Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2002-01-03
2003-10-28
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S405000, C424S470000, C424S471000
Reexamination Certificate
active
06638533
ABSTRACT:
FIELD OF THE INVENTION
Applicant's invention relates to improved dosing of medications. In particular, the present invention relates to improved dosing of a medication whereby two or more effective pulse dosages may be provided by administration of a pulse release formulation. Effective administration of the second pulse dosage is time-delayed following oral ingestion of Applicant's pulse release formulation.
Applicant's dosage forms and methods are particularly suitable for the administration of methylphenidate hydrochloride, and especially for the administration of a single isomer, d-threo-methylphenidate hydrochloride (“DTMP”). Applicant's method of administration of a pulse release formulation which contains a first pulse release dosage in combination with a second pulse release dosage provides for reduced abuse potential, improved convenience of administration, and better patient compliance, especially when methylphenidate is used to treat certain central nervous system disorders.
BACKGROUND OF THE INVENTION
Attention Deficit Disorder (ADD), a commonly diagnosed nervous system illness in children, is often treated with methylphenidate hydrochloride. Methylphenidate is sold in commerce under the name Ritalin®. Ritalin is a registered trademark owned by Novartis Corporation.
Symptoms of ADD include distractibility and impulsivity. A related disorder, termed Attention Deficit Hyperactivity Disorder (ADHD), is further characterized by symptoms of hyperactivity, and is also treated with methylphenidate hydrochloride. Methylphenidate drugs have also been used to treat cognitive decline in patients with Acquired Immunodeficiency Syndrome (AIDS) or AIDS related conditions. See, e.g., Brown, G., Intl. J. Psych. Med. 25(1): 21-37 (1995); Holmes et al., J. Clin. Psychiatry 50:5-8 (1989). Other embodiments of the present invention provide symptomatic treatment for narcolepsy, depression, as well as for mood elevation, particularly, in terminally ill patients with diseases such as cancer. These various treatment regimes comprise administering to the patient one of Applicant's pulse release formulations providing once-daily oral administration of a methylphenidate drug such as methylphenidate hydrochloride.
Methylphenidate exists as four separate optical isomers. These four optical isomers are shown below.
Pharmaceutically acceptable salts of Methylphenidate, the hydrochloride for example, are sometimes administered clinically. Other phenidate drugs can also can be administered according to Applicant's invention.
Clinically, the threo pair of enantiomers of methylphenidate hydrochloride is generally administered for the treatment of ADD and ADHD. The hydrochloride salt is commonly referred to simply as “methylphenidate”. Unless indicated otherwise, the term “Methylphenidate” is used broadly herein to include methylphenidate and pharmaceutically acceptable salts thereof, including methylphenidate hydrochloride.
The threo racemate (pair of enantiomers) of Methylphenidate is a mild central nervous system stimulant with pharmacological activity qualitatively similar to that of amphetamines. Undesirable side effects associated with the use of the dl-threo racemate of Methylphenidate include anorexia, weight loss, insomnia, dizziness and dysphoria. Furthermore, the racemate, which is a Schedule II controlled substance, produces a euphoric effect when administered intravenously or through inhalation or ingestion, and thus carries a high potential for abuse.
It is known in the art that the pharmacodynamic activity of dl-threo-methylphenidate resides in the d-threo isomer (Clin. Pharmacol. Ther., 52:561-568 (1992)). Therefore, while dl-threo-methylphenidate is generally used therapeutically, this racemate includes the l isomer which apparently makes no significant contribution to the pharmacological effectiveness of the drug, but likely contributes to the associated side effects. It is thus desirable to administer only the active d-threo form of the drug.
Children being treated with dl-threo methylphenidate must generally take one or more doses during the day. This creates a problem for school administrators who must store a controlled substance on school premises, with the associated risk that it may be stolen for illicit use. Furthermore, children may be traumatized by ridicule from peers when they must take medication at school.
A need exists for a pulse release formation, and method to prepare same, that delivers Methylphenidate with maximum effectiveness, and with minimal potential for abuse. Furthermore, a need exists for a dosage form which provides, in one administration, an initial release followed, at a predictable delay, by a second release, of maximally effective methylphenidate. This will eliminate the risk of theft or loss of the second dose, while minimizing undesirable side effects and maximizing ease of administration. Applicant's invention is directed to these, as well as other, important ends.
SUMMARY OF THE INVENTION
Applicant's invention includes a dosage form for the oral administration of Methylphenidate, where that dosage form includes a first pulse dosage and a second pulse dosage. Applicant's first pulse dosage includes a Methylphenidate portion and a sealing layer disposed over that Methylphenidate portion. Applicant's second pulse dosage includes a Methylphenidate portion, a first sealing layer disposed over that Methylphenidate portion, a polymeric coating layer disposed over the first sealing layer, and a second sealing layer disposed over the polymeric coating layer.
Applicant's invention further includes a method to prepare Applicant's first pulse dosage, Applicant's second pulse dosage, and Applicant's pulse release formulations. Applicant's invention further includes methods to treat ADD, ADHD, AIDs-related conditions, narcolepsy, acute depression, and for elevating the mood of terminally ill patients.
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Srinivas, et al., “Enantioselective Pharmacokinetics and Pharmacodynamics of dl-threo-methylphenidate in Children with Attention Deficit Hyperactivity Disorder”, 1992, pp. 561-568.
Patrick, et al., “Pharmacology of the Enantiomers of threo-Methylphenidate”, 1987, pp. 152-158; Patrick, et al., The Absorption of Sustained-Release Methylphenidate Formulations Compared to an Immediate-Release Formulation, 1989, pp. 165-171.
Ding, et al., “Chiral Drugs: Comparison of the Pharmacokinetics of [11C]d-threo and l-threo-methylphenidate in the Human and Baboon Brain”, 1997, pp. 131:71-78.
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Hubbard, et al., Enantioselective Aspects of the Disposition of all-threo-Methylphenidate after the Administration of a Sustained-Release Formulation to Children . . . , 1989, pp. 944-947.
Regelman Dale F.
Young Micah-Paul
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