Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-02
2003-04-29
Pryor, Alton (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S259100
Reexamination Certificate
active
06555544
ABSTRACT:
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a National Stage application under 35 U.S.C. §371 of PCT/EP98/07321 filed Nov. 10, 1998, which claims priority from EP 97.203.568.7, filed Nov. 17, 1997.
The present invention is concerned with a pharmaceutical composition suitable as a depot formulation for administration via intramuscular or subcutaneous injection, comprising:
(1) as an active ingredient a therapeutically effective amount of a 9-hydroxy-risperidone fatty acid ester or a salt, or a stereoisomer or a stereoisomeric mixture thereof in submicron form and
(2) a pharmaceutically acceptable carrier; wherein the pharmaceutically acceptable carrier is water and the active ingredient is suspended therein;
and with a process of preparing such a composition.
The invention further involves such a pharmaceutical composition for use as a medicament in the treatment of psychosis, schizophrenia, schizoaffective disorders, non-schizophrenic psychoses, behavioural disturbances associated with neurodegenerative disorders, e.g. in dementia, behavioural disturbances in mental retardation and autism, Tourette's syndrome, 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-tetrahydro-2-methyl-4H-pyrido[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.
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
2-20
alkanoic acid esters thereof are described in EP-0,368,388 (corresponding to U.S. Pat. Nos. 5,158,952 and 5,254,556). Said esters are considered to be potentially valuable prodrugs of the active metabolite of risperidone for use in depot formulations.
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, in particular about 1 month.
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.
PCT/EP97/02504 discloses aqueous suspensions of 9-hydroxyrisperidone fatty acid esters in water wherein the prodrug of the active ingredient is in micronized fonn. Unexpectedly, these formulations prove to be far too longlasting in humans to be therapeutically useful.
Consequently, there is still a need for an effective and readily available depot formulation of risperidone or a risperidone-like compound.
Nanoparticles are well known in the prior art, having been described, for example, in EP-A-0,499,299. These particles consist essentially of a crystalline drug substance having a surface modifier absorbed on the surface of the particles such that the effective average particle size is less than about 400 nm. It is also known that said particles are particularly useful to formulate poorly water soluble active ingredients.
The present invention results from the investigations into the development of an efficient, well-tolerated, sustained or delayed release (depot) formulation of a 9-hydroxyrisperidone alkanoic acid ester which is therapeutically effective for at least three weeks or more, in particular about 1 month. By the expression “effective for at least three weeks or more”, one means that the plasma level of the active ingredient, 9-hydroxyrisperidone (free alcohol liberated by hydrolysis from the alkanoic acid ester), should be above approximately 10 ng/ml. On the other hand, said plasma level should remain at all times below a threshold value of approximately 100 ng/ml in order for one to call the formulation “efficient”. The threshold value is the mean plasma level during a considerable period of time, e.g. for more than 15 minutes, above which patients may experience undesirable side effects, or conversely, the value of the plasma level under which the systemic tolerance of the formulation in question is still acceptable. The threshold value does not hold for transient, high plasm levels during a short period of time, e.g. for less than 15 minutes, which are due, for example to unexpected burst-release of the active ingredient.
Both of the foregoing features—plasma levels above a minimal therapeutical concentration but below a side-effect producing threshold value—are considered to be basic requirements that a contemporary depot formulation should fulfil in order to be acceptable for the intended patients. Limiting the number of drug administrations and the occurrence of undesirable side effects after each administration will undoubtedly improve the patients' compliance with the therapy. However, beyond these basic requirements, a number of further desiderata can be identified which would further improve patients' compliance; the two most notable being good local tolerance and ease of administration.
Good local tolerance means minimal irritation and inflammation at the site of injection; ease of administration refers to the size of needle and length of time required to administer a dose of a particular drug formulation. In addition, depot formulations should be stable and have a shelf-life of at least two years under normal conditions.
The investigations into the development of an efficient, well-tolerated, sustained or delayed release (depot) formulation of a 9-hydroxyrisperidone alkanoic acid ester which fulfils the above mentioned requirements, led to the finding that a pharmaceutical composition suitable as a depot formulation for administration by intramuscular or subcutaneous injection should comprise:
a dispersion of particles consisting essentially of a therapeutically effective amount of a crystalline 9-hydroxyrisperidone fatty acid ester ha
Basstanie Esther Dina Guido
Dries Willy Maria Albert Carlo
François Marc Karel Jozef
Appollina Mary
Janssen Pharmaceutica N.V.
Pryor Alton
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