Classifications

• • 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
  • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • 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

Definitions

• the present invention relates to parenteral compositions of bendamustine and process for preparation thereof.
• Chemically bendamustine hydrochloride is lH-benzimidazole-2-butanoic acid, 5- [bis(2-chloroethyl)amino]-l methyl-, mono hydrochloride. Its empirical formula is C) 6H2 i Ci 2 N 3 0 2 . HC1, with structural formula as follows:
• bendamustine is available as powder for IV infusion strengths of 100 mg/vial, 25 mg/vial and also as solution for IV infusion in the strengths of 180 mg/2ml (90 mg/ml) and 45 mg/0.5ml (90 mg/ml), with trade name Treanda ® - by- - Cephalon.
• US 8,436,190 disclose lyophilized pharmaceutical composition of bendamustine.
• Inventors of the present invention have developed stable ready to use parenteral compositions of bendamustine using alternative solvent systems.
• the present invention relates to parenteral compositions of bendamustine.
• One embodiment of the present invention relates to ready to use parenteral composition
• parenteral composition comprising bendamustine or its pharmaceutically acceptable salt, diethylene glycol monoethyl ether and a polar solvent selected from N-Methyl-2-pyrrolidone (NMP), and Polyethylene glycol.
• NMP N-Methyl-2-pyrrolidone
• polar solvent selected from N-Methyl-2-pyrrolidone (NMP), and Polyethylene glycol.
• bendamustine compositions for the treatment of chronic lymphocytic leukemia and B-cell non-Hodgkin lymphoma.
• the present invention relates to parenteral compositions of bendamustine. More particularly, the present invention disclose ready to use parenteral compositions of bendamustine in the form of solution.
• active ingredient or “active agent” or “drug” used interchangeably, is defined to mean active drug (e.g. bendamustine), that induce a desired pharmacological or physiological effect.
• bendamustine as used herein according to the present invention includes bendamustine in the form of free base, a pharmaceutically acceptable salt thereof, amorphous bendamustine, crystalline bendamustine or any isomer, derivative, ' hydrate, solvate, or prodrug or combinations thereof.
• bendamustine hydrochloride More preferably, bendamustine hydrochloride monohydrate.
• pharmaceutically acceptable means that which is useful in preparing a pharmaceutical composition that is generally safe and non-toxic.
• excipients as used herein means a component of a pharmaceutical product that is not an active ingredient.
• the excipients that are useful in preparing a pharmaceutical composition are generally safe and non-toxic.
• parenteral means administration through intravenous, intramuscular, subcutaneous, intracutaneous, intra-articular, intrathecal routes of administration, preferably, intravenous.
• ready to use composition refers to the composition which avoids reconstitution and may require dilution with a suitable diluent before administration to the patient.
• solvent refers to an ingredient used for dissolving an active ingredient.
• Suitable polar solvents that can be used according to the present invention includes N- Methyl-2-pyrrolidone, l,3-dimethyl-2-imidazolidinone, dimethylacetamide, acetone, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethyl formamide, propylene carbonate, alkyl alcohols, ethylene glycol, propylene glycol, butylene glycol, glycerin, polysorbates, polyalkylene glycols such as polyethylene glycol, and primary amides and combinations thereof.
• N-methyl-2-pyrrolidone polyethylene glycol and combinations thereof.
• N-Methyl-2-pyrrolidone as used in the present invention is synonymously referred as l-Methyl-2-pyrrolidinone, 1 -methyl- 5 -pyrrolidinone, lS methyl-a- pyrrolidinone, N-methyl-g-butyrolactam, Nmethyl-2-pyrrolidinone, 1- methylazacyclopentan-2-one, N methylpyrrolidonum, MP, NMP, Pharmasolve, m-Pyrol.
• Diethylene glycol monoethyl ether marketed by Gattefosse under the brand name
• Transcutol ® is used as a co-solvent in the present invention in an amount of from 0.01ml to 1 ml preferably, from 0.1 to 0.5ml.
• One embodiment of the present invention relates to ready to use parenteral composition
• parenteral composition comprising bendamustine or its pharmaceutically acceptable salt, diethylene glycol monoethyl ether and a polar solvent selected from N-Methyl-2-pyrrolidone (NMP), and Polyethylene glycol.
• NMP N-Methyl-2-pyrrolidone
• composition according to the present invention is in the form of solution, suspension, emulsion or lyophilized powder.
• polar solvent selected from N-Methyl-2-pyrrolidone (NMP), and Polyethylene glycol.
• the present invention further comprise one or more other pharmaceutically acceptable excipients selected from a bulking agent, a solubilizer, a buffer, a pH adjustment aid, a chelating agent, an antioxidant, an antibacterial preservative or combinations thereof.
• Bulking agents that may be included along with the present invention includes but not limited to mannitol, lactose, sucrose, sodium chloride, trehalose, dextrose, starch, hydroxyethylstarch, cellulose, cyclodextrins, glycine, or mixtures thereof.
• SOlubilizers used according to the present invention can ⁇ be ⁇ surface ⁇ active ⁇ agents7 co-solvents and complexing agents or combinations thereof.
• Surface active agents that may be included along with the present invention are hydrophilic in nature and includes but are not limited to sorbitan fatty acid esters, polysorbates, poloxamers, oleoyl and linoleoyl polyoxylglycerides (such as Labrafil), caprylocaproyl polyoxylglycerides (such as Labrasol), Medium-chain triglycerides (such as Labrafac lipophile), propylene glycol dicaprylocaprate (such as Labrafac ® PG) or mixtures thereof.
• Buffers as used in the present invention includes an acid or a base and its conjugate base or acid, respectively.
• Suitable buffers include mixtures of weak acids and alkali metal salts (e.g., sodium, potassium) of the weak acids, such as acetate, citrate, tartarate, phosphate, benzoate and bicarbonate buffers and combinations thereof.
• pH adjustment aids according to the present invention includes but are not limited to tartaric acid, citric acid, malic acid, sodium chloride, potassium chloride, sodium hydroxide, potassium hydroxide,' sodium carbonate, meglumine and combinations thereof.
• Chelating agents according to the present invention includes but are not limited to ethyl enetetraamineacetic acid, ethylenediaminetetraacetic acid (EDTA), and salts, derivatives and combinations thereof.
• Antioxidants according to the present invention includes but are not limited to ascorbic acid, sodium sulfite, sodium bisulfite and sodium metabisulfite and combinations thereof.
• Antibacterial preservatives includes but not limited to phenylmercuric nitrate, thiomersal, benzalkonium chloride, benzethonium chloride, phenol, cresol and chlorobutanol and combinations thereof.
• compositions of the present invention can preferably be diluted using 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/ 0.45% Sodium Chloride Injection, USP before parenteral administration.
• the composition of the present invention is useful for the treatment of chronic lymphocytic leukemia and B-cell non-Hodgkin lymphoma.
• step 2 was pre-filtered using 0.45 ⁇ sterile grade filters
• step 3 pre-filtered solution of step 3 was filtered through 0.22 ⁇ sterile grade filters
• step 4 filtered bulk solution of step 4 was filled into USP Type I amber glass vials,
• step 5 vials of step 5 were stoppered, sealed and stored at 2 to 8 °C.
• step 2 was pre-filtered using 0.45 ⁇ sterile grade filters
• step 3 pre-filtered solution of step 3 was filtered through 0.22 ⁇ sterile grade filters
• step 4 filtered bulk solution of step 4 was filled into USP Type I amber glass vials,
• step 2 was pre-filtered using 0.45 ⁇ sterile grade filters
• step 3 pre-filtered solution of step 3 was filtered through 0.22 ⁇ sterile grade filters
• step 4 filtered bulk solution of step 4 was filled into USP Type I amber glass vials,
• step 5 vials of step 5 were stoppered, sealed and stored at 2 to 8 °C.
• step 3 solution of step 3 was pre-filtered using 0.45 ⁇ sterile grade filters
• step 4 pre-filtered solution of step 4 was filtered through 0.22 ⁇ sterile grade filters
• step 6 filtered bulk solution of step 5 was filled into USP Type I amber glass vials, 7. vials of step 6 were stoppered, sealed and stored at 2 to 8 °C.
• step 3 solution of step 3 was pre-filtered using 0.45 ⁇ sterile grade filters
• step 4 pre-filtered solution of step 4 was filtered through 0.22 ⁇ sterile grade filters
• step 5 filtered bulk solution of step 5 was filled into USP Type I amber glass vials,
• step 6 vials of step 6 were stoppered, sealed and stored at 2 to 8 °C.
• composition prepared according to the example 4 was stored at 2-8°C and was tested for impurities at specific intervals. Results of which are as follows:

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

Priority Applications (2)

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Related Child Applications (1)

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• 2015
  • 2015-01-12 WO PCT/IN2015/000015 patent/WO2015104720A2/en active Application Filing
  • 2015-01-12 IN IN151CH2014 patent/IN2014CH00151A/en unknown
• 2016
  • 2016-07-07 US US15/203,999 patent/US20160310598A1/en not_active Abandoned
• 2017
  • 2017-07-10 US US15/645,237 patent/US20170304451A1/en not_active Abandoned

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