WO2021090183A1 - Liquid melphalan composition - Google Patents

Liquid melphalan composition Download PDF

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Publication number
WO2021090183A1
WO2021090183A1 PCT/IB2020/060334 IB2020060334W WO2021090183A1 WO 2021090183 A1 WO2021090183 A1 WO 2021090183A1 IB 2020060334 W IB2020060334 W IB 2020060334W WO 2021090183 A1 WO2021090183 A1 WO 2021090183A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
melphalan
pharmaceutically acceptable
stable
liquid pharmaceutical
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IB2020/060334
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French (fr)
Inventor
Nimitt CHOKSHI
Rushabh Shah
Nagnath G GOBADE
Kamal Kumar Upadhyay
Alex K George
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Intas Pharmaceuticals Ltd
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Intas Pharmaceuticals Ltd
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Publication date
Application filed by Intas Pharmaceuticals Ltd filed Critical Intas Pharmaceuticals Ltd
Priority to EP20886165.8A priority Critical patent/EP4055005A4/en
Publication of WO2021090183A1 publication Critical patent/WO2021090183A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/38—Separation; Purification; Stabilisation; Use of additives
    • C07C227/44—Stabilisation; Use of additives
    • 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 related to a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salts thereof.
  • the said stable ready to dilute pharmaceutical composition is further diluted to obtain a final diluted melphalan composition before administering to the patient in need thereof.
  • the present invention provides process for the preparation of the said composition and its use for the treatment of multiple myeloma.
  • Melphalan is a bifunctional alkylating agent, which is a phenylalanine derivative of nitrogen mustard. It is also known as L-phenylalanine mustard, phenylalanine mustard, L-PAM, or L-sarcolysin which is chemically known 4-[bis(2- chloroethyl)amino]-L-phenylalanine and molecular formula is C13H18C12N2O2.
  • FIG. 1 Melphalan Melphalan primarily degrades through sequential hydrolysis to the hydrolytic degradants monohydroxymelphalan and dihydroxymelphalan. Individual hydrolysis products, monohydroxymelphalan and dihydroxymelphalan, are observed as the main degradants in room temperature stored samples, along with small quantities of melphalan dimer. To overcome the hydrolytic degradation of Melphalan and preparing commercially available products, following approaches appear to have been made:
  • US4997651 patent discloses two-component pharmaceutical formulation of Melphalan comprising freeze-dried Melphalan hydrochloride and a solvent- diluent comprising a citrate, propylene glycol and ethanol.
  • US2013131174 patent application discloses a solid lyophilized composition of Melphalan hydrochloride having a pH between 4 and 6.
  • WO2017085696 patent application disclose a stable, parenteral formulation comprising Melphalan and cyclodextrin or its derivative thereof, wherein the formulation is free of propylene glycol.
  • US2018193255 patent application disclose ready to use liquid parenteral formulation comprising of Melphalan and pharmaceutically acceptable adjuvants thereof.
  • Commercially available parenteral preparations of Melphalan are manufactured by lyophilization.
  • Melphalan is commercially available in tablet form (Alkeran®) and Injectable form (Alkeran®) and (Evomela®), for the treatment of multiple myeloma.
  • the commercial injectable formulation of Melphalan injectable Alkeran® is supplied as a sterile, nonpyrogenic, freeze-dried powder. Each single use vial contains Melphalan hydrochloride equivalent to 50 mg Melphalan and 20 mg povidone. Alkeran® is reconstituted using the sterile diluent containing sodium citrate, propylene glycol, ethanol and water for injection to a volume of 10 mL.
  • the Alkeran® to be infused must be diluted to not more than 0.45 mg/ml in normal saline and infused over 15 minutes.
  • the diluted product needs to be administered within 60 minutes from time of reconstitution.
  • the said reconstituted solution cause precipitation while store at 2- 8 °C. Further slow addition of diluent or delay in shaking during reconstitution which resulting in formation of insoluble solid particles in solution.
  • the commercially available formulation of melphalan injectable Evomela® (50mg/vial) is a lyophilized composition and comprises of Melphalan and Betadex sulfobutyl ether sodium.
  • the lyophilized composition must be reconstituted using 0.9% sodium chloride solution.
  • the reconstituted solution is stable for 24 hours at refrigerated temperature without any precipitation due to the high solubility and stable for 1 hour at room temperature. On further dilution in sodium chloride, the solution is stable for 4 hours at room temperature in addition to the 1 hour following reconstitution.
  • the inventors of the present invention have developed a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the said pharmaceutical composition of Melphalan is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salts thereof.
  • the said stable ready to dilute pharmaceutical composition has improved stability and can be stored for at least 72 hours at 2-8 °C without any precipitation.
  • the said stable ready to dilute pharmaceutical composition is further diluted in 0.9% sodium chloride or 5% dextrose to obtain a final diluted melphalan composition and wherein the said final diluted melphalan composition is stable for at least 2 hours when stored at room temperature.
  • the primary object of the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
  • Another object of the present invention is to provide a stable liquid pharmaceutical composition
  • a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients.
  • Another object of the present invention is to provide a process for preparation of liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients comprises the step of:
  • step a) dissolving sodium chloride to the clear solution obtained in step a);
  • step b) dissolving one or more antioxidant to the solution obtained in step b);
  • step c) dissolving melphalan or its pharmaceutically acceptable salt in solution obtained in step c) and making up the volume.
  • step d) filtering the solution obtained in step d) and filling the filtered solution in suitable vials.
  • Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients, wherein the said liquid pharmaceutical composition is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle comprising cyclodextrin derivative, sodium chloride, one or more solvents and optionally buffering agent to provide a stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a stable liquid pharmaceutical composition
  • a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients
  • the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle comprising cyclodextrin derivative, sodium chloride, one or more solvents and optionally buffering agent to provide a stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salt thereof, and wherein cyclodextrin derivative is present in a weight ratio of less than 50: 1 relative to the melphalan or its pharmaceutically acceptable salt.
  • Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle comprising cyclodextrin derivative, sodium chloride, one or more solvents and optionally buffering agent to provide a stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salt thereof, wherein the said stable ready to dilute composition is stable for at least 72 hours when stored at 2-8 °C and for at least 1 hour when stored at room temperature (25 °C).
  • Another object of the present invention is to provide a stable liquid pharmaceutical composition
  • a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition, and the said stable ready to dilute composition is further diluted with sodium chloride solution or dextrose solution to obtain final diluted melphalan composition before administering to the patient in need thereof.
  • Another object of the present invention is to provide a stable liquid pharmaceutical composition
  • a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients
  • the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition, and the said stable ready to dilute composition is further diluted with 0.9% sodium chloride solution or 5% dextrose solution to obtain final diluted melphalan composition before administering to the patient in need thereof.
  • Another object of the present invention is to provide a stable liquid pharmaceutical composition
  • a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to obtain a stable ready to dilute pharmaceutical composition, and the said stable ready to dilute pharmaceutical composition is further diluted with 0.9% sodium chloride solution or 5% dextrose solution to obtain a final diluted melphalan composition.
  • Another object of the present invention is to provide a stable liquid pharmaceutical composition
  • a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients
  • the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to obtain a stable ready to dilute pharmaceutical composition
  • the said stable ready to dilute pharmaceutical composition is further diluted with 0.9% sodium chloride solution and 5% dextrose solution to obtain a final diluted melphalan composition
  • the said final diluted melphalan composition is stable for at least 2 hours when stored at 25 °C.
  • Another object of the present invention is to provide a stable liquid pharmaceutical composition
  • a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 7.5% (w/w) of Impurity D, more preferably the said composition does not have more than 2% of Impurity D when stored at 2-8 °C for at least 3 months.
  • Another object of the present invention is to provide a stable liquid pharmaceutical composition
  • a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 7.5% (w/w) of Impurity D, more preferably the said composition does not have more than 2% (w/w) of Impurity D when stored at 25 °C for at least 3 months.
  • Another object of the present invention is to provide a stable liquid pharmaceutical composition
  • a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 1% (w/w) of Impurity G, more preferably the said composition does not have more than 0.6% (w/w) of Impurity G when stored at 2-8 °C for at least 3 months.
  • Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 1% (w/w) of Impurity G, more preferably the said composition does not have more than 0.6% (w/w) of Impurity G when stored at 25 °C for at least 3 months.
  • Another object of the present invention is to provide a stable liquid pharmaceutical composition
  • a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 10% (w/w) of total impurity, more preferably the said composition does not have more than 5% of total impurity when stored at 2-8 °C for at least 3 months.
  • Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 10% (w/w) of total impurity, more preferably the said composition does not have more than 5% of total impurity when stored at 25 °C for at least 3 months.
  • Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition is used for the treatment of multiple myeloma.
  • the present invention related to stable liquid pharmaceutical composition
  • stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients
  • the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition and the said ready to dilute composition is stable for at least 72 hours when stored at 2-8 °C and for at least 1 hour when stored at room temperature (25 °C) without any precipitation.
  • the said stable ready to dilute pharmaceutical composition is further diluted with sodium chloride solution or dextrose solution to obtain a final diluted melphalan composition before administering to the patient in need thereof.
  • the present invention provides process for the preparation of the said composition and its use for the treatment of multiple myeloma.
  • the present invention related to stable liquid pharmaceutical composition
  • melphalan or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
  • the present invention provides process for the preparation of the said composition and its use for the treatment of multiple myeloma.
  • Melphalan used throughout the specification refers to not only their base per se, but also their other pharmaceutically acceptable salt, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof, preferably Melphalan Hydrochloride.
  • liquid pharmaceutical composition refers to a pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients.
  • This liquid pharmaceutical composition is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition, which is further diluted with sodium chloride or dextrose to obtain final diluted melphalan composition before administering to the patient in the need thereof.
  • pharmaceutically acceptable means salt, carriers, excipients, and other formulation ingredients that are compatible with all other pharmaceutical ingredients of a composition and are not deleterious to an individual treated with composition.
  • diluent vehicle refers to a vehicle composition which is used to first dilute the liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof.
  • the diluent vehicle comprises of cyclodextrin derivative, sodium chloride, one or more solvents and optionally buffering agent.
  • ready to dilute pharmaceutical composition refers to a stable, liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, which is first diluted with a diluent vehicle comprising cyclodextrin derivative, sodium chloride, one or more solvents and optionally buffering agent to obtain a stable ready to dilute pharmaceutical composition.
  • the said stable ready to dilute pharmaceutical composition is stable for at least 72 hours when stored at 2-8 °C and for at least 1 hour when stored at room temperature (25 °C).
  • final diluted melphalan composition refers to liquid pharmaceutical composition of melphalan diluted with diluent vehicle wherein diluent vehicle contains cyclodextrin derivative, sodium chloride, one or more solvents and optionally buffering agent to obtain stable ready to dilute melphalan composition, wherein the obtained stable ready to dilute melphalan composition is further diluted with sodium chloride solution or dextrose solution to obtain a final diluted melphalan composition, which is administered to the patient in need thereof.
  • stable refers to a pharmaceutical composition in which the active pharmaceutical ingredients melphalan is present in an amount of at least 90% of the original label specified amount for each such ingredient during storage at 2-8 °C and 25 °C.
  • Impurity D of melphalan as used throughout the specification, refers to below structure:
  • Impurity G of melphalan as used throughout the specification, refers to below structure:
  • total impurities of melphalan as used throughout the specification, refers to identified or unidentified degradation product or impurity structurally related with Melphalan which are arising from a manufacturing process or during storage of material.
  • the present invention is to provide a stable liquid pharmaceutical composition
  • a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof and one or more pharmaceutical acceptable excipients.
  • the present invention is to provide a stable liquid pharmaceutical composition
  • a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients.
  • the present invention is to provide a process for preparation of liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients comprises the step of:
  • step a) dissolving sodium chloride to the clear solution obtained in step a);
  • step c) dissolving one or more antioxidant to the solution obtained in step b); (d) dissolving melphalan or its pharmaceutically acceptable salt in solution obtained in step c) and making up the volume.
  • step d) filtering the solution obtained in step d) and filling the filtered solution in suitable vials.
  • the one or more solvents can be selected from the group comprising of but not limited to dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N- methylpyrrolidone, dimethylisosorbide, ethanol, propylene glycol, glycerine, polyethylene alcohol, propylene glycol esters, polyethylene glycols and the like.
  • DMA dimethylacetamide
  • DMSO dimethyl sulfoxide
  • N- methylpyrrolidone N- methylpyrrolidone
  • dimethylisosorbide ethanol
  • propylene glycol glycerine
  • polyethylene alcohol propylene glycol esters
  • polyethylene glycols and the like Preferred solvents are polyethylene glycols (PEG) and propylene glycol.
  • the anti-oxidant can be selected from the group comprising of but not limited to butylated hydroxyanisole, butylated hydroxyltoluene, tocopherol, ethylenediaminetetraacetic acid, monothioglycerol, ascorbic acid and their esters, L-cysteine, parabens, benzyl alcohol, propyl gallate, thioglycolic acid, tartaric acid, citric acid, or mixture thereof. Most preferred anti-oxidant is Monothioglycerol.
  • liquid pharmaceutical composition comprising melphalan HC1, monothioglycerol, sodium chloride, propylene glycol and polyethylene glycol.
  • the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salt thereof.
  • the diluent vehicle comprises cyclodextrin derivative, sodium chloride, one or more solvents and optionally buffering agent.
  • the diluent vehicle may be present in vial or Pre-Filled Syringe (PFS).
  • PFS Pre-Filled Syringe
  • cyclodextrin derivative is present in less than 270 mg/ ml of total volume of diluent vehicle, more preferably less than 250 mg/ml of cyclodextrin, most preferably less than 200 mg/ ml of cyclodextrin of total volume of diluent vehicle.
  • the diluent vehicle having a volume of 9 mL shall contain around 400 mg to 2450 mg, 500 mg to 2250 mg, 600 to 1800 mg of cyclodextrin derivatives of total weight of the diluent vehicle composition.
  • Cyclodextrins (CDs) derivatives are water soluble macrocyclic oligosaccharides with a-D-glucose units linked by a-(l- 4) glycosidic bonds, widely used to solubilize various water insoluble drugs. It is driven by non-covalent interactions such as van der Waals forces, hydrogen bonding and hydrophobic interactions. Additionally, complex formation of CDs with drugs improve stability due to decrease in hydrolysis.
  • the cyclodextrin derivative can be selected from the group comprising of but not limited to a, b and g-cyclodextrin and cyclodextrins modified with alkyl-, hydroxy alkyl, dialkyl-, and sulfoalkyl-ether modified cyclodextrins such as methyl or hydroxypropyl b-cyclodextrins (HPpCD), methyl-and-ethyl-P-cyclodextrin, sulfoalkylether-substituted beta-cyclodextrin, Betadex sulfobutyl ether sodium, sulfobutylether-P-cyclodextrin (SBECD) and the like. Most preferred cyclodextrin is Betadex sulfobutyl ether sodium.
  • sodium chloride may be present in 0.9% of the total weight of the diluent vehicle.
  • the diluent vehicle comprises cyclodextrin derivative, sodium chloride, one or more solvents and optionally buffering agent, wherein the said diluent vehicle is used to dilute the stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, to provide a stable ready to dilute pharmaceutical composition having pH of about 2-5.
  • the diluent vehicle comprises cyclodextrin derivative, sodium chloride, one or more solvents and buffering agent, wherein the said diluent vehicle is used to dilute the liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, to provide a stable ready to dilute pharmaceutical composition having pH of about 4-5.
  • the said buffering agents are, such as, but not limited to, citrate buffer, acetate buffers, phosphate buffer, amino acids, and the like.
  • Preferred buffers are sodium citrate anhydrous and sodium acetate monohydrate.
  • the diluent vehicle also contains water for injection as a preferred solvent.
  • stable liquid pharmaceutical composition comprising 50 mg/ml of melphalan HC1, which is first diluted with 9 ml of diluent vehicle to provide the 5mg/ml of stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salt.
  • the stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salts has a pH of about 2-5.
  • the stable ready to dilute pharmaceutical composition comprises cyclodextrin derivative, wherein the said cyclodextrin derivative is present in a ratio of less than 50: 1 relative to the melphalan or its pharmaceutically acceptable salt.
  • the present invention is to provide a stable liquid pharmaceutical composition
  • a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients
  • the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salt thereof, wherein the said stable ready to dilute composition is stable for at least 72 hours when stored at 2-8 °C and for at least 1 hour when stored at room temperature (25 °C) .
  • the stable ready to dilute pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt and cyclodextrin derivatives is stable for at least 72 hours when stored at 2-8 °C and for at least 1 hour when stored at room temperature (25 °C), wherein the cyclodextrin derivative is present in a ratio of less than 50:1 relative to the melphalan or its pharmaceutically acceptable salts.
  • the present invention is to provide a stable liquid pharmaceutical composition
  • a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients
  • the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition, and the said stable ready to dilute composition is further diluted with sodium chloride solution or dextrose solution to obtain final diluted melphalan composition, which is administered to the patient in need thereof.
  • the stable ready to dilute pharmaceutical composition is further diluted with 0.9% sodium chloride solution or 5% dextrose solution to obtain final diluted melphalan composition, which is administered to the patient in need thereof.
  • the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition, and the said stable ready to dilute composition is further diluted with 0.9% sodium chloride solution or 5% dextrose solution to obtain a final diluted melphalan composition for the stability study.
  • the present invention is to provide a stable liquid pharmaceutical composition
  • a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients
  • the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to obtain a stable ready to dilute pharmaceutical composition
  • the said stable ready to dilute pharmaceutical composition is further diluted with 0.9% sodium chloride solution and 5% dextrose solution to obtain a final diluted melphalan composition, wherein the said final diluted composition is stable for at least 2 hours when stored at 25 °C.
  • the present invention is to provide a stable liquid pharmaceutical composition
  • a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 7.5% (w/w) of Impurity D when stored at 2-8 °C for at least 3 months.
  • the present invention is to provide a stable liquid pharmaceutical composition
  • a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 2% (w/w) of Impurity D when stored at 2-8 °C for at least 3 months.
  • the present invention is to provide a stable liquid pharmaceutical composition
  • a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 7.5% (w/w) of Impurity D when stored at 25 °C for at least 3 months.
  • the present invention is to provide a stable liquid pharmaceutical composition
  • a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 2% (w/w) of Impurity D when stored at 25 °C for at least 3 months.
  • the present invention is to provide a stable liquid pharmaceutical composition
  • a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 1% (w/w) of Impurity G when stored at 2-8 °C for at least 3 months.
  • the present invention is to provide a stable liquid pharmaceutical composition
  • a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 0.6% (w/w) of Impurity G when stored at 2-8 °C for at least 3 months.
  • the present invention is to provide a stable liquid pharmaceutical composition
  • a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 1% (w/w) of Impurity G when stored at 25 °C for at least 3 months.
  • the present invention is to provide a stable liquid pharmaceutical composition
  • a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 0.6% (w/w) of Impurity G when stored at 25 °C for at least 3 months.
  • the present invention is to provide a stable, ready to dilute pharmaceutical composition
  • a stable, ready to dilute pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 10% (w/w) of total impurity, when stored at 2-8 °C for at least 3 months.
  • the present invention is to provide a stable, ready to dilute pharmaceutical composition
  • a stable, ready to dilute pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 5% of total impurity when stored at 2-8 °C for at least 3 months.
  • the present invention is to provide a stable, ready to dilute pharmaceutical composition
  • a stable, ready to dilute pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 10% (w/w) of total impurity after being stored at 25 °C for at least 3 months.
  • the present invention is to provide a stable, ready to dilute pharmaceutical composition
  • a stable, ready to dilute pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 5% of total impurity after being stored at 25 °C for at least 3 months.
  • the present invention is to provide a stable, ready to dilute pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition is used for the treatment of multiple myeloma.
  • Example 1 Liquid melphalan composition
  • Manufacturing Process (a) mixing the solvents to obtain the clear solution;
  • step a) dissolving sodium chloride to the clear solution obtained in step a);
  • step b) dissolving one or more antioxidant to the solution obtained in step b);
  • step c) dissolving melphalan or its pharmaceutically acceptable salt in solution obtained in step c) and making up the volume.
  • step d) filtering the solution obtained in step d) and filling the filtered solution in suitable vials.
  • Example 2 Liquid melphalan composition
  • step a) mixing propylene glycol and polyethylene glycol 400 to obtain the clear solution; (b) dissolving sodium chloride to the clear solution obtained in step a);
  • step c) dissolving melphalan or its pharmaceutically acceptable salt in solution obtained in step c) and making up the volume.
  • step d) filtering the solution obtained in step d) and filling the filtered solution in suitable vials.
  • Example 3 Liquid melphalan composition
  • Manufacturing Process (a) mixing propylene glycol and polyethylene glycol 400 to obtain the clear solution;
  • step a) dissolving sodium chloride to the clear solution obtained in step a);
  • step c dissolving butylated hydroxytoluene and citric acid to the solution obtained in step b); (d) dissolving melphalan or its pharmaceutically acceptable salt in solution obtained in step c) and making up the volume. (e) filtering the solution obtained in step d) and filling the filtered solution in suitable vials.
  • Example 4 Liquid melphalan composition
  • step b dissolving sodium chloride to the clear solution obtained in step a); (c) dissolving alpha tocopherol to the solution obtained in step b);
  • step c) dissolving melphalan or its pharmaceutically acceptable salt in solution obtained in step c) and making up the volume.
  • step d) filtering the solution obtained in step d) and filling the filtered solution in suitable vials.
  • Example 5 Composition of diluent vehicle
  • Table 2 Stability data of diluted melphalan solution with diluent solution of 50 mg/mL SBE-CD in 0.9% Sodium chloride under different time interval at storage conditions of 2-8 °C and 25 °C
  • Table 3 Stability data of diluted melphalan solution with diluent solution of 200 mg/mL SBE-CD in 0.9% Sodium chloride under different time interval at storage condition of 2-8 °C and 25 °C.
  • Table 4 Stability data of diluted melphalan solution with diluent solution of 250 mg/mL SBE-CD in 0.9% Sodium chloride under different time interval at storage condition of 2-8 °C and 25 °C
  • Table 5 Stability data of diluted melphalan solution with diluent solution of 250 mg/mL SBE-CD and 4.5 mg/mL Sodium Citrate in 0.9% Sodium chloride under different time interval at storage condition of 2-8 °C and 25 °C
  • Table 6 Stability data of diluted melphalan solution with diluent solution of 250 mg/mL SBE-CD and 4.5 mg/mL Sodium Acetate in 0.9% Sodium chloride under different time interval at storage condition of 2-8 °C and 25 °C
  • the liquid pharmaceutical composition of melphalan diluted with diluent vehicle where in diluent vehicle contains 250 mg/mL SBE-CD and 4.5 mg/mL Sodium Acetate in 0.9% Sodium chloride to obtained ready to dilute melphalan composition and stored at 25 °C for 1 hour.
  • the resulted ready to dilute melphalan composition is further diluted with 0.9% Sodium Chloride and 5% dextrose injection to obtain 0.45 mg/mL concentration of final diluted melphalan composition.
  • the results of stability data for final diluted melphalan composition is summarized in below table.
  • the above data shows impurity D, impurity G and total impurity are not more than specified limit in the formulation, which is indicative of stability of melphalan HC1 in the drug product at 25 °C.
  • the stability data as mentioned above indicate that the liquid pharmaceutical composition of melphalan or its pharmaceutically acceptable salt thereof are stable. Further, the ready to dilute melphalan composition is stable for at least 72 hours at 2-8 °C and for at least 1 hours at 25 °C. Also, the final diluted melphalan composition obtained after dilution with 0.9% sodium chloride or 5% dextrose is stable for at least 2 hours at 25 °C.

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Abstract

The present invention related to a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salts thereof. The said stable ready to dilute pharmaceutical composition is further diluted to obtain a final diluted melphalan composition before administering to the patient in need thereof. Further, the present invention provides process for the preparation of the said composition and its use for the treatment of multiple myeloma.

Description

LIQUID MELPHALAN COMPOSITION
RELATED APPLICATIONS
This application is related to Indian Provisional Application No. IN201921044683 filed on 4th November, 2019 and is incorporated herein in its entirety.
FIELD OF THE INVENTION
The present invention related to a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salts thereof. The said stable ready to dilute pharmaceutical composition is further diluted to obtain a final diluted melphalan composition before administering to the patient in need thereof. Further, the present invention provides process for the preparation of the said composition and its use for the treatment of multiple myeloma.
BACKGROUND OF THE INVENTION
Melphalan is a bifunctional alkylating agent, which is a phenylalanine derivative of nitrogen mustard. It is also known as L-phenylalanine mustard, phenylalanine mustard, L-PAM, or L-sarcolysin which is chemically known 4-[bis(2- chloroethyl)amino]-L-phenylalanine and molecular formula is C13H18C12N2O2.
Figure imgf000002_0001
Figure 1: Melphalan Melphalan primarily degrades through sequential hydrolysis to the hydrolytic degradants monohydroxymelphalan and dihydroxymelphalan. Individual hydrolysis products, monohydroxymelphalan and dihydroxymelphalan, are observed as the main degradants in room temperature stored samples, along with small quantities of melphalan dimer. To overcome the hydrolytic degradation of Melphalan and preparing commercially available products, following approaches appear to have been made:
US4997651 patent discloses two-component pharmaceutical formulation of Melphalan comprising freeze-dried Melphalan hydrochloride and a solvent- diluent comprising a citrate, propylene glycol and ethanol.
US2013131174 patent application discloses a solid lyophilized composition of Melphalan hydrochloride having a pH between 4 and 6.
US2010311838, US2014213650 and US2014221488 patent application disclose parenteral compositions comprising Melphalan and a cyclodextrin derivative.
WO2017085696 patent application disclose a stable, parenteral formulation comprising Melphalan and cyclodextrin or its derivative thereof, wherein the formulation is free of propylene glycol.
US2014005148 patent application disclose a liquid formulations of nitrogen mustards.
US2018193255 patent application disclose ready to use liquid parenteral formulation comprising of Melphalan and pharmaceutically acceptable adjuvants thereof. Commercially available parenteral preparations of Melphalan are manufactured by lyophilization. Melphalan is commercially available in tablet form (Alkeran®) and Injectable form (Alkeran®) and (Evomela®), for the treatment of multiple myeloma.
The commercial injectable formulation of Melphalan injectable Alkeran® is supplied as a sterile, nonpyrogenic, freeze-dried powder. Each single use vial contains Melphalan hydrochloride equivalent to 50 mg Melphalan and 20 mg povidone. Alkeran® is reconstituted using the sterile diluent containing sodium citrate, propylene glycol, ethanol and water for injection to a volume of 10 mL.
The Alkeran® to be infused must be diluted to not more than 0.45 mg/ml in normal saline and infused over 15 minutes. However, the presence of high amounts of propylene glycol in the formulation often presents acceptability limitations. The diluted product needs to be administered within 60 minutes from time of reconstitution. The said reconstituted solution cause precipitation while store at 2- 8 °C. Further slow addition of diluent or delay in shaking during reconstitution which resulting in formation of insoluble solid particles in solution.
The commercially available formulation of melphalan injectable Evomela® (50mg/vial) is a lyophilized composition and comprises of Melphalan and Betadex sulfobutyl ether sodium. The lyophilized composition must be reconstituted using 0.9% sodium chloride solution. The reconstituted solution is stable for 24 hours at refrigerated temperature without any precipitation due to the high solubility and stable for 1 hour at room temperature. On further dilution in sodium chloride, the solution is stable for 4 hours at room temperature in addition to the 1 hour following reconstitution.
The inventors of the present invention have developed a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the said pharmaceutical composition of Melphalan is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salts thereof. The said stable ready to dilute pharmaceutical composition has improved stability and can be stored for at least 72 hours at 2-8 °C without any precipitation. The said stable ready to dilute pharmaceutical composition is further diluted in 0.9% sodium chloride or 5% dextrose to obtain a final diluted melphalan composition and wherein the said final diluted melphalan composition is stable for at least 2 hours when stored at room temperature.
OBJECT OF THE INVENTION
The primary object of the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients.
Another object of the present invention is to provide a process for preparation of liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients comprises the step of:
(a) mixing the solvents to obtain the clear solution;
(b) dissolving sodium chloride to the clear solution obtained in step a);
(c) dissolving one or more antioxidant to the solution obtained in step b);
(d) dissolving melphalan or its pharmaceutically acceptable salt in solution obtained in step c) and making up the volume. (e) filtering the solution obtained in step d) and filling the filtered solution in suitable vials.
Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients, wherein the said liquid pharmaceutical composition is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salt thereof.
Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle comprising cyclodextrin derivative, sodium chloride, one or more solvents and optionally buffering agent to provide a stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salt thereof.
Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle comprising cyclodextrin derivative, sodium chloride, one or more solvents and optionally buffering agent to provide a stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salt thereof, and wherein cyclodextrin derivative is present in a weight ratio of less than 50: 1 relative to the melphalan or its pharmaceutically acceptable salt. Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle comprising cyclodextrin derivative, sodium chloride, one or more solvents and optionally buffering agent to provide a stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salt thereof, wherein the said stable ready to dilute composition is stable for at least 72 hours when stored at 2-8 °C and for at least 1 hour when stored at room temperature (25 °C).
Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition, and the said stable ready to dilute composition is further diluted with sodium chloride solution or dextrose solution to obtain final diluted melphalan composition before administering to the patient in need thereof.
Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition, and the said stable ready to dilute composition is further diluted with 0.9% sodium chloride solution or 5% dextrose solution to obtain final diluted melphalan composition before administering to the patient in need thereof. Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to obtain a stable ready to dilute pharmaceutical composition, and the said stable ready to dilute pharmaceutical composition is further diluted with 0.9% sodium chloride solution or 5% dextrose solution to obtain a final diluted melphalan composition.
Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to obtain a stable ready to dilute pharmaceutical composition, and the said stable ready to dilute pharmaceutical composition is further diluted with 0.9% sodium chloride solution and 5% dextrose solution to obtain a final diluted melphalan composition, wherein the said final diluted melphalan composition is stable for at least 2 hours when stored at 25 °C.
Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 7.5% (w/w) of Impurity D, more preferably the said composition does not have more than 2% of Impurity D when stored at 2-8 °C for at least 3 months.
Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 7.5% (w/w) of Impurity D, more preferably the said composition does not have more than 2% (w/w) of Impurity D when stored at 25 °C for at least 3 months.
Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 1% (w/w) of Impurity G, more preferably the said composition does not have more than 0.6% (w/w) of Impurity G when stored at 2-8 °C for at least 3 months.
Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 1% (w/w) of Impurity G, more preferably the said composition does not have more than 0.6% (w/w) of Impurity G when stored at 25 °C for at least 3 months.
Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 10% (w/w) of total impurity, more preferably the said composition does not have more than 5% of total impurity when stored at 2-8 °C for at least 3 months.
Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 10% (w/w) of total impurity, more preferably the said composition does not have more than 5% of total impurity when stored at 25 °C for at least 3 months. Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition is used for the treatment of multiple myeloma.
SUMMARY OF THE INVENTION
The present invention related to stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition and the said ready to dilute composition is stable for at least 72 hours when stored at 2-8 °C and for at least 1 hour when stored at room temperature (25 °C) without any precipitation. The said stable ready to dilute pharmaceutical composition is further diluted with sodium chloride solution or dextrose solution to obtain a final diluted melphalan composition before administering to the patient in need thereof. Further, the present invention provides process for the preparation of the said composition and its use for the treatment of multiple myeloma.
DETAILED DESCRIPTION
Unless otherwise indicated, terms in this specification are intended to have their ordinary meaning in the relevant art.
The present invention related to stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. Further, the present invention provides process for the preparation of the said composition and its use for the treatment of multiple myeloma. The term “Melphalan” used throughout the specification refers to not only their base per se, but also their other pharmaceutically acceptable salt, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof, preferably Melphalan Hydrochloride.
The term “liquid pharmaceutical composition” refers to a pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients. This liquid pharmaceutical composition is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition, which is further diluted with sodium chloride or dextrose to obtain final diluted melphalan composition before administering to the patient in the need thereof.
The term “pharmaceutically acceptable” means salt, carriers, excipients, and other formulation ingredients that are compatible with all other pharmaceutical ingredients of a composition and are not deleterious to an individual treated with composition.
The term “diluent vehicle” refers to a vehicle composition which is used to first dilute the liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof. The diluent vehicle comprises of cyclodextrin derivative, sodium chloride, one or more solvents and optionally buffering agent.
The term “ready to dilute pharmaceutical composition” refers to a stable, liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, which is first diluted with a diluent vehicle comprising cyclodextrin derivative, sodium chloride, one or more solvents and optionally buffering agent to obtain a stable ready to dilute pharmaceutical composition. The said stable ready to dilute pharmaceutical composition is stable for at least 72 hours when stored at 2-8 °C and for at least 1 hour when stored at room temperature (25 °C).
The term “final diluted melphalan composition” refers to liquid pharmaceutical composition of melphalan diluted with diluent vehicle wherein diluent vehicle contains cyclodextrin derivative, sodium chloride, one or more solvents and optionally buffering agent to obtain stable ready to dilute melphalan composition, wherein the obtained stable ready to dilute melphalan composition is further diluted with sodium chloride solution or dextrose solution to obtain a final diluted melphalan composition, which is administered to the patient in need thereof. The term “stable” as used throughout the specification, refers to a pharmaceutical composition in which the active pharmaceutical ingredients melphalan is present in an amount of at least 90% of the original label specified amount for each such ingredient during storage at 2-8 °C and 25 °C. The term “Impurity D” of melphalan as used throughout the specification, refers to below structure:
Figure imgf000012_0001
The term “Impurity G” of melphalan as used throughout the specification, refers to below structure:
Figure imgf000013_0001
The term “total impurities” of melphalan as used throughout the specification, refers to identified or unidentified degradation product or impurity structurally related with Melphalan which are arising from a manufacturing process or during storage of material.
In one of the embodiments, the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof and one or more pharmaceutical acceptable excipients.
In one of another embodiments, the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients.
In yet another embodiment, the present invention is to provide a process for preparation of liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients comprises the step of:
(a) mixing the solvents to obtain the clear solution;
(b) dissolving sodium chloride to the clear solution obtained in step a);
(c) dissolving one or more antioxidant to the solution obtained in step b); (d) dissolving melphalan or its pharmaceutically acceptable salt in solution obtained in step c) and making up the volume.
(e) filtering the solution obtained in step d) and filling the filtered solution in suitable vials.
The one or more solvents can be selected from the group comprising of but not limited to dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N- methylpyrrolidone, dimethylisosorbide, ethanol, propylene glycol, glycerine, polyethylene alcohol, propylene glycol esters, polyethylene glycols and the like. Preferred solvents are polyethylene glycols (PEG) and propylene glycol.
The anti-oxidant can be selected from the group comprising of but not limited to butylated hydroxyanisole, butylated hydroxyltoluene, tocopherol, ethylenediaminetetraacetic acid, monothioglycerol, ascorbic acid and their esters, L-cysteine, parabens, benzyl alcohol, propyl gallate, thioglycolic acid, tartaric acid, citric acid, or mixture thereof. Most preferred anti-oxidant is Monothioglycerol.
In one of the preferred embodiments, liquid pharmaceutical composition comprising melphalan HC1, monothioglycerol, sodium chloride, propylene glycol and polyethylene glycol.
In some of the embodiment, the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salt thereof. In some of the embodiments, the diluent vehicle comprises cyclodextrin derivative, sodium chloride, one or more solvents and optionally buffering agent.
In some of the embodiment, the diluent vehicle may be present in vial or Pre-Filled Syringe (PFS).
In one of the preferred embodiments, cyclodextrin derivative is present in less than 270 mg/ ml of total volume of diluent vehicle, more preferably less than 250 mg/ml of cyclodextrin, most preferably less than 200 mg/ ml of cyclodextrin of total volume of diluent vehicle. Accordingly, the diluent vehicle having a volume of 9 mL shall contain around 400 mg to 2450 mg, 500 mg to 2250 mg, 600 to 1800 mg of cyclodextrin derivatives of total weight of the diluent vehicle composition.
Cyclodextrins (CDs) derivatives are water soluble macrocyclic oligosaccharides with a-D-glucose units linked by a-(l- 4) glycosidic bonds, widely used to solubilize various water insoluble drugs. It is driven by non-covalent interactions such as van der Waals forces, hydrogen bonding and hydrophobic interactions. Additionally, complex formation of CDs with drugs improve stability due to decrease in hydrolysis.
The cyclodextrin derivative can be selected from the group comprising of but not limited to a, b and g-cyclodextrin and cyclodextrins modified with alkyl-, hydroxy alkyl, dialkyl-, and sulfoalkyl-ether modified cyclodextrins such as methyl or hydroxypropyl b-cyclodextrins (HPpCD), methyl-and-ethyl-P-cyclodextrin, sulfoalkylether-substituted beta-cyclodextrin, Betadex sulfobutyl ether sodium, sulfobutylether-P-cyclodextrin (SBECD) and the like. Most preferred cyclodextrin is Betadex sulfobutyl ether sodium.
In some of the embodiment, sodium chloride may be present in 0.9% of the total weight of the diluent vehicle. In some of the embodiment, the diluent vehicle comprises cyclodextrin derivative, sodium chloride, one or more solvents and optionally buffering agent, wherein the said diluent vehicle is used to dilute the stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, to provide a stable ready to dilute pharmaceutical composition having pH of about 2-5.
In some of the embodiment, the diluent vehicle comprises cyclodextrin derivative, sodium chloride, one or more solvents and buffering agent, wherein the said diluent vehicle is used to dilute the liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, to provide a stable ready to dilute pharmaceutical composition having pH of about 4-5. The said buffering agents are, such as, but not limited to, citrate buffer, acetate buffers, phosphate buffer, amino acids, and the like. Preferred buffers are sodium citrate anhydrous and sodium acetate monohydrate.
In some of the embodiment, the diluent vehicle also contains water for injection as a preferred solvent.
In some of the embodiments, stable liquid pharmaceutical composition comprising 50 mg/ml of melphalan HC1, which is first diluted with 9 ml of diluent vehicle to provide the 5mg/ml of stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salt.
In some of the embodiment, the stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salts has a pH of about 2-5.
In one of the preferred embodiments, the stable ready to dilute pharmaceutical composition comprises cyclodextrin derivative, wherein the said cyclodextrin derivative is present in a ratio of less than 50: 1 relative to the melphalan or its pharmaceutically acceptable salt. In some of the embodiment, the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salt thereof, wherein the said stable ready to dilute composition is stable for at least 72 hours when stored at 2-8 °C and for at least 1 hour when stored at room temperature (25 °C) .
In one of the preferred embodiments, the stable ready to dilute pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt and cyclodextrin derivatives is stable for at least 72 hours when stored at 2-8 °C and for at least 1 hour when stored at room temperature (25 °C), wherein the cyclodextrin derivative is present in a ratio of less than 50:1 relative to the melphalan or its pharmaceutically acceptable salts.
In yet another embodiment, the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition, and the said stable ready to dilute composition is further diluted with sodium chloride solution or dextrose solution to obtain final diluted melphalan composition, which is administered to the patient in need thereof.
In one of the preferred embodiments, the stable ready to dilute pharmaceutical composition is further diluted with 0.9% sodium chloride solution or 5% dextrose solution to obtain final diluted melphalan composition, which is administered to the patient in need thereof. In yet another embodiment, the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition, and the said stable ready to dilute composition is further diluted with 0.9% sodium chloride solution or 5% dextrose solution to obtain a final diluted melphalan composition for the stability study.
In yet another embodiment, the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to obtain a stable ready to dilute pharmaceutical composition, and the said stable ready to dilute pharmaceutical composition is further diluted with 0.9% sodium chloride solution and 5% dextrose solution to obtain a final diluted melphalan composition, wherein the said final diluted composition is stable for at least 2 hours when stored at 25 °C.
In yet another embodiment, the present invention is to provide a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 7.5% (w/w) of Impurity D when stored at 2-8 °C for at least 3 months.
In one of the preferred embodiments, the present invention is to provide a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 2% (w/w) of Impurity D when stored at 2-8 °C for at least 3 months.
In yet another embodiment, the present invention is to provide a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 7.5% (w/w) of Impurity D when stored at 25 °C for at least 3 months.
In one of the preferred embodiments, the present invention is to provide a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 2% (w/w) of Impurity D when stored at 25 °C for at least 3 months.
In yet another embodiment, the present invention is to provide a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 1% (w/w) of Impurity G when stored at 2-8 °C for at least 3 months.
In one of the preferred embodiments, the present invention is to provide a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 0.6% (w/w) of Impurity G when stored at 2-8 °C for at least 3 months.
In yet another embodiment, the present invention is to provide a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 1% (w/w) of Impurity G when stored at 25 °C for at least 3 months.
In one of the preferred embodiments, the present invention is to provide a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 0.6% (w/w) of Impurity G when stored at 25 °C for at least 3 months.
In yet another embodiment, the present invention is to provide a stable, ready to dilute pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 10% (w/w) of total impurity, when stored at 2-8 °C for at least 3 months.
In one of the preferred embodiments, the present invention is to provide a stable, ready to dilute pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 5% of total impurity when stored at 2-8 °C for at least 3 months.
In yet another embodiment, the present invention is to provide a stable, ready to dilute pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 10% (w/w) of total impurity after being stored at 25 °C for at least 3 months.
In one of the preferred embodiments, the present invention is to provide a stable, ready to dilute pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 5% of total impurity after being stored at 25 °C for at least 3 months.
In yet another embodiment, the present invention is to provide a stable, ready to dilute pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition is used for the treatment of multiple myeloma.
EXAMPLES:
The present invention has been described by way of example only. It is to be recognized that modifications falling within the scope and spirit of the claims, which would be obvious to a person skilled in the art based upon the disclosure herein, are also considered to be included within the scope of this invention. The scope of the invention is in no manner limited by the disclosed example.
Example 1: Liquid melphalan composition
Figure imgf000021_0001
Manufacturing Process: (a) mixing the solvents to obtain the clear solution;
(b) dissolving sodium chloride to the clear solution obtained in step a);
(c) dissolving one or more antioxidant to the solution obtained in step b);
(d) dissolving melphalan or its pharmaceutically acceptable salt in solution obtained in step c) and making up the volume. (e) filtering the solution obtained in step d) and filling the filtered solution in suitable vials.
Example 2: Liquid melphalan composition
Figure imgf000022_0001
Manufacturing Process:
(a) mixing propylene glycol and polyethylene glycol 400 to obtain the clear solution; (b) dissolving sodium chloride to the clear solution obtained in step a);
(c) dissolving monothioglycerol to the solution obtained in step b);
(d) dissolving melphalan or its pharmaceutically acceptable salt in solution obtained in step c) and making up the volume.
(e) filtering the solution obtained in step d) and filling the filtered solution in suitable vials.
Example 3: Liquid melphalan composition
Figure imgf000022_0002
Manufacturing Process: (a) mixing propylene glycol and polyethylene glycol 400 to obtain the clear solution;
(b) dissolving sodium chloride to the clear solution obtained in step a);
(c) dissolving butylated hydroxytoluene and citric acid to the solution obtained in step b); (d) dissolving melphalan or its pharmaceutically acceptable salt in solution obtained in step c) and making up the volume. (e) filtering the solution obtained in step d) and filling the filtered solution in suitable vials.
Example 4: Liquid melphalan composition
Figure imgf000023_0001
Manufacturing Process:
(a) mixing propylene glycol and polyethylene glycol 400 to obtain the clear solution;
(b) dissolving sodium chloride to the clear solution obtained in step a); (c) dissolving alpha tocopherol to the solution obtained in step b);
(d) dissolving melphalan or its pharmaceutically acceptable salt in solution obtained in step c) and making up the volume.
(e) filtering the solution obtained in step d) and filling the filtered solution in suitable vials.
Example 5: Composition of diluent vehicle
Figure imgf000023_0002
Stability Study: Table 1: Stability data of Liquid melphalan composition of Example 2 at 25 °C/65% RH and 2-8 °C storage condition
Figure imgf000024_0001
Table 2: Stability data of diluted melphalan solution with diluent solution of 50 mg/mL SBE-CD in 0.9% Sodium chloride under different time interval at storage conditions of 2-8 °C and 25 °C
Figure imgf000024_0002
Table 3: Stability data of diluted melphalan solution with diluent solution of 200 mg/mL SBE-CD in 0.9% Sodium chloride under different time interval at storage condition of 2-8 °C and 25 °C.
Figure imgf000024_0003
Figure imgf000025_0001
Table 4: Stability data of diluted melphalan solution with diluent solution of 250 mg/mL SBE-CD in 0.9% Sodium chloride under different time interval at storage condition of 2-8 °C and 25 °C
Figure imgf000025_0002
Table 5: Stability data of diluted melphalan solution with diluent solution of 250 mg/mL SBE-CD and 4.5 mg/mL Sodium Citrate in 0.9% Sodium chloride under different time interval at storage condition of 2-8 °C and 25 °C
Figure imgf000025_0003
Figure imgf000026_0001
Table 6: Stability data of diluted melphalan solution with diluent solution of 250 mg/mL SBE-CD and 4.5 mg/mL Sodium Acetate in 0.9% Sodium chloride under different time interval at storage condition of 2-8 °C and 25 °C
Figure imgf000026_0002
The above data shows impurity D and total impurity not more than 2% and 4% respectively in the ready to dilute melphalan formulation, indicative of stability of melphalan HC1 in the drug product. Further there is no precipitation observed even after 72 hours when stored at 2-8 °C Storage.
Table 7: Stability data of final diluted melphalan composition
The liquid pharmaceutical composition of melphalan diluted with diluent vehicle where in diluent vehicle contains 250 mg/mL SBE-CD in 0.9% Sodium chloride to obtained ready to dilute melphalan composition and stored at 25 °C for 1 hour. The resulted ready to dilute melphalan composition is further diluted with 0.9% Sodium Chloride to obtain 0.45 mg/mL concentration of final diluted melphalan composition. The results of stability data for final diluted melphalan composition is summarized in below table.
Figure imgf000027_0001
Table 8: Stability data of final diluted melphalan composition
The liquid pharmaceutical composition of melphalan diluted with diluent vehicle where in diluent vehicle contains 250 mg/mL SBE-CD and 4.5 mg/mL Sodium Acetate in 0.9% Sodium chloride to obtained ready to dilute melphalan composition and stored at 25 °C for 1 hour. The resulted ready to dilute melphalan composition is further diluted with 0.9% Sodium Chloride and 5% dextrose injection to obtain 0.45 mg/mL concentration of final diluted melphalan composition. The results of stability data for final diluted melphalan composition is summarized in below table.
Figure imgf000028_0001
The above data shows impurity D, impurity G and total impurity are not more than specified limit in the formulation, which is indicative of stability of melphalan HC1 in the drug product at 25 °C.
The stability data as mentioned above indicate that the liquid pharmaceutical composition of melphalan or its pharmaceutically acceptable salt thereof are stable. Further, the ready to dilute melphalan composition is stable for at least 72 hours at 2-8 °C and for at least 1 hours at 25 °C. Also, the final diluted melphalan composition obtained after dilution with 0.9% sodium chloride or 5% dextrose is stable for at least 2 hours at 25 °C.

Claims

We Claims:
1. A stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salts thereof, wherein the said stable ready to dilute pharmaceutical composition is stable for at least 72 hours when stored at 2-8°C.
2. The stable liquid pharmaceutical composition according to claim 1 , wherein the said stable ready to dilute pharmaceutical composition is stable for at least 1 hour when stored at 25°C.
3. The stable liquid pharmaceutical composition according to claim 1, comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients.
4. The stable liquid pharmaceutical composition according to claims 1, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salt thereof, wherein the said diluent vehicle comprises cyclodextrin derivative, sodium chloride, one or more solvents and optionally buffering agent.
5. The stable liquid pharmaceutical composition according to claims 1 , wherein the stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salts thereof comprises cyclodextrin derivative, wherein the said cyclodextrin derivative is present in a ratio of less than 50:1 relative to the melphalan or its pharmaceutically acceptable salt.
6. The stable liquid pharmaceutical composition according to claims 1 , wherein the stable ready to dilute pharmaceutical composition is further diluted with 0.9% sodium chloride solution or 5% dextrose solution to obtain final diluted melphalan composition, which is administered to the patient in need thereof.
7. The stable liquid pharmaceutical composition according to claims 1 , wherein the stable ready to dilute pharmaceutical composition is further diluted with 0.9% sodium chloride solution or 5% dextrose solution to obtain final diluted melphalan composition, wherein the said final diluted composition is stable for at least 2 hours when stored at 25°C.
8. The stable liquid pharmaceutical composition according to claims 1, wherein the said stable liquid pharmaceutical composition contains not more than 7.5% (w/w) of Impurity D, not more than 1% (w/w) of Impurity G, and not more than 10% of total impurity, when stored at 2-8 °C and 25 °C for at least 3 months.
9. The stable liquid pharmaceutical composition according to claims 1, wherein the said composition is used for the treatment of multiple myeloma.
10. A process for the preparation of stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients comprising the steps of: a) mixing the solvents to obtain the clear solution; b) dissolving sodium chloride to the clear solution obtained in step a); c) dissolving one or more antioxidant to the solution obtained in step b); d) dissolving melphalan or its pharmaceutically acceptable salt in solution obtained in step c) and making up the volume. e) filtering the solution obtained in step d) and filling the filtered solution in suitable vials.
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