Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-11-12
2000-06-20
MacMillan, Keith D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
A61K 31505
Patent
active
060778431
DESCRIPTION:
BRIEF SUMMARY
The present invention is concerned with a pharmaceutical composition suitable as a depot formulation for administration via intramuscular or subcutaneous injection, comprising: 9-hydroxyrisperidone fatty acid ester or a salt, or a stereoisomer or a stereoisomeric mixture thereof and acceptable carrier is water and the active ingredient is suspended therein; involves such a pharmaceutical composition for use as a medicament in the treatment of schizophrenia, non-schizophrenic psychoses, behavioural disturbances associated with neurodegenerative disorders, e.g. in dementia, behavioural disturbances in mental retardation and autism, bipolar mania, depression, anxiety.
Risperidone is generic to 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetr ahydro-2-methyl-4H-pyridol[1,2-a]pyrimidin-4-one. The preparation and pharmacological activity thereof are described in EP-0,196,132 (corresponding to U.S. Pat. No. 4,804,663). Various conventional pharmaceutical dosage forms, including tablets, capsules, drops, suppositories, oral solutions and injectable solutions are exemplified therein. In practice, risperidone is normally administered as the base in a tablet or in a buffered, oral or intramuscular solution. Particular solutions for oral or intramuscular administration are described in WO-96/01652.
Risperidone is a highly potent drug having a relatively narrow therapeutic index. It may produce undesirable side effects on overdosage, most notably extra pyramidal syndrome (EPS) and to a lesser extent hypotension (due to peripheral alpha-adrenergic activity). For the purpose of producing an antipsychotic effect in a patient the total daily dose of risperidone ranges from about 2 to about 8 mg; for the alleviation of behavioral disturbances associated with neurodegenerative disorders the total daily dose is usually less and typically ranges from about 0.5 to about 2 mg. Inter-individual differences and co-medication may necessitate dose titrating in patients.
For a number of reasons, it is desirable to administer risperidone in a sustained or delayed release (depot) formulation which is effective over an extended period of time, preferably about 3 weeks or more.
WO-94/25460 (corresponding to EP-0,697,019) relates to a first such depot formulation and concerns the risperidone pamoate salt, a poorly water-soluble salt form of risperidone, which may be suspended in a pharmaceutically acceptable carrier, such as water or an oil, and may be administered subcutaneously or intramuscularly. This salt, however, has pharmacokinetic properties which are suboptimal. The release of the active ingredient from the formulations appears to be too rapid, which results in relatively high initial plasma levels and an inadequate mean duration of action, both characteristics which should be improved upon in a truly effective depot formulation.
WO-95/13814 concerns sustained release formulations for parenteral administration wherein risperidone is microencapsulated in a biocompatible, biodegradable wall-forming material (e.g. a polymer such as dl-(polylactide-co-glycolide)). The micro-encapsulated formulations have suitable pharmacokinetic properties, but require sophisticated processes of preparation in a purpose-built plant.
Consequently, there is still a need for an effective and readily available depot formulation of risperidone or a risperidone-like compound.
It is known that risperidone is metabolized to 9-hydroxyrisperidone which has a pharmacological profile and potency comparable with that of the parent drug risperidone, but which has a longer elimination half-life. Risperidone is distributed to and eliminated from the brain tissues more rapidly than its metabolite 9-hydroxy-risperidone. 9-hydroxyrisperidone, its enantiomeric forms and the C.sub.2-20 alkanoic acid esters thereof are described in EP-0,368,388 (corresponding to U.S. Pat No. 5,158,952 and U.S. Pat. No. 5,254,556). Said esters are considered to be potentially valuable prodrugs of the active metabolite of risperidone for use in depot formulations.
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Borghijs Herman Karel
Embrechts Roger Carolus Augusta
Fran.cedilla.ois Marc Karel Jozef
Monbaliu Johan
Appollina Mary
Janssen Pharmaceutica N.V.
MacMillan Keith D.
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