Classifications

• • 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
  • A61K31/28—Compounds containing heavy metals
  • A61K31/282—Platinum compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
  • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
  • C07F15/0086—Platinum compounds
  • C07F15/0093—Platinum compounds without a metal-carbon linkage

Definitions

• the present invention relates to an oxaliplatin active substance for a pharmaceutical composition, which active substance has a very low content of oxalic acid, to a process for preparing said active substance, to the use thereof for preparing a pharmaceutical composition, in particular by dissolving thereof in an aqueous medium, and to pharmaceutical compositions thereby obtained, notably in the form of a lyophilisat formulation, a liquid formulation or a sustained release formulation for parenteral or oral administration.
• Oxaliplatin or cis-oxalato(trans-/-1,2-diaminocyclohexane)-platinum (II) (CAS RN: 61825-94-3), is a diamine cyclohexane platinum derivative which is active in several solid tumour types such as colorectal cancers.
• PCT Patent Publication No. 99/43355 discloses the stabilizing effect of adding oxalic acid as a buffering agent to oxaliplatin aqueous pharmaceutical formulations.
• the present invention is based on the unexpected discovery by the Applicant that oxaliplatin active substance which contains a very small amount of oxalic acid, e.g. a weight content of about 0.40% or 0.20%, has a significantly higher in vivo toxicity than oxaliplatin active substance without detectable oxalic acid or with a weight content of oxalic acid of not more 0.08%.
• the problem addressed by the invention is to find an oxaliplatin active substance and a process for preparing that active substance, wherein a pharmaceutical composition containing that active substance has a reduced toxicity.
• the invention thus relates to an oxaliplatin active substance for a pharmaceutical composition, wherein its weight content in oxalic acid is not more than 0.08%, in particular not more than 0.05%, most preferably less than 0.02%.
• That oxaliplatin active substance may be prepared by a process close to that described in U.S. Pat. No. 5,290,961, which further includes compared to either of those processes, washing 2 to 5 times with water having a pH 4.5-7.0 the oxaliplatin crystals separated by filtration after reaction with alkali metal salt of oxalic acid, and washing 2 to 5 times the recrystallised crystals with water having a pH 4.5-7.0, the amount of water being used in those washings being sufficient for attaining the desired weight content in oxalic acid.
• the invention thus also concerns a process for preparing the above-defined active substance comprising the following steps
• step (d) or step (e) the appropriate volume of water having a pH 4.5-7.0 used at each washing in step (d) or step (e) in view of the desired content of oxalic acid in the oxaliplatin active substance and the acceptable yield in oxaliplatin. That volume is generally not more than 10 ml per gram of active substance.
• the respective content of residual oxalic acid in each crop is quantified by an appropriate high performance liquid chromatography method.
• the above-defined oxaliplatin active substance may be used for preparing a pharmaceutical composition useful in cancer treatment which presents a reduced toxicity compared to pharmaceutical compositions prepared using an oxaliplatin active substance of the prior art.
• the preparation of such a pharmaceutical composition includes the step of dissolving the active substance in an aqueous medium.
• the invention is thus related to the use of the above oxaliplatin active substance for preparing a pharmaceutical composition, to a process for preparing the same comprising the step of dissolving the active substance in an aqueous medium, to a pharmaceutical composition obtainable by that process and to a new pharmaceutical composition which contains that active substance, along with pharmaceutically acceptable excipients.
• the oxalic acid weight content may be higher when the oxaliplatin active substance is in aqueous medium than when it is in anhydrous state.
• the pharmaceutical composition may be a lyophilisate pharmaceutical formulation for parenteral or oral administration.
• a formulation is conveniently obtained by completely dissolving, at a temperature about 40° C. and under stirring, oxaliplatin in a solution of an excipient such as lactose monohydate in sterile water, then filtering once for clarification and one or more times for sterilisation, aliquoting the filtrate solution into vials and performing freeze-drying using cycles of freezing, primary drying (sublimation) and secondary drying according to techniques well known in the art.
• the weight content of oxalic acid in the lyophilisate pharmaceutical formulation is preferably not more than 0.60%, more preferably not more than 0.30%, most preferably not more than 0.20%.
• the pharmaceutical composition may also be a liquid pharmaceutical formulation for parenteral administration.
• a liquid pharmaceutical formulation for parenteral administration is generally obtained by completely dissolving oxaliplatin in sterile water, at a temperature about 40° C. and under stirring, then filtering once for clarification and one or more times for sterilisation, as described in PCT Patent Publication No. 96/04904.
• the weight content of oxalic acid in the liquid pharmaceutical formulation is preferably not more than 0.60%, more preferably not more than 0.30%, in particular not more than 0.20%.
• the pharmaceutical composition may also be a sustained release formulation including biodegradable polymeric material, notably in the form of microparticles, microspheres, microgranules, implants or gels.
• a sustained release formulation including biodegradable polymeric material, notably in the form of microparticles, microspheres, microgranules, implants or gels.
• Preparation of such an oxaliplatin sustained release formulation may be performed according to techniques well known in the art, with the limitation that all steps must be performed at a pH where the oxaliplatin active substance is stable, preferably between 4,5 and 7.0.
• An example of an appropriate method for preparing a sustained release formulation of microspheres is the process for preparing oxaliplatin encapsulating poly(D,L-lactide-co-glycolide)/poly(D,L-lactide) (PLGA/PLA) microspheres described in PCT Patent Publication No. 02/28386.
• the weight content of oxalic acid in the oxaliplatin active substance was determined using a hereafter briefly described specific ion-pair reverse phase HPLC test which has a detection limit of 0.02 w/w % for oxalic acid.
• the test solution consists of oxaliplatin dissolved using sonication at the concentration of 2 mg/ml in water.
• the specific ion-pair reverse phase HPLC test is conducted at pH 6.0 ⁇ 0.05 and a temperature of 40° C.
• oxaliplatin active substance (as obtained in Example 1) necessary to obtain a final concentration for example of 5 mg/ml is separately weighed, then added in preheated sterile water to the sterile water in the glass or inox container.
• the weighing container is rinsed three times with sterile water, the rinsing solution being added to the above mixture.
• the latter is stirred at the above temperature during 30 to 60 minutes, until complete dissolution of oxaliplatin.
• the water is bubbled with nitrogen to lower its oxygen content.
• the volume or weight of the solution is adjusted to its desired value by adding sterile water.
• the solution is stirred at 40 ⁇ 5° C. during about 10 minutes then cooled to 30° C. under stirring. Samples of the solution are then collected for the usual control tests.
• the solution is then subjected to aseptic filtration on a 0.2 ⁇ m membrane or alternatively autoclaving under conditions close to those described in European Pharmacopia 1997 Edition page 283-284 (minimum of 121° C. for 15 minutes). The solution is kept at 15-30° C. before being conditioned.
• the oxaliplatin solution for example at 5 mg/ml is then aseptically and preferably under nitrogen atmosphere conditioned in 5 ml cylindrical vials (volume of added solution about 4 ml corresponding to 20 mg available oxaliplatin), 15 ml cylindrical vials (volume of added solution about 10 ml corresponding to 50 mg available oxaliplatin), and 25 ml cylindrical vials (volume of added solution about 20 ml corresponding to 100 mg available oxaliplatin).
• oxaliplatin active substance (as obtained in Example 1) necessary to obtain a final concentration for example of 5 mg/ml is separately weighed, then added in preheated sterile water to the sterile water in the glass or inox container.
• the weighing container is rinsed three times with sterile water, the rinsing solution being added to the above mixture.
• the latter is stirred at the above temperature during 30 to 60 minutes, until complete dissolution of oxaliplatin.
• the water is bubbled with nitrogen to lower its oxygen content.
• the volume or weight of the solution is adjusted to its desired value by adding sterile water.
• the solution is stirred at 40 ⁇ 5° C. during about 10 minutes then cooled to 15-30° C. under stirring. Samples of the solution are then collected for the usual control tests.
• the solution is subjected to aseptic filtration on a 0.2 ⁇ m membrane, then aseptically filled into 50 ml cylindrical vials to give 100 mg oxaliplatin per vial. Freeze-drying is performed using cycles of freezing, primary drying (sublimation) and secondary drying, according to techniques well known in the art.
• the vials containing the lyophilisate pharmaceutical formulation are stoppered and sealed.
• Lethal doses LD 10 of a cytostatic active substance determinated in mice is generally considered as being a significative correlation with the maximum tolerated doses (MTD) in man.
• a first group of CD-1 mice has received a solution of the oxaliplatin active substance as obtained in Example 1 and LD 10 is around 18.0 mg7kg.
• a second group of animals has received the same solution as for the first group, but with the addition of oxalic acid at a final concentration of 0.2 mM, and LD 10 is around 14.4.
• LD10 along with clinical symptoms demonstrate that the oxaliplatin active substance as obtained in Example 4, while administrated in solution, is less toxic as the same active substance, but administrated with oxalic acid.

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• 2002
  • 2002-07-02 US US10/482,367 patent/US20040186172A1/en not_active Abandoned
  • 2002-07-02 WO PCT/CH2002/000358 patent/WO2003004505A1/fr not_active Ceased
  • 2002-07-02 EP EP02734974A patent/EP1404689A1/fr not_active Withdrawn
• 2009
  • 2009-10-09 US US12/576,383 patent/US8211940B2/en not_active Expired - Fee Related

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