WO2006085336A2 - Stabilized anthracycline glycoside pharmaceutical compositions - Google Patents

Stabilized anthracycline glycoside pharmaceutical compositions Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
solution
pharmaceutical composition
group
sodium
inert gas
Prior art date
Application number
PCT/IN2006/000010
Other languages
French (fr)
Other versions
WO2006085336A3 (en
Inventor
Satish Chandra Upadhyay
Manoj Kumar Pananchukunnath
Ajeet Kumar Singh
Deepti Jain
Deepak Judgelal Parshottamdas
Rama Mukherjee
Anand C Burman
Original Assignee
Dabur Pharma Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dabur Pharma Limited filed Critical Dabur Pharma Limited
Priority to AU2006213440A priority Critical patent/AU2006213440A1/en
Publication of WO2006085336A2 publication Critical patent/WO2006085336A2/en
Publication of WO2006085336A3 publication Critical patent/WO2006085336A3/en

Links

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
    • A61K47/02—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.

Landscapes

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

Abstract

A stable pharmaceutical composition comprising an anthracycline glycoside in an aqueous solvent is disclosed. The composition optionally includes an inert gas.

Description

STABILIZED ANTHRACYCLINE GLYCOSIDE PHARMACEUTICAL COMPOSITIONS
FIELD OF THE INVENTION The present invention relates to a stabilized, intravenously injectable anthracycline glycoside pharmaceutical composition and a process for preparation thereof. BACKGROUND OF THE INVENTION
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. Amongst the known 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.
Earlier, 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.
Even though, stability of such reconstituted solutions were not of an issue, since such solutions had to be administered immediately or at the most within 8 to 24 hours of its preparation, however, such 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. c) Health Hazard:- Improper reconstitution of a lyophilized product sometimes results in the formation of air-borne droplets ("blow-back"), which, in the case of a potent antitumor agent such as an anthracycline glycoside may be a health hazard to the personnel making up the solution for injection. d) Improper Dose: There is always a problem in reconstituting a lyophilized formulation in that an inappropriate quantity of diluents may be used because of a different vial size. This could result in a improper dose being administered to a patient e) Cost of manufacture: The manufacture of a lyophilized formulation is quite costly, since it not only requires capital investment for installation of a lyophiliser, but also its maintenance. Research efforts all over the world have been directed towards development of ready-to-use solutions of anthracycline glycosides in suitable solvents to overcome the limitations associated with a freeze-dried/lyophilized composition. The important advances made in this direction are summarized hereinbelow: i) Ketchum et. al. in AmJ. Intrav.Ther.Clin Nutr., 1981, 8 , 15-18 have demonstrated that reconstituted solutions of a lyophilized powder of doxorubicin hydrochloride in 0.9% NaCl solution remain stable at room temperature or 50C for seven days.
However, this article does not indicate whether such compositions would have long-term stability. ii) Studies have been conducted to co-relate the stability of aqueous solutions of doxorubicin hydrocholoride with changes in pH and temperature as disclosed by Poochikinan et. al. in AmJ.Hosp.Pharm., 1981, 38, 483-486; Wesserman et. al. in Int. J. Pharmaceutics, 1983, H, 73-78; and Janssen et. al. in Int. J. Pharmaceutics, 1985, 23, 1-11, wherein the optimum stability was found at a pH in the range of 3-4, and temperature of about 4°C, with the rate of degradation increasing with increase in temperature, or at pH lower or higher of the above mentioned range, iii) Based, on the disclosures made by Poochikinan, Wesserman and Janssen, Gatti et. al. in US 4,946,831; US 5,124,318; US 5,124,317; US 6,107,285; US 5,977,082; US 6,284,738; US 6,087,340; US 6,632,799; US 6,596,697; US 2003/013666; US 2004/077559; and US 2004/077560 collectively disclose pharmaceutical compositions of an anthracycline glycoside, specially doxorubicin hydrochloride and epirubicin hydrochloride in a suitable aqueous solvent having a pH in the range of between 2.5 to 6.5, which exhibit good storage stability. The inventive step, if any, residing in the above publications specifically relates to adjustment of pH of the solution with a physiologically acceptable acid or a buffer.
Even though, the above mentioned patents collectively claim that an acid or a buffer could be utilized for adjustment of pH, however, from the data given in the above mentioned patent specifications as well as the declarations made by the applicants during prosecution of the said applications it would be abundantly evident that in the applicant's view adjustment of the pH with an acid shows vastly improved storage stability compared to those wherein pH has been adjusted with buffer, even though the pH in both the cases remain the same. Incidentally, a ready-to-use solution of both doxorubicin hydrochloride and epirubicin hydrochloride in water having a pH of 3.0, wherein, the said pH is adjusted using hydrochloric acid is currently marketed by M/S Pharmacia & Upjohn under the brand names Adriamycin® RDF / PFS and Ellence® respectively, which are apparently covered under US 4,946,831; US 5,124,318; US 5,124,317; US 6,107,285; US 5,977,082; US 6,284,738; US 6,087,340; US 6,632,799; US 6,596,697; US 2003/013666; US 2004/077559; and US 2004/077560 mentioned hereinbefore, (iv) Gatti el. al. in EP 0 273 603 claim a ready-to-use, storage stable, intravenously injectable, sterile, pyrogen-free injectable anthracycline glycoside compositions in an aqueous solution, wherein said solution has a pH adjusted to 2.5 to 3.5 with a glycine buffer.
It is rather intriguing to note that 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.
(v) 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 α - 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.
However, apart from α - tocopherol, rest of the anti-oxidants specified therein are not pharmaceutically acceptable, and hence their scope is limited. From the foregoing, it would be evident that numerous studies have been carried out for not only understanding the degradation pathways of solutions of anthracycline glycosides, specially in water but also in manufacture of a stabilized composition of the said anthracycline glycosides. It would be further evident that stability of such solutions has been found to be dependent on pH and temperature.
Because of the sensitivity of 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. OBJECTS OF THE INVENTION
An object of the present invention is to provide a pharmaceutical composition comprising anthracycline glycosides which are storage stable.
Another object of the invention is to provide a pharmaceutical composition comprising anthracycline glycosides, which are stable and undergo less degradation. Yet another object of the present invention is to provide a pharmaceutical composition comprising anthracycline glycosides, which are safe for administration.
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. SUMMARY OF THE INVENTION
In their endeavor to meet the objectives, the present inventors have found to their surprise thai a solution of an anthracycline glycoside in an aqueous solvent could be made stable i.e minimize formation of degradation products through contact of the said solution with an inert gas.
In particular, it was found that formation of degradation products could be minimized by purging a solution of an anthracycline glycoside with an inert gas and filling the said solution into containers and optionally providing a blanket of the inert gas in the overhead space of the container, prior to sealing of the containers.
Further, the inventors have found to their surprise that both minimization of degradation products as well as enhanced stability is achieved only through contact of an inert gas and are not particularly sensitive or dependent on the pH modification of the solution.
Furthermore, 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.
As mentioned hereinbefore, the solutions were found to be stabilized by contacting the said solutions with an inert gas. Typically, an inert gas is purged into the solution of an anthracycline glycoside, which is filled thereafter into containers and sealed. Alternatively, prior to sealing of the containers, 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. 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. Further, 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.
While, an inert gas such as nitrogen, argon, carbon dioxide etc. could be used for stabilization of the composition, however, carbon dioxide was found to give vastly superior results and hence, is the inert gas of choice. This would be evident from the comparative stability/degradation pattern of aqueous Epirubicin hydrochloride solutions made with or without purging of the inert gas and with or without pH adjustment as summarized in Table - 1. Table-l
Effect of Gas Purging and pH on Stability of Epirubicin Hydrochloride Aqueous Solutions
Solutions with Carbon dioxide purging and Solutions without purging and blanketing blanketing with carbon dioxide
Assay pH D Dooxxoorruubbii T Toottaall Assay pH Doxorubi Total cinone Impurities cinone Impurities
(% w/w) (% w/w)
NO pH ADJUSTMENT
Initial 99.70 3.96 0.012 0.770 95.15 4.24 0.144 3.077
7 D @ 400C 96.20 3.91 0.085 0.941 88.50 4.02 0.370 4.880 3M @ 25°C 95.15 4.07 0.083 1.689 74.90 3.74 0.520 7.695
pH ADJUSTED WITH HCl
Initial 102.20 2.92 0.016 0.496 101.50 2.88 0.040 1.270
7 D @ 400C 98.20 3.00 0.353 1.199 94.50 2.92 1.200 3.020 3M @ 25°C 93.60 3.32 0.496 1.772 89.05 2.98 1.600 3.032
pH ADJUSTED WITH GLYCINE BUFFER
Initial 98.25 2.92 0.014 0.717 100.80 2.37 0.038 0.670
7 D @ 400C 94.20 3.09 0.469 1.468 98.80 2.39 1.431 2.198 3M @ 25°C 88.45 3.15 0.519 2.326 90.70 2.79 1.959 3.389
pH ADJUSTED WITH MALEATE BUFFER
Initial 98.35 2.86 0.024 0.792 103.05 2.46 0.034 0.856
7 D @ 40°C 91.70 2.87 1.259 2.504 96.35 2.46 2.100 3.073 3M @ 25°C 83.75 3.09 1.539 4.124 86.80 2.77 3.126 5.346
pH ADJUSTED WITH PHOSPHATE BUFFER
Initial 97.15 3.01 0.030 0.600 103.00 2.66 0.021 0.699
7 D @ 40°C 93.15 3.14 0.991 1.937 96.60 2.67 0.678 1.715 3M @ 25°C 86.25 3.08 1.301 2.888 83.15 2.93 1.264 4.181
D-Days; M-Months
Thus, in accordance with the above, in one aspect, the present invention provides a stabilized pharmaceutical composition comprising of an anthracycline glycoside in an aqueous solution.
In another aspect, the present invention provides a stabilized pharmaceutical composition comprising of an anthracycline glycoside in an aqueous solution having an intrinsic pH of 3.5 - 4.0.
In yet another aspect, the present invention provides 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.
In still another aspect, 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.
In a further aspect, the present invention provides 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.
In yet further aspect, the present invention provides 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.
In another aspect, 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. In yet another aspect, 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.
In still another aspect, 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.
In a further aspect, the present invention provides 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.
In yet further aspect, 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.
In another aspect, the present invention provides 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.
In yet another aspect, 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.
In still another aspect, the present invention provides 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.
In a further aspect, 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.
In yet further aspect, the present invention provides a process for preparation of stabilized pharmaceutical compositions of anthracycline glycosides in an aqueous solvent comprising the steps of:
(i) preparing a solution of said anthracycline glycoside 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 (v) optionally, blanketing the overhead space of the containers with an inert gas prior to sealing of the containers.
In another aspect, 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
(v) optionally, blanketing the overhead space of the containers with an inert gas prior to sealing of the containers.
In yet another aspect, the present invention provides a process for preparation of a stabilized pharmaceutical composition of Doxorubicin Hydrochloride in an aqueous solvent comprising of steps:
(i) preparing a solution of doxorubicin 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 (v) optionally, blanketing the overhead space of the containers with an inert gas prior to sealing of the containers. In still another aspect, 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.
In a further aspect, 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.
In yet further aspect, 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. DETAILED DESCRIPTION OF THE INVENTION
The pharmaceutical compositions of the present invention comprise of an aqueous solution of an anthracycline glycoside, an inert gas and optionally a pH modifying agent.
As mentioned hereinbefore, the pharmaceutical 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. Illustrative of such 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. iii) 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. iv) 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. v) A Chloride Buffer of pH 2.0 is prepared by dissolving 6.57 g of potassium
/ chloride in water, adding 119.0 ml of 0.1 M hydrochloric acid VS and diluting to 1000 ml with water. vi) 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). vii) 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. viii) 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 that can be employed 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 that can be employed 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 that can be employed 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.
Typically the anthracycline glycoside is present in a concentration from about 0.1 mg/ml to 100 mg/ml. In particular the 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.
Typically the pharmaceutical composition of the present invention can be prepared first, by dissolution of the respective anthracycline glycoside in the respective aqueous solvent. Typically depending on the anthracycline glycoside used and the 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.
By definition, 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 m3 (STP)/h per m3. The inert gas is introduced into the carrier through thousands of tiny pores, creating small fine bubbles.
The pharmaceutical 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.
The pharmaceutical 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.
The pharmaceutical 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 Hodgkϊn and no-Hodgkin, neuroblastoma, leukaemias including acute lymphoblastic leukemia and acute myeloblasts leukemia, Wilm's tumor, melanoma, myeloma etc.
The pharmaceutical compositions can be administered by rapid intravenous injection or infusion. Fυr e.g. a composition containing Epirubicin Hydrochloride can be administered by a rapid intravenous infusion or injection of 75 to 90 mg/m2 given in a single infusion to be repeated at 21 days. Similarly a composition containing Doxorubicin Hydrochloride can be administered by a rapid intravenous infusion or injection of 60 to 75 mg/m2 given in a single infusion to be repeated at 21 days.
These and other aspects of the present invention will become apparent upon reference to the following detailed description of experiments, which are incorporated here for the purpose of illustration only and should in no way be considered as limiting the scope of the present invention. Example - 1
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.
- 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
To a solution of epirubicin hydrochloride in double distilled water, a solution of sodium chloride in double distilled water was added. Hydrochloric acid was then added drop wise, under stirring to adjust the pH of the solution to 3.0. Further double distilled water was added to bring the solution to its final volume.
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
To a solution of sodium chloride in double distilled water, epirubicin hydrochloride was added and stirred until the entire drug dissolved. Hydrochloric acid was then added drop wise, under stirring to adjust the pH of the solution to 3.0. Further double distilled water was added to bring the solution to its final volume.
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 1 , 2 and 3 was tested. The vials were stored at temperatures of 25°C for up to 3 months. The stability data obtained, using high performance (HPLC) for the determination of potency, are summarized in Table - 2.
Table - 2
Effect of Gas on Stability of Epirubicin Hydrochloride solutions, the pH of which is adjusted with Hydrochloric Acid
Solutions with Carbon Solutions with Nitrogen Solutions without purging dioxide purging and purging and blanketing and blanketing with carbon blanketing dioxide or Nitrogen pH D T.I PH D TJ pH D T.I
Figure imgf000016_0001
A - Assay of Epirubicin; D - Doxorubicinone content (% w/w); T.I. - Total Impurities
Example - 4
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 μ 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. Example - 5
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. Example - 6
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 μ micro porous membrane. Volumes of 25 ml of the solution were distributed into Type I cυlυrless 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 4O0C 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
Stability Data of Epirubicin Hydrochloride solutions the pH of which is adjusted with Glycine Buffer
Figure imgf000017_0001
A - Assay of Epirubicin; D - Doxorubicinone content (% w/w); T.I. - Total Impurities
Example - 7
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 μ 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. Example - 8
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. Example - 9
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 μ 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 400C 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.
Table - 4
Stability Data of Epirubicin Hydrochloride solutions the pH of which is adjusted with Maleate Buffer
Figure imgf000018_0001
A - Assay of Epirubicin; D - Doxorubicinone content (% w/w); T.I. - Total Impurities
Example - 10
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 μ 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. Example - 11
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. Example - 12
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 μ 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 10, 11 & 12 was tested. The vials were stored at temperatures of 400C 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 - 5. , Table - 5
Stability Data of Epirubicin Hydrochloride solutions the pH of which is adjusted with Phosphate Buffer
Figure imgf000019_0001
A - Assay of Epirubicin; D - Doxorubicinone content (% w/w); T.I. - Total Impurit es Example - 13
Epirubicin Hydrochloride was added to double distilled water, and stirred until the entire drug dissolved. The solution was then sparged with carbon dioxide. 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. Example - 14
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 400C 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.
Table - 6 Effect of Various Gases on the Stability of Epirubicin Hydrochloride solutions
Without pH adjustment
Figure imgf000020_0001
Figure imgf000021_0001
A - Assay of Epirubicin; D - Doxorubicinone content (% w/w); T.I. - Total Impurities

Claims

We claim:
1. A stable pharmaceutical composition comprising an anthracycline glycoside in an aqueous solvent.
2. A stable pharmaceutical composition comprising an anthracycline glycoside in an aqueous solvent and an inert gas.
3. A pharmaceutical composition as claimed in claim 1 or 2, wherein the said solution has a pH of from about 2.5 to 4.5.
4. A pharmaceutical composition as claimed in claim 1 or 2, wherein the anthracycline glycoside is selected from the group consisting of doxorubicin hydrochloride, epirubicin hydrochloride, idarubicin hydrochloride and daunorubicin hydrochloride.
5. A pharmaceutical composition as claimed in any preceding claim, wherein the aqueous solvent is water or mixtures of water with physiologically acceptable water miscible solvents.
6. A pharmaceutical composition as claimed in claim 5, wherein the physiologically acceptable water miscible solvent is selected from the group consisting of ethanol, propylene glycol, and polyethylene glycols.
7. A pharmaceutical composition as claimed in claim 5, wherein the final water content in the solution of anthracycline glycoside ranges from 0.1 to 99.99%.
8. A pharmaceutical composition as claimed in any preceding claim, wherein the said solution additionally contains a co-solvent, a tonicity-adjusting agent, an anti-oxidant, a chelating agent, and a preservative.
9. A pharmaceutical composition as claimed in claim 8, wherein the co-solvent is selected from the group consisting of benzyl benzoate, N, N Dimethylacetamide, ethanol, glycerin, polyethylene glycol, and propylene glycol.
10. A pharmaceutical composition as claimed in claim 8, wherein the tonicity adjusting agent is selected from the group consisting of sodium chloride, dextrose, lactose, mannitol, sorbitol and sucrose.
11. A pharmaceutical composition as claimed in claim 8, wherein the antioxidant is selected from the group consisting of sodium bisulfite, ascorbic acid, 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, and sodium thioglycolate.
12. A pharmaceutical composition as claimed in claim 8, wherein the chelating agent is selected from the group consisting of calcium disodium EDTA, disodium EDTA, sodium EDTA and diethylenetriaminepentaacetic acid.
13. A pharmaceutical composition as claimed in claim 8, wherein the preservative is selected from the group consisting of esters of parahydroxybenzoic acid, benzalkonium chloride, benzethonium chloride, benzyl alcohol, chlorobutanol, m-cresol, phenol, phenyl mercuric nitrate and thiomersal.
14. A pharmaceutical composition as claimed in any one of claims 2 to 13, wherein the inert gas is selected from nitrogen, argon or carbon dioxide.
15. A process for preparation of a stable pharmaceutical composition of claims 1 and 2 comprising the steps of:
• preparing a solution of said anthracycline glycoside in an aqueous solvent;
• optionally adjusting the pH with a physiologically acceptable acid or buffer;
• optionally adding a co-solvent, tonicity-adjusting agent, anti-oxidant, chelating agent, and/or preservatives; • contacting the solution with an inert gas;
• filling the solution into containers; and
• optionally, blanketing the overhead space of the containers with an inert gas prior to sealing.
16. Λ process as claimed in claim 15, wherein the anthracycline glycoside is selected from the group consisting of Doxorubicin Hydrochloride, Epirubicin hydrochloride, Idarubicin Hydrochloride and Daunorubicin Hydrochloride.
17. A process as claimed in claim 15 or 16, wherein the aqueous solvent is water or mixtures of water with physiologically acceptable water miscible solvents.
18. A process as claimed in claim 17, wherein the physiologically acceptable water miscible solvent is selected from the group consisting of ethanol, propylene glycol, and polyethylene glycols.
19. A process as claimed in claim 17, wherein the final water content in the solution of anthracycline glycoside ranges from 0.1 to 99.99%.
20. A process as claimed in any one of claims 15 to 19, wherein the co-solvent is selected from the group consisting of from benzyl benzoate, N, N Dimethylacetamide, ethanol, glycerin, polyethylene glycol, and propylene glycol,
21. A process as claimed in any one of claims 15 to 20, wherein the tonicity adjusting agent is selected from the group consisting of sodium chloride, dextrose, lactose, mannitol, sorbitol and sucrose.
22. A process as claimed in any one of claims 15 to 21, wherein the antioxidant is selected from the group consisting of sodium bisulfite, ascorbic acid, butylated hydroxy anisole, butylated hydroxy toluene, cystein, dithionite sodium, gentisic acid, gentisic acid ethanolamine, glutamate monosodium, sodium metabisulfϊte, potassium metabisulfϊte, monothioglycerol, propyl gallate, sodium sulfite, and sodium thioglycolate.
23. A process as claimed in any one of claims 15 to 22, wherein the chelating agent is selected from the group consisting of calcium disodium EDTA, disodium
EDTA, sodium EDTA and diethylenetriaminepentaacetic acid.
24. A process as claimed in any one of claims 15 to 23, wherein the preservative is selected from the group consisting of esters of parahydroxybenzoic acid, benzalkonium chloride, benzethonium chloride, benzyl alcohol, chlorobutanol, m-cresol, phenol, phenyl mercuric nitrate and thiomersal.
25. A process as claimed in any one of claims 15 to 24, wherein the contact of the inert gas with the drug solution is by means of purging the said inert gas into the drug solution.
26. A process as claimed in claim 25, wherein the inert gas is carbon dioxide, argon or nitrogen.
27. A process as claimed in claim 25, wherein the purging of the gas into the drug solution is carried out for a period from about 30 minutes to about 240 minutes.
28. A process as claimed in claim 25, wherein the purging process is carried out in an assembly having sparger surface pore size from 0.2 μm to the 0.31 inch.
29. A method for treatment of a human or an animal cancerous disease, comprising administration of a pharmaceutical composition of anthracycline glycosides of claims 1 and 2, to the human or animal in need of said treatment.
PCT/IN2006/000010 2005-02-11 2006-01-16 Stabilized anthracycline glycoside pharmaceutical compositions WO2006085336A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2006213440A AU2006213440A1 (en) 2005-02-11 2006-01-16 Stabilized anthracycline glycoside pharmaceutical compositions

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN301/DEL/2005 2005-02-11
IN301DE2005 2005-02-11

Publications (2)

Publication Number Publication Date
WO2006085336A2 true WO2006085336A2 (en) 2006-08-17
WO2006085336A3 WO2006085336A3 (en) 2007-05-10

Family

ID=36649839

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2006/000010 WO2006085336A2 (en) 2005-02-11 2006-01-16 Stabilized anthracycline glycoside pharmaceutical compositions

Country Status (2)

Country Link
AU (1) AU2006213440A1 (en)
WO (1) WO2006085336A2 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102078303A (en) * 2010-12-30 2011-06-01 深圳万乐药业有限公司 Preparation method of freeze-dried idamycin hydrochloride preparation
CN102614118A (en) * 2012-03-15 2012-08-01 北京协和药厂 Preparation method for epirubicin hydrochloride preparation for injection and preparation

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0273603A2 (en) * 1986-12-05 1988-07-06 FARMITALIA CARLO ERBA S.r.l. Injectable ready-to-use solutions containing an antitumor anthracycline glycoside
EP0299527A1 (en) * 1987-07-16 1989-01-18 Bristol-Myers Squibb Company Doxorubicin hydrochloride aqueous solutions
EP0372888A1 (en) * 1988-12-05 1990-06-13 Bristol-Myers Squibb Company Doxorubicin aqueous solutions
WO2004011033A1 (en) * 2002-07-24 2004-02-05 Universite Catholique De Louvain Method for the synthesis of anthracycline-peptide conjugates
US20040077559A1 (en) * 1985-08-02 2004-04-22 Pharmacia & Upjohn Company Injectable ready-to-use solutions containing an antitumor anthracycline glycoside

Patent Citations (5)

* Cited by examiner, † Cited by third party
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 (en) * 1986-12-05 1988-07-06 FARMITALIA CARLO ERBA S.r.l. Injectable ready-to-use solutions containing an antitumor anthracycline glycoside
EP0299527A1 (en) * 1987-07-16 1989-01-18 Bristol-Myers Squibb Company Doxorubicin hydrochloride aqueous solutions
EP0372888A1 (en) * 1988-12-05 1990-06-13 Bristol-Myers Squibb Company Doxorubicin aqueous solutions
WO2004011033A1 (en) * 2002-07-24 2004-02-05 Universite Catholique De Louvain Method for the synthesis of anthracycline-peptide conjugates

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
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 (en) * 2010-12-30 2011-06-01 深圳万乐药业有限公司 Preparation method of freeze-dried idamycin hydrochloride preparation
CN102614118A (en) * 2012-03-15 2012-08-01 北京协和药厂 Preparation method for epirubicin hydrochloride preparation for injection and preparation
CN102614118B (en) * 2012-03-15 2014-04-30 北京协和药厂 Preparation method for epirubicin hydrochloride preparation for injection and preparation

Also Published As

Publication number Publication date
WO2006085336A3 (en) 2007-05-10
AU2006213440A1 (en) 2006-08-17

Similar Documents

Publication Publication Date Title
RU2101018C1 (en) Injection lyophilized preparations containing anthracycline glycosides or their pharmaceutically acceptable salts
EP1782816B1 (en) Water-based medicinal composition containing azithromycin and method of preparing the same
US5616588A (en) Rapamycin formulation for IV injection
RU2321412C2 (en) Novel solid preparation comprising block-copolymer and anthracycline antitumor preparation and method for its preparing
WO1999002158A1 (en) Stable medicinal compositions containing 4,5-epoxymorphinane derivatives
KR20010034240A (en) Medicinal compositions
BG60425B2 (en) Inoculation solutions containing antitumour anthracylin glycoside
AU2003223120B2 (en) Lyophilized and liquid preparations comprising a polysaccharide derivative of camptothecin
CN108601730B (en) Formulations of vancomycin
EP2922530B1 (en) Caspofungin acetate formulations
EP0299527B1 (en) Doxorubicin hydrochloride aqueous solutions
WO2022129263A1 (en) Aqueous solution
WO2008023807A1 (en) Stabilized pharmaceutical composition
WO2006085336A2 (en) Stabilized anthracycline glycoside pharmaceutical compositions
EP2911648B1 (en) Stable pharmaceutical composition of 5-aza-2'peoxyotipine
KR20020059592A (en) Formulations for parenteral use of estramustine phosphate and amino acids
AU632036B2 (en) Injectable ready-to-use solutions containing an antitumor anthracycline glycoside
CA2486571C (en) Pharmaceutical composition
KR20030009426A (en) Medicinal compositions containing camptothecin derivative and pH regulating agent
JP2020533318A (en) Pharmaceutical composition and preparation method of docetaxel conjugate
AU612916B2 (en) Doxorubicin aqueous solutions
KR100279341B1 (en) Stable injection solution of anti-malignant tumor drug doxorubicin and its preparation method
US20210137958A1 (en) Pharmaceutical compositions of decitabine
CN115671267A (en) Subcutaneous antibiotic pharmaceutical composition
JPH08231398A (en) Lyophilized preparation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2006213440

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 12007501710

Country of ref document: PH

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2006213440

Country of ref document: AU

Date of ref document: 20060116

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 2006213440

Country of ref document: AU

122 Ep: pct application non-entry in european phase

Ref document number: 06711353

Country of ref document: EP

Kind code of ref document: A2