Chronic, bolus administration of D-threo methylphenidate

Details Chronic, bolus administration of D-threo methylphenidate Chronic, bolus administration of D-threo methylphenidate

1999-06-21

2001-07-03

Henley, III, Raymond (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

Reexamination Certificate

active

06255325

ABSTRACT:

FIELD OF THE INVENTION
The present invention is directed to methods and compositions for treating nervous system disorders such as attention deficit disorder, attention deficit hyperactivity disorder, cognitive decline associated with acquired immunodeficiency syndrome, and similar conditions. The methods involve the administration of a single, bolus dose of a composition comprising
D
-threo methylphenidate. The compositions are substantially free of
L
-threo methylphenidate and of erythro forms of methylphenidate.
BACKGROUND OF THE INVENTION
Attention Deficit Disorder (ADD), a commonly diagnosed nervous system illness in children, is generally treated with methylphenidate hydrochloride (available commercially as, e.g., Ritalin®. 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).
Methylphenidate exists as four separate optical isomers as follows:
wherein R
2
is phenyl. Pharmaceutically acceptable salts are generally administered clinically. Other phenidate drugs, which also can be administered according to the invention, include those in which the methyl group in the above structures is replaced by C
2
-C
4
alkyl and those in which R
2
is optionally substituted with C
1
-C
4
alkyl.
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.
Srinivas et al. studied the administration of
DL
-threo-,
D
-threo, and
L
-threo-methylphenidate to children suffering from ADHD, and reported that the pharmacodynamic activity of
DL
-threo-methylphenidate resides in the
D
-threo isomer (
Clin. Pharmacol. Ther
., 52: 561-568 (1992)). 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. The removal of the
L
isomer is expensive, however, and there has been no reason to do so.
An additional problem is that, generally, children being treated with dl-threo methylphenidate must take one or more doses during the day in order to receive optimal benefit from the treatment. 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.
Sustained release formulations of
DL
-threo methylphenidate have been developed, which provide for slow release of the drug over the course of the day. However, it has been observed that peak plasma concentrations of the drug are lower when sustained release formulations are used as compared to conventional dosage forms administered throughout the day. In some studies, sustained release formulations of
DL
-threo methylphenidate have been shown to have lower efficacy than conventional dosage forms.
Pulsed-release dosage forms, wherein a single dosage form contains two doses, one of which is released shortly after ingestion and the other of which is released following a delay of several hours, have recently been proposed as a method for administering a maximally effective dose regime. While pulsed dosage forms provide for efficient release of multiple doses of medication at predetermined intervals, such dosage forms can be complex and expensive to manufacture. Furthermore, while pulsed-release dosage forms are suitable for administration of medications such as methyl phenidate to children, multiple releases of the medication are not required for all patients. However, it is desirable to administer to all patients the most effective and efficient dosage of mediation and, in the case of methyl phenidate, it is now believed that this end is best achieved by administering the single, effective isomer, i.e.
D
-threo methylphenidate.
While the
D
-threo isomer of methylphenidate has been shown to be the pharmacodynamically active isomer, the administration of the single isomer has been neither studied nor administered clinically on a chronic basis. Thus, the effects of administering a single isomer on a chronic basis as compared to the conventionally administered racemate have not heretofore been recognized or understood.
There remains a need for methods for delivering methylphenidate with maximum effectiveness and minimal potential for abuse. Furthermore, there is a need for a dosage form which provides, in a single administration, a patient's daily dose requirement of optimally effective methylphenidate, eliminating the need to take a second dose, while minimizing undesirable side effects and maximizing ease of administration.
SUMMARY OF THE INVENTION
The present invention provides, in one aspect, a method for treating at least one of the following disorders: attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADD), or AIDS-related dementia. The method involves the chronic administration of
D
-threo-methylphenidate or a pharmaceutically acceptable salt thereof, substantially free of both
L
-threo-methylphenidate and erythro methylphenidates. It is now believed that the
L
isomer likely contributes to the side effects associated with the commercial drug. It is thus desirable to administer only the active
D
-threo form of the drug. The
D
-threo methylphenidate is administered in single, bolus dosages, with one dose being administered in each twenty-four hour period.
Another aspect of the present invention provides pharmaceutical compositions for treating a nervous system disorder in a patient needing treatment, comprising a bolus dosage form of
D
-threo-methylphenidate or a pharmaceutically acceptable salt thereof, in an amount sufficient for daily effectiveness, which dosage is substantially free of both
L
-threo-methylphenidate and erythro methylphenidates. The administration of only the pharmacodynamically active
D
-threo form of methylphenidate can provide efficacious treatment for an entire day without undesirable side effects such as interference with patient sleep patterns or anoretic behavior. It has been surprisingly and unexpectedly discovered that the beneficial effects of the
D
-threo isomer persist for a longer period time when the
D
-threo isomer is administered alone than when it is administered in combination with the
L
-threo isomer.
While it is not intended that the present invention be bound by any particular theory, it is believed that the
L
isomer functions as an antagonist to the
D
isomer. Thus, another aspect of the present invention provides methods for ameliorating or counteracting the effects of methylphenidate drugs, comprising administering
L
-threo methylphenidate to a patient who has a serum level of
D
-threo methylphenidate.
The present inventors have observed that 6 to 8 hours follow

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