U.S. patent application number 12/580800 was filed with the patent office on 2010-02-11 for method of treating attention deficit disorders with d-threo methylphenidate.
Invention is credited to Maghsoud M. Dariani, David L. Stirling, Andrew L. Zeitlin.
Application Number | 20100035928 12/580800 |
Document ID | / |
Family ID | 25470261 |
Filed Date | 2010-02-11 |
United States Patent
Application |
20100035928 |
Kind Code |
A1 |
Zeitlin; Andrew L. ; et
al. |
February 11, 2010 |
Method Of Treating Attention Deficit Disorders With D-Threo
Methylphenidate
Abstract
Methods for treating Attention Deficit Disorder, Attention
Deficit Hyperactivity Disorder, AIDS Dementia Complex and cognitive
decline in HIV-AIDS while minimizing drug hypersensitivity,
toxicity, side effects, euphoric effect, and drug abuse potential
by administration of d-threo-methylphenidate or pharmaceutically
acceptable salts thereof.
Inventors: |
Zeitlin; Andrew L.;
(Millington, NJ) ; Dariani; Maghsoud M.; (Fanwood,
NJ) ; Stirling; David L.; (Branchburg, NJ) |
Correspondence
Address: |
WOODCOCK WASHBURN LLP
CIRA CENTRE, 12TH FLOOR, 2929 ARCH STREET
PHILADELPHIA
PA
19104-2891
US
|
Family ID: |
25470261 |
Appl. No.: |
12/580800 |
Filed: |
October 16, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11244924 |
Oct 6, 2005 |
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12580800 |
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10961122 |
Oct 8, 2004 |
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11244924 |
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10395444 |
Mar 24, 2003 |
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10961122 |
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09864617 |
May 24, 2001 |
6602887 |
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10395444 |
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09337310 |
Jun 21, 1999 |
6255325 |
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09864617 |
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08937684 |
Sep 29, 1997 |
5922736 |
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09337310 |
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08827230 |
Apr 2, 1997 |
5908850 |
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08937684 |
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08647642 |
May 15, 1996 |
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08827230 |
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08583317 |
Jan 5, 1996 |
5733756 |
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08647642 |
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08567131 |
Dec 4, 1995 |
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08583317 |
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Current U.S.
Class: |
514/317 |
Current CPC
Class: |
A61K 9/2886 20130101;
A61K 31/4458 20130101; A61K 9/5078 20130101; A61K 9/5084 20130101;
C12P 17/12 20130101; A61P 25/28 20180101; C12P 41/006 20130101;
A61K 31/445 20130101; A61K 9/1676 20130101; A61P 25/00 20180101;
C07D 211/34 20130101 |
Class at
Publication: |
514/317 |
International
Class: |
A61K 31/445 20060101
A61K031/445; A61P 25/00 20060101 A61P025/00 |
Claims
1. A method of treating Attention Deficit Hyperactivity Disorder
comprising administrating on a daily basis to a human having
Attention Deficit Hyperactivity Disorder, 5 to 50 mg of D-threo
methylphenidate, or a pharmaceutically acceptable salt thereof,
substantially free of L-threo methylphenidate, wherein the D-threo
methylphenidate, or pharmaceutically acceptable salt, is mixed with
a pharmaceutically acceptable carrier, diluent, or excipient.
2. The method according to claim 1 wherein the amount of D-threo
methylphenidate administered is 5 mg per day.
3. The method according to claim 1 wherein the amount of said
D-threo methylphenidate, or a pharmaceutically equivalent salt
thereof, is greater than 90% of the total amount of
methylphenidate.
4. The method according to claim 4 wherein the amount of said
D-threo methylphenidate, or a pharmaceutically equivalent salt
thereof, is greater than 99% of the total amount of
methylphenidate.
5. The method according to claim 1 wherein the amount of D-threo
methylphenidate enhances therapeutic activity compared to racemic
methylphenidate.
6. The method according to claim 1 wherein the administration is
one to four times per day.
7. The method according to claim 1 wherein the amount of D-threo
methylphenidate administered is 20 mg per day.
8. The method according to claim 1 wherein the amount of D-threo
methylphenidate administered is 50 mg per day.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 11/244,924, filed Oct. 6, 2005, which is a continuation of U.S.
application Ser. No. 10/961,122 (now abandoned), filed Oct. 8,
2004; which is a continuation of U.S. application Ser. No.
10/395,444, filed Mar. 24, 2003 (now abandoned); which is a
continuation of U.S. application Ser. No. 09/864,617, filed May 24,
2001 (now U.S. Pat. No. 6,602,887; which is a divisional of U.S.
application Ser. No. 09/337,310, filed Jun. 21, 1999 (now U.S. Pat.
No. 6,255,325); which is a divisional of U.S. application Ser. No.
08/937,684, filed Sep. 29, 1997 (now U.S. Pat. No. 5,922,736);
which is a continuation-in-part of U.S. application Ser. No.
08/827,230, filed Apr. 2, 1997 (now U.S. Pat. No. 5,908,850), which
is a continuation-in-part of U.S. App. No. 08,647,642, filed May
15, 1996, (now abandoned), which is a continuation-in-part of U.S.
application Ser. No. 08/583,317, filed Jan. 5, 1996, (now U.S. Pat.
No. 5,733,756), which is a continuation of U.S. application Ser.
No. 08/567,131, filed Dec. 4, 1995 (now abandoned); all of which
are incorporated herein.
FIELD OF THE INVENTION
[0002] The present invention relates to methods of 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 with decreased side
effects, reduced euphoric effect, and reduced drug abuse
potential.
BACKGROUND OF THE INVENTION
[0003] Attention Deficit Disorder (ADD) is the most commonly
diagnosed illness in children. Patrick et al., J. Pharmacol. &
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.RTM.) is a mild Central
Nervous System stimulant with pharmacological activity
qualitatively similar to amphetamines, and has 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,
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.
[0004] 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, personality change,
and thought disturbance are common in patients with Human
Immunodeficiency Virus (HIV) disease. Douzenis et al., Proc. 7th
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 which is a Schedule II controlled substance,
produces a euphoric effect when administered intravenously or
through inhalation, and thus carries a high potential for drug
abuse in AIDS patients.
[0005] 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 therefore
desirable to provide for the administration of methylphenidate in
reduced dosages among patients with drug hypersensitivity due to
HIV infection.
[0006] Methylphenidate possesses two centers of chirality and thus
can exist as four separate optical isomers. The four isomers of
methylphenidate are as follows:
##STR00001##
[0007] Diastereomers are known in the art to possess differing
physical properties, such as melting point and boiling point. For
example, while the threo-racemate of methylphenidate produces the
desired Central Nervous System action, the erythro-racemate
contributes to hypertensive side effects and exhibits lethality in
rats.
[0008] Additional 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). Although the role of the 1-isomer
in toxicity or adverse side effects has not been thoroughly
examined, the potential for isomer ballast in methylphenidate is of
concern for many patient groups, particularly those drug
hypersensitive patients as described above.
[0009] Although l-threo-methylphenidate is rapidly and
stereo-selectively metabolized upon oral administration,
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 the methods of choice by drug abusers of current
methylphenidate formulations. The present invention postulates that
the euphoric effect produced by current formulations of
methylphenidate is due to the action of
l-threo-methylphenidate.
[0010] Accordingly, it has been discovered that the use of the
d-threo isomer (2R:2'R) of methylphenidate, substantially free of
the l-threo isomer produces a methylphenidate medication which
retains high activity levels and simultaneously possesses reduced
euphoric effect and reduced potential for abuse among patients.
[0011] U.S. Pat. No. 2,507,631, to Hartmann et al. describes
methylphenidate and processes for making the same.
[0012] U.S. Pat. No. 2,957,880, to Rometsch et al. describes the
conversion of .alpha.-aryl-.alpha.-piperidyl-(2)-acetic acids and
derivatives thereof (including methylphenidate) into their
respective racemates.
[0013] Holmes et al., J. Clin. Psychiatry, 50:5-8 (1989) reported
on the use of racemic methylphenidate (Ritaline.RTM.) and
dextroamphetamines in the treatment of cognitive impairment in AIDS
patients.
[0014] Srinivas et al., J. Pharmacol. & Exp. Therap.,
241:300-306 (1987) described use of racemic
dl-threo-methylphenidate (Ritalin.RTM.) 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.
[0015] Srinivas et al., Clin. Pharmacol. Ther., 52:561-568 (1992)
studied the administration of dl-threo, d-threo and
l-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 l-threo
isomer, nor the euphoric effects of the single isomers or racemate.
Single isomer dosages below 1/2 of the racemate dosage were not
studied.
[0016] Patrick et al., J. Pharmacol. & Exp. Therap.,
241:152-158 (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.RTM..
[0017] Brown, G., Intl. J. Psych. Med., 25(1):21-37 (1995) reported
the use of racemic methylphenidate for the treatment of AIDS
cognitive decline.
[0018] 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 l-threo isomer, and that
d-threo methylphenidate may be responsible for the therapeutic
activity in the racemic drug.
[0019] Aoyama et al., Clin. Pharmacol. Ther., 55:270-276 (1994)
reported on the use of (+)-threo-methylphenidate in the treatment
of hypersomnia. Aoyama et al. describe a correlation between sleep
latency in patients and plasma concentration or
(+)-threo-methylphenidate.
SUMMARY OF THE INVENTION
[0020] The present invention is based on the discovery that
d-threo-methylphenidate (2R:2'R) possesses enhanced therapeutic
activity with reduced side effects, and l-threo-methylphenidate
produces undesirable side effects, euphoria and drug abuse
potential in patients suffering from Attention Deficit Disorder,
Attention Deficit Hyperactivity Disorder, AIDS cognitive decline,
and AIDS Dementia Complex.
[0021] The present invention thus relates to methods of treating
Attention Deficit Disorder and Attention Deficit Hyperactivity
Disorder in children and adults while providing for reduced side
effects, reduced euphoric effect and reduced potential for abuse
potential through administration of d-threo-methylphenidate
(2R:2'R) of the formula:
##STR00002##
or a pharmaceutically acceptable salt thereof, substantially free
of the l-threo isomer.
[0022] The invention further relates to methods of treating
AIDS-related dementia and related cognitive disorders while
providing for reduced side effects, reduced euphoric effect, and
reduced abuse potential through administration of
d-threo-methylphenidate (2R:2'R) of the formula:
##STR00003##
or a pharmaceutically acceptable salt thereof, substantially free
of the l-threo isomer.
[0023] Prescription of methylphenidate to treat AIDS cognitive
decline and AIDS Dementia Complex associated with HIV infection is
becoming increasingly popular. However, high doses in excess of 40
mg/day are not well tolerated by a substantial number of
HIV-infected patients when treated over weeks or months. Brown, G.,
Int'l J. Psychiatry. Med., 25:21-37 (1995). The d-threo isomer use
of the present invention thus enables a lowered dosing therapy
resulting in improved efficacy for diseased patients and
particularly HIV-infected patients.
[0024] Moreover, administration of the d-threo isomer to patients
will result in decreased side effects, reduced euphoric effect, and
substantially reduce the potential for abuse of the product.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
[0025] Racemic methylphenidate and its individual isomers are
known. See U.S. Pat. Nos. 2,507,631 and 2,957,880. They can be
prepared by conventional techniques, and can be obtained from a
variety of commercial sources.
[0026] The d-threo isomer of the present invention can be
administered orally, rectally, parenterally, or transdermally,
alone or in combination with other psychostimulants,
antidepressants, and the like to a patient in need of treatment.
Oral dosage forms include tablets, capsules, dragees, and similar
shaped compressed pharmaceutical forms. Isotonic saline solutions
containing 20-100 milligrams/milliliter can be used for parenteral
administration which includes intramuscular, intrathecal,
intravenous and intra-arterial routes of administration. Rectal
administration can be effected through the use of suppositories
formulated from conventional carriers such as cocoa butter.
Transdermal administration can be effected through the use of
transdermal patch delivery systems and the like. The preferred
routes of administration are oral and parenteral.
[0027] The dosage employed must be carefully titrated to the
patient, considering age, weight, severity of the condition, and
clinical-profile. Typically, the amount of d-threo-methylphenidate
administered will be in the range of 5-50 mg/day, but the actual
decision as to dosage must be made by the attending physician.
[0028] The present invention provides enhanced relief for patients
suffering from Attention Deficit Disorder and Attention Deficit
Hyperactivity Disorder while providing for reduced side effects,
reduced euphoric effect, and reduced abuse potential through
administration of d-threo-methylphenidate substantially free of the
l-threo isomer.
[0029] The invention further provides for treatment of AIDS-related
dementia and related cognitive disorders with
d-threo-methylphenidate substantially free of the l-threo isomer
while providing for reduced side effects, reduced euphoric effect,
and reduced abuse potential.
[0030] The term, "substantially free of the l-threo-isomer" means
that the composition contains at least 90% by weight of
d-threo-methylphenidate, and 10% by weight of
l-threo-methylphenidate. In the most preferred embodiment, the term
"substantially free of the l-threo isomer" means that the
composition contains at least 99% by weight of
d-threo-methylphenidate and 1% or less of
l-threo-methylphenidate.
[0031] The following examples will serve to further typify the
nature of the invention, but should not be construed as a
limitation on the scope thereof, which is defined solely by the
appended claims.
Example 1
[0032] Tablets for chewing, each containing 5 milligrams of
d-threo-methylphenidate, can be prepared in the following
manner:
TABLE-US-00001 Composition (for 1000 tablets)
d-threo-methylphenidate 5.00 grams mannitol 15.33 grams lactose
10.00 grams talc 1.40 grams glycine 0.83 grams stearic acid 0.66
grams saccharin 0.10 grams 5% gelatin solution q.s.
[0033] All the solid ingredients are first forced through a sieve
of 0.25 mm mesh width. The mannitol and the lactose are mixed,
granulated with the addition of gelatin solution, forced through a
sieve of 2 mm mesh width, dried at 50.degree. C. and again forced
through a sieve of 1.7 mm mesh width. The d-threo-methylphenidate,
the glycine and the saccharin are carefully mixed, the mannitol,
the lactose granulate, the stearic acid and the talc are added and
the whole is mixed thoroughly and compressed to form tablets of
approximately 10 mm diameter which are concave on both sides and
have a breaking groove on the upper side.
Example 2
[0034] Tablets, each containing 10 milligrams of
d-threo-methylphenidate, can be prepared in the following
manner:
TABLE-US-00002 Composition (for 1000 tablets)
d-threo-methylphenidate 10.0 grams lactose 328.5 grams corn starch
17.5 grams polyethylene glycol 6000 5.0 grams talc 25.0 grams
magnesium stearate 4.0 grams demineralized water q.s.
[0035] The solid ingredients are first forced through a sieve of
0.6 mm mesh width. Then the d-threo-methylphenidate, lactose, talc,
magnesium stearate and half of the starch are intimately mixed. The
other half of the starch is suspended in 65 milliliters of water
and this suspension is added to a boiling solution of the
polyethylene glycol in 260 milliliters of water. The resulting
paste is added to the pulverulent substances, and the whole is
mixed and granulated, if necessary with the addition of water. The
granulate is dried overnight at 35.degree. C., forced through a
sieve of 1.2 mm mesh width and compressed to form tablets of
approximately 10 mm diameter which are concave on both sides and
have a breaking notch on the upper side.
Example 3
[0036] Gelatin dry-filled capsules, each containing 20 milligrams
of d-threo-methylphenidate, can be prepared in the following
manner:
TABLE-US-00003 Composition (for 1000 capsules)
d-threo-methylphenidate 20.0 grams microcrystalline cellulose 6.0
grams sodium lauryl sulfate 0.4 grams magnesium stearate 1.6
grams
Example 3
[0037] The sodium lauryl sulfate is sieved into the
d-threo-methylphenidate through a sieve of 0.2 mm mesh width and
the two components are intimately mixed for 10 minutes. The
microcrystalline cellulose is then added through a sieve of 0.9 mm
mesh width and the whole is again intimately mixed for 10 minutes.
Finally, the magnesium stearate is added through a sieve of 0.8 mm
width and, after mixing for a further 3 minutes, the mixture is
introduced in portions of 28 milligrams each into size 0
(elongated) gelatin dry-fill capsules.
Example 4
[0038] A 0.2% injection or infusion solution can be prepared, for
example, in the following manner:
TABLE-US-00004 d-threo-methylphenidate 5.0 grams sodium chloride
22.5 grams phosphate buffer pH 7.4 300.0 grams demineralized water
to 2500 mL.
[0039] The d-threo-methylphenidate is dissolved in 1000 milliliters
of water and filtered through a microfilter or slurried in 1000 mL
of H.sub.2O. The buffer solution is added and the whole is made up
to 2500 milliliters with water. To prepare dosage unit forms,
portions of 1.0 or 2.5 milliliters each are introduced into glass
ampoules (each containing respectively 2.0 or 5.0 milligrams of
d-threo-methylphenidate).
* * * * *