WO2007134354A1 - Formulation pharmaceutique - Google Patents

Formulation pharmaceutique Download PDF

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Publication number
WO2007134354A1
WO2007134354A1 PCT/AT2007/000245 AT2007000245W WO2007134354A1 WO 2007134354 A1 WO2007134354 A1 WO 2007134354A1 AT 2007000245 W AT2007000245 W AT 2007000245W WO 2007134354 A1 WO2007134354 A1 WO 2007134354A1
Authority
WO
WIPO (PCT)
Prior art keywords
docetaxel
acid
base solution
solution according
solution
Prior art date
Application number
PCT/AT2007/000245
Other languages
German (de)
English (en)
Inventor
Reinhard Rametsteiner
Heinz Schnait
Original Assignee
Ebewe Pharma Ges.M.B.H. Nfg. Kg
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 Ebewe Pharma Ges.M.B.H. Nfg. Kg filed Critical Ebewe Pharma Ges.M.B.H. Nfg. Kg
Publication of WO2007134354A1 publication Critical patent/WO2007134354A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a stable ready-to-use docetaxel base solution for the preparation of an infusion solution.
  • Docetaxel is the international free name (INN) for a compound of the formula
  • Docetaxel belongs to the group of taxanes and is effective against cancer, in particular against breast and certain forms of lung cancer.
  • Docetaxel is marketed under the name "Taxotere" in the form of a concentrate for solution for infusion, each pack of Taxotere consisting of a vial containing the active substance docetaxel in polysorbate 80 as a solubilizer and an adjunct containing the solvent ethanol in water for injections
  • each pack of Taxotere consisting of a vial containing the active substance docetaxel in polysorbate 80 as a solubilizer and an adjunct containing the solvent ethanol in water for injections
  • the contents of the solvent vial must be aseptically removed by syringe and injected into the vial containing docetaxel in polysorbate 80.
  • the ready-to-use docetaxel base solution prepared in this way then contains, for example, 10 mg / ml docetaxel and must be used immediately for the Z preparation of an infusion solution are used, since this base solution according to the manufacturer at 2-8 0 C is stable for only about 8 hours.
  • a disadvantage is in particular the absolutely necessary and experience fehteransociiige dilution of the docetaxel-containing drug concentrate on the prescribed concentration of the base solution and the lack of durability of the basic solution.
  • the object of the present invention is therefore to provide such a basic solution.
  • the base solution prepared as described above from a package of Taxotere (ie, after dilution of the concentrate of docetaxine in polysorbate 80 with ethanol / water to a concentration of 10 mg / ml) has a pH of 4.93 by itself, containing 95.77 % Docetaxe! and is, as already mentioned, stable at about 2-8 ° C for about 8 hours, according to the technical information enclosed with each pack of Taxotere. In fact, it was found that when the base solution was stored at 40 ° C. for more than one month, a crystalline precipitate formed, rendering the base solution unusable.
  • a formulation was prepared analogously to the original product Taxotere, ie docetaxel was dissolved in a concentration of 40 mg / ml in polysorbate 80 and 0.5 ml of this solution were It.
  • the base solution thus prepared contained only 24.31% of the desired amount of docetaxel and had a pH of 6.63. After storage of the base solution at 40 ° C. for one month, the solution turned slightly yellow, had a pH of 6.52 and contained only 16.82% of the desired docetaxel amount of 10 mg / ml.
  • the solubilizer is selected from the group comprising a polyethylene glycol, a derivative thereof, polyethylene glycol-polypropylene glycol copolymer, polysorbate or mixtures thereof
  • the at least one acid present in the base solution according to the invention is a pharmaceutically acceptable organic acid, more preferably selected from the group consisting of lactic acid, tartaric acid, malic acid, citric acid, benzoic acid, acetic acid, toluenesulfonic acid, methanesulfonic acid and mixtures thereof.
  • the at least one acid present in the base solution according to the invention is a pharmaceutically acceptable inorganic acid, more preferably it is selected from the group comprising hydrochloric acid, phosphoric acid, sulfuric acid and mixtures thereof.
  • buffer solutions based on inorganic acids which provide a pH in the range according to the invention is also possible and within the scope of the present invention.
  • phosphoric acid (or phosphate buffer) as a pharmaceutically acceptable inorganic acid has been shown that in the course of storage of such a base solution, a characteristic decomposition or conversion product of docetaxel, namely the epimeric 7-epidocetaxe), surprisingly no longer occurs.
  • the ready-to-use docetaxel base solution of the invention comprises from 5 to 30 mg / ml of docetaxel.
  • the ready-to-use docetaxel base solution has a pH of less than 5, more preferably less than 4.5, and even more preferably less than 4.
  • the present invention will now be explained by way of some examples, to which it should not be limited. All percentages are in wt .-%.
  • An amount greater than 100% means that the formulation has a concentration of slightly more than 10 mg / ml (for example, due to weight or dilution).
  • the formulations are composed in detail as follows:
  • the pH was measured potentiometrically in the corresponding formulations after 1:10 dilution of the mobile phase base solution (40% ACN and 60% water). In determining the contaminants, the epimeric 7-epidocetaxel was measured at RRT 1.67.
  • the ready-to-use base solution When formulated with 50 mg tartaric acid, the ready-to-use base solution has a pH of 4.44 and contains 100.88% docetaxel. After one month of storage at 40 ° C., the base solution is still clear, has a pH of 4.38, and still contains 98.06% docetaxel (contamination RRT 1.670.45%).
  • the ready-to-use base solution When formulated with 100 mg tartaric acid, the ready-to-use base solution has a pH of 3.67 and contains 101. 88% docetaxel. After one month storage at 40 ° C., the base solution is still clear, has a pH of 3.66, and still contains 100.64% docetaxel (RRT 1 contamination, 49.10%).
  • the ready-to-use base solution When formulated with 200 mg tartaric acid, the ready-to-use base solution has a pH of 3.40 and contains 102.19% docetaxel. After one month of storage at 4O 0 C the base solution remains clear, has a pH of 3.33, and still contains 100.46% docetaxel (RRT 1.50 0.10% contamination).
  • the ready-to-use base solution When formulated with 50 mg citric acid, the ready-to-use base solution has a pH of 4.82 and contains 102.19% docetaxel. After one month storage at 4O 0 C, the basic solution still is clear, has a pH of 4.83, and still contains 99.57% Docetaxel (RRT 1.67 impurity 1, 15%).
  • the ready-to-use base solution When formulated with 100 mg citric acid, the ready-to-use base solution has a pH of 4.34 and contains 100.70% docetaxel. After one month storage at 40 ° C, the base solution is still clear, has a pH of 4.32 and still contains 99.59% docetaxel (contamination RRT 1, 670.24%).
  • the ready-to-use base solution When formulated with 200 mg citric acid, the ready-to-use base solution has a pH of 3.88 and contains 100.80% docetaxel. After one month storage at 4O 0 C, the basic solution still is clear, has a pH of 3.98, and still contains 99.23% Docetaxel (impurity RRT 1, 67 0,10%).
  • the ready-to-use base solution When formulated with 50 mg lactic acid, the ready-to-use base solution has a pH of 4.93 and contains 100.33% docetaxel. After one month of storage at 40 ° C., the base solution is still clear, has a pH of 5.00, and still contains 96.79% docetaxel (RRT 1.67 1.52% contamination).
  • the ready-to-use base solution When formulated with 100 mg lactic acid, the ready-to-use base solution has a pH of 4.70 and contains 103.21% docetaxel. After one month storage at 4O 0 C, the basic solution still is clear, has a pH of 4.79, and still contains 99.81% Docetaxel (impurity RRT 1, 67 1,20%).
  • the ready-to-use base solution When formulated with 200 mg of lactic acid, the ready-to-use base solution has a pH of 4.38 and contains 100.13% docetaxel. After one month storage at 4O 0 C, the basic solution still is clear, has a pH of 4.38, and still contains 97.68% Docetaxel (impurity RRT 1, 67 0,50%).
  • the formulations are composed in detail as follows:
  • the formulation was stable for 8 weeks at 40 ° C.
  • the formulation was found to be about 8 weeks at 4O 0 C stable.
  • the formulation was stable for over 8 weeks at 40 ° C.
  • the formulation was stable for 8 weeks at 40 ° C. 7)
  • the formulation was stable for 8 weeks at 40 ° C.
  • the formulation was stable in the stress test over 2 weeks even at 60 0 C. Noteworthy is the surprising absence or the low concentration of 7-epimers as degradation product in comparison with the other compositions according to the invention.

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

Abstract

La présente invention concerne une solution à base de docétaxel stable et prête à l'emploi, avec un pH inférieur à 6,6, comprenant du docétaxel, au moins un acide pharmaceutiquement acceptable et un agent de solubilisation approprié.
PCT/AT2007/000245 2006-05-23 2007-05-23 Formulation pharmaceutique WO2007134354A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AT8952006 2006-05-23
ATA895/2006 2006-05-23

Publications (1)

Publication Number Publication Date
WO2007134354A1 true WO2007134354A1 (fr) 2007-11-29

Family

ID=36586164

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AT2007/000245 WO2007134354A1 (fr) 2006-05-23 2007-05-23 Formulation pharmaceutique

Country Status (1)

Country Link
WO (1) WO2007134354A1 (fr)

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997023208A1 (fr) * 1995-12-21 1997-07-03 Genelabs Technologies, Inc. Composition de taxane et procede s'y rapportant
US6040330A (en) * 1999-01-08 2000-03-21 Bionumerik Pharmaceuticals, Inc. Pharmaceutical formulations of taxanes
US6319943B1 (en) * 1999-10-25 2001-11-20 Supergen, Inc Oral formulation for paclitaxel
US6348215B1 (en) * 1999-10-06 2002-02-19 The Research Foundation Of State University Of New York Stabilization of taxane-containing dispersed systems
WO2002043765A2 (fr) * 2000-11-28 2002-06-06 Transform Pharmaceuticals, Inc. Formulations pharmaceutiques contenant du paclitaxel, ses derives et ses sels pharmaceutiquement acceptables
US20020192280A1 (en) * 2001-05-01 2002-12-19 Angiotech Pharmaceuticals, Inc. Compositions and methods for treating inflammatory conditions utilizing protein or polysaccharide containing anti-microtubule agents
WO2003053350A2 (fr) * 2001-12-20 2003-07-03 Bristol-Myers Squibb Company Compositions pharmaceutques de derives de taxane actifs par voie buccale a biodisponibilite amelioree
JP2005225818A (ja) * 2004-02-13 2005-08-25 Otsuka Pharmaceut Factory Inc パクリタキセル又はドセタキセルの医薬組成物
US20060067952A1 (en) * 2004-09-28 2006-03-30 Sd Pharmaceuticals, Inc. Low oil emulsion compositions for delivering taxoids and other insoluble drugs
WO2007020085A2 (fr) * 2005-08-19 2007-02-22 Sandoz Ag Nouvelles compositions renfermant des derives de taxane

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997023208A1 (fr) * 1995-12-21 1997-07-03 Genelabs Technologies, Inc. Composition de taxane et procede s'y rapportant
US6040330A (en) * 1999-01-08 2000-03-21 Bionumerik Pharmaceuticals, Inc. Pharmaceutical formulations of taxanes
US6348215B1 (en) * 1999-10-06 2002-02-19 The Research Foundation Of State University Of New York Stabilization of taxane-containing dispersed systems
US6319943B1 (en) * 1999-10-25 2001-11-20 Supergen, Inc Oral formulation for paclitaxel
WO2002043765A2 (fr) * 2000-11-28 2002-06-06 Transform Pharmaceuticals, Inc. Formulations pharmaceutiques contenant du paclitaxel, ses derives et ses sels pharmaceutiquement acceptables
US20020192280A1 (en) * 2001-05-01 2002-12-19 Angiotech Pharmaceuticals, Inc. Compositions and methods for treating inflammatory conditions utilizing protein or polysaccharide containing anti-microtubule agents
WO2003053350A2 (fr) * 2001-12-20 2003-07-03 Bristol-Myers Squibb Company Compositions pharmaceutques de derives de taxane actifs par voie buccale a biodisponibilite amelioree
JP2005225818A (ja) * 2004-02-13 2005-08-25 Otsuka Pharmaceut Factory Inc パクリタキセル又はドセタキセルの医薬組成物
US20060067952A1 (en) * 2004-09-28 2006-03-30 Sd Pharmaceuticals, Inc. Low oil emulsion compositions for delivering taxoids and other insoluble drugs
WO2007020085A2 (fr) * 2005-08-19 2007-02-22 Sandoz Ag Nouvelles compositions renfermant des derives de taxane

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PATENT ABSTRACTS OF JAPAN vol. 2003, no. 12 5 December 2003 (2003-12-05) *

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