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WO2006085336A2 - Compositions pharmaceutiques stabilisees comprenant un glycoside d'anthracycline - Google Patents

Compositions pharmaceutiques stabilisees comprenant un glycoside d'anthracycline Download PDF

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Publication number
WO2006085336A2
WO2006085336A2 PCT/IN2006/000010 IN2006000010W WO2006085336A2 WO 2006085336 A2 WO2006085336 A2 WO 2006085336A2 IN 2006000010 W IN2006000010 W IN 2006000010W WO 2006085336 A2 WO2006085336 A2 WO 2006085336A2
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Prior art keywords
solution
pharmaceutical composition
group
sodium
inert gas
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PCT/IN2006/000010
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English (en)
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WO2006085336A3 (fr
Inventor
Satish Chandra Upadhyay
Manoj Kumar Pananchukunnath
Ajeet Kumar Singh
Deepti Jain
Deepak Judgelal Parshottamdas
Rama Mukherjee
Anand C Burman
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Dabur Pharma Limited
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Priority to AU2006213440A priority Critical patent/AU2006213440A1/en
Publication of WO2006085336A2 publication Critical patent/WO2006085336A2/fr
Publication of WO2006085336A3 publication Critical patent/WO2006085336A3/fr

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/549—Sugars, nucleosides, nucleotides or nucleic 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
    • A61K9/0012—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 relates to a stabilized, intravenously injectable anthracycline glycoside pharmaceutical composition and a process for preparation thereof.
  • Anthracycline glycosides are a class of therapeutically and commercially valuable antineoplastic compounds widely used for treatment of tumors, such as sarcomas, carcinomas, lymphomas, melanoma, myeloma and leukaemias in both human and animal hosts.
  • anthracycline glycosides such as doxorubicin hydrochloride (US 3,590,028), epirubicin hydrochloride (US 4,058,519), idarubicin hydrochloride (US 4,046,878) and daunorubicin hydrochloride (US 3,997,662)
  • the former two are widely prescribed in clinical practice.
  • doxorubicin hydrochloride and epirubicin hydrochloride were available to patients as freeze-dried/lyophilized dry powders, which could be reconstituted prior to administration with diluting fluids such as sodium chloride.
  • compositions are associated with certain limitations such as: a) Double Handling: To administer a lyophilized preparation, double handling of the drug is required. The lyophilized cake has to be first reconstituted and then administered. b) Dissolution Time of the cake: In some cases, the complete dissolution of the powder may require prolonged shaking because of solubilization problems.
  • EP 0 273 603 derived out of same priority applications of the twelve Gatti et al patents, mentioned hereinbefore, claims a ready- to-use, storage stable solution of anthracycline glycoside wherein pH is adjusted using a glycine buffer, the claims for which were already given up by the applicants/ inventors during the prosecution of the corresponding applications in the USA.
  • Kaplan et. al. in EP 0,299,527; EP 0,299,528; EP 0,372,888; and EP 0,372,889 teach the use of an anti-oxidant in stabilization of both aqueous and non-aqueous solutions of doxorubicin!
  • the anti-oxidants disclosed by Kaplan et al are selected from the group of ⁇ - tocopherol, sodium formaldehyde bisulphate, tert-butylhydroquinone and sodium acetone bisulfite, and the solvent medium are selected from the group of water, 90-110% (v/v) propylene glycol, 1,2 -dihydroxybutane or 1,3-dihydroxypropane and 0-10% (v/v) water.
  • anthracycline glycosides in general, to pH, temperature, nature of solvent used, type of anti-oxidant used etc., and, moreover, because of their therapeutic and commercial importance a need exists for pharmaceutical compositions of the said anthracycline glycosides which not only exhibit excellent storage stability but also are not very much sensitive to the vagaries of critical parameters like pH, temperature etc.
  • the present invention is a step forward in this direction and provides a stable pharmaceutical composition comprising anthracycline glycosides.
  • An object of the present invention is to provide a pharmaceutical composition comprising anthracycline glycosides which are storage stable.
  • a further object of the present invention is to provide a process for preparation of storage stable pharmaceutical compositions comprising anthracycline glycosides.
  • Yet further object of the present invention is to provide a method for treatment of tumors in both humans or animals, comprising administration of the stable pharmaceutical composition of anthracycline glycosides to the human or animal, in need of said treatment.
  • the present inventors have found that essentially the same stability could be obtained in solutions of anthracycline glycosides in an aqueous solvent wherein the pH of the said solution is either not adjusted with a pH modifying agent or wherein the pH of the solution is adjusted using a pH modifier such as physiologically acceptable acids or buffers, by contacting the said solutions of anthracycline glycosides with the inert gas.
  • the solutions were found to be stabilized by contacting the said solutions with an inert gas.
  • an inert gas is purged into the solution of an anthracycline glycoside, which is filled thereafter into containers and sealed.
  • the containers could be blanketed with the inert gas.
  • One of the most prominent degradation product formed during storage of a solution of anthracycline glycoside is its corresponding aglycone compound, which essentially is produced by hydrolysis of the anthracycline glycoside.
  • the major degradation product for Epirubicin Hydrochloride is its aglycone part viz. doxorubicinone.
  • doxorubicinone Besides doxorubicinone, other impurities may exist in the solution, the amount of which varies depending upon the conditions employed for manufacturing and/or storage of anthracycline solutions such as temperature, pH etc.
  • the present inventors have found that formation of prominent degradation product viz., corresponding aglycone compound in an aqueous solution of an anthracycline glycoside is drastically reduced by contacting the said solution of the anthracycline glycosides with an inert gas, thereby stabilizing the solution.
  • the present invention provides a stabilized pharmaceutical composition comprising of an anthracycline glycoside in an aqueous solution.
  • the present invention provides a stabilized pharmaceutical composition
  • a stabilized pharmaceutical composition comprising of an anthracycline glycoside in an aqueous solution having an intrinsic pH of 3.5 - 4.0.
  • the present invention provides a stabilized pharmaceutical composition
  • a stabilized pharmaceutical composition comprising of an anthracycline glycoside in an aqueous solution having an intrinsic pH of 3.5 - 4.0, wherein the solution is purged with an inert gas.
  • the present invention provides a stabilized pharmaceutical composition in a hermetically sealed vial or other container comprising of an anthracycline glycoside in an aqueous solution having an intrinsic pH of 3.5 - 4.0, wherein the solution is purged with an inert gas and filled into containers, and optionally providing a blanket of inert gas in the overhead space of the container, prior to sealing of the containers.
  • the present invention provides a stabilized pharmaceutical composition
  • a stabilized pharmaceutical composition comprising of an anthracycline glycoside in an aqueous solution having a pH in the range of between 2.5 to 4.5, adjusted with a physiologically acceptable pH modifier.
  • the present invention provides a stabilized pharmaceutical composition
  • a stabilized pharmaceutical composition comprising of an anthracycline glycoside in an aqueous solution having a pll in the range of between 2.5 to 4.5, adjusted with a physiologically acceptable pH modifier, wherein the solution is purged with an inert gas.
  • the present invention provides a stabilized pharmaceutical composition in a hermetically sealed vial or other container comprising of an anthracycline glycoside in an aqueous solution having a pH in the range of between 2.5 to 4.5, adjusted with a physiologically acceptable pH modifier, wherein the solution is purged with an inert gas and filled into containers, and optionally providing a blanket of an inert gas in the overhead space of the container, prior to the sealing of the containers.
  • the present invention provides a stabilized pharmaceutical composition comprising of Epirubicin Hydrochloride in an aqueous solution, having an intrinsic pH of 3.5 - 4.0 and purged with an inert gas.
  • the present invention provides a stabilized pharmaceutical composition in a hermetically sealed vial or other container comprising of Epirubicin Hydrochloride in an aqueous solution having an intrinsic pH of 3.5-4.0, purged with an inert gas and optionally providing a blanket of inert gas in the overhead space of the container, prior to sealing of the containers.
  • the present invention provides a stabilized pharmaceutical composition
  • a stabilized pharmaceutical composition comprising of Epirubicin Hydrochloride in an aqueous solution having a pH in the range of between 2.5 to 4.5, adjusted with a physiologically acceptable pH modifier, wherein the solution is purged with an inert gas.
  • the present invention provides a stabilized pharmaceutical composition in a hermetically sealed vial or other container, comprising of Epirubicin Hydrochloride in an aqueous solution having a pH in the range of between 2.5 to 4.5 adjusted with a physiologically acceptable pH modifier, wherein the solution is purged with an inert gas and optionally providing a blanket of inert gas in the overhead space of the container, prior to sealing of the containers.
  • the present invention provides a stabilized pharmaceutical composition
  • a stabilized pharmaceutical composition comprising of Doxorubicin Hydrochloride in an aqueous solution having an intrinsic pH of 3.5 - 4.0 and purged with an inert gas.
  • the present invention provides a stabilized pharmaceutical composition in a hermetically sealed vial or other container comprising of Doxorubicin
  • Hydrochloride in an aqueous solution having an intrinsic pH of 3.5-4.0 purged with an inert gas and optionally providing a blanket of inert gas in the overhead space of the container, prior to sealing of the containers.
  • the present invention provides a stabilized pharmaceutical composition
  • a stabilized pharmaceutical composition comprising of Doxorubicin Hydrochloride in an aqueous solution having a pH in the range of between 2.5 to 4.5, adjusted with a physiologically acceptable pH modifier, and purged with an inert gas.
  • the present invention provides a stabilized pharmaceutical composition in a hermetically sealed vial or other container, comprising of Doxorubicin Hydrochloride in an aqueous solution having a pH in the range of between 2.5 to 4.5 adjusted with a physiologically acceptable pH modifier, purged with an inert gas and optionally providing a blanket of inert gas in the overhead space of the container, prior to sealing of the containers.
  • the present invention provides a process for preparation of stabilized pharmaceutical compositions of anthracycline glycosides in an aqueous solvent comprising the steps of:
  • the present invention provides a process for preparation of a stabilized pharmaceutical composition of Epirubicin Hydrochloride in an aqueous solvent comprising of steps: (i) preparing a solution of epirubicin hydrochloride in an aqueous solvent; (ii) optionally adjusting the pH with a physiologically acceptable pH modifier; (iii) purging the solution with an inert gas; (iv) filling the solution into containers; and
  • the present invention provides a process for preparation of a stabilized pharmaceutical composition of Doxorubicin Hydrochloride in an aqueous solvent comprising of steps:
  • the present invention provides a stable pharmaceutical composition of anthracycline glycosides for treatment of tumors in both human and animal hosts, such as sarcomas, carcinomas, lymphomas, melanoma, myeloma and leukaemias.
  • the present invention provides a stable pharmaceutical composition of Epirubicin Hydrochloride for treatment of tumors in both human and animal hosts, such as sarcomas, carcinomas, lymphomas, melanoma, myeloma and leukaemias.
  • the present invention provides a stable pharmaceutical composition of Doxorubicin Hydrochloride for treatment of tumors in both human and animal hosts, such as sarcomas, carcinomas, lymphomas, melanoma, myeloma and leukaemias.
  • compositions of the present invention comprise of an aqueous solution of an anthracycline glycoside, an inert gas and optionally a pH modifying agent.
  • compositions of the present invention comprising of an aqueous solution of an anthracycline glycoside having a pH in the range of between 2.5 to 4.5, wherein the pH of the solution is achieved by simple dissolution of the anthracycline glycoside in an aqueous solvent or it could be achieved through adjustment with a pH modifying agent.
  • pH modifying agents that can be used for adjustment of pH includes both physiologically acceptable acids and buffers.
  • Physiologically acceptable acids that can be employed are selected from the group of citric acid, acetic acid, tartaric acid, ascorbic acid, aspartic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, hydrochloric acid, sulphuric acid, phosphoric acid, formic acid, diatrozoic acid, glutamic acid, lactic acid, maleic acid, succinic acid, carbonic acid and the like.
  • Physiologically acceptable buffers that can be employed are selected from the group of a chloride buffer, an acetate buffer, a phosphate buffer, a maleate buffer, a glycine buffer and the like.
  • the buffer solutions used in adjusting the pH of the said pharmaceutical composition of an aqueous solutions of an anthracycline glycoside are prepared as per the method described in the British Pharmacopoeia, 2004, Volume IV, Appendix I D, wherein for instance: i) An Acetate Buffer of pH 2.8 is prepared by dissolving 4 gm of anhydrous sodium acetate in about 840 ml of water, adding sufficient glacial acetic acid to adjust pH to 2.8 (about 155 ml) and diluting to 1000 ml with water, ii) An Acetate Buffer of pH 3.4 is prepared by mixing 5 volumes of 0.1M sodium acetate with 95 volumes of O. IM acetic acid.
  • An Acetate Buffer of pH 3.5 is prepared by dissolving 25 gm of ammonium acetate in 25 ml of water and adding 38 ml of 7M hydrochloric acid. Adjusting the pH to 3.5 with either 2M hydrochloric acid or 6M ammonia and diluting to 100 mi with water.
  • An Acetate Buffer of pH 3.7 is prepared by dissolving 10 g of anhydrous sodium acetate in 300 ml of water, adjusting to pH 3.7 with glacial acetic acid and diluting to 1000 ml with water. If necessary, readjusting to pH 3.7, with glacial acetic acid or anhydrous sodium acetate as required, before use.
  • a Chloride Buffer of pH 2.0 is prepared by dissolving 6.57 g of potassium
  • a Glycine Buffer of pH 2.9 is prepared by dissolving 6.0 gm of glycine and 4.68 gm of sodium chloride in 10 litres of water. Adjusting the pH with 1 M hydrochloric acid (about 30 ml).
  • a Phosphate Buffer of pH 3.0 is prepared by dissolving 34 gm of potassium dihydrogen orthophosphate in 250 ml of water and adjusting the pH of the solution to 3.0 with orthophosphoric acid.
  • a Phosphate Buffer of pH 3.5 is prepared by dissolving 68 gm of potassium dihydrogen orthophosphate in 1000 ml of water and adjusting the pH of the solution to 3.5 with orthophosphoric acid.
  • Suitable aqueous solvents are those which are physiologically acceptable and include but are not limited to water, or mixtures of water with physiologically acceptable water miscible solvents such as ethanol, propylene glycol, polyethylene glycols, and the like.
  • the pharmaceutical composition may further contain a co-solvent, tonicity adjusting agent, anti-oxidant, chelating agent, and preservatives.
  • Suitable co-solvents that can be employed include but are not limited to, benzyl benzoate, N, N Dimethylacetamide, ethanol, glycerin, polyethylene glycol, propylene glycol, etc.
  • Suitable tonicity adjusting agents include but are not limited to, physiologically acceptable inorganic chlorides, e.g. sodium chloride; dextrose; lactose; mannitol; sorbitol; sucrose and the like.
  • Suitable anti-oxidants include but are not limited to, acetone sodium bisulfite, ascorbic acid, sodium bisulfite, butylated hydroxy anisole, butylated hydroxy toluene, cystein, dithionite sodium, gentisic acid, gentisic acid ethanolamine, glutamate monosodium, sodium metabisulfite, potassium metabisulfite, monothioglycerol, propyl gallate, sodium sulfite, sodium thioglycolate and the like.
  • Suitable chelating agents that can be employed include but are not limited to, calcium disodium EDTA, disodium EDTA, sodium EDTA, diethylenetriaminepentaacetic acid and the like.
  • Suitable preservatives include but are not limited to, esters of parahydroxybenzoic acid (e.g. methyl, ethyl, propyl and butyl esters or their mixtures), benzalkonium chloride, benzethonium chloride, benzyl alcohol, chlorobutanol, m-cresol, phenol, phenyl mercuric nitrate, thiomersal and the like.
  • esters of parahydroxybenzoic acid e.g. methyl, ethyl, propyl and butyl esters or their mixtures
  • benzalkonium chloride benzethonium chloride
  • benzyl alcohol chlorobutanol
  • m-cresol phenol
  • phenyl mercuric nitrate thiomersal and the like.
  • the anthracycline glycoside is present in a concentration from about 0.1 mg/ml to 100 mg/ml.
  • concentration is from about 1.0 mg/ml to 20 mg/ml and most preferably it is present in a concentration of about 2 mg/ml.
  • the pharmaceutical composition of the present invention can be prepared first, by dissolution of the respective anthracycline glycoside in the respective aqueous solvent.
  • the pH of such solutions are in the range of about 3.5 to 4.0, which if necessary can be adjusted to the desired range from about 2.5 to 4.5 through addition of the pH modifying agent mentioned hereinbefore.
  • the solution is purged with an inert gas for a suitable period of time, whereafter the solution is passed through a sterilizing grade filter, the sterilized solution is then further filled into suitable containers and optionally, blanketing the overhead space of the container with an inert gas prior to sealing of the container.
  • an inert gas is one, which does not react with any one of the ingredients or the carriers present in the pharmaceutical composition.
  • One or more additional ingredients such as tonicity adjusting agents, chelating agents, anti-oxidants, preservatives, of the kind specified herein before, may be added to the solution prior to passing the solution through the sterilizing filter.
  • the inert gas is introduced into the aqueous solution of anthracycline glycoside by means of a sparger.
  • Sparging is a means of bubbling of a desired gas through a solution under suitable pressure to saturate the solution with the said gas.
  • the sparger can be constructed from a material selected from the group consisting of carbon steel and low-alloy steels or elastomeric material.
  • the tube sparger preferably consists of a perforated elastomer tube, or perforated / sintered steel tube the volumetric flow rate of the inert gas, for e.g. carbon dioxide introduced via the tube sparger is 0.01 to 0.4 m 3 (STP)/h per m 3 .
  • the inert gas is introduced into the carrier through thousands of tiny pores, creating small fine bubbles.
  • compositions of the invention can be prepared using conventional pharmaceutical batch tanks, filters and holding vessels. All the containers are of pharmaceutical 316L grade. Suitable packaging for the anthracycline glycoside solutions may be the approved containers for parenteral use, such as plastic and glass containers, ready-to- use syringes and the like. Preferably the container is a sealed glass container, e.g vial or an ampoule. A hermetically sealed glass vial is the preferred container.
  • compositions thus prepared exhibit excellent storage stability as would be evident from the examples given hereinbelow, which are not limiting and should not be construed as limiting the scope of the invention.
  • compositions are highly effective for treatment in both human and animal hosts, of tumors, such as sarcomas, carcinomas of prostate, lung, breast, bladder, thyroid, ovary etc., lymphomas including Hodgk ⁇ n and no-Hodgkin, neuroblastoma, leukaemias including acute lymphoblastic leukemia and acute myeloblasts leukemia, Wilm's tumor, melanoma, myeloma etc.
  • tumors such as sarcomas, carcinomas of prostate, lung, breast, bladder, thyroid, ovary etc.
  • lymphomas including Hodgk ⁇ n and no-Hodgkin
  • neuroblastoma including acute lymphoblastic leukemia and acute myeloblasts leukemia
  • Wilm's tumor melanoma
  • myeloma myeloma etc.
  • compositions can be administered by rapid intravenous injection or infusion.
  • F ⁇ r e.g. a composition containing Epirubicin Hydrochloride can be administered by a rapid intravenous infusion or injection of 75 to 90 mg/m 2 given in a single infusion to be repeated at 21 days.
  • a composition containing Doxorubicin Hydrochloride can be administered by a rapid intravenous infusion or injection of 60 to 75 mg/m 2 given in a single infusion to be repeated at 21 days.
  • Double distilled water was taken in a vessel and hydrochloric acid added dropwise to adjust the pH of the water to 3.0.
  • Epirubicin Hydrochloride was added to the above solution and stirred until the entire drug dissolved.
  • Example - 2 The solution was then sparged with carbon dioxide. Volumes of 5 ml of the solution were distributed into Type I colorless glass vials. The overhead space was blanketed with carbon dioxide and then immediately stoppered with rubber stoppers and sealed with aluminium caps.
  • Example - 2 The solution was then sparged with carbon dioxide. Volumes of 5 ml of the solution were distributed into Type I colorless glass vials. The overhead space was blanketed with carbon dioxide and then immediately stoppered with rubber stoppers and sealed with aluminium caps.
  • Example - 2 The solution was then sparged with carbon dioxide. Volumes of 5 ml of the solution were distributed into Type I colorless glass vials. The overhead space was blanketed with carbon dioxide and then immediately stoppered with rubber stoppers and sealed with aluminium caps.
  • Example - 3 The solution was then sparged with Nitrogen gas. Volumes of 5 ml of the solution were distributed into Type I colorless glass vials. The overhead space was blanketed with nitrogen and then immediately stoppered with rubber stoppers and sealed with aluminium caps.
  • Example - 3
  • volumes of 5 ml of the solution were distributed into polypropylene vials.
  • the vials were immediately stoppered with rubber stoppers and sealed with, aluminium caps.
  • Glycine buffer solution was prepared by dissolving the required ingredients in double distilled water taken in a vessel. Epirubicin hydrochloride was added to the glycine buffer solution and stirred to dissolve the entire drug. The solution was then sparged with carbon dioxide and then the solution was filtered through a 0.22 ⁇ micro porous membrane. Volumes of 25 ml of the solution were distributed into Type I colorless glass vials. The overhead space was blanketed with carbon dioxide and then immediately stoppered with rubber stoppers and sealed with aluminium caps.
  • Glycine buffer solution was prepared by dissolving the required ingredients in double distilled water taken in a vessel. Epirubicin hydrochloride was added to the glycine buffer solution and stirred to dissolve the entire drug. Volumes of 25 ml of the solution were distributed into Type I colorless glass vials. The vials were immediately stoppered with rubber stoppers and sealed with aluminium caps.
  • Glycine buffer solution was prepared by dissolving the required ingredients in double distilled water taken in a vessel. Epirubicin hydrochloride was added to the glycine buffer solution and stirred to dissolve the entire drug. The solution was then sparged with nitrogen and then the solution was filtered through a 0.22 ⁇ micro porous membrane. Volumes of 25 ml of the solution were distributed into Type I c ⁇ l ⁇ rless glass vials. The overhead space was blanketed with nitrogen and then immediately stoppered with rubber stoppers and sealed with aluminium caps The stability of the solution in the vials as obtained from Examples 4, 5 & 6 was tested. The vials were stored at temperatures of 4O 0 C for up to 7 days and 25°C for up to 3 months. The stability data obtained, using high performance (HPLC) for the determination of potency, are summarized in Table - 3. Table -3
  • Maleate buffer solution was prepared by dissolving the required ingredients in double distilled water taken in a vessel. Epirubicin hydrochloride was added to the maleate buffer solution and stirred to dissolve the entire drug. The solution was then sparged with carbon dioxide and then the solution was filtered through a 0.22 ⁇ micro porous membrane. Volumes of 25 ml of the solution were distributed into Type I colorless glass vials. The overhead space was blanketed with carbon dioxide and then immediately stoppered with rubber stoppers and sealed with aluminium caps.
  • Maleate buffer solution was prepared by dissolving the required ingredients in double distilled water taken in a vessel. Epirubicin hydrochloride was added to the maleate buffer solution and stirred to dissolve the entire drug. Volumes of 25 ml of the solution were distributed into Type I colorless glass vials. The vials were immediately stoppered with rubber stoppers and sealed with aluminium caps.
  • Maleate buffer solution was prepared by dissolving the required ingredients in double distilled water taken in a vessel. Epirubicin hydrochloride was added to the maleate buffer solution and stirred to dissolve the entire drug. The solution was then sparged with nitrogen and then the solution was filtered through a 0.22 ⁇ micro porous membrane. Volumes of 25 ml of the solution were distributed into Type I colorless glass vials. The overhead space was blanketed with nitrogen and then immediately stoppered with rubber stoppers and sealed with aluminium caps.
  • the stability of the solution in the vials as obtained from Examples 7, 8 & 9 was tested.
  • the vials were stored at temperatures of 40 0 C for up to 7 days and 25°C for up to 3 months.
  • the stability data obtained, using high performance (HPLC) for the determination of potency, are summarized in Table - 4.
  • Phosphate buffer solution was prepared by dissolving the required ingredients in double distilled water taken in a vessel. Epirubicin hydrochloride was added to the phosphate buffer solution and stirred to dissolve the entire drug. Sodium chloride solution in double distilled water was added to the drug solution. The final solution was then sparged with carbon dioxide and the solution was filtered through a 0.22 ⁇ micro porous membrane. Volumes of 25 ml of the solution were distributed into Type I colorless glass vials. The overhead space was blanketed with carbon dioxide and then immediately stoppered with rubber stoppers and sealed with aluminium caps.
  • Phosphate buffer solution was prepared by dissolving the required ingredients in double distilled water taken in a vessel. Epirubicin hydrochloride was added to the phosphate buffer solution and stirred to dissolve the entire drug. Volumes of 25 ml of the solution were distributed into Type I colorless glass vials. The vials were immediately stoppered with rubber stoppers and sealed with aluminium caps.
  • Phosphate buffer solution was prepared by dissolving the required ingredients in double distilled water taken in a vessel. Epirubicin hydrochloride was added to the phosphate buffer solution and stirred to dissolve the entire drug. Sodium chloride solution in double distilled water was added to the drug solution. The final solution was then sparged with nitrogen and the solution was filtered through a 0.22 ⁇ micro porous membrane. Volumes of 25 ml of the solution were distributed into Type I colorless glass vials. The overhead space was blanketed with nitrogen and then immediately stoppered with rubber stoppers and sealed with aluminium caps.
  • Epirubicin Hydrochloride was added to double distilled water, and stirred until the entire drug dissolved. The solution was then sparged with nitrogen. Volumes of 5 ml of the solution were distributed into Type I colorless glass vials. The overhead space was blanketed with nitrogen and then immediately stoppered with rubber stoppers and sealed with aluminium caps.
  • Example - 15 Epirubicin Hydrochloride was added to double distilled water, and stirred until the entire drug dissolved. Volumes of 5 ml of the solution were distributed into polypropylene vials. The vials were immediately stoppered with rubber stoppers and sealed with aluminium caps.
  • the stability of the solution in the vials as obtained from Examples 13, 14 & 15 was tested.
  • the vials were stored at temperatures of 40 0 C for up to 7 days and 25°C for up to 3 months.
  • the stability data obtained, using high performance (HPLC) for the determination of potency, are reported in Table - 6.

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Abstract

L'invention porte sur une composition pharmaceutique stable comprenant un glycoside d'anthracycline dans un solvant aqueux. La composition comprend éventuellement un gaz inerte.
PCT/IN2006/000010 2005-02-11 2006-01-16 Compositions pharmaceutiques stabilisees comprenant un glycoside d'anthracycline WO2006085336A2 (fr)

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AU2006213440A AU2006213440A1 (en) 2005-02-11 2006-01-16 Stabilized anthracycline glycoside pharmaceutical compositions

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102078303A (zh) * 2010-12-30 2011-06-01 深圳万乐药业有限公司 盐酸依达比星冻干制剂的制备方法
CN102614118A (zh) * 2012-03-15 2012-08-01 北京协和药厂 注射用盐酸表柔比星制剂的制备方法及制剂

Citations (5)

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Publication number Priority date Publication date Assignee Title
EP0273603A2 (fr) * 1986-12-05 1988-07-06 FARMITALIA CARLO ERBA S.r.l. Solutions injectables prêtes à l'emploi contenant un agent antitumeur du type anthracycline glucoside
EP0299527A1 (fr) * 1987-07-16 1989-01-18 Bristol-Myers Squibb Company Solutions aqueuses de chlorhydrate de doxorubicine
EP0372888A1 (fr) * 1988-12-05 1990-06-13 Bristol-Myers Squibb Company Solutions aqueuses de doxorubicine
WO2004011033A1 (fr) * 2002-07-24 2004-02-05 Universite Catholique De Louvain Méthode de synthèse de conjugués anthracycline-peptide
US20040077559A1 (en) * 1985-08-02 2004-04-22 Pharmacia & Upjohn Company Injectable ready-to-use solutions containing an antitumor anthracycline glycoside

Patent Citations (5)

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Publication number Priority date Publication date Assignee Title
US20040077559A1 (en) * 1985-08-02 2004-04-22 Pharmacia & Upjohn Company Injectable ready-to-use solutions containing an antitumor anthracycline glycoside
EP0273603A2 (fr) * 1986-12-05 1988-07-06 FARMITALIA CARLO ERBA S.r.l. Solutions injectables prêtes à l'emploi contenant un agent antitumeur du type anthracycline glucoside
EP0299527A1 (fr) * 1987-07-16 1989-01-18 Bristol-Myers Squibb Company Solutions aqueuses de chlorhydrate de doxorubicine
EP0372888A1 (fr) * 1988-12-05 1990-06-13 Bristol-Myers Squibb Company Solutions aqueuses de doxorubicine
WO2004011033A1 (fr) * 2002-07-24 2004-02-05 Universite Catholique De Louvain Méthode de synthèse de conjugués anthracycline-peptide

Non-Patent Citations (1)

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Title
LOPEZ-COLON D ET AL: "Sonochemistry of antitumor quinones in argon-saturated aqueous solutions: enhanced ferricytochrome c reduction" ULTRASONICS: SONOCHEMISTRY, BUTTERWORTH-HEINEMANN, GB, vol. 11, no. 5, July 2004 (2004-07), pages 311-316, XP004510847 ISSN: 1350-4177 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102078303A (zh) * 2010-12-30 2011-06-01 深圳万乐药业有限公司 盐酸依达比星冻干制剂的制备方法
CN102614118A (zh) * 2012-03-15 2012-08-01 北京协和药厂 注射用盐酸表柔比星制剂的制备方法及制剂
CN102614118B (zh) * 2012-03-15 2014-04-30 北京协和药厂 注射用盐酸表柔比星制剂的制备方法及制剂

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