Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-05-25
2002-03-12
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
06355656
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to phenidate drug compositions for treating certain Central Nervous System disorders such as Attention Deficit Disorder (ADD), Attention Deficit Hyperactivity Disorder (ADHD), HIV/AIDS cognitive decline, and AIDS Dementia Complex. This invention features such drugs having decreased side effects, reduced euphoric effect, and reduced drug abuse potential.
BACKGROUND OF THE INVENTION
Attention Deficit Disorder (ADD) is the most commonly diagnosed nervous system illness in children. Patrick et al., J. Phamacol. & Exp. Therap., 241:152-158 (1987). Symptoms of ADD include distractibility and impulsivity. A related disorder, termed Attention Deficit Hyperactivity Disorder (ADHD), is further characterized by increased symptoms of hyperactivity in patients. Racemic methylphenidate (e.g., Ritalin®) is a mild Central Nervous System stimulant with pharmacological activity qualitatively similar to amphetamines, and has long been the drug of choice for symptomatic treatment of ADD in children. Greenhill, L., Child & Adol. Psych. Clin. N.A., Vol. 4, Number 1:123-165 (1995).
Current administration of racemic methylphenidate, however, often results in notable side effects such as anorexia, weight loss, insomnia, dizziness and dysphoria. Additionally, racemic methylphenidate, which is a Schedule II controlled substance, produces a euphoric effect when administered intravenously or through inhalation, and thus carries a high potential for substance abuse in patients.
At least 70% of HIV-infected individuals who have developed Acquired Immunodeficiency Syndrome (AIDS) eventually manifest cognitive defects, and many display signs and symptoms of dementia. See Navia et al.,
Annals of Neurology
, 19:517-524 (1986). Complaints of forgetfulness, loss of concentration, fatigue, depression, loss of attentiveness, mood swings, and thought disturbance are common in patients with Human Immunodeficiency Virus (HIV) disease. Douzenis et al.,
Proc
. 7
th Int'l. Conf. AIDS
, 1, MB, 2135:215 (1991); Holmes et al.,
J. Clin. Psychiatry
, 50:5-8 (1989). Racemic methylphenidate has been used to treat cognitive decline in AIDS/ARC patients. Brown, G., Intl.
J. Psych. Med
. 25(1): 21-37 (1995). As described above, racemic methylphenidate, a Schedule II controlled substance, produces a euphoric effect when administered intravenously or through inhalation, and thus carries a high potential for drug abuse.
U.S. Pat. No. 2,507,631, to Hartmann et al. describes methylphenidate and processes for making the same. U.S. Pat. No. 2,957,880, to Rometsch et al. describes the conversion of &agr;-aryl-&agr;-piperidyl-(2)-acetic acids and derivatives thereof (including methylphenidate) into their respective racemates. Each of these patents is incorporated herein by reference.
Holmes et al.,
J. Clin. Psychiatry
, 50:5-8 (1989) reported on the use of racemic methylphenidate (Ritalin®) and dextroamphetamines in the treatment of cognitive impairment in AIDS patients.
Srinivas et al.,
J. Pharmacol
. &
Exp. Therap.
, 241:300306 (1987) described use of racemic dl-threo-methylphenidate (Ritalin®) in the treatment of ADD in children. This study noted a 5-fold increase in plasma levels of d-threo-methylphenidate in children treated with racemic methylphenidate, but was otherwise inconclusive with regard to the efficacy of a single methylphenidate isomer at therapeutically significant doses.
Srinivas et: al.,
Clin. Pharmacol. Ther
., 52:561-568 (1992) studied the administration of dl-threo, d-threo and 1-threo-methylphenidate to children suffering from ADHD. While Srinivas et al. reported the pharmacodynamic activity of dl-threo-methylphenidate resides in the d-threo isomer, this study investigated neither the adverse side effects of the 1-threo isomer, nor the euphoric effects of the single isomers or racemate. Single isomer dosages below ½ of the racemate dosage were not studied.
Patrick et al.,
J. Pharmacol
. &
Exp. Therap
., 241:152158 (1986) examined the pharmacology of the enantiomers of threo-methylphenidate, and assessed the relative contribution of each isomer to central and peripheral actions of Ritalin®.
Brown, G., Intl.
J. Psych. Med
., 25 (1): 21-37 (1995) reported the use of racemic methylphenidate for the treatment of AIDS 'cognitive decline.
Patrick et al., Psychopharmacology: The Third Generation of Progress, Raven Press, N.Y. (1987) examined the pharmacokinetics and actions of methylphenidate in the treatment of Attention Deficit Hyperactivity Disorder (ADHD). Patrick noted the d-threo isomer possesses higher activity than the 1-threo isomer, and that d-threo methylphenidate may be responsible for the therapeutic activity in the racemic drug.
Aoyama et al.,
Clin. Pharmacol. Ther
., 55:270-276 (1994) reported on the use of (+)-threo-methylphenidate in the treatment of hypersomnia. Aoyama at al. describe a correlation between sleep latency in patients and plasma concentration of (+)-threo-methylphenidate.
Glutathione is an important antioxidative agent that protects the body against electrophilic reactive compounds and intracellular oxidants. It has been postulated that HIV-AIDS patients suffer from drug hypersensitivity due to drug overload and an acquired glutathione deficiency. See Uetrecht et al.,
Pharmacol. Res
., 6:265-273 (1989). Patients with HIV infection have demonstrated a reduced concentration of glutathione in plasma, cells and broncho-alveolar lavage fluid. Staal et al.,
Lancet
, 339:909-912 (1992). Clinical data suggests that HIV-seropositive individuals display adverse reactions to the simultaneous administration of several otherwise therapeutic drugs. Rieder et al.,
Ann. Intern. Med
., 110:286-289 (1989). It is desirable to provide for the administration of methylphenidate in reduced dosages among patients with drug hypersensitivity due to HIV infection.
There is a long-felt and very intense need for phenidate drug compositions, especially methyl phenidate, which are less susceptible to unlawful abuse and which exhibit diminished side effects while retaining therapeutic efficacy.
SUMMARY OF INVENTION
Phenidate drugs in accordance with this invention have the structure:
where R
1
is C
1
-C
4
alkyl and R
2
is either C
1
-C
4
alkyl or hydrogen. Of this family of drugs, methylphenidate, where R
1
is methyl and R
2
is hydrogen, is the most well known, having long been prescribed under the trade mark Ritalin®. Phenidate drugs are &agr;-aryl-&agr;-piperidyl-2-acetic acids and comprise two centers of asymmetry, existing as four separate optical isomers as follows:
It is known that certain physiological properties of methylphenidate and other phenidate drugs are dependent upon stereochemistry. Thus, while the threo racemate of methylphenidate is understood to produce the desired central nervous system action, the erythro racemate is thought to contribute to hypertensive side effects.
It is now believed, however, that another stereochemical distinction also applies. Studies in animals, children and adults have demonstrated pharmacological activity in the
D
-threo isomer of methylphenidate (2R,2′R). See Patrick et al.,
J. Pharmacol
. &
Exp. Therap
., 241:152-158 (1987). The role of the
L
-threo isomer in toxicity or adverse side effects has not been examined heretofore although the potential for isomer ballast in methylphenidate and other phenidate drugs is of concern for many patient groups, particularly those drug hypersensitive patients as described above.
Although
L
-threo-methylphenidate is rapidly and stereoselectively metabolized upon oral administration by extensive first pass metabolism, intravenous administration or inhalation results in high
L
-threo methylphenidate serum levels. Srinivas et al.,
Pharmacol. Res
., 10:14-21 (1993). Intravenous administration and inhalation are methods of choice by drug abusers of current, racemic methylphenidate formulations. It is now believed that the euphoric effect produced by current formulations of methylphenidate is due to the action of
L
-threo-methylphe
Dariani Maghsoud M.
Zeitlin Andrew L.
Celgene Corporation
Henley III Raymond
Woodcock Washburn Kurtz Mackiewicz & Norris LLP
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