Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-09-22
1997-03-18
Grumbling, Matthew V.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544282, C07D41314, A61K 31505
Patent
active
056123469
DESCRIPTION:
BRIEF SUMMARY
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is based upon PCT application Ser. No. PCT/EP 94/01296, filed Apr. 22, 1994, which claims priority from European Patent Application Ser. No. 93.201.216.4, filed on Apr. 28, 1993.
EP-0,196,132 discloses the compound 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetr ahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, that is known genetically as risperidone and is a potent antipsychotic. Unfortunately, the current formulations of risperidone only yield effective plasma levels during a limited time interval. Long-acting injectable risperidone dosage forms would be valuable in maintenance therapy and would enhance patient compliance.
Currently available long-acting neuroleptics include solutions in oils, e.g. sesame oil, of poorly water-soluble ester derivatives of the neuroleptic compounds. Trials to prolong the activity of some particular phenothiazine neuroleptics by the use of poorly water-soluble salts such as the pamoates proved to be little successful (e.g. Florence et al., 1976, J. Pharm. Sci., 65(11), 1665-1668). Unexpectedly, the use of the pamoate salt of risperidone in dogs significantly prolonged the release of risperidone, yielding plasma levels of risperidone and its active metabolite that were effective against apomorphine induced emesis during several weeks.
Accordingly, the present invention is concerned with the pamoate acid addition salts of risperidone. In particular, the invention is concerned with the compound having the formula ##STR1## The period during which effective plasma levels are obtained depends on the physical characteristics of the risperidone pamoate powder sample, such as particle size and crystal form.
Risperidone, its preparation and the pharmacological activity thereof are described in EP-0,196,132. The pamoate salt of risperidone can be prepared by the treatment of risperidone with parnoic acid or a salt derivative thereof, e.g. the disodium pamoate, in a reaction-inert solvent. In particular, risperidone pamoate can be prepared by adding a solution of risperidone in an appropriate solvent, e.g. ethanol, to a solution of pamoic acid in an appropriate solvent, e.g. N,N-dimethylformamide, and stirring the mixture until precipitation of the risperidone pamoate salt. The reaction product may be isolated from the medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization and chromatography. Micronized forms of the subject compounds can be prepared by micronization techniques known in the art, e.g. by milling in appropriate mills and sieving through appropriate sieves.
In a particular aspect, the invention relates to the mixed pamoate addition salts of risperidone, e.g. the monosodium pamoate salt of risperidone.
The subject compounds are potent antagonists of neurotransmitters and in particular of dopamine. Antagonizing said neurotransmitter suppresses a variety of phenomena induced by the release, in particular the excessive release, of dopamine. Central dopamine receptor blockers are known to have neuroleptic properties, for example, they counteract the positive symptoms of schizophrenia, e.g. hallucinations, delusional thinking, severe excitement and unusual behaviour. Therapeutic indications for using the present compound therefore are mainly in the CNS area, particularly as potent antipsychotic agents and especially as agents useful in treating chronic psychoses. The present compounds also show central serotonin antagonism. Central acting serotonin antagonists appear to improve the negative symptoms of schizophrenia, e.g. anergy, apathy, social withdrawal and depressive mood, and also to reduce the incidence of extrapyramidal side-effects (EPS) during maintenance therapy with classical neuroleptics, i.e. dopamine antagonists. Combined dopamine-serotonin antagonists are especially interesting as they offer relief of both the positive and negative symptoms of schizophrenia with low EPS liability.
The subjec
REFERENCES:
patent: 4804663 (1989-02-01), Kennis et al.
Mesens Jean L.
Peeters Jozef
Grumbling Matthew V.
Janssen Pharmaceutica N.V.
Metz Charles J.
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