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WO2018038687A1 - Formulations pharmaceutiques comprenant un complexe bortézomib-cyclodextrine - Google Patents

Formulations pharmaceutiques comprenant un complexe bortézomib-cyclodextrine Download PDF

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Publication number
WO2018038687A1
WO2018038687A1 PCT/TR2016/000122 TR2016000122W WO2018038687A1 WO 2018038687 A1 WO2018038687 A1 WO 2018038687A1 TR 2016000122 W TR2016000122 W TR 2016000122W WO 2018038687 A1 WO2018038687 A1 WO 2018038687A1
Authority
WO
WIPO (PCT)
Prior art keywords
lyophilized
pharmaceutical composition
bortezomib
cyclodextrin
amount
Prior art date
Application number
PCT/TR2016/000122
Other languages
English (en)
Inventor
Turgay AYDINLAR
Original Assignee
Mustafa Nevzat Ilaç Sanayii A.Ş.
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 Mustafa Nevzat Ilaç Sanayii A.Ş. filed Critical Mustafa Nevzat Ilaç Sanayii A.Ş.
Priority to PCT/TR2016/000122 priority Critical patent/WO2018038687A1/fr
Publication of WO2018038687A1 publication Critical patent/WO2018038687A1/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
    • A61K31/69—Boron compounds
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the pharmaceutical formulations comprising a bortezomib- cyclodextrin complex; to the preparation processes of the pharmaceutical formulations comprising a bortezomib-cyclodextrin complex; and to the pharmaceutical formulations comprising a bortezomib-cyclodextrin complex for use in the treatment of certain types of cancer, such as multiple myeloma and mantle cell lymphoma.
  • the present invention relates to the pharmaceutical formulations comprising a bortezomib- cyclodextrin complex.
  • Bortezomib is the first anti-neoplastic dipeptidyl boronic acid proteasome inhibitor.
  • the chemical name for bortezomib is [(lR)-3-methyl-l-[[(2S)-l-oxo-3-phenyl-2- [(pyrazinylcarbonyl)amino] propyl]amino]butyl]boronic acid.
  • Bortezomib has the following chemical structure:
  • Bortezomib a potent and selective inhibitor of the proteolytic activity of the proteasome, has shown anti-neoplastic activity against multiple myeloma and mantle cell lymphoma.
  • Multiple myeloma is a cancer of the blood. It affects the part of bone called bone marrow. Myeloma cells multiply quickly and prevent bone marrow from making enough blood cells for the body to fight the diseases.
  • Mantle cell lymphoma is a type of blood cancer that affects white blood cells called lymphocytes. It affects lymphocytes in the mantle zone of a lymph node. Mantle cell lymphoma is considered to be an aggressive cancer.
  • Bortezomib is currently available on the market as a lyophilized powder containing bortezomib in the form of a mannitol boronic ester under the brand name of Velcade ® .
  • Lyophilized formulation in a single-dose vial contains 3.5 mg bortezomib and 35 mg mannitol.
  • each ml contains 1 mg bortezomib and 10 mg mannitol.
  • Said invention provides potent and highly selective proteasome inhibitors, a method for reducing the rate of muscle protein degradation in a cell comprising contacting said cell with a proteasome inhibitor, a method for reducing the activity of NF- ⁇ in a cell comprising contacting the cell with a proteasome inhibitor, a method of reducing the rate of degradation of p53 protein in a cell comprising administering to the cell a proteasome inhibitor, a method for inhibiting cyclin degradation in a cell comprising contacting said cells with a proteasome inhibitor, a method for inhibiting the growth of a cancer cell comprising contacting said cell with a proteasome inhibitor, a method for inhibiting antigen presentation in a cell comprising administering to the cell a proteasome inhibitor, a method for inhibiting inducible NF-KB dependent cell adhesion in an animal comprising administering to said animal a proteasome inhibitor, a method
  • Formulation of the Velcade ® has been disclosed in the PCT application WO 02/059130 Al .
  • Said invention provides pharmaceutical compositions prepared by the lyophilization of an aqueous mixture comprising a boronic acid compound, which is bortezomib, and a compound having at least two hydroxyl groups, which is mannitol.
  • Said composition readily releases the boronic acid compound from the mannitol boronic ester upon dissolution in aqueous media.
  • Boronic acids including bortezomib are difficult to be formulated due to their solubility and stability issues. As mentioned in WO 02/059130 Al, alkylboronic acids are relatively difficult to obtain in analytically pure form. Snyder et al., J. Am. Chem. Soc, Vol. 80, Issue 14, 1958, p. 361 1, teaches that alkylboronic acid compounds readily form boroxines (anhydrides) under dehydrating conditions. Also, alkylboronic acids and their boroxines are often air-sensitive. Korcek et al., J. Chem. Soc, Perkin Trans. 2, 1972, p. 242, teaches that butylboronic acid is readily oxidized by air to generate 1-butanol and boric acid.
  • the PCT applications WO 2014/015016 Al, WO 2014/015027 Al, WO 2013/169282 Al, WO 2013/169897 Al, WO 2006/063154 Al relate to pharmaceutical compositions comprising a peptide epoxy ketone proteasome inhibitor and a cyclodextrin.
  • the inventions are merely limited to the peptide epoxy ketone proteasome inhibitors that differ structurally and mechanistically from the boronate-based proteasome inhibitor bortezomib.
  • the PCT application WO 2010/039762 A2 relates to sugar-free pharmaceutical compositions of bortezomib.
  • Many basic sugar-free pharmaceutical compositions have been disclosed in the patent specification such as pharmaceutical compositions comprising bortezomib, 'sodium chloride, a vitamin, a carboxylic acid, or an amino acid', and optionally a stabilizing agent (EDTA); pharmaceutical compositions comprising bortezomib and a solvent which comprises at least one alcohol; pharmaceutical compositions comprising bortezomib and 'a solubilizer or a cyclodextrin'.
  • any technical data relating to the cyclodextrin compositions has not been given to demonstrate the stability.
  • the only stability data being related to the pharmaceutical compositions comprising a solvent as the single excipient indicates that the subject-matter of the patent application is actually directed to the use of solely a solvent.
  • the EPC application EP2238973 Al relates to pharmaceutical compositions comprising a drug selected from a group of proteasome inhibitors and a cyclodextrin.
  • Preferred compounds of the invention are novel proteasome inhibitors other than bortezomib and all of the examples have illustrated pharmaceutical compositions comprising these novel compounds. Any example relating to the compositions of bortezomib has not been given.
  • the present invention relates to a lyophilized pharmaceutical composition
  • a lyophilized pharmaceutical composition comprising bortezomib, hydroxypropyl ⁇ -cyclodextrin and at least one disaccharide.
  • the present invention relates to a process for preparing a lyophilized pharmaceutical composition of bortezomib, wherein the process comprises the steps of:
  • the present invention also relates to a lyophilized pharmaceutical composition
  • a lyophilized pharmaceutical composition comprising bortezomib, hydroxypropyl ⁇ -cyclodextrin and at least one disaccharide for use in the treatment of cancer.
  • lyophilized pharmaceutical compositions of bortezomib comprising a cyclodextrin derivative and at least one bulking agent, wherein the cyclodextrin derivative is hydroxypropyl ⁇ -cyclodextrin and wherein the at least one bulking agent is selected from disaccharides, provide enhanced solubility, stability and longer shelf life.
  • Said pharmaceutical compositions of the invention in the form of a powder for solution for injection readily release bortezomib upon dissolution in aqueous media.
  • Process for preparing said lyophilized pharmaceutical compositions of the invention comprises the steps of:
  • Embodiments of the present invention are directed to the pharmaceutical compositions comprising a bortezomib-cyclodextrin complex and the preparation processes thereof.
  • the drug On parenteral administration, especially after intravenous injection, the drug is both rapidly and quantitatively released from the cyclodextrin complex upon dilution, competitive replacement, and binding of drug molecules to plasma proteins and tissue.
  • cyclodextrins are rapidly eliminated in the urine, cyclodextrins can increase renal clearance of lipophilic water- insoluble drugs.
  • hydrophilic cyclodextrin derivatives such as hydroxypropyl ⁇ - cyclodextrin (HPCD) and sulfobutylether ⁇ -cyclodextrin (SBECD), are relatively non-toxic compared with organic solvents and surfactant formulations.
  • compositions of the invention comprise bortezomib and a cyclodextrin in molar ratios of a cyclodextrin to bortezomib ranging from about 0.5:1 to about 100:1.
  • Pharmaceutical compositions of the invention comprise the cyclodextrin in an amount up to about 99% w/w, preferably in an amount more than about 40% w/w, more preferably in an amount from about 60% to about 95% w/w of the lyophilized composition.
  • compositions of the present invention include at least one further pharmaceutically acceptable excipient.
  • Further pharmaceutically acceptable excipients of the invention may be selected from the group comprising, without limitation, bulking agents, solvents or cosolvents, surfactants, or a combination thereof.
  • Bulheti et al. Excipients used in lyophilization of small molecules. J. Excipients and Food Chem., Vol. 1, Issue 1, 2010, pp. 41-54, teaches that bulking agents are used in the lyophilized products in order to form the bulk of the lyophilized product, provide an adequate structure to the lyophilized cake and prevent the degradation of a molecule both during freeze-drying and during storage.
  • mannitol and glycine are the most commonly used bulking agents, followed by glucose, sucrose, lactose, trehalose and dextran.
  • Bulking agent(s) of the invention may include, but are not limited to, monosaccharides (i.e. fructose, galactose, glucose, etc.), disaccharides (i.e. lactose, maltose, sucrose, trehalose, etc.), oligosaccharides (i.e. maltodextrins, etc.), polysaccharides (i.e. cellulose, starches, etc.), sugar alcohols (i.e. mannitol, sorbitol, xylitol, etc.), amino acids (i.e. arginine, glycine, etc.) and/or mixtures thereof.
  • monosaccharides i.e. fructose, galactose, glucose, etc.
  • disaccharides i.e. lactose, maltose, sucrose, trehalose, etc.
  • oligosaccharides i.e. maltodextrins, etc
  • Bulking agent(s) of the invention preferably include at least one disaccharide.
  • Pharmaceutical compositions of the invention comprise the bulking agent in an amount up to about 99% w/w, preferably in an amount less than about 60% w/w, more preferably in an amount from about 5% to about 40% w/w of the lyophilized composition.
  • Organic solvents of the invention are miscible with water and removable by lyophilization.
  • Organic solvent(s) of the invention may include, but are not limited to, alcohols such as ethanol, propanol and tert-butanol.
  • Cosolvent system of the invention preferably include tert-butanol/water combination.
  • Pre-lyophilized pharmaceutical compositions of the invention comprise the organic solvent in an amount up to about 90% v/v, preferably in an amount less than about 60% v/v, more preferably in an amount from about 5% to about 50% v/v of the pre-lyophilized composition.
  • surfactants may also be used in the lyophilized products.
  • many of the commonly used surfactants have toxic side effects such as hemolysis, damage to membrane permeability, changes to protein conformation, alteration of bioactivity of other compounds, and the like. These side effects are enhanced by the non-degradable nature of some surfactants.
  • compositions of the invention in the dosage form of a lyophilized powder for solution for injection comprising bortezomib and a cvclodextrin
  • surfactant-free lyophilized pharmaceutical compositions comprising bortezomib, hydroxypropyl ⁇ -cyclodextrin and at least one disaccharide, display enhanced solubility, stability and longer shelf life as well as less toxic side effects.
  • N.D. refers to "not detected” for related substances
  • D.L. refers to "disregard limit” which is 0.1 % for related substances.
  • low-concentrate refers to the cyclodextnn derivative amount up to about 70% w/w
  • mid-concentrate refers to the cyclodextrin derivative amount from about 70% to 90% w/w
  • high-concentrate refers to the cyclodextrin derivative amount more than about 90% w/w.
  • low to mid-concentrate refers to the cyclodextrin derivative amount near the lower limit of the indicated range of “mid-concentrate”
  • mid to high- concentrate refers to the cyclodextrin derivative amount near the upper limit of the indicated range of "mid-concentrate”.
  • low-concentrate refers to the bulking agent amount up to about 10% w/w
  • mid-concentrate refers to the bulking agent amount from about 10% to 30% w/w
  • high-concentrate refers to the bulking agent amount more than about 30% w/w.
  • low to mid-concentrate refers to the bulking agent amount near the lower limit of the indicated range of “mid-concentrate”
  • mid to high-concentrate refers to the bulking agent amount near the upper limit of the indicated range of "mid-concentrate”.
  • alcohol/water combination (preferably, 40:60 or 50:50) is the preferred cosolvent system.
  • compositions with bulking agents without a cyclodextrin
  • compositions did not provide a suitable impurity profile.
  • compositions with a cyclodextrin; without a bulking agent are provided.
  • compositions did not provide a suitable impurity profile and/or desired solubility.
  • stability-enhancing effect in the presence of HPCD and tert- butanol was promising.
  • 6-month stability data at 25°C / 60% RH was comparable to the stability data obtained from the original formulation of Velcade ® .
  • solubility of the active ingredient was low.
  • the increase in dissolution time resulted in the increase of impurities.
  • compositions with a cyclodextrin and a bulking agent comprising:
  • compositions with SBECD did not provide a suitable impurity profile. However, the solubility and stability-enhancing effect in the presence of HPCD, disaccharides and tert-butanol was promising.
  • HPCD Optimum cyclodextrin
  • bulking agent disaccharide
  • the most suitable amount of the cyclodextrin (HPCD) was determined to be preferably from about 60% to about 95% w/w of the lyophilized composition.
  • the most suitable amount of the bulking agent (at least one disaccharide) was determined to be preferably from about 5% to about 40% w/w of the lyophilized composition.
  • surfactant-free lyophilized pharmaceutical compositions comprising bortezomib, a cyclodextrin derivative and at least one bulking agent, wherein the cyclodextrin derivative is hydroxypropyl ⁇ -cyclodextrin and wherein the at least one bulking agent is selected from disaccharides, provided the desired solubility, stability and safety.
  • tert-butanol/water combination used in the pre- lyophilized composition as cosolvent system contributed to the enhanced solubility and stability.
  • compositions of the invention provided clear, colorless and particulate-free solutions upon reconstitution.
  • compositions with a bulking agent and without a cyclodextrin derivative comprising: pharmaceutical compositions with a cyclodextrin derivative and without a bulking agent; pharmaceutical compositions with SBECD and a bulking agent failed to provide the desired stability.
  • compositions with ethanol/water system together with a cyclodextrin derivative and/or bulking agent also failed to provide the desired solubility and stability.
  • Solvents are removed during lyophilization.
  • tert-butanol Before preparing stock solution 2, tert-butanol should be liquified in a suitable water bath heated to 30°C in order to avoid tert-butanol crystallization.
  • Stock solution 1 is transferred into the production container containing stock solution 2 and stirred.
  • the bulk solution is filtered through 0.2 micron filter and filled in the vials prior to freeze-drying. Filling volume per vial is: 3.5 mL ⁇ 2%.
  • the pharmaceutical compositions of the invention can readily be reconstituted by adding an aqueous solvent. Examples of solvents suitable for reconstitution include, without limitation, water, saline, and phosphate buffered saline.
  • the pharmaceutical compositions of the invention are preferably reconstituted with sterile saline (0.9% w/v).
  • compositions of the invention comprising bortezomib, hydroxypropyl ⁇ -cyclodextrin and at least one disaccharide are for use in the treatment of certain types of cancer, such as multiple myeloma and mantle cell lymphoma.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne les formulations pharmaceutiques comprenant un complexe bortézomib-cyclodextrine ; les procédés de préparation des formulations pharmaceutiques comprenant un complexe bortézomib-cyclodextrine ; et les formulations pharmaceutiques comprenant un complexe bortézomib-cyclodextrine destinées à être utilisées dans le traitement de certains types de cancer, tels qu'un myélome multiple et un lymphome à cellules du manteau.
PCT/TR2016/000122 2016-08-22 2016-08-22 Formulations pharmaceutiques comprenant un complexe bortézomib-cyclodextrine WO2018038687A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/TR2016/000122 WO2018038687A1 (fr) 2016-08-22 2016-08-22 Formulations pharmaceutiques comprenant un complexe bortézomib-cyclodextrine

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/TR2016/000122 WO2018038687A1 (fr) 2016-08-22 2016-08-22 Formulations pharmaceutiques comprenant un complexe bortézomib-cyclodextrine

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WO2018038687A1 true WO2018038687A1 (fr) 2018-03-01

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996013266A1 (fr) 1994-10-28 1996-05-09 Proscript, Inc. Composes d'esters et d'acides boroniques, leur synthese et leurs utilisations
WO2002059130A1 (fr) 2001-01-25 2002-08-01 The United States Of America, Represented By The Secretary, Department Of Health And Human Services Formulation de composes d'acide boronique
WO2006063154A1 (fr) 2004-12-07 2006-06-15 Proteolix, Inc. Composition destinee a inhiber le proteasome
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
WO2013169897A1 (fr) 2012-05-08 2013-11-14 Onyx Therapeutics, Inc. Procédés de complexation de cyclodextrine pour la formulation d'inhibiteurs peptidiques du protéasome
WO2013169282A1 (fr) 2012-05-08 2013-11-14 Onyx Therapeutics, Inc. Procédés de complexation de cyclodextrine pour la formulation d'inhibiteurs peptidiques du protéasome
WO2014015027A1 (fr) 2012-07-18 2014-01-23 Onyx Therapeutics, Inc. Compositions liposomales d'inhibiteurs du protéasome à base d'époxycétone
WO2016001905A2 (fr) * 2014-07-04 2016-01-07 Dr. Reddy’S Laboratories Limited Préparation injectable liquide stable et prête à l'emploi de bortézomib

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996013266A1 (fr) 1994-10-28 1996-05-09 Proscript, Inc. Composes d'esters et d'acides boroniques, leur synthese et leurs utilisations
WO2002059130A1 (fr) 2001-01-25 2002-08-01 The United States Of America, Represented By The Secretary, Department Of Health And Human Services Formulation de composes d'acide boronique
WO2006063154A1 (fr) 2004-12-07 2006-06-15 Proteolix, Inc. Composition destinee a inhiber le proteasome
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
WO2013169897A1 (fr) 2012-05-08 2013-11-14 Onyx Therapeutics, Inc. Procédés de complexation de cyclodextrine pour la formulation d'inhibiteurs peptidiques du protéasome
WO2013169282A1 (fr) 2012-05-08 2013-11-14 Onyx Therapeutics, Inc. Procédés de complexation de cyclodextrine pour la formulation d'inhibiteurs peptidiques du protéasome
WO2014015027A1 (fr) 2012-07-18 2014-01-23 Onyx Therapeutics, Inc. Compositions liposomales d'inhibiteurs du protéasome à base d'époxycétone
WO2014015016A1 (fr) 2012-07-18 2014-01-23 Onyx Therapeutics, Inc. Compositions liposomales contenant des inhibiteurs du protéasome à base d'époxycétone
WO2016001905A2 (fr) * 2014-07-04 2016-01-07 Dr. Reddy’S Laboratories Limited Préparation injectable liquide stable et prête à l'emploi de bortézomib

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BAHETI ET AL.: "Excipients used in lyophilization of small molecules", J. EXCIPIENTS AND FOOD CHEM., vol. 1, no. 1, 2010, pages 41 - 54
KORCEK ET AL., J. CHEM. SOC., PERKIN TRANS., vol. 2, 1972, pages 242
LOFTSSON ET AL., EXPERT OPIN. DRUG DELIV., vol. 2, no. 2, 2005, pages 335 - 351
SNYDER ET AL., J. AM. CHEM. SOC., vol. 80, no. 14, 1958, pages 3611

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