U.S. patent application number 10/660058 was filed with the patent office on 2004-06-17 for pharmaceutical formulations of modafinil.
Invention is credited to Heacock, Craig, Parikh, Alpa, Patel, Piyush.
Application Number | 20040116532 10/660058 |
Document ID | / |
Family ID | 32511269 |
Filed Date | 2004-06-17 |
United States Patent
Application |
20040116532 |
Kind Code |
A1 |
Heacock, Craig ; et
al. |
June 17, 2004 |
Pharmaceutical formulations of modafinil
Abstract
Compositions of modafinil and methods of treating neurologically
related conditions with the administration of modafinil. Also
compositions that include modafinil and one or more excipients such
as diluents, disintegrants, binders and lubricants.
Inventors: |
Heacock, Craig;
(Downingtown, PA) ; Parikh, Alpa; (Avondale,
PA) ; Patel, Piyush; (Wallingford, PA) |
Correspondence
Address: |
CEPHALON, INC.
145 BRANDYWINE PARKWAY
WEST CHESTER
PA
19380-4245
US
|
Family ID: |
32511269 |
Appl. No.: |
10/660058 |
Filed: |
September 11, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60410395 |
Sep 13, 2002 |
|
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Current U.S.
Class: |
514/618 |
Current CPC
Class: |
A61K 9/2027 20130101;
A61K 31/165 20130101; A61P 9/10 20180101; A61K 9/2054 20130101;
A61P 3/00 20180101; A61K 9/2018 20130101; A61P 25/00 20180101; A61P
25/14 20180101; A61P 25/26 20180101 |
Class at
Publication: |
514/618 |
International
Class: |
A61K 031/165 |
Claims
What is claimed is:
1. A pharmaceutical unit dose consisting essentially of about 250
to about 450 mg of modafinil.
2. A pharmaceutical unit dose consisting essentially of about 250
to about 350 mg of modafinil.
3. The unit dose of claim 1 consisting essentially of about 275 to
about 325 mg of modafinil.
4. The unit dose of claim 1 consisting essentially of about 325 to
about 450 mg of modafinil.
5. The unit dose of claim 1 consisting essentially of 275 to 325 mg
of modafinil.
6. The unit dose of claim 1 consisting essentially of 325 to 450 mg
of modafinil.
7. The unit dose of claim 1 consisting essentially of 255 mg of
modafinil.
8. The unit dose of claim 1 consisting essentially of 300 mg of
modafinil.
9. The unit dose of claim 1 consisting essentially of 340 mg of
modafinil.
10. The unit dose of claim 1 consisting essentially of 425 mg of
modafinil.
11. A method of treating ADHD in a human subject comprising the
step of administering a single dose of about 250 to about 450 mg of
modafinil within a 24 hour period to the human subject.
12. A method of treating ADHD in a human subject comprising the
step of administering a single dose of about 250 to about 350 mg of
modafinil within a 24 hour period to the human subject.
13. The method of claim 11, wherein the subject is a pediatric
subject.
14. The method of claim 11, wherein about 425 mg of modafinil is
administered to the subject.
15. The method of claim 11, wherein about 340 mg of modafinil is
administered to the subject.
16. The method of claim 11, wherein about 300 mg of modafinil is
administered to the subject.
17. The method of claim 11, wherein about 255 mg of modafinil is
administered to the subject.
18. A pharmaceutical unit dose of modafinil that, following oral
administration to a human, results in a blood profile of modafinil
substantially as shown in FIG. 3.
19. A method of treating ADHD in a human subject with modafinil,
comprising the step of administering to the subject a single dose
of modafinil in a 24 hour period that is sufficient to induce a
blood profile of modafinil substantially as shown in FIG. 3.
20. The unit dose of claim 1, wherein the amount of modafinil in
the unit dose is selected from the group consisting essentially of
250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310,
315, 320, 325, 330, 335, 340, 345 and 350 mgs of modafinil.
21. The unit dose of claim 1, wherein the amount of modafinil in
the unit dose is selected from the group consisting essentially of
355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415,
420, 425, 430, 435, 440, 445, and 450 mg of modafinil.
22. The unit dose of claim 1, wherein the amount of modafinil in
the pharmaceutical unit dose is selected from the group consisting
of 255, 300. 340 and 425 mgs of modafinil.
23. The unit dose of claim 1, wherein about 70 to 75% of the total
tablet weight is modafinil.
24. The unit dose of claim 1, wherein about 80% of the total tablet
weight is modafinil.
25. A pharmaceutical composition comprising about 250 to about 450
mg of modafinil.
26. A pharmaceutical composition comprising about 250 to about 350
mg of modafinil.
27. The composition of claim 25 comprising about 275 to about 325
mg of modafinil.
28. The composition of claim 25 comprising about 325 to about 450
mg of modafinil.
29. The composition of claim 25 comprising 275 to 325 mg of
modafinil.
30. The composition of claim 25 comprising 325 to 450 mg of
modafinil.
31. The composition of claim 25 comprising 255 mg of modafinil.
32. The composition of claim 25 comprising 300 mg of modafinil.
33. The composition of claim 25 comprising 340 mg of modafinil.
34. The composition of claim 25 comprising 450 mg of modafinil.
35. A pharmaceutical composition comprising about 250 to about 450
mg of modafinil that is free of magnesium silicate or talc.
36. The composition of claim 35 comprising one or more diluents,
each independently chosen from a starch, a lactose monohydrate or a
microcrystalline cellulose; one or more disintegrants, each
independently chosen from a pregelatinized starch or a cross-linked
sodium carboxymethyl cellulose; a binder; and a lubricant.
37. The composition of claim 36, wherein the binder is a polyvinyl
pyrrolidone, and the lubricant is magnesium stearate.
38. The composition of claim 35, wherein the composition is a
tablet.
39. The composition of claim 35, wherein about 90% of the tablet
weight is modafinil.
40. The composition of claim 35, wherein about 80% of the tablet
weight is modafinil.
41. The unit dose of claim 1, wherein the modafinil is
R-(-)2-[(diphenylmethyl)sulfinyl] acetamide.
42. The composition of claim 25, wherein the modafinil is
R-(-)2-[(diphenylmethyl)sulfinyl] acetamide.
43. The unit dose of claim 1, wherein the modafinil is
R-(-)2-[(diphenylmethyl)sulfinyl] acetamide.
44. The composition of claim 25, wherein the modafinil is
R-(-)2-[(diphenylmethyl)sulfinyl] acetamide.
Description
FIELD OF THE INVENTION
[0001] The present invention is related to compositions of
modafinil and methods of treating neurologically related conditions
with the administration of modafinil. The present invention also
relates to compositions that include modafinil and one or more
excipients such as diluents, disintegrants, binders and
lubricants.
BACKGROUND OF THE INVENTION
[0002] Modafinil, C.sub.15H.sub.15NO.sub.2S, also known as
2-(benzhydrylsulfinyl) acetamide, or 2-[(diphenylmethyl) sulfinyl]
acetamide, is a synthetic acetamide derivative with wake-promoting
activity, the structure of which has been described in French
Patent No. 78 05 510 and in U.S. Pat. No. 4,177,290 ('290), and
which has been approved by the United States Food and Drug
Administration for use in the treatment of excessive daytime
sleepiness associated with narcolepsy. Modafinil has been tested
for treatment of several behavioral conditions in combination with
various agents including apomorphine, amphetamine, reserpine,
oxotremorine, hypnotics, yohimbine, 5-hydroxytryptophan, and
monoamine oxidase inhibitors, as described in the cited patents. A
method of preparation of a racemic mixture is described in the '290
patent and a method of preparation of a levorotatory isomer is
described in U.S. Pat. No. 4,927,855 (both incorporated herein by
reference). The levorotatory isomer is reported to be useful for
treatment of hypersomnia, depression, Alzheimer's disease and to
have activity towards the symptoms of dementia and loss of memory,
especially in the elderly. Modafinil has also been found to have
application in the treatment of fatigue, and in particular the
treatment of fatigue associated with multiple sclerosis, as well as
sleepiness, Parkinson's disease, cerebral ischemia, stroke, sleep
apneas, eating disorders, attention deficit hyperactivity disorder
(described further below), for stimulation of appetite or weight
gain, for promotion of wakefulness, or for improvement of cognitive
dysfunction.
[0003] The primary pharmacological activity of modafinil is to
promote wakefulness. Modafinil promotes wakefulness in rats (Touret
et al., 1995; Edgar and Seidel, 1997), cats (Lin et al., 1992),
canines (Shelton et al, 1995) and non-human primates (Hernant et
al, 1991) as well as in models mimicking clinical situations, such
as sleep apnea (English bulldog sleep disordered breathing model)
(Panckeri et al, 1996) and narcolepsy (narcoleptic canine) (Shelton
et al, 1995).
[0004] Modafinil has also been described as an agent with activity
in the central nervous system, and as a useful agent in the
treatment of Parkinson's disease (U.S. Pat. No. 5,180,745); in the
protection of cerebral tissue from ischemia (U.S. Pat. No.
5,391,576); in the treatment of urinary and fecal incontinence
(U.S. Pat. No. 5,401,776); and in the treatment of sleep apneas and
disorders of central origin (U.S. Pat. No. 5,612,379). U.S. Pat.
No. 5,618,845 describes modafinil preparations of a defined
particle size less than about 200 microns. In addition, modafinil
may be used in the treatment of eating disorders, or to promote
weight gain or stimulate appetite in humans or animals (U.S.
Provisional Patent Application No. 60/150,071, incorporated herein
by reference), or in the treatment of attention deficit
hyperactivity disorder (ADHD) as described in U.S. Pat. No.
6,346,548, or fatigue, especially fatigue associated with multiple
sclerosis (U.S. Provisional Patent Application No. 60/149,612,
incorporated herein by reference). ADHD is a chronic
neuropsychiatric disorder in children that is characterized by
developmentally inappropriate hyperactivity, impulsivity, and
inattention. ADHD is estimated to affect 3%-5% of school-age
children. The core ADHD symptoms in adults include a frequent and
persistent pattern of inattention/distractibility and/or
hyperactivity-impulsivity. The most common symptoms exhibited in
ADHD adults are marked inattention, poor concentration, easy
distractibility, day dreaming, forgetfulness, and a frequent shift
in activities. ADHD adults also report marked impulsivity,
intrusiveness, low frustration/stress tolerance, temper tantrums,
irritability, and extreme impatience. Less commonly reported
symptoms in adults include hyperactivity, which may be confined to
fidgeting, or an inward feeling of jitteriness or restlessness. In
addition to the core ADHD symptoms, adults with ADHD often exhibit
associated clinical characteristics such as boredom, social
inappropriateness, and chronic conflicts in social situations.
[0005] Modafinil was known in the art in the form of a therapeutic
package, marketed under the name Provigil.RTM.. Provigil.RTM. is a
pharmaceutical product sold by Cephalon, Inc. of West Chester, Pa.
Provigil.RTM. is supplied as tablets containing 100 mg or 200 mg
modafinil, with several excipients, including magnesium silicate
and talc. In commercial use, modafinil-containing therapeutic
packages are labeled for use in treating excessive daytime
sleepiness associated with narcolepsy.
SUMMARY OF THE INVENTION
[0006] The present invention is directed to a pharmaceutical
composition containing about 250 to about 350 mg of modafinil.
[0007] The present invention is also directed to a pharmaceutical
composition containing about 250 to about 450 mg of modafinil.
[0008] The present invention is also directed to methods of
treating attention deficit hyperactivity disorder and attention
deficit disorder by administering between about 250 to about 350 mg
of modafinil to a subject.
[0009] The present invention is also directed to methods of
treating attention deficit hyperactivity disorder and attention
deficit disorder by administering between about 250 to about 450 mg
of modafinil to a subject.
[0010] The present invention is also directed to a unit dose of
modafinil having a reduced overall unit dose size and/or volume
while simultaneously having a higher percentage, by weight, of
modafinil. The unit dose can be free of magnesium silicate or talc,
and can contain about 250 to about 350 mg of modafinil, wherein
about 70-90% of the total weight of the unit dose is modafinil.
[0011] The present invention is also directed to a unit dose of
modafinil having a reduced overall unit dose size and/or volume
while simultaneously having a higher percentage, by weight, of
modafinil. The unit dose can be free of magnesium silicate or talc,
and can contain about 250 to about 450 mg of modafinil, wherein
about 70-90% of the total weight of the unit dose is modafinil.
BRIEF DESCRIPTION OF THE DRAWING
[0012] FIG. 1 represents a human blood plasma concentration curve
of modafinil after an initial dose of 100 mg of modafinil followed
4 hours later by a 200 mg dose of modafinil.
[0013] FIG. 2 represents a human blood plasma concentration curve
of modafinil after an initial dose of 200 mg of modafinil followed
4 hours later by a 100 mg dose of modafinil.
[0014] FIG. 3 represents a human blood plasma concentration curve
of modafinil after a single dose of 300 mg of modafinil.
[0015] FIG. 4 represents a human blood plasma concentration curve
of modafinil after a single dose of 100 mg of modafinil.
[0016] FIG. 5 represents a graph depicting the results of a
clinical study showing the efficacy of 340 mg and 425 mg doses of
modafinil in ADHD patients.
DETAILED DESCRIPTION OF THE INVENTION
[0017] As used herein, "about" refers to a range of values .+-.10%
of a specified value. For example, "about 20" includes .+-.10% of
20, or from 18 to 22, inclusive.
[0018] As used herein, "modafinil" refers to modafinil, its racemic
mixtures, individual isomers (for example, the (-) isomer or the
"R" isomer of modafinil), acid addition salts, such as a metabolic
acid of modafinil, benzhydrylsulfinylacetic acids, and its sulfone
forms, hydroxylated forms, polymorphic forms, analogs, derivatives,
cogeners and prodrugs thereof. Prodrugs are known in the art as
compounds that are converted to the active agent (modafinil) in the
body of a subject.
[0019] As used herein, the term "pharmaceutically acceptable"
refers to those compounds, materials, compositions, and/or unit
doses which are, within the scope of sound medical judgment,
suitable for administration to human beings, e.g., without
unacceptable toxicity, irritation, allergic response, or other
problems or complications commensurate with a reasonable
benefit/risk ratio.
[0020] A "pharmaceutical composition", as used herein, means a
medicament for use in treating a mammal, e.g., a human, that
comprises modafinil. A pharmaceutical composition according to the
invention may also, but does not of necessity, include one or more
non-toxic pharmaceutically acceptable carrier.
[0021] As used herein, "therapeutically effective amount" refers to
an amount that is effective in reducing, eliminating, treating,
preventing or controlling the symptoms of herein-described diseases
and conditions.
[0022] Similarly, a "method of treating" is a method of reducing,
eliminating, treating, preventing or controlling the symptoms of
herein-described diseases and conditions. It is understood that the
effect of pharmacological agents will vary among a large population
of subjects.
[0023] As used herein, "pharmaceutical unit dose," "unit dose" or
"unit dose form" means a single dose which is capable of being
administered to a subject, and which can be readily handled and
packaged, remaining as a physically and chemically stable unit dose
comprising either modafinil, or a pharmaceutically acceptable
composition comprising modafinil.
[0024] As used herein, "consisting essentially of" a specified
amount of a pharmaceutically active agent means that there is no
additional amount of that agent. The presence of other ingredients,
e.g., excipients and/or lubricants, etc., is not precluded. The
presence of additional other pharmaceutically active agents is also
not precluded.
[0025] As used herein, "substantially" means approximating to a
great extent or degree.
[0026] 1. Amounts of Modafinil of the Present Invention
[0027] In one embodiment, a composition of the present invention
includes a pharmaceutical composition of modafinil. The
pharmaceutical composition can further include at least one
pharmaceutical unit dose (hereafter "unit dose") of modafinil,
typically in a solid unit dose form, such as a tablet or capsule.
For the reasons set forth below, a composition of the present
invention can include between about 250 to about 350 mg of
modafinil or between about 250 to about 450 mg of modafinil. In
other embodiments, a composition can include between about 275 to
about 325 mg of modafinil or about 325 to about 425 mg of
modafinil. In another embodiment, a composition can include about
255 mg of modafinil, about 300 mg of modafinil, about 340 mg of
modafinil or about 425 mg of modafinil. In yet other embodiments, a
composition of the invention can include about 250, 255, 260, 265,
270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330,
335, 340, 345, or 350 mg of modafinil, or about 355, 360, 365, 370,
375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435,
440, 445, or 450 mg of modafinil. Preferably, a unit dose can
include about 255, 300, 340 or 425 mg of modafinil. Most
preferably, a unit dose can include 355, 300, 340 or 425 mg of
modafinil.
[0028] In yet another embodiment, a composition of the invention
consists essentially of about 250 to about 350 mg of modafinil or
about 250 to about 450 mg of modafinil. In another embodiment, a
pharmaceutical composition of the invention consists essentially of
about 275 to 325 mg of modafinil or about 325 to about 425 mg of
modafinil. In yet another embodiment, a composition of the
invention consists essentially of about 255 mg of modafinil, about
300 mg of modafinil, about 340 mg of modafinil or about 425 mg of
modafinil, i.e., it does not contain more or less modafinil, but
can contain other ingredients, e.g., excipients or other active
agents. In yet another embodiment, a composition of the invention
consists essentially of about 250, 255, 260, 265, 270, 275, 280,
285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345 or
350 mg of modafinil, or about 355, 360, 365, 370, 375, 380, 385,
390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, or 450
mg of modafinil. Preferably, a unit dose consists essentially of
about 255, 300, 340 or 425 mg of modafinil. Most preferably, a unit
dose consists essentially of 255, 300, 340 or 425 mg of
modafinil.
[0029] A pharmaceutical composition of the invention can also be a
liquid, softgel, suspension, emulsion, microemulsion, complex, as
well as a solid solution form which can be dispensed in a manner
that delivers a requisite amount of modafinil as set forth herein.
A pharmaceutical composition of the present invention can also be a
modified release form such as, but not limited to, a bi-modal or
extended release form.
[0030] Conventional administrations of modafinil included discrete
effective amounts of modafinil, typically either single 100 mg or
200 mg unit doses. To treat ADHD using these conventional unit
doses in clinical studies, modafinil was administered as a 100 mg
dose followed 4-6 hours later by a 200 mg dose, or alternatively, a
200 mg dose followed 4-6 hours later by a 100 mg dose. Such dosing
regimens are referred to as a "split dose," and are particularly
effective for treating ADHD and were considered necessary to
prevent blood levels of modafinil from obtaining undesirable
levels.
[0031] From previous 100 mg studies, generally summarized by FIG.
4, it was also predicted that the treatment of ADHD from a single
300 mg dose might produce an unacceptable incidence of side effects
because the 300 mg dose could generate undesirable blood levels of
modafinil. Thus the use of a split dose of 100 mg and 200 mg doses
of modafinil administered in the manner described above was
expected to provide the most favorable results, and particularly in
the afternoon.
[0032] However, it has been surprisingly found that a single unit
dose of modafinil containing between about 250 to about 350 mg of
modafinil or between about 250 to about 450 mg, and in particular
about 255, 300, 340 or 425 mg of modafinil, induces a beneficial
neurological response with respect to the treatment of ADHD.
Specifically, a single unit dose containing between about 250 to
about 350 mg or between about 250 to about 450 mg, or between about
275 to about 325 mg or between about 325 to about 425 or about 255,
300, 340 or 425 mg of modafinil can be as effective as a 200 mg
dose followed by a 100 mg dose or 200 mg dose, or a 100 mg dose
followed by a 200 mg dose when the two doses are administered
according to the split dose regimen described above, without the
previously predicted incidence of undesirable side effects.
[0033] It has also been surprisingly found that the compositions of
modafinil of the present invention provide significantly improved
attention and significantly improved ADHD symptoms. The improvement
in attention and ADHD symptoms was substantially the same as, and
continued for a duration of time comparable to, both a) 100 mg of
modafinil followed 4-6 hours later by 200 mg of modafinil, and b)
200 mg of modafinil followed 4-6 hours later by 100 mg of
modafinil. Thus, a single dose of the present invention
unexpectedly achieves improved attention and ADHD symptoms to a
degree comparable to the double dosing regimen described
hereinabove.
[0034] As shown in FIGS. 1 and 2, the blood plasma concentration of
modafinil begins to decrease after about two hours post
administration of modafinil. In particular, FIGS. 1 and 2 show
blood plasma concentrations of modafinil when a 100 mg dose is
administered before (FIG. 1) or after (FIG. 2) a 200 mg dose is
administered according to the regimen described above and in the
brief description of FIGS. 1 and 2 above. FIGS. 1 and 2 also show
that after blood levels of modafinil begin to decrease, the second
dose of modafinil increases modafinil blood levels to a
concentration that can be greater than the maximum blood levels
achieved from the first dose.
[0035] FIG. 3 provides the blood plasma concentration of modafinil
after the administration of a single dose according to the present
invention, namely 300 mg of modafinil. FIG. 3 shows that the blood
level of modafinil also begins to decrease after about 2 hours post
administration of the dose. From FIG. 3, it was also surprisingly
found that the improved attention and improved ADHD symptoms
resulted from blood concentrations of modafinil which were about
20-30% less than predicted, based upon an extrapolation of 100 mg
unit dose data, and thus the predicted incidence of undesirable
side effects can be avoided. Furthermore, it was concluded that the
blood profile shown in FIG. 3 provides a desirable blood profile of
modafinil blood concentration for the treatment of certain
neurological conditions that are treatable by modafinil and
described herein, such as ADHD. Accordingly, the present invention
also includes a unit dose such that the oral administration of the
unit dose to a human results in a blood profile of modafinil
substantially as shown in FIG. 3.
[0036] As shown in FIG. 5, significant and surprising improvements
in ADHD were also obtained with single doses of 340 mg and 425 mg
of modafinil.
[0037] Thus, the compositions and unit doses of the present
invention can be beneficial to subjects in need of modafinil
relative to conventional unit doses containing 100 mg and 200 mg of
modafinil. Specifically, the present invention can increase the
amount of time between required dosings of a subject and/or
decrease the total number of doses of modafinil which may be
required by a subject over a given period of time (e.g., in a 24
hour period or per day), i.e., a reduced need for split dose
regimens.
[0038] 2. The Composition of Modafinil of the Present Invention
[0039] As described above, the present invention provides
pharmaceutical compositions containing between about 250 and about
350 mg of modafinil or between about 250 and about 450 mg of
modafinil as well as compositions containing between about 275 and
about 325 mg of modafinil, between about 325 and about 425 mg of
modafinil or about 255, 300, 340 or 425 mg of modafinil. A
pharmaceutical composition of the present invention can be a unit
dose of modafinil, and in a preferred embodiment of the present
invention a unit dose of modafinil, in tablet or capsule form
including 250 to 350 mg of modafinil, 250 to 450 mg of modafinil,
275 to 325 mg of modafinil, 325 to 425 mg of modafinil, 255 mg of
modafinil, 300 mg of modafinil, 340 mg of modafinil or 425 mg of
modafinil.
[0040] In some embodiments, a unit dose of the invention can be
prepared in a conventional manner, so as to maintain the relative
proportions of modafinil and other pharmaceutical composition
ingredients (e.g. lubricants and fillers) as compared to
conventional 100 mg and 200 mg unit doses of modafinil. These
embodiments are typically larger (in size and/or volume) than
conventional 100 mg and 200 mg unit doses. Such unit doses of the
present invention can also be prepared with or without one or more
of magnesium silicate or talc.
[0041] In other embodiments of the present invention, the
proportion of modafinil in the unit dose can be significantly
higher than that of conventional 100 mg and 200 mg modafinil unit
doses. The increase in weight percent of modafinil, while
simultaneously reducing the weight percent of other ingredients,
facilitates the manufacture of smaller (in size and/or volume) unit
doses while still supplying the same amount of modafinil, i.e., 250
mg to 450 mg, to a subject. Such unit doses of the present
invention can also be prepared with or without one or more of
magnesium silicate or talc.
[0042] Typical embodiments include compositions of modafinil with
one or more pharmaceutically acceptable excipients including but
not limited to diluents, disintegrants, binders and lubricants.
Preferably, the excipients meet the standards of the National
Formulary ("NF") or United States Pharmacopoeia ("USP"). In a
particular embodiment, there is provided a composition consisting
of modafinil with one or more diluents, disintegrants, binders and
lubricants.
[0043] In certain preferred embodiments, the composition comprises
modafinil; one or more diluents, each independently chosen from a
starch, a lactose monohydrate or a microcrystalline cellulose; one
or more disintegrants, each independently chosen from a
pregelatinized starch or a cross-linked sodium carboxymethyl
cellulose; a binder; and a lubricant. In other preferred
embodiments, the binder is a polyvinyl pyrrolidone, and the
lubricant is magnesium stearate. In certain more preferred
embodiments, a diluent is Fast Flo.RTM. #316, a second diluent is
Avicel.RTM. PH 102; a disintegrant is Starch 1500.RTM., a second
disintegrant is Ac-Di-Sol.RTM.; and the binder is Povidone K-29/32.
In other preferred embodiments, the diluent is Lactose Monohydrate,
NF; the disintegrant is Croscarmellose Sodium, NF or
Ac-Di-Sol.RTM.; and the binder is Povidone K90 D, USP. In other
embodiments, the unit dose can be free of one or more of
microcrystalline cellulose and pregelatinized starch.
[0044] In certain more preferred embodiments, the lactose
monohydrate is Fast Flo.RTM. #316; the microcrystalline cellulose
is Avicel.RTM. PH 102; the pregelatinized starch is Starch
1500.RTM., the cross-linked sodium carboxymethyl cellulose is
Ac-Di-Sol.RTM. and the polyvinyl pyrrolidone is Povidone
K-29/32.
[0045] In one embodiment, modafinil is a substantial proportion of
the composition by weight. In other embodiments, Fast Flo.RTM. #316
can be about 28.7%, the Avicel.RTM. PH 102 can be about 10.4%, the
Starch 1500.RTM. can be about 10.9%, the Ac-Di-Sol.RTM. can be
about 4.0%, the Povidone K-29/32 can be about 5.2% and the
magnesium stearate can be about 0.8%.
[0046] In some embodiments, the total amount of modafinil present
in the unit dose can be from about 45% to about 90% of the total
unit dose weight. Preferably, the total amount of modafinil present
in the unit dose can be about 60% to 80%, 85% to 90%, preferably
70% to 90%, 70% to 75%, most preferably 70% to 80% of the total
unit dose weight.
[0047] In other embodiments, modafinil comprises from about 80-90%
of the composition by weight. The composition can further include a
diluent, such as a lactose monohydrate, preferably from about 3-15%
of the composition by weight; a disintegrant, such as a
cross-linked sodium carboxymethyl cellulose, preferably from about
2-10% of the composition by weight; a binder such as a polyvinyl
pyrrolidone, preferably from about 2-10% of the composition by
weight; and a lubricant such as magnesium stearate, preferably from
about 0.2-2.0% of the composition by weight. In certain more
preferred embodiments, the diluent is Lactose Monohydrate, NF, the
disintegrant is Croscarmellose Sodium, NF, the binder is Povidone
K90D, USP, and the lubricant is Magnesium Stearate, NF.
[0048] In one embodiment, modafinil is about 70% composition by
weight. In the composition, Lactose Monohydrate, NF is about 20%,
the Croscarmellose Sodium, NF about 4%, the Povidone, USP is about
5.2%, and the Magnesium Stearate, NF is about 0.8%.
[0049] In one embodiment, modafinil is about 75% composition by
weight. In the composition, the Lactose Monohydrate, NF is about
15%, the Croscarmellose Sodium, NF is about 4%, the Povidone, USP
is about 5.2%, and the Magnesium Stearate, NF is about 0.8%.
[0050] In another embodiment, modafinil is included in a
composition of the present invention at about 80% of the
composition by weight, the Lactose Monohydrate, NF is about 10%,
the Croscarmellose Sodium, NF is about 4%, the Povidone K90 D, USP
is about 5.2%, and the Magnesium Stearate, NF is about 0.8%. In a
further embodiment, the Magnesium Stearate, NF is about 1%.
[0051] In yet another embodiment, the composition of the present
invention includes modafinil at about 90% of the composition by
weight, the Lactose Monohydrate, NF is about 3.5%, the
Croscarmellose Sodium, NF is about 3%, the Povidone K90 D, USP is
about 3%, and the Magnesium Stearate, NF is about 1%.
[0052] In embodiments where the modafinil is included in a unit
dose such as a tablet, the tablet can include 300 mg of a modafinil
in a 375 mg tablet (about 80% of the total tablet weight is
attributed to modafinil). In other embodiments, the tablet can
include 300 mg of modafinil in a 336 mg tablet (about 90% of the
tablet weight is attributed modafinil). Similar calculations can be
made for tablets containing between about 250 and 450 mg of
modafinil.
[0053] Similarly, a capsule can contain 300 mg of a modafinil in a
375 mg capsule. A capsule can also contain 300 mg of modafinil in a
336 mg capsule. Similar calculations can be made for capsules
containing between about 250 and 450 mg of modafinil.
[0054] Both the larger and smaller (higher weight percent of
modafinil) size unit doses of the present invention, which include
about 250 to 450 mg of modafinil, can exhibit the advantages over
conventional unit doses as described above, such as enhanced
treatment of ADHD and a reduction in the total number of doses of
modafinil required per day by a subject, thereby enhancing patient
compliance. However, the unit doses containing a higher percentage,
by weight, of modafinil also can exhibit additional advantages, as
described below.
[0055] First, patient compliance can increase because a unit dose
of the present invention can be easier to swallow by subjects, in
particular a solid unit dose form such as a tablet. Additionally,
some of the unit doses of the present invention can facilitate
administration of modafinil to pediatric subjects because the unit
doses can contain a higher percentage, by weight, of modafinil and
thus can have a smaller overall size and/or volume relative to the
conventionally prepared unit doses containing 250 to 450 mg of
modafinil.
[0056] When modafinil is administered in solid forms, the particle
size of modafinil is preferably such that at least about 95% of the
particles are less than about 200 .mu.m in diameter. See, U.S. RE
37,516, the content of which is hereby incorporated by reference as
though fully set forth herein.
[0057] In accordance with the present invention, the modafinil can
also be formulated in liquid forms and administered in multiple
ways, e.g., by spoon, mixed with foods or drinks, capsules, etc.
Liquid unit doses of modafinil are described in U.S. RE 37,516, and
other alternative dosage forms are described in U.S. Patent Pub.
Nos.: 02-0099097 and 02-0098240 and PCT Publication No. 02/056915,
the contents of which are hereby incorporated by reference as
though fully set forth herein.
3. EXAMPLES
Example 1
[0058] A group of 248 children (average age: 9 years, average
weight: 35.5 kilograms) were studied to determine the effect of
modafinil on ADHD.
[0059] After a 1 week washout period, children with moderate to
severe ADHD received 4 weeks of treatment with placebo or modafinil
in split morning/midday dosages of 100/200 mg, 200/100 mg, a single
300 mg dose, and 200/200 mg (400 mg total). Randomization called
for equal distribution of the children by weight, except for the
200/200 mg dose group, which contained only children having a
weight greater than or equal to 30 kg. The primary efficacy measure
was the teacher rated ADHD Rating Scale-IV.
[0060] Results indicated that modafinil significantly improved ADHD
symptoms for the primary outcome measure for the 200/100 mg and 300
mg once daily dose. The results of the study also indicated that
modafinil was safe and generally well tolerated, however, studies
have also revealed that 400 mg of modafinil has a higher adverse
event profile than the other doses.
Example 2
[0061] Safety and efficacy of the fixed doses of 340-mg and 425-mg
were evaluated following a 2-week dosing period (1-week of
titration and 1-week at steady state). The 340-mg dose was
administered to children weighing <30 kg, and the 425-mg dose
was administered to children weighing .gtoreq.30 kg.
[0062] The 24 children enrolled in this study were predominately
male (17M:7F) and predominately white (13W:9B:2Other). The average
age (9.0 yrs), weight (32.9 kg) and height (133.7 cm) were similar
to those seen in previous ADHD trials in children. The children
<30 and .gtoreq.30 kg were approximately equaled divided. The
average Attention Deficit Hyperactivity Disorder Rating Scale
(ADHD-RS) total score at baseline was 46.3.
[0063] Following 2-weeks of treatment with either 340 mg or 425 mg
modafinil, single dose per day, the baseline ADHD-RS total scores
(46.3) decreased significantly, representing approximately a 70%
improvement from baseline. This data is represented in FIG. 5.
Example 3
[0064]
1 Formulations Amount Amount Amount per per 255 mg per 340 mg 425
mg Excipients tablet (mg) tablet (mg) tablet (mg) Modafinil drug
substance 255.0 340.0 425.0 Lactose, NF 51.0 68.0 85.0 Povidone USP
17.7 23.6 29.5 Croscarmellose Sodium, NF 13.5 18.0 22.5 Purified
Water, USP q.s. q.s. q.s. Magnesium Stearate, NF 2.7 3.6 4.5 Total
Tablet Weight 339.9 453.2 566.5
[0065] Although the present invention has been described in
considerable detail, those skilled in the art will appreciate that
numerous changes and modifications may be made to the embodiments
and preferred embodiments of the invention and that such changes
and modifications are within the scope of the present invention.
Additionally, each reference cited herein is hereby incorporated by
reference.
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