Methods and dosage forms for controlled delivery of paliperidone and risperidone

Abstract

Dosage forms and methods for providing a substantially ascending rate of release of paliperidone or risperidone are provided. The sustained release dosage forms provide therapeutically effective average steady-state plasma paliperidone or risperidone concentrations when administered once per day. This once-a-day dosing regimen results in only one peak plasma paliperidone or risperidone concentration occurrence in each 24 hour period. In addition, the peak plasma paliperidone or risperidone concentration occurs at a later time following dose administration and exhibits a lesser magnitude than the peak plasma paliperidone or risperidone concentration that occurs following administration of paliperidone or risperidone in an immediate-release dosage form.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation-in-part or application Serial No. 10 / 629,211 and claims benefit, under 35 USC 119(e), to U.S. provisional patent application No. 60 / 399,590, filed Jul. 29, 2002, and 60 / 406,005 filed Aug. 26, 2002, all of which are incorporated herein by reference.FIELD OF THE INVENTION [0002] This invention pertains to the controlled delivery of pharmaceutical agents and methods, dosage forms and devices. In particular, the invention is directed to methods, dosage forms and devices for the controlled delivery of paliperidone or risperidone, with reduced degradation of the active agent. BACKGROUND OF THE INVENTION [0003] The art is replete with descriptions of oral dosage forms for the controlled release of pharmaceutical agents. While a variety of sustained release dosage forms for delivering certain drugs exhibiting short half-life may be known, not every drug may be suitably delivered from those dosage forms because...

AI Technical Summary

Benefits of technology

[0032] The present invention is designed for once-a-day administration of an oral dosage form to deliver paliperidone or risperidone for more than about 22 hours utilizing a capsule-shaped tablet. This approximately 22 hours of release is at a substantially ascending rate of release from the core with 90% delivery occurring at about 20 hours. This novel profile provides therapeutic delivery above the MPC while keeping the plasma levels below the MTC and low enough such that side effects will be reduced and the development of tolerance is increased to the side effects that are associated with paliperidone and risperidone. This delivery profile provides 24 hours of efficacy without initially undesirable high plasma levels.

[0033] The present invention provides for a substantially ascending release rate. It has been surprisingly discovered that the instant ascending release profile (that provides a maximum blood plasma concentration that occurs at more than about 6 hours following the initial dose, preferably more than 8 hours following the initial dose such as between 14 and 22 hours after the dose) best provides efficacious therapy over 24 hours while potentially reducing negative side effects associated with administration of the drug.

[0035] It has been surprisingly found that the described ascending release rate can provide for a substantially ascending blood plasma concentration of drug with peak concentration occurring later than about 16 hours after administration. This ascending blood plasma concentration increases the intraday tolerance to side effects.

[0040] The dosage form incorporating the present invention is designed to be a once-a-day dosage form that is therapeutically effective while providing increased stability.

[0046] The present invention is designed to be a once-a-day dosage form that is therapeutically effective while producing fewer side effects than an immediate release dosage form administered multiple times per day. The present invention provides two key features: a substantially ascending delivery that affects the pharmacodynamics and development of tolerance to the side effect, and the substantially ascending delivery provides adequate plasma concentrations for pharmacological effect.

Problems solved by technology

Additionally, since paliperidone has a long half-life of about one day, it is not a typical candidate for extended delivery.

However, side effects such as anxiety, somnolence, dizziness, constipation, extrapyramidal symptoms, and orthostatic hypotension may be related to high blood plasma concentration levels restricting the ability to administer a single daily immediate release dose.

The low drug loading requirement presents problems in formulating compositions and fabricating dosage forms that are suitable for oral administration that deliver at the desired rate of release for an extended period of time.

Furthermore, this art does not identify delivery of paliperidone much less delivery of paliperidone through oral controlled release delivery.

This art does not disclose preferred release rates and does not teach or motivate toward an ascending rate of release, much less such release through an oral delivery system.

Prior art for oral delivery does not address delivery of extended, controlled release paliperidone.

While dosage forms delivering the drug composition to the environment of use in the dry state may provide suitable release of drug at various drug loadings over a prolonged period of time, the exposure of the drug layer to the environment of use may result in agitation-dependent release of drug that in some circumstances is difficult to control.

The Risperdal® mode of therapy, however, continues to lead to an initial high dose of risperidone in the blood plasma after administration, followed by a decreased level of risperidone in the blood plasma.

The concentration differences in dosing patterns are related to the presence and absence of administered drug, which is a major disadvantage, associated with this prior dosage form and mode of administration.

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