphite, where in the pH of pre-lyophilized solution is between 4 to 5.
  • a pharmaceutical composition comprising Bortezomib, polyvinylpyrrolidone, lactic acid and sodium metabisulphite; wherein the Bortezomib is in the range of 1 to 3.5mg.
  • a pharmaceutical composition comprising Bortezomib, polyvinylpyrrolidone, lactic acid and sodium metabisulphite; wherein the polyvinylpyrrolidone is in the range of 20 to 200 mg, for 3.5mg of bortezomib.
  • a pharmaceutical composition comprising Bortezomib, polyvinylpyrrolidone, lactic acid and sodium metabisulphite; wherein the lactic acid is in the range of 0.1 to 0.8 mg, for 3.5mg of bortezomib.
  • a pharmaceutical composition comprising Bortezomib, polyvinylpyrrolidone, lactic acid and sodium metabisulphite; wherein, sodium metabisulfite is in the range of 3 to 6 mg, for 3.5mg of bortezomib.
  • a pharmaceutical composition comprising Bortezomib, polyvinylpyrrolidone, lactic acid and sodium metabisulphite; wherein the impurity 2 in the composition is not more than 0.5%.
  • a pre-lyophilized solution comprising Bortezomib, polyvinylpyrrolidone, lactic acid and sodium metabisulphite; wherein the impurity 2 in the solution is BLD.
  • bortezomib lyophilized composition comprising Bortezomib, polyvinylpyrrolidone, lactic acid and sodium metabisulphite; and the reconstitution time of the lyophilized composition is in the range of below 1 to 2 minutes.
  • a lyophilized composition comprising Bortezomib Form-SB, polyvinylpyrrolidone, lactic acid and sodium metabisulphite; and the reconstitution time of the lyophilized composition is below 1 minute.
  • a lyophilized composition comprising Bortezomib Form-SB, polyvinylpyrrolidone, lactic acid and sodium metabisulphite, wherein the pH of the reconstituted solution is between 6-8.
  • pharmaceutical composition shall mean a composition that is made under conditions such that it is suitable for administration to humans, e.g., it is made under GMP conditions and optionally contains pharmaceutically acceptable excipients, e.g., without limitation, stabilizers, bulking agents, antioxidants, buffers, carriers, diluents, vehicles, solubilizers, and binders.
  • pharmaceutical composition includes but is not limited to a pre-lyophilization solution or dispersion, lyophilized composition, as well as a liquid form ready for injection, or a reconstituted solution of a lyophilized composition, meant for IV bolus and/or for subcutaneous administration.
  • composition or “lyophilized composition” or “lyophilized formulation” are used interchangeably, and is meant for any composition having sufficient stability to have utility as a pharmaceutical agent.
  • the formulation has sufficient stability to allow storage at a convenient temperature, preferably between 0°C and 40°C, for a reasonable period of time, preferably longer than one month, more preferably longer than three months, even more preferably longer than six months, and most preferably longer than one year.
  • lyophilized composition means that the pharmaceutical composition when in the form of a lyophilized cake or powder that is the composition is not reconstituted, remains unaltered in terms of physical and chemical parameters for a prolonged period of time when packed in container which are either protected or unprotected against light, under various storage conditions. For instance, when the containers such as vials are not opened and are stored at controlled room temperature 25°C (77°F) with variation to a range of about 15 to 30°C (59 °F to 86°F) the pharmaceutical composition of the present invention remains stable for 6 months.
  • a suitable reconstitution medium such as water for injection or physiological saline
  • pharmaceutically acceptable refers to an ingredient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes those acceptable for veterinary use as well as human pharmaceutical use.
  • Specified impurities refer to any of impurity- 1, impurity-2 and impurity-3.
  • Specified impurity- 1 (S)-3-Phenyl-2-(Pyrazine-2-Carboxamido) Propanoic acid.
  • Specified impurity-2 (N-(l-[((R)-l-Hydroxy-3-Methylbutyl) amino)- l-oxo-3-Phenylpropan- 2yl]Pyrazine-2-carboxamide).
  • Specified impurity-3 N-(l-amino-l-oxo-3-phenylpropan-2-yl) pyrazine-2-carboxamide.
  • Total impurities as referred in the specification relates to sum of all Specified impurities and unspecified impurities.
  • BLD binary low-density detector
  • LOD limit of detection
  • LOQ LOQ
  • water for injections or WFI water for injections or WFI
  • WFI water for injections
  • PPM Parts Per Million
  • NMT as referred in the specification relates to Not more than.
  • Lyophilization is sometimes employed to process injectable pharmaceuticals that exhibit poor active ingredient stability in aqueous solutions.
  • Lyophilization processing is suitable for injectables because it can be conducted under sterile conditions, which is a primary requirement for parenteral dosage forms.
  • Lyophilization or freeze-drying is a process in which 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). These processes may be optimized to enhance the product stability as well as decrease the manufacturing costs. Freezing Phase:
  • a primary function of the freezing phase is to ensure that the entire container having the complex solution is completely frozen, prior to proceeding to a subsequent phase. Additionally, it is usually desired that these containers freeze in a uniform manner. While there are different ways that this can be accomplished, one option is to chill the containers after they are loaded onto the lyophilizer shelves and holding for 30-60 minutes prior to initiation of the freezing cycle. It is generally not practical to equilibrate the shelves to a freezing temperature, because of frost accumulation during the filling and loading of the containers.
  • the primary drying phase involves the removal of bulk water or solvent, at a product temperature below the ice transition temperature under a vacuum (pressures typically between 50-300 mTorr).
  • This phase can be a critical one for stabilizing an active.
  • the goal is to identify the glass transition temperature (Tg') for the formulation.
  • Tg' is the temperature at which there is a reversible change of state between a viscous liquid and a rigid, amorphous glassy state.
  • DSC differential scanning calorimeter
  • the collapse temperature is observed to be about 2-5°C greater than the Tg'.
  • the shelf temperature is set such that the target product temperature is maintained near or below the Tg' of the formulation throughout the removal of solvent during the primary dry phase.
  • the removal of solvent vapor can be tracked using a moisture detector, or by monitoring the decrease in pressure difference between a capacitance manometer and a thermocouple pressure gauge or by a pressure drop measurement.
  • the optimization of the primary dry cycle involves a removal of solvent as quickly as possible without causing cake collapse and subsequent product instability.
  • the secondary drying phase is the final segment of the lyophilization cycle, where residual moisture is removed from a formulation's interstitial matrix by desorption with elevated temperatures and/or reduced pressures.
  • the final moisture content of a lyophilized formulation which can be measured by Karl Fischer or other methods, is important because if the solid cake contains too much residual moisture, the stability of the active can be compromised. Hence, it is imperative that one achieves a moisture level as low as possible.
  • the shelf temperature is typically elevated to accelerate desorption of water molecules.
  • the duration of the secondary drying phase is usually short.
  • the residual moisture is generally significantly greater than desired.
  • One alternative is to purge the sample chamber of the lyophilizer with alternating cycles of an inert gas such as nitrogen, to facilitate displacement of bound water.
  • an inert gas such as nitrogen
  • step (iv) Filtering the solution obtained in step (iii) to obtain a filtered solution; v) Lyophilizing the filtered solution of step (iv), wherein the lyophilized composition is having moisture content of 3.5%-6.5 %w/w; wherein the lyophilization cycle involves following steps: a. Precooling of shelf at -5°C.
  • Test method Assay by HPLC -
  • Preparation of Diluent Prepare a filtered and degassed mixture of 250 volumes of water and 750 volumes of Acetonitrile, mixed well and filtered.
  • Sample preparation Take 5 vials and reconstitute each with 3.5 ml of diluent and pool the sample in 25 ml volumetric flask and dilute to volume with diluent. Further transfer 2 mL of this sample solution and transfer in to a 10 mL volumetric flask, add 5 mL of diluent. Sonicate and dilute to volume with diluent.
  • Sample preparation Take 1 vial and reconstitute with 5 ml of diluent. Further transfer 2 mL of this sample solution in to a 10 mL volumetric flask, add 5 mL of diluent and dilute to volume with diluent.
  • the % relative standard deviation (RSD) for 5 injections of standard solution should be NMT 2.0.
  • Tailing factor for Bortezomib peak in standard solution should be NMT 2.0.
  • WS Weight of Bortezomib Standard taken in mg.
  • V Number of vials taken for sample preparation
  • LC Label claim Bortezomib 3.5mg powder for solution for injection.
  • Diluent 1 Weigh and transfer 9.0gm of NaCl into a 1000ml volumetric flask and dilute to volume with water.
  • Diluent 2 Prepare a filtered and degassed mixture of 250 ml of water and 750 ml of Acetonitrile.
  • Run Time 60 minutes for Blank, System sensitivity solution Sample & Placebo; 20 minutes for Diluted standard.
  • Retention time of Bortezomib 14.5 -15.5 minutes.
  • Example 1 bortezomib lyophilized cake is analyzed for Assay & Related substances:
  • the reconstitution time of lyophilized cake of example- 1 formulation in 0.9% sodium chloride solution is 2 minutes.
  • Example 2 pre-lyophilized solution
  • Example 3 Assay and Related substances results of Example 3 pre-lyophilized solution are given under table below:
  • the volume of the above solution was made up to 100% using WFI and stirred for 5 minutes. 6.
  • the above bulk solution was filled in to 10mL/20mm flint vial with a fill volume of 2mL and half stoppered and loaded into lyophillizer and lyophilization carried out under the below recipe:
  • the lyophilized cake of example-6 is characterized for the following:
  • Example 7 Related substances of Example 7 formulation, at initial and after storage of vials under RT condition; are discussed under table below:
  • the lyophilized cake of example-7 is characterized for the following:
  • Examples 4&5 The pre-lyophilized solutions containing Bortezomib, polyvinyl pyrrolidone and lactic acid do not have adequate chemical stability of bortezomib in solution form, as evident from high levels of impurity 2. Further, the temperature (25°C or 2-8°C) do not show any effect in improvement of the bortezomib chemical stability in solution state.
  • Examples 6&7 The pre-lyophilized solutions containing Bortezomib, polyvinyl pyrrolidone, lactic acid and sodium metabisulphite have superior chemical stability of bortezomib in solution form, as evident from BLD levels of impurity 2, at zero hours.
  • Example 6&7 Bortezomib lyophilized cakes are subjected to accelerated stability at 40°/75%RH and real time stability at 25°C/60%RH, and at each appropriate stability time intervals, the product characteristics can be observed like the assay, related substances and reconstitution time.

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  • 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)
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  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

La présente invention concerne des compositions pharmaceutiques de Bortézomib et ses procédés de préparation.
PCT/IB2013/061430 2012-12-31 2013-12-31 Formulations de bortézomib WO2014102755A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN5517CH2012 2012-12-31
IN5517/CHE/2012 2012-12-31
IN5769/CHE/2013 2013-12-13
IN5769CH2013 IN2013CH05769A (fr) 2013-12-13 2013-12-31

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WO2014102755A1 true WO2014102755A1 (fr) 2014-07-03
WO2014102755A4 WO2014102755A4 (fr) 2014-08-21

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016059515A1 (fr) * 2014-10-18 2016-04-21 Shilpa Medicare Limited Formulations de bortézomib
US20190290718A1 (en) * 2015-08-06 2019-09-26 Ftf Pharma Private Limited Composition comprising bortezomib
EA038105B1 (ru) * 2018-06-13 2021-07-07 Тютор С.А.С.И.Ф.И.А. Способ получения фармацевтической композиции, содержащей бортезомиб, продукт способа

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2628178A1 (fr) * 2005-11-18 2007-05-31 Nageswara Palepu Procede de lyophilisation et produits obtenus selon ledit procede
WO2009036281A2 (fr) * 2007-09-12 2009-03-19 Dr. Reddy's Laboratories Ltd. Bortézomib et procédé de production de celui-ci
WO2010039762A2 (fr) * 2008-10-01 2010-04-08 Dr. Reddy's Laboratories Ltd. Compositions pharmaceutiques comprenant des composés d’acide boronique
EP2238973A1 (fr) * 2009-04-07 2010-10-13 Cephalon France Préparations lyophilisées d'inhibiteurs du protéasome
US20120172808A1 (en) * 2010-03-18 2012-07-05 Innopharma, Llc Stable Bortezomib Formulations
WO2012131707A2 (fr) * 2011-03-28 2012-10-04 Laurus Labs Private Limited Nouvelle forme cristalline de bortezomib, son procédé de préparation et composition pharmaceutique l'utilisant

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2628178A1 (fr) * 2005-11-18 2007-05-31 Nageswara Palepu Procede de lyophilisation et produits obtenus selon ledit procede
WO2009036281A2 (fr) * 2007-09-12 2009-03-19 Dr. Reddy's Laboratories Ltd. Bortézomib et procédé de production de celui-ci
WO2010039762A2 (fr) * 2008-10-01 2010-04-08 Dr. Reddy's Laboratories Ltd. Compositions pharmaceutiques comprenant des composés d’acide boronique
EP2238973A1 (fr) * 2009-04-07 2010-10-13 Cephalon France Préparations lyophilisées d'inhibiteurs du protéasome
US20120172808A1 (en) * 2010-03-18 2012-07-05 Innopharma, Llc Stable Bortezomib Formulations
WO2012131707A2 (fr) * 2011-03-28 2012-10-04 Laurus Labs Private Limited Nouvelle forme cristalline de bortezomib, son procédé de préparation et composition pharmaceutique l'utilisant

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016059515A1 (fr) * 2014-10-18 2016-04-21 Shilpa Medicare Limited Formulations de bortézomib
US20190290718A1 (en) * 2015-08-06 2019-09-26 Ftf Pharma Private Limited Composition comprising bortezomib
EA038105B1 (ru) * 2018-06-13 2021-07-07 Тютор С.А.С.И.Ф.И.А. Способ получения фармацевтической композиции, содержащей бортезомиб, продукт способа

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