Pharmaceutical dosage form for pulsatile delivery of methylphenidate

#The present invention relates generally to drug delivery, and more specifically relates to novel pharmaceutical dosage forms that provide pulsatile delivery of methylphenidate. The invention additionally relates to methods for administering methylphenidate using the novel dosage forms.

#Pharmaceutical dosage forms are known which provide a variety of drug release profiles, including immediate release, sustained release, and delayed release. That is, it may be desirable, for a particular drug, to prevent drug release after drug administration until a certain amount of time has passed (so-called “timed release”), to provide substantially continuous release over a predetermined time period (so-called “sustained release”) or to provide release immediately following drug administration (i.e., “immediate release”). For some types of drugs, it is preferred to release the drug in “pulses,” wherein a single dosage form provides for an initial dose of drug followed by a release-free interval, after which a second dose of drug is released, followed by one or more additional release-free intervals and drug release “pulses.” Pulsatile drug delivery is useful, for example, with active agents that have short half-lives and must be administered two or three times daily, with active agents that are extensively metabolized presystemically, and with active agents which lose the desired therapeutic effect when constant blood levels are maintained. These types of agents have pharmacokinetic-pharmacodynamic relationships that are best described by a clockwise “hysteresis loop.” A drug dosage form that provides a pulsatile drug release profile is also useful for minimizing the abuse potential of certain types of drugs, i.e., drugs for which tolerance, addiction and deliberate overdose can be problematic.

#Because a precise and effective pulsatile drug delivery system is difficult to formulate and manufacture, there are few such dosage forms that have been commercialized. There are, however, several patents and literature references pertaining to pulsatile drug delivery. See, for example, U.S. Pat. No. 5,413,777 to Sheth et al., directed to a pulsatile once-a-day delivery system for the administration of minocycline; U.S. Pat. No. 5,260,068 to Chen, directed to a multiparticulate pulsatile drug delivery system; U.S. Pat. No. 4,777,049 to Magruder et al., directed to an osmotic delivery system for constant release of a drug with intermittent release “pulses”; U.S. Pat. No. 5,391,381 to Wong et al., directed to a drug dispenser for delivering individual drug-containing units in a “pulsatile” manner; PCT Publication No. WO 98/32424, pertaining to pulsatile delivery of diltiazem hydrochloride; U.S. Pat. Nos. 5,472,708 and 5,260,069 to Chen; Ishino et al. (1992) “Design and Preparation of Pulsatile Release Tablet as a New Oral Drug Delivery System,”Chem. Pharm. Bull. 40(11):3036-3041; Cohen et al. (1994), “Pulsatile Release from Microencapsulated Liposomes,”J. Liposome Res. 349-360; and Gazzaniga et al. (1994), “Chronotopic Drug Delivery Systems for Pulsatile and/or Site-Specific Release,”21st. Proc. Int. Symp. Controlled Release Bioact. Mater., pp. 744-745.

#A pulsatile release dosage form for administration of d,l-threo methylphenidate is prepared by (1) formulating three individual compressed tablets, each having a different release profile, followed by (2) encapsulating the three tablets into a gelatin capsule and then closing and sealing the capsule. The components of the three tablets are as follows. 1 TABLET 1 (IMMEDIATE RELEASE): Component Function Amount per tablet d,l-threo methylphenidate Active agent 5.0 mg Dicalcium phosphate dihydrate Diluent 26.6 mg Microcrystalline cellulose Diluent 26.6 mg Sodium starch glycolate Disintegrant 1.2 mg Magnesium Stearate Lubricant 0.6 mg

#2 TABLET lA (IMMEDIATE RELEASE): Component Function Amount per tablet d,l-threo methylphenidate Active agent 2.5 mg Dicalcium phosphate dihydrate Diluent 26.6 mg Microcrystalline cellulose Diluent 26.6 mg Sodium starch glycolate Disintegrant 1.2 mg Magnesium Stearate Lubricant 0.6 mg

#3 TABLET 2 (RELEASE DELAYED 3-5 HOURS FOLLOWING ADMINISTRATION): Component Function Weight Tablet 1 “Core” containing 60.0 mg the active agent Eudragit RS30D Delayed release 4.76 mg coating material Talc Coating component 3.3 mg Triethyl citrate Coating component 0.95 mg