U.S. patent application number 10/963460 was filed with the patent office on 2005-03-03 for chronic, bolus administration of d-threo methylphenidate.
This patent application is currently assigned to Celegene Corporation. Invention is credited to Dariani, Maghsoud M., Zeitlin, Andrew L., Zeldis, Jerome B..
Application Number | 20050049279 10/963460 |
Document ID | / |
Family ID | 25470261 |
Filed Date | 2005-03-03 |
United States Patent
Application |
20050049279 |
Kind Code |
A1 |
Dariani, Maghsoud M. ; et
al. |
March 3, 2005 |
Chronic, bolus administration of D-threo methylphenidate
Abstract
Chronic bolus administration of D-threo methylphenidate is
provided. The administration of the D-threo isomer eliminates
adverse side effects associated with the DL racemate, and provides
improved effectiveness. The compositions and methods of the
invention are useful in treating nervous system disorders including
attention deficit disorder, attention deficit hyperactivity
disorder, and cognitive decline associated with systemic diseases
such as acquired immunodeficiency syndrome.
Inventors: |
Dariani, Maghsoud M.;
(Fanwood, NJ) ; Zeitlin, Andrew L.; (Millington,
NJ) ; Zeldis, Jerome B.; (Princeton, NJ) |
Correspondence
Address: |
WOODCOCK WASHBURN LLP
ONE LIBERTY PLACE, 46TH FLOOR
1650 MARKET STREET
PHILADELPHIA
PA
19103
US
|
Assignee: |
Celegene Corporation
|
Family ID: |
25470261 |
Appl. No.: |
10/963460 |
Filed: |
October 12, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10963460 |
Oct 12, 2004 |
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10395444 |
Mar 24, 2003 |
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10395444 |
Mar 24, 2003 |
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09864617 |
May 24, 2001 |
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6602887 |
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09864617 |
May 24, 2001 |
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09337310 |
Jun 21, 1999 |
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6255325 |
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09337310 |
Jun 21, 1999 |
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08937684 |
Sep 29, 1997 |
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5922736 |
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08937684 |
Sep 29, 1997 |
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08827230 |
Apr 2, 1997 |
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5908850 |
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08937684 |
Sep 29, 1997 |
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08647642 |
May 15, 1996 |
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08937684 |
Sep 29, 1997 |
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08567131 |
Dec 4, 1995 |
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08937684 |
Sep 29, 1997 |
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08583317 |
Jan 5, 1996 |
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5733756 |
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Current U.S.
Class: |
514/317 |
Current CPC
Class: |
C12P 41/006 20130101;
A61K 31/4458 20130101; A61K 9/1676 20130101; A61P 25/28 20180101;
C07D 211/34 20130101; A61P 25/00 20180101; A61K 9/5084 20130101;
A61K 31/445 20130101; A61K 9/2886 20130101; C12P 17/12 20130101;
A61K 9/5078 20130101 |
Class at
Publication: |
514/317 |
International
Class: |
A61K 031/445 |
Claims
What is claimed is:
1. A drug dosage form for the bolus parenteral administration of a
methylphenidate drug comprising an injectable composition
comprising D-threo-methylphenidate or pharmaceutically acceptable
salt thereof in an amount sufficient for daily effectiveness for
the treatment of a nervous disorder.
2. The drug dosage form of claim 1 that is substantially free of
L-threo-methylphenidate.
3. The dosage form of claim 1 wherein the administration is
subcutaneous, intravenous, intramuscular, or interperitoneal.
4. The dosage form of claim 1 wherein the administration is via a
pharmaceutical carrier selected from the group consisting of a
sterile liquid or mixture of liquids, an alcohol, glycols, glycerol
ketals, and ethers.
5. The dosage form of claim 4 wherein said sterile liquid or
mixture of liquids is water, saline, aqueous dextrose, or related
sugar solutions.
6. The dosage form of claim 4 wherein said alcohol is ethanol.
7. The dosage form of claim 4 wherein said glycols are propylene
glycol or polyethylene glycol.
8. The dosage form of claim 4 wherein said glycerol ketal is
2,2-dimethyl-1,3-dioxolane-4-methanol.
9. The dosage form of claim 5 wherein said ether is
poly(ethyleneglycol)400, oils, fatty acids, fatty acid esters, or
glycerides.
10. The dosage form of claim 9 further comprising at least one
pharmaceutically acceptable surfactant, a suspending agent, an
emulsifying agent, or other pharmaceutically acceptable
adjuvants.
11. The dosage form of claim 10 wherein said surfactant is a soap,
detergent, or mixture of detergents.
12. The dosage form of claim 10 wherein said suspending agent is
pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose,
or carboxymethylcellulose.
13. The dosage form of claim 9 wherein said oils are selected from
the group consisting of petroleum, animal, vegetable, or synthetic
oils.
14. The dosage form of claim 13 wherein said oils are peanut oil,
soybean oil, sesame oil, cottonseed oil, corn oil, olive oil,
petrolatum, or mineral oil.
15. The dosage form of claim 9 wherein said fatty acids are
selected from the group consisting of oleic acid, stearic acid, and
isostearic acid.
16. The dosage form of claim 9 wherein said fatty acid esters are
selected from the group consisting of ethyl oleate and isopropyl
myristate.
17. The dosage form of claim 11 wherein said soap is alkaline
metal, ammonium and triethanolamine salts of fatty acids.
18. The dosage form of claim 11 wherein said detergent is selected
from the group consisting of cationic detergents, anionic
detergents, nonionic detergents, and amphoteric detergents.
19. The dosage form of claim 18 wherein said detergent is dimethyl
dialkyl ammonium halides, alkyl pyridinium halides, alkyl, aryl and
olefin sulfonates, monoglyceride sulfates, sulfasucciantes, fatty
amine oxides, fatty acid alkanolamides, polyoxyethylenepropylene
copolymers, alkyl-aminopropoionates, or 2-alkylimidazoline
quaternary ammonium salts.
20. The dosage form of claim 1 wherein said amount is 0.01% by
weight of D-threo-methylphenidate or salt thereof.
21. The dosage form of claim 1 further comprising a viscosity
increasing substance selected from the group consisting of sodium
carboxymethylcellulose, sorbitol, dextran, and stabilizers.
22. The dosage form of claim 10 wherein said surfactant has a
hydrophile-lipophile balance (HLB) of about 12 to about 17.
23. The dosage form of claim 10 wherein said surfactant is about 5%
to about 15% by weight of the dosage form.
24. The dosage form of claim 10 wherein said surfactant is selected
from the group consisting of polyethene sorbitan fatty acid
esters.
25. The dosage form of claim 24 wherein the surfactant is sorbitan
monooleate.
Description
[0001] This application is a continuation application of Ser. No.
10/395,444, filed Mar. 24, 2003; which is a continuation of Ser.
No. 09/864,617, filed May 24, 2001; which is a divisional
application of application Ser. No. 09/337,310, filed Jun. 21, 1999
(now U.S. Pat. No. 6,255,325); which is a divisional of 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 application Ser. No.
08/827,230, filed Apr. 2, 1997 (now U.S. Pat. No. 5,908,850) and of
application Ser. No. 08/647,642, filed May 15, 1996 (now
abandoned); the former being a continuation of Ser. No. 08/567,131,
filed Dec. 4, 1995, (now abandoned) and the latter being a
continuation-in-part of application Ser. No. 08/583,317, filed Jan.
5, 1996, (now U.S. Pat. No. 5,733,756. The above are incorporated
herein by reference in their entirety.
FIELD OF THE INVENTION
[0002] 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
[0003] Attention Deficit Disorder (ADD), a commonly diagnosed
nervous system illness in children, is generally treated with
methylphenidate hydrochloride (available commercially as, e.g.,
Ritalin.RTM.). 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).
[0004] Methylphenidate exists as four separate optical isomers as
follows: 1
[0005] wherein R2 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
C2-C4 alkyl and those in which R2 is optionally substituted with
C1-C4 alkyl.
[0006] 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.
[0007] 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.
[0008] 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.
[0009] 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.
[0010] 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.
[0011] 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.
[0012] 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.
[0013] 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
[0014] 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.
[0015] 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.
[0016] 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.
[0017] The present inventors have observed that 6 to 8 hours
following administration of DL-threo methylphenidate, D-threo
methylphenidate, or a placebo, patients who were given the D-threo
isomer free of the L isomer performed better in objective tests
than patients who received the DL-threo racemate or a placebo. In
contrast, the patients who received DL-threo racemate did not
perform better after that time period than those who received a
placebo. Furthermore, subjective observations of the same patients
indicated that those who received only the D-threo isomer
experienced beneficial effects of the drug for longer times than
did those who received the DL-threo racemate. Accordingly, it is
now believed that the bolus administration of D-threo
methylphenidate can give rise to beneficial effects for far longer
than administration of the racemate. Moreover, it is now possible
for these effects to last for entire working or school days
following administration of a bolus dose on a chronic basis.
[0018] It is expected that D-threo methylphenidate will be
particularly useful in treating patients affected by ADD when who
must function in a structured environment such as school or work.
Any formulation which provides a dosage sufficient to provide from
about 6 to about 8 hours of efficacy should allow an ADD-affected
individual to function in a structured environment without having
to take another dose during the day.
[0019] According to one method of the present invention, bolus
dosage forms are administered of D-threo methylphenidate
substantially free of L-threo methylphenidate and of erythro
methylphenidates. "Substantially free", as used herein, means that
the dosage forms comprise at least about 95 percent, preferably at
least about 97 percent, and more preferably at least about 99
percent of the D-threo isomer, to the exclusion of the L-threo and
erythro forms. The D-threo form can be isolated by methods known to
those skilled in the art.
[0020] "Chronic", as used herein, refers to continuous, regular,
long-term therapeutic administration, i.e. periodic administration
without substantial interruption, such as, for example, daily, for
a time period of at least several weeks or months to several years,
for the purpose of treating a nervous disorder in a patient needing
treatment.
[0021] "Bolus", as used herein, refers to administration of a drug
as a single event. The term "bolus" is intended to exclude dosage
forms such as sustained release, pulsed release, and time release,
and includes any dosage form which can be used to deliver a single
dose. According to the present invention, a bolus is preferably
administered to a patient in need of treatment once daily, more
preferably in the morning. The bolus dosages of the present
invention may be administered in any conventional form known to
those skilled in the art. Suitable methods for administration
include oral dosage forms, injection, and infusion.
[0022] For pharmaceutical use, the compounds described herein may
be taken up in pharmaceutically acceptable carriers, such as, for
example, solutions, suspensions, tablets, capsules, ointments,
elixirs and injectable compositions. Pharmaceutical preparations
generally can contain from about 1% to about 90% by weight of
active ingredient. Preparations which are in single dose form,
"unit dosage form", preferably contain from about 20% to about 90%
active ingredient. As used herein, the term "active ingredient"
refers to compounds described herein, salts thereof, and mixtures
of compounds described herein with other pharmaceutically active
compounds. Dosage unit forms such as, for example, tablets or
capsules, typically contain from about 0.001 to about 1.0 g of
active ingredient. Pharmaceutical preparations may be administered
orally, parenterally, or topically.
[0023] Pharmaceutical preparations containing compounds described
herein may be prepared by methods known to those skilled in the
art, such as, for example, conventional mixing, granulating,
dissolving, or lyophilizing. Oral dosage forms include capsules,
pills, tablets, troches, lozenges, melts, powders, solutions,
suspensions and emulsions. The oral dosage forms provided by the
invention can be in the form of tablets, caplets, and the like and
can be of any shape suitable for oral administration of a drug,
such as spheroidal, cube-shaped, oval, bean shaped, or ellipsoidal.
For oral dosage forms, for example, the compounds may be combined
with one or more solid pharmaceutically acceptable carriers,
optionally granulating the resulting mixture. Pharmaceutically
acceptable adjuvants may optionally be included, such as, for
example, flow regulating agents and lubricants. Suitable carriers
include, for example, fillers such as sugars, cellulose
preparations, calcium phosphates; and binders such as
methylcellulose, hydroxymethylcellulose, and starches, such as, for
example, maize starch, potato starch, rice starch, and wheat
starch. The dosage form may be in the form of granules, which may
be irregularly shaped. The dosage form can comprise a capsule
containing particles. Examples of orally administrable
pharmaceutical preparations are dry filled capsules consisting of
gelatin, and soft sealed capsules consisting of gelatin and a
plasticizer such as glycerol or sorbitol. The dry filled capsules
may contain the active ingredient in the form of a granulate, for
example in admixture with fillers, binders, glidants, and
stabilizers. In soft capsules, the active ingredient is preferably
dissolved or suspended in a suitable liquid adjuvant, such as, for
example, a fatty oil, paraffin oil, or liquid polyethylene glycol,
optionally in the presence of stabilizers. Other oral administrable
forms include syrups containing active ingredient, for example, in
suspended form at a concentration of from about .01% to 20%, or in
a similar concentration that provides a suitable single dose when
administered, for example, in measures of from about 2 to about 5
milliliters. Suitable excipients for use in oral liquid dosage
forms include diluents such as water and alcohols, for example
ethanol, benzyl alcohol and polyethylene alcohols, either with or
without the addition of a pharmaceutically acceptable surfactant,
suspending agent, or emulsifying agent. Also suitable are powdered
or liquid concentrates for combining with liquids such as milk.
Such concentrates may also be packed in single dose quantities.
[0024] The compounds described herein may be administered
parenterally, that is, subcutaneously, intravenously,
intramuscularly, or interperitoneally, as injectable dosages of the
compound in a physiologically acceptable diluent with a
pharmaceutical carrier. Solutions for parenteral administration may
be in the form of infusion solutions. A pharmaceutical carrier may
be, for example, a sterile liquid or mixture of liquids such as
water, saline, aqueous dextrose and related sugar solutions, an
alcohol such as ethanol, glycols such as propylene glycol or
polyethylene glycol, glycerol ketals such as 2,2 dimethyl 1,3
dioxolane 4 methanol, ethers such as poly(ethyleneglycol)400, oils,
fatty acids, fatty acid esters or glycerides, with or without the
addition of a pharmaceutically acceptable surfactant such as a soap
or detergent, suspending agent such as pectin, carbomers,
methylcellulose, hydroxypropylmethylcellulose, or
carboxymethylcellulose, or emulsifying agent or other
pharmaceutically acceptable adjuvants. Examples of oils which may
be used in parenteral formulations include petroleum, animal,
vegetable, or synthetic oils such as, for example, peanut oil,
soybean oil, sesame oil, cottonseed oil, corn oil, olive oil,
petrolatum, and mineral oil. Suitable fatty acids include, for
example, oleic acid, stearic acid, and isostearic acid. Suitable
fatty acid esters include ethyl oleate and isopropyl myristate.
Suitable soaps include alkaline metal, ammonium and triethanolamine
salts of fatty acids. Suitable detergents include cationic
detergents such as dimethyl dialkyl ammonium halides and alkyl
pyridinium halides; anionic detergents such as alkyl, aryl and
olefin sulfonates, monoglyceride sulfates and sulfosuccinates;
nonionic detergents such as fatty amine oxides, fatty acid
alkanolamides and polyoxyethylenepropylene copolymers; and
amphoteric detergents such as alkyl (aminopropionates and 2
alkylimidazoline quaternary ammonium salts; as well as mixtures of
detergents. Parenteral preparations will typically contain at least
about 0.01% by weight of active ingredient in solution.
Preservatives and buffers may also be used advantageously.
Injection suspensions may include viscosity increasing substances
such as, for example, sodium carboxymethylcellulose, sorbitol or
dextran, and may also include stabilizers. In order to minimize
irritation at the site of injection, injectable compositions may
contain a non ionic surfactant having a hydrophile lipophile
balance (HLB) of from about 12 to about 17. The quantity of
surfactant in such formulations ranges from about 5% to about 15%
by weight. The surfactant may be a single component having the
above HLB or a mixture of two or more components having the desired
HLB. Particular examples of useful surfactants include polyethylene
sorbitan fatty acid esters, such as, for example, sorbitan
monooleate.
[0025] The preferred quantity of D-threo methylphenidate to be used
in a dosage for treating a particular patient can be readily
determined by one skilled in the art. Factors determining the
appropriate dosage include the weight and age of the patient, the
type and extent of the disorder being treated, and other conditions
of the patient including other disorders and other medications, if
any, that the patient is taking. Generally, the dosage of D-threo
methylphenidate will be from about 0.01 mg/kg of patient body
weight to about 1 mg/kg of patient body weight. Appropriate
quantities can be determined by one skilled in the art. For
example, a relatively small child will generally require a dose of
from about 0.03 to about 0.3 mg/kg, while a larger child or an
adult may require a dose of from about 0.1 mg/kg to about 0.4 or
0.5 mg/kg.
[0026] A physician treating a patient with ADD will generally
titrate the dose of methylphenidate until the desired therapeutic
effects is achieved. For example, a patient with ADD will start by
taking 2.5 mg of d-MPH approximately 30 to 60 minutes before
beginning school or work. If the patient's behavior is not
well-controlled by this dose after two or three days and the
patient has not experienced "incapacitating" anxiety, the dose will
be raised to 5 mg. After two days, a lack of therapeutic effect
will necessitate increasing the dose to 10 mg or higher safe doses.
Once a dose of d-MPH is determined to be effective, this dose will
remain stable unless the child is growing. It is not unusual for
the dose of methylphenidate that was effective in a 7 year old to
be increased when the child becomes 9 or 10 years old. On the other
hand, most teenagers can achieve appropriate effectiveness from a
particular dose for many years.
[0027] Response by patients with ADD or ADHD is generally
determined by two types of measurements: objective measures of a
patient's ability to concentrate and remain focused on a task such
as performing a math test; and subjective scores of a patient's
performance. The inventors have discovered that children who had
been treated with racemic methylphenidate (DL-threo
methylphenidate) showed significantly better responses when treated
with a formulation containing only the D enantiomer. Furthermore,
it has been surprisingly observed that the beneficial effects of
administration of the D-enantiomer alone, when measured by both
objective and subjective tests, persisted for a significantly
longer time than when the same patients were treated with the
racemic mixture.
[0028] The following examples are merely illustrative of the
present invention and should not be considered limiting of the
scope of the invention in any way. These examples and equivalents
thereof will become more apparent to those skilled in the art in
light of the present disclosure and the accompanying claims.
EXAMPLE 1
[0029] Double blind, Randomized Patient Study
[0030] A total of 35 children aged 9 to 12 years with ADHD (of
which 31 were evaluable) were enrolled, at three sites, in a
double-blind, randomized, placebo-controlled, crossover study
consisting of nine consecutive weekly visits (i.e., a total of nine
weeks duration). At each visit, serial blood samples were taken for
pharmacokinetic analysis. A battery of safety and pharmacodynamic
measurements were performed.
[0031] At Visit 1 (which served as the baseline visit), all
subjects were given a placebo in a single-blind manner. For Visits
2-8, subjects received one of two treatment regimens and a placebo
in a double blind, randomized manner. The randomization occurred
within each treatment regimen. One group of subjects received three
single doses of DL methylphenidate (DL-MPH) and then, at the
crossover, received three single doses of D-MPH; while the other
group received three single doses of D-MPH followed by three single
doses of DL-MPH. The placebo was given at one of the visits within
either treatment regimen. The D-MPH was provided in capsules of
2.5, 5, and 10 mg. The DL-MPH was matched and provided in capsules
of 5, 10, and 20 mg, accounting for the equimolar presence of two
isomers. A matching placebo was also provided. All capsules were
administered orally.
[0032] At Visit 9, subjects were randomly given one of the
treatments unless they had missed a study visit. In that case,
Visit 9 was used to repeat the missed study visit. A minimum of six
days separated each of the 9 visits, during which time subjects
received their standard medication.
[0033] Mean Plasma Concentration
[0034] D-MPH and DL-MPH were found to have equivalent
pharmacokinetics and safety profiles, and resulted in no serious
adverse effects. The amount of D-MPH delivered by a 2.5 mg dose of
ONLY D-MPH is approximately equal to the amount of D-MPH delivered
by the 5 mg close of racemic DL-MPH. Similarly, a 5 mg dose of only
D-MPH provides the same amount of the D isomer as a 10 mg dose of
the racemic DL mixture. Below are listed the mean plasma
concentrations of D-MPH as determined 4, 6, and 8 hours after
Ingestion.
1TABLE 1 Mean plasma concentration, nanograms per milliliter
(ng/ml) of D-MPH after ingesting D-MPH or DL-MPH. Formulation 4
hours 6 hours 8 hours 2.5 mg D-MPH 3.00 1.82 0.67 5 mg DL-MPH 2.94
1.91 0.85 5 mg D-MPH 5.86 3.75 1.84 10 mg DL-MPH 7.66 5.20 2.66 10
mg D-MPH 11.73 7.65 3.81 20 mg DL-MPH 12.50 8.15 3.85
[0035] Objective Measure: Math Test
[0036] A computerized math test provided a measure of attention,
concentration and work output. This test was administered 30
minutes before, and 4 hours, 6 hours, and 8 hours after medication
administration. Table 2 lists statistical significance (p values)
for comparisons between test results obtained after administration
of D-MPH or DL-MPH and test results obtained after administration
of a placebo. Similar notation is used in other data tables below.
Data in Table 2 were obtained 30 minutes before, and at 4, 6, and 8
hours after, administration.
[0037] Four hours following administration, 10 mg of the D isomer
was as effective as 20 mg of the DL racemate, as measured by
improvement on the math test. The effectiveness as measured by
improvement on the math test was evident only with 10 mg D-MPH 6
and 8 hours after administration of medication, and not with its
equivalent dose as contained within 20 mg of DL-MPH. Superiority in
effectiveness over the placebo was not observed with doses of D-MPH
of less than 10 mg, and no significant effect was observed with
even twice the dose of racemic DL-MPH beyond 4 hours. At 6 hours
and 8 hours after administration, superiority over placebo was not
achieved with lower doses than 10 mg of D-MPD or with any dose of
DL-MPH used in this study.
2TABLE 2 P values of the comparisons of math scores achieved at
various time intervals after taking placebo, with math scores
achieved after taking 20 mg DL-threo methylphenidate or 10 mg
D-threo methylphenidate. Test 1 Test 4 Test 5 Test 6 (-30 min) (4
hours) (6 hours) (8 hours) placebo - DL 20 mg NS* <0.001 NS NS
placebo - D 10 mg NS <0.001 <0.001 0.289 *NS, here and below,
indicates no statistically significant difference. If results of
comparison are statistically significant (p < 0.05), the p value
is listed.
[0038] Connors, Loney, and Milich (CLAM) Rating
[0039] The CLAM Rating Scale is a standard, subjective measure of
inattention, overactivity, aggression, and defiance. Rating was
completed 6 hours after drug administration by observers who were
blind as to which study medication each subject received. The scale
contains 16 items:
3 1. Restless or Overactive 2. Disturbs other children 3. Mood
changes quickly and dramatically 4. Cries often and easily 5.
Demands must be met immediately 6. Teases other children and
interferes with their activities 7. Fidgeting 8. Hums 9. Excitable,
impulsive 10. Inattentive, easily distracted 11. Fails to finish
things started 12. Quarrelsome 13. Acts smart 14. Temper outbursts
15. Defiant 16. Uncooperative
[0040] While all three doses of D-MPH significantly reduced the
overall CLAM score, indicating clinical benefit over the placebo,
only the 10 mg and 20 mg doses of DL-MPH remained effective six
hours after drug administration.
4TABLE 3 P values for comparison of overall CLAM scores 6 hours
after administration of D-MPH or DL-MPH, with overall CLAM scores 6
hours after administration of placebo placebo-DL 5 mg NS* placebo-D
2.5 mg 0.0065 placebo-DL 10 mg 0.216 placebo-D 5 mg <0.001
placebo-DL 20 mg <0.001 placebo-D 10 mg <.001 *NS, no
significant difference; if statistically significant (p < 0.05),
the p value is listed
[0041] Two subscales were calculated from the CLAM: the
aggression/defiance (A/D) subscale and the inattention/overactivity
(I/O) subscale. All doses of D-MPH were superior to the placebo
using the AID subscale. However, only the highest dose (20 mg) of
DL-MPH was superior to placebo for the A/D subscale. The highest
doses of both the D-MPH and DL-MPH formulations were superior to
the placebo in the I/O subscale. While the 5 mg dose of D-MPH was
also superior to the placebo, the equivalent as administered in a
10 mg dose of DL-MPH was not.
[0042] Shown below are p values for the comparisons of scores on
the two CLAM subscales obtained 6 hours after administration of DL
or D-MPH with scores obtained 6 hours after administration of a
placebo.
5TABLES 4 and 5 Comparison of scores on CLAM subscales 6 hours
after administration of DL or D-MPH or a placebo.
Aggression-Defiance (A/D)Score placebo-DL 5 mg NS placebo-D 2.5 mg
0.0279 placebo-DL 10 mg NS placebo-D 5 mg <0.001 placebo-DL 20
mg <0.001 placebo-D 10 mg <.001 Inattention-Over-activity
(I/O) Score placebo-DL 5 mg NS placebo-D 2.5 mg NS placebo-DL 10 mg
NS placebo-D 5 mg <0.0097 placebo-DL 20 mg <0.001 placebo-D
10 mg <0.001
[0043] Scores for the individual behaviors were also determined.
According to several observed individual behaviors (fidgeting,
quarrelsome and defiant), 2.5 mg D-MPH was determined to provide
efficacy superior to that of a placebo, but 5 mg of DL-MPH was not
similarly effective. Also, 5 mg D-MPH provided efficacy superior to
that of a placebo while 10 mg of DL-MPH did not, for the following
behaviors: disturbs, demands, fidgeting, excitable, inattentive,
and defiant.
[0044] For two behaviors, quarrelsome and acts smart, 10 mg d-MPH
provided efficacy superior to that of the placebo while 20 mg of
DL-MPH did not.
[0045] Results for individual behaviors are summarized below. Shown
in the tables are p values for the comparisons of the results of
individual behavior rating as obtained 6 hours after administration
of D-MPH and DL-MPH to the results obtained 6 hours after
administration of a placebo.
6TABLES 6-13 P values for comparison of effectiveness of D-MPH and
DL-MPH with that of placebo, as indicated by individual behaviors.
Disturbs placebo-dl 5 mg NS placebo-d 2.5 mg NS placebo-dl 10 mg NS
placebo-d 5 mg <0.0280 placebo-dl 20 mg <0.001 placebo-d 10
mg <0.001 Demands placebo-dl 5 mg NS placebo-d 2.5 mg NS
placebo-dl 10 mg NS placebo-d 5 mg 0.494 placebo-dl 20 mg 0.0335*
placebo-d 10 mg 0.0011 Fidgeting placebo-dl 5 mg NS placebo-d 2.5
mg 0.0360 placebo-dl 10 mg NS placebo-d 5 mg 0.0067 placebo-dl 20
mg <0.001 placebo-d 10 mg <0.001 Excitable placebo-dl 5 mg NS
placebo-d 2.5 mg NS placebo-dl 10 mg NS placebo-d 5 mg 0.494
placebo-dl 20 mg 0.0014 placebo-d 10 mg 0.001 Inattentive
placebo-dl 5 mg NS placebo-d 2.5 mg NS placebo-dl 10 mg NS
placebo-d 5 mg 0.0149 placebo-dl 20 mg 0.0016 placebo-d 10 mg
<0.001 Quarrelsome placebo-dl 5 mg NS placebo-d 2.5 mg 0.0115
placebo-dl 10 mg NS placebo-d 5 mg NS placebo-dl 20 mg NS placebo-d
10 mg 0.0016 Acts Smart placebo-dl 5 mg NS placebo-d 2.5 mg NS
placebo-dl 10 mg NS placebo-d 5 mg NS placebo-dl 20 mg NS placebo-d
10 mg 0.001 Defiant placebo-dl 5 mg NS placebo-d 2.5 mg 0.0010
placebo-dl 10 mg 0.0038 placebo-d 5 mg 0.0166 placebo-dl 20 mg
<0.001 placebo-d 10 mg <0.001
[0046] At a dose of 5 mg, the D isomer provided efficacy for at
least 6 hours following administration, as compared to the DL
racemate, which required a twice that dosage to provide 6 hours of
efficacy. Even more significantly, a 2.5 mg dose of the D isomer
provided efficacy in controlling several behaviors, while even
twice the dose of the DL racemate was ineffective against the same
behaviors. For two behaviors (fidgeting and quarrelsome), even four
times the dose of the racemate, i.e. 10 mg, showed no statistically
significant improvement over the placebo as compared to 2.5 mg of
the D isomer.
[0047] In conclusion, the data show that, according to both
objective and subjective measures, D-MPH was not only more
effective than a placebo in controlling subjective behaviors and in
improving objective performance on a math test, but clearly
provided efficacy for a significantly longer period of time than
did an equivalent dose of DL-MPH.
EXAMPLE 2
[0048] Exemplary D-MPH Formulations
7 Formulations for 2.5 mg D-MPH Formulation (mg/tablet) Ingredient
#1 #2 #3 Starch 1500, NF (pre-gelatinized starch) 30.0 30.0 23.4
Active Drug 2.5 2.5 2.5 D&C Yellow Lake #10 0.9 0.6 1.5 Lactose
Monohydrate, NF (flast flow 61.9 61.6 75.0 #316) Sodium Starch
Glycolate, NF 1.5 4.0 27.35 Micro-crystalline Cellulose, NF 42.7
50.0 30.0 Magnesium Stearate, NF 0.5 1.3 0.25 Total Weight Per
Tablet 140 150 160 Formulations for 5 mg D-MPH Formulation
(mg/tablet) Ingredient #1 #2 #3 Starch 1500, NF (pre-gelatinized
starch) 30.0 30 23.4 Active Drug 5 5 5 D&C Yellow Lake #10 0.9
0.6 1.5 Lactose Monohydrate, NF (flast flow 59.4 61.6 72.5 #316)
Sodium Starch Glycolate, NF 1.5 4.0 27.35 Micro-crystalline
Cellulose, NF 42.7 47.5 30.0 Magnesium Stearate, NF 0.5 1.3 0.25
Total Weight Per Tablet 140 150 160 Formulations for 10 D-MPH
Formulation (mg/tablet) Ingredient #1 #2 #3 Starch 1500, NF
(pre-gelatinized starch) 30.0 30.0 23.4 Active Drug 10 10 10
D&C Yellow Lake #10 0.9 0.6 1.5 Lactose Monohydrate, NF (flast
flow 54.4 61.6 67.5 #316) Sodium Starch Glycolate, NF 1.5 4.0 27.35
Micro-crystalline Cellulose, NF 42.7 42.5 30.0 Magnesium Stearate,
NF 0.5 1.3 0.25 Total Weight Per Tablet 140 150 160
[0049] Various modifications of the invention, in addition to those
described herein, will be apparent to those skilled in the art from
the foregoing description. Such modifications are intended to fall
within the scope of the appended claims.
* * * * *