Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-03-01
2001-07-31
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C424S078150
Reexamination Certificate
active
06268368
ABSTRACT:
FIELD OF THE INVENTION
This invention relates broadly to buspirone and improved means for dosing patients to achieve a desired therapeutic effect with a complex of buspirone and anionic exchange polymer.
BACKGROUND OF THE INVENTION
Buspirone, chemically: 8-4-4-2-pyrimidinyl)-piperazinyl[butyl]-8-azaspiro(4,5)-decane-7, 9-dione is a pharmaceutically active compound disclosed in U.S. Pat. No. 3,717,634. This compound has been found to be effective for the treatment of anxiety disorders including depression.
Buspirone suffers from the drawback of a very high first pass metabolism. Only about 4% of a therapeutic dose will ordinarily reach the systemic circulation unchanged after oral administration (Mayol et al., Clin. Pharmacol. Ther., 37, 210, 1985).
Buspirone also exhibits great intra- and inter-individual variations in absorption. This variability has been demonstrated by up to 10-fold differences in the maximum plasma concentrations resultant from a given dose of this drug (Gammans et al., American J. Med., 80, Suppl. 3B, 41-51, 1986).
Several metabolites of buspirone have been identified, including several hydroxylated derivatives that show little pharmacological activity. The major metabolite, 1-(2-pyrimidinyl piperazine (1-PP), has been found to be about 20-25% as potent an anxiolytic agent as buspirone in pharmacologic testing.
The biological half-life of buspirone is very short and variable in man, on an order of 2-11 hours. The much less active metabolite, 1-PP, exhibits much slower elimination (Mayol et al., Clin. Pharmacol. Ther., 37, 210 1985). These pharmacokinetic properties necessitate a rather frequent daily dosing regimen which would be expected to have a negative effect on patient compliance.
Since buspirone is rapidly absorbed after an oral dose, high peak plasma values normally occur shortly after drug administration. These peak values are associated with the occurrence of undesired or adverse events commonly observed during the first days of treatment. These adverse effects can also seriously impact patient compliance because they can result in deliberate disruption of the drug therapy.
Since its clinical introduction, buspirone has suffered from a perceived lack of immediate effect. Much of this perception may be attributable to patient failures in compliance. Patient monitoring has evidenced inappropriate dosing—either using buspirone as a night-time dose or taking it as necessary (prn)—instead of using it in the consistent manner in which it is ordinarily prescribed.
Wide variation and unpredictability in the delivery of buspirone have been reported in articles such as Metabolism and Disposition of Buspirone by Gammans et al, the
American Journal of Medicine
, Mar. 31, 1988, Vol. 80. These studies reflect that systemic availability and plasma levels of buspirone may differ by 1,000% or more, dependant on the individual and other factors.
Attempts to improve the oral delivery of buspirone have been only partially successful. U.S. Pat. No. 5,431,922 describes formulations of buspirone or a salt thereof imbedded in an inert matrix; formed into micro pellets; and in coated micro pellets to obtain an intermediate in vitro dissolution rate. This intermediate dissolution rate is said to permit less frequent dosing and reduced production of 1-(2-pyrimidinyl-2-piperazine (1-PP) metabolite. However, the comparative data in the examples of that patent continue to reflect wide variation in the buspirone plasma concentration levels, both over time and between patients.
SUMMARY OF THE INVENTION
This invention concerns an improved oral dosage formulation for the controlled release of buspirone medicament. This formulation comprises an intimate admixture of buspirone or a pharmaceutically acceptable salt thereof with an anionic exchange polymer complexing agent. The desired complex of these components is ordinarily formed in situ on contact with water incident administration of the formulation. Alternatively, the component can be pre-complexed in water and then administered to a patient.
Solid forms of these buspirone and anionic exchange polymer components may be incorporated into pills, tablets, capsules, pellets or micro pellets using any convenient carrier agents. These dosage forms preferably include a viscosity enhancing or gelling agent such as hydroxypropylmethyl cellulose.
These medicament tablets or other solid forms comprising buspirone or a pharmaceutically accepted addition salt thereof with an anionic exchange polymer may be orally administered in an anxiolytically effective dose to an anxious individual for the palliative treatment of anxiety neurosis.
In addition to facilitating the controlled release of buspirone, the present complexes moderate the pharmacokinetics of this drug. This results in dramatic mitigation of the common variations in individual reception of buspirone. Therefore the buspirone-ion exchange polymer complexes of the present invention permit enhanced targeting of therapeutic amounts and effects of this drug.
REFERENCES:
patent: 5431922 (1995-07-01), Nicklasson
patent: 5980882 (1999-11-01), Eichman
Goldberg Arthur H.
Sakr Ahmed Adel
American Pharmaceuticals International
French Philip M.
Krass Frederick
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