Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2001-11-13
2003-04-29
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S451000, C424S452000, C424S457000, C424S458000, C424S459000, C424S463000, C424S464000, C424S465000, C424S468000, C424S474000, C424S475000, C424S481000, C424S482000
Reexamination Certificate
active
06555136
ABSTRACT:
BACKGROUND
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,” 21
st
. Proc. Int. Symp. Controlled Release Bioact. Mater.,
pp. 744-745.
The present invention is directed in part to a novel pulsatile drug delivery system which is straightforward to manufacture and provides precisely timed drug release “pulses” at desired intervals.
Methylphenidate hydrochloride (HCl), the hydrochloride salt of &agr;-phenyl-2-piperidine-acetic acid methyl ester (available commercially as Ritalin®), is a central nervous system stimulant that is used in the treatment of Attention Deficit Disorder (“ADD”), a commonly diagnosed nervous system illness in children that is characterized by both distractability and impulsivity. Methylphenidate HCl is also used to treat a related disorder, Attention Deficit Hyperactivity Disorder (“ADHD”), in which symptoms of hyperactivity are present along with the symptoms of ADD. The drug is additionally used in the symptomatic treatment of narcolepsy, depression, and the cognitive decline associated with Acquired Immunodeficiency Syndrome (“AIDS”) or AIDS-related conditions, as well as for mood elevation, particularly in terminally ill patients with diseases such as cancer. Methylphenidate exists as four distinct isomers, as follows:
The drug as used in therapy is a racemic mixture of the d- and l-threo enantiomers, which have been acknowledged as more active than the erythro pair.
Because of its potential for tolerance (loss of clinical efficacy when constant blood levels are maintained), short-half life and potential for abuse, methylphenidate is a primary candidate for use in conjunction with the drug delivery systems of the invention.
Accordingly, the present invention provides novel pharmaceutical dosage forms for the administration of methylphenidate in its conventional form, i.e., as a racemic mixture of the d-threo and l-threo enantiomers. The novel dosage forms provide for pulsatile drug release, thereby maximizing efficacy (i.e., the loss of clinical efficacy over time), reducing the potential for abuse or noncompliance. The invention thus represents a significant advance in the art, particularly in the administration of drugs such as methylphenidate that have short half-lives, tend to be extensively metabolized presystemically, have pharmacokinetic-pharmacodynamic relationships which are best described by positive (clockwise) hysteresis loops (hence resulting in tolerance when constant blood levels are maintained), or are likely candidates for drug abuse. No art of which applicants are aware describes pulsatile drug delivery systems as now provided herein.
To the best of applicants' knowledge, the pharmaceutical dosage forms of the invention are previously unknown and completely unsuggested by the art.
SUMMARY OF THE INVENTION
Accordingly, it is a primary object of the invention to address the above-mentioned need in the art by providing a pharmaceutical dosage form for pulsatile delivery of methylphenidate.
It is another object of the invention to provide such a dosage form comprising at least two individual drug-containing dosage units, each of which has a different drug release profile.
It is another object of the invention to provide such a dosage form wherein the dosage units are housed in a closed capsule.
It is still another object of the invention to provide such a dosage form wherein the dosage units are compressed tablets.
It is yet another object of the invention to provide such a dosage form wherein the dosage units are drug-containing particles or beads.
It is a further object of the invention to provide such a dosage form comprised of a single tablet of which the drug-containing dosage units represent integral but discrete segments.
It is a further object of the invention to provide such a dosage form for administering methylphenidate optionally in combination with one or more other active agents such as CNS stimulants (including analeptic agents and psychostimulants), antidepressant drugs, antianxiety agents and the like.
It is an additional object of the invention to provide methods for administering methylphenidate using the novel dosage forms.
Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.
DETAILED DESCRIPTION OF THE INVENTION
Definitions and Nomenclature
Before the present formulations and methods of use are disclosed and described, it is to be understood that unless otherwise indicated this invention is not limited to specific pharmacologically active agents, specific pharmaceutical carriers, or to particular administration regimens, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an active agent” includes mixtures of active agents, reference to “a pharmaceutical carrier” includes combinations of two or more carriers, and the like.
In th
Canaan Karen
Di Nola-Baron Liliana
Page Thurman K.
PharmaQuest, Ltd.
Reed Dianne E.
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