Title of Invention

A METHOD OF FORMULATING A PHARMACEUTICAL COMPOSITION MODAFINIL

Abstract A pharmaceutical composition comprising two or more portions of solid modafinil particles from a bulk batch of modafinil, wherein each portion has a bounded particle size range and wherein one or more particle size ranges present in the bulk batch are not represented in the pharmaceutical composition.
Full Text MODAFINIL PHARMACEUTICAL COMPOSITIONS
FIELD OF THE INVENTION
This invention relates to the acetamide derivative modafinil. Modafinil (C15H15
NO2S), is 2-(benzhydrylsulfinyl)acetamide, and is also known as 2-
[(diphenylmethyl)sulfinyl]acetamide.
BACKGROUND OF THE INVENTION
Modafinil has been described as presenting a "neuropsychophamnacological
spectrum characterized by the presence of excitation with hyperactivity and of
hypermotility; and by the absence of stereotypy (except in high doses) and of
potentialisation of the effects of apomorphine and amphetamine" (U.S. Pat. No.
4,177,290; hereinafter "the '290 patent," which is incorporated herein by reference). A
single administration of modafinil results in increased locomotor activity in mice and
increased nocturnal activity in monkeys (Duteil et al., Eur. J. Pharmacol. 180:49
(1990)). The neuropsychopharmacological profile of modafinil has been distinguished
from that of amphetamines (Saletu et al., Int. J. Clin. Pharm. Res. 9:183(1989)).
Modafmil is thought to modulate the central postsynaptic alpha -adrenergic receptor,
without participation of the dopaminergic system (Duteil et al., supra). Modafmil has
been successfully tested in humans for treatment of idiopathic hypersomnia and
narcolepsy (Bastuji et al., Prog. Neuro-Psych. Biol. Psych. 12:695(1988)).
Narcolepsy is a chronic disorder characterized by intermittent sleep attacks,
persistent, excessive daytime sleepiness and abnormal rapid eye movement ("REM")
sleep manifestations, such as sleep-onset REM periods, cataplexy, sleep paralysis and
hypnagogic hallucinations, or both (Assoc, of Sleep Disorders Centers, Sleep 2:1
(1979)). Most patients with narcolepsy also have disrupted nocturnal sleep (Montplaisir,
in Guilleminault et al. eds.. Narcolepsy, Spectrum Pub., New York, pp. 43-56).
Pathological somnolence, whether due to narcolepsy or other causes, is disabling and
potentially dangerous. Causes of pathological somnolence, other than narcolepsy,
include chronic sleep loss (Carskadon et al.. Sleep, 5:S73 (1982); Carskadon et al.,
Psychophysiology, 18:107 (1981)); sleep apnea (Kryger et al., Principles and Practice of
Sleep Medicine, W. B. Saunders Co., Philadelphia, Pa. (1989)); and other sleep
disorders (International Classification of Sleep Disorders: Diagnostic and Coding
Manual, American Sleep Disorder Association, Rochester, Minn. (1990)). Whether due
to narcolepsy or other causes, pathological somnolence produces episodes of unintended
sleep, reduced attention, and performance errors. Consequently, it is linked to a variety
of transportation and industrial accidents (Mitler et al.. Sleep 11:100(1988)). A
therapeutic agent that reduces or eliminates pathological somnolence would have
important implications not only for individual patients, but also for public health and
safety.
Other uses of modafinil have been presented. U.S. Pat. No. 5,180,745 discloses
the use of modafinil for providing a neuroprotective effect in humans, and in particular
for the treatment of Parkinson's disease. The levorotatory form of modafinil, i.e., (-)
benzhydrylsulfinyl-acetamide, may have potential benefit for treatment of depression,
hypersomnia and Alzheimer's disease (U.S. Pat. No. 4,927,855). European Published
Application 547952 (published Jun. 23, 1993) discloses the use of modafinil as an anti-
ischemic agent. European Published Application 594507 (published Apr. 27, 1994)
discloses the use of modafinil to treat urinary incontinence.
U.S. Pat. No. RE37,516 discloses pharmaceutical compositions having a defined
particle size, and in particular compositions wherein 95% of the cumulative total of the
effective amount of modafinil particles in the composition have a diameter less than
about 200 microns.
SUMMARY OF THE INVENTION
The present invention discloses a composition including, but not limited to, a
pharmaceutical composition, of modafinil in the form of a particle blend of "small
particles," "large particles" and optionally "very large particles." By properly controlling
the distribution and quantity of small particles, large particles, and very large particles in
the blend, dissolution and absorption post-ingestion of the pharmaceutical composition
can be optimized, thereby providing a composition that is effective to alter the somnolent
state of a subject.
In one embodiment, the present invention includes a pharmaceutical composition
having two or more portions of solid modafinil particles from a bulk batch of modafinil.
Each portion of modafinil has a bounded particle size range and one or more particle size
ranges present in the bulk batch are not represented in the pharmaceutical composition.
In another embodiment, the present invention includes a pharmaceutical
composition also having two or more portions of solid modafinil particles. However,
each portion has a bounded particle size range and there is a particle size range between
the size ranges represented in the two or more portions that is not represented in the
pharmaceutical composition.
In one embodiment, the present invention is a pharmaceutical dosage form
including an amount of modafinil effective to alter the somnolent state of a mammal
upon oral administration. The dosage form is made from a pharmaceutical composition
of the present invention which includes at least a first portion and a second portion of
modafinil being in the form of solid modafinil particles and each having a bounded
particle size distribution. The second portion can be from the same bulk batch as the first
portion or from a different bulk batch. When combined, the first portion and the second
portion yield a mixture having a bounded particle size distribution that is different than
the particle size distribution of the bulk batches.
The pharmaceutical composition can also include a second portion of modafinil
being in the form of solid modafinil particles having a particle size distribution different
than the particle size distribution of the first portion.
In another embodiment, the method of formulating a pharmaceutical composition
of modafinil includes the steps of providing a batch of modafinil, wherein the particles in
the batch have a distribution of particle diameters. The next step is separating the
particles in the batch of modafinil into at least two discrete lots of modafinil particles,
wherein each discrete lot contains modafinil of a bounded range of particle diameters,
thereby forming at least a first discrete lot and a second discrete lot. Then, a next step is
blending a portion of the first lot with all or a portion of the second lot and then forming
a pharmaceutical composition of modafinil from the blend of the first lot and the second
lot portions.
In another embodiment, the present invention includes a pharmaceutical dosage
unit comprising an effective amount of modafinil wherein at least about 10% of the total
cumulative modafinil particles are smaller than about 25 microns in diameter and more
than about 5% of the total cumulative particles are greater than 220 microns in diameter.
In yet another embodiment, the present invention includes a method of
formulating a pharmaceutical composition of modafinil including the steps of providing a
first batch and a second batch of modafinil, wherein the particles in each batch have a
distribution of particle diameters, separating the particles of the first batch of modafinil
into at least two discrete lots of modafinil particles, wherein each discrete lot contains
modafinil of a defined particle diameter, thereby forming at least a first discrete lot and a
second discrete lot, recombining at least one of the discrete lots with the second batch,
and then altering the distribution of particle diameters of the particles in the second
batch.
In yet another embodiment, the present invention includes a method of altering
the somnolent state of a mammal, such as a human, by administering to the mammal an
effective amount of the composition of the present invention.
BRIEF DESCRIPTION OF THE Accompanying DRAWINGS
Fig. I is a graph depicting particle size distributions for six batches of modafinil.
Fig. 2 is a graph depicting a particle size distribution of a blended modafinil
composition that can be prepared in accordance with the present invention.
Fig. 3 is a graph depicting dissolution profiles for four tablets that can be made in
accordance with the present invention.
DETAILED DESCRIPTION
The present invention results from the discovery that the particle size distribution
of modafinil, and the consistency of the particle sizes that make up the distribution,
affects the effective dissolution and absorption of modafinil from a dosage form
containing the modafinil particles. Specifically, by customizing and controlling the
particle size distribution of a blend of small, large and optionally very large particles of
modafinil, the dissolution and absorption properties of a dosage form of modafinil, post-
ingestion, can be optimized. The optimized modafinil provides drug products which 1)
can have substantially similar dissolution profiles to currently marketed and FDA
approved modafinil products, and 2) can be bioequivalent to currently marketed and
FDA approved modafinil products. Drug product comparative study techniques designed
to show whether drug products exhibit substantially similar profiles are described in the
FDA/CDER guidance document "Dissolution Testing of Immediate Release Solid Oral
Dosage Forms (Aug 1997)," which is hereby incorporated by reference. Other suitable
references also can include "In Vitro Dissolution Profile Comparison - Statistics and
Analysis of the Similarity Factor, f2" by V.P. Shah et al. in Volume 15, No. 6, pages
889-896 of Pharmaceutical Research (1998), as well as another FDA/CDER guidance
document entitled "Immediate Release Solid Dosage Forms: Scale-up and Post Approval
Changes (SUPAC-IR): Chemistry, Manufacturing and Controls, In Vitro Dissolution
Testing and In Vivo Bioequivalence Documentation (Nov 1995)," the contents of which
are hereby incorporated by reference.. Bulk batches of modafinil, which are typically
used to make dosage forms containing modafinil, such as Provigil® (modafinil), can be

manufactured in accordance with methods understood by one of ordinary skill in the art,
including those described in the '290 Patent. These bulk batches of modafinil can
contain particles having a distribution of particle diameters from smaller than 10 microns
to larger than 1500 microns. Fig. 1 shows the particle size distribution for six bulk
batches of modafmil which can be used to make the composition of the present
invention. As further shown in Fig. 1, each of the six bulk batches contains small, large
and in some cases very large particles, and each bulk batch has a different particle size
distribution curve relative to the other five bulk batches. It follows that dosage forms
made from these bulk batches typically exhibit similar particle size distribution curves to
the bulk batch from which the dosage forms originated. Of the six bulk batches, L-2 and
L-1 are closest to the particle size distribution of currently marketed and FDA approved
modafinil products, such as Provigil® (modafinil). As disclosed herein and as used in
the compositions and methods of the present invention, a modafinil compound can
include a racemic mixture, and can optionally be in an acid form, such as a metabolic
acid of modafinil or a benzhydrylsulfinylacetic acid, a sulfone form, a hydroxylated
form, a conjugated form such as a modafinil compound conjugated to a protein, a
polysaccharide, a glucuronide or a sulfate, or a polymorphic form, it may include
compounds containing isosteric replacements of the phenyl groups of modafinil, and
polymorphic species or analogs of modafinil, or derivatives of cogeners and prodrugs. In
preferred embodiments, the modafinil compound is modafinil. Prodrugs are known in
the art as compounds that are converted to the active agent (modafinil) in the body of a
subject.
As described above, an aspect of the present invention involves the discovery that
the consistency of the particle sizes that make up a particle distribution of modafinil can
affect the dissolution and absorption of a dosage form containing modafinil.
Accordingly, the present invention is directed to a more consistent particle size
distribution of particles in a pharmaceutical composition and/or dosage forms containing
modafinil. To this end, the particles in a bulk batch can be separated into discrete lots
having a more narrowly defined and/or consistent particle size distribution as compared
to the bulk batch.
DISCRETE PARTICLE SIZE LOTS OF MODAFINIL
To achieve a more consistent particle size distribution of particles of modafinil
for use in making a pharmaceutical composition and/or dosage form of the present
invention, particles of the bulk batch can be passed through a series of separation screens
or filters. Each separation screen has openings from about 500 microns or more in
diameter to about 10 microns or less in diameter. It is preferred that each separation
screen has openings with consistently sized openings such that substantially all of the
openings of the screen are the same size.
The particles can be first passed through a separation screen having the largest
openings. The size of the openings of subsequent separation screens can be
incrementally reduced by 5 microns, 10 microns, 20 microns, or 50 microns in diameter.
However, it will be apparent to one of skill in the art that the diameter of the openings in
a separation screen can be reduced (relative to a preceding separation screen) by any
appropriate amount to meet the particular needs of the artisan.
Further, in another embodiment, it is recognized that the particles can first be
passed through a separation screen having the smallest openings to sift out the smaller
diameter particles and retain larger particles. The larger particles can then be transferred
to a second screen (or additional screens) with slightly larger openings than the preceding
screen to sift out larger particles. Typically, the openings of subsequent separation
screens are typically incrementally increased by 5 microns, 10 microns, 20 microns, or
50 microns in diameter. Although separating the bulk modafinil into discrete lots using
incrementally larger openings is practicable and within the ability of one skilled in the art
in light of the teachings herein, the remainder of this disclosure refers to particles
sequentially separated into discrete lots using screens with incrementally reduced sized
openings.
Thus, the particles retained on a separation screen have diameters which are
larger or equal to the diameters of the separation screen's openings, but smaller in
diameter than the preceding separation screen's openings.
The particles of modafinil that are retained by each separation screen are then
deposited into an acceptable container to form discretely sized particle lots (hereafter
"discrete lots") having a bounded particle diameter range. The formation of discrete lots
is further detailed in Example 1. The containers preferably have a label indicating the
diameter of the modafinil particles in the container as defined by the diameters of the
retaining and preceding screens' openings, thereby setting the contained particles'
diameter boundaries. For example, one container may indicate modafinil particles
having a diameter of "smaller than or equal to 200 microns, larger than or equal to 180
microns" or "180 and the diameter of each of the particles in the discrete lot can also be measured using

techniques known in the art to provide more detailed statistical information such as, but
not limited to, mean particle size and standard deviations from the mean particle size.
The discrete lot can also be assigned a "predicted mean particle diameter," which is the
mean of the two separation screens used to separate the modafinil of the discrete lot.
Accordingly a container indicating particles having a diameter of "smaller than 200
microns, larger than or equal to 180 microns" would have a predicted mean particle
diameter of 190 microns. The predicted mean particle diameter may or may not be equal
to the actual mean particle diameter of the discrete lot.
Furthermore, in this manner multiple bulk batches can be easily processed
together and simultaneously separated into discrete lots. The discrete lots, each
containing particles of modafmil within a bounded range of particle diameters, can then
be used in the manner described herein, thereby reducing the difficulties associated with
particle size inconsistencies between bulk batches in the formation of pharmaceutical
compositions and dosage forms.
The discrete lots can be separated into small particle discrete lots, large particle
discrete lots, and very large particle discrete lots. Typical small particle discrete lots can
include particles (P) in about the following bounded ranges (values of "P" are particle
diameters in microns): 0.01 50 P Typical large particle ranges include particles (P) in the following bounded
ranges (in microns): 220 P 260 320, 330 P Typical very large particle ranges include particles (P) in the following bounded
ranges (in microns): 400 P and combin.ations thereof.
In some instances, particles of modafinil can be retained on a separation screen
wherein a portion of the retained particles are smaller than the separation screen's
openings. Thus, a discrete lot may contain a portion of particles of modafinil having
smaller diameters than the particles' diameters which have been defined by the
separation screen. This retention can be the result of many factors such as static charge
on the modafinil particles. Typically, less than about 15% of the cumulative total of all
modafinil particles retained on a separation screen have diameters smaller than the
diameters of the separation screen's openings. Preferably, less than about 5% and most
preferably less than about 2% of the cumulative total of all modafinil particles retained
on a separation screen have diameters smaller than the diameters of the separation
screen's openings.
Similarly, because of the irregular shape of modafinil particles, and in particular
because the particles are not truly spherical, in some instances particles of modafinil can
be retained on a separation screen which are larger in theoretical diameter than the
preceding separation screen's openings. Essentially, larger particles of modafinil pass
through a screen having opening diameters which are smaller than the theoretical
diameter of the modafinil particles. Accordingly, the next separation screen may retain
particles that have diameters which are larger than the preceding separation screen.
Typically, less than about 15% of the cumulative total of all modafinil particles retained
on a separation screen have diameters larger than the diameters of the preceding
separation screen's openings. Preferably, less than about 5% and most preferably less
than about 2% of the cumulative total of all modafinil particles retained on a separation
screen have diameters larger than the diameters of the preceding separation screen's
openings.
In some embodiments, it is preferred that the particles of modafinil in each
discrete lot have diameters which are as consistent as practicable with the other particles
in the discrete lot. To this end, the discrete lots can be repeatedly subdivided, filtered,
and/or screened in the manner described above.
Other methods, such as milling, micronization, separation by weight, separation
by density, etc., can also be employed to form lots of pre-determined or bounded particle
sizes. The particles can then be placed in the appropriate discrete lot container.
Alternatively, small, large and very large particles can be compacted into larger particles.
The compacted particles can then be placed in the appropriate discrete lot container.
BLENDS OF DISCRETE LOTS
After the modafinil particles have been separated by particle diameter into
discrete lots, the contents of one or more of the discrete lots can be used to create
pharmaceutical compositions of the present invention. In one embodiment, at least two
discrete lots can be combined to create a pharmaceutical composition of the present
invention. The modafinil from the discrete lots can be combined together either by
weight or by number of particles, as described in more detail below.
In accordance with the present invention, the optimal ratio (by weight or by
cumulative total of particles) of small to large (and optionally very large) modafinil
particles in a blend of the present invention further depends upon the size of the particles
used in the final pharmaceutical composition. By appropriately blending small, large,
and optionally very large particles, the dissolution profile of the blended lot can be made
to simulate the dissolution profile of the modafinil composition in which greater than or
equal to 95% of the particles in the effective amount are small particles, i.e., less than
about 200 microns. For example, if a greater amount of particles having a nnean/average
diameter smaller than about iOO microns are employed in a pharmaceutical composition,
then the diameter of the modafinil particles which make up the balance of the
pharmaceutical composition can be larger than if the small particles are, e.g., smaller
than or equal to about 200 microns in diameter, were used.
In one embodiment of the present invention, particles of modafinil from at least
one discrete lot are processed to provide a pharmaceutical composition and dosage forms
having a similar dissolution profile to PROVIGIL® (modafinil), 100 milligram (mg) or
2(X) milligram pharmaceutical compositions, and in particular pharmaceutical
compositions that release at least 80% of the modafinil in 45 minutes in a 0.1 N HCl
solution.
The present invention also extends to formulations which are bioequivalent to
available formulations of modafinil, in terms of both rate and extent of absorption, for
instance as defined by the US Food and Drug Administration and discussed in the so-
called "Orange Book" (Approved Drug Products with Therapeutic Equivalence
Evaluations, US Dept of Health and Human Services, 22nd edn., 2(X)2), the content of
which is hereby incorporated by reference. In one embodiment, particles of modafinil
from at least one discrete lot are processed to provide a pharmaceutical composition
having bioequivalence to PROVIGIL® (modafinil), 100 milligram or 200 milligram
pharmaceutical compositions. Preferably, an embodiment of the present invention

contains particles of modafinil which are blended in such a manner to have the same
dissolution profile and be bioequivalent to PROVIGIL® (modafinil), 100 milligram or
200 milligram pharmaceutical compositions.
In another embodiment, the present invention includes a pharmaceutical
composition of modafinil, or a dosage form including modafinil having an amount of
modafinil effective to alter the somnolent state of a mammal upon oral administration.
The effective amount of modafinil includes modafinil from at least one discrete lot from
a bulk batch, and typically at least two discrete lots. In certain embodiments, the
components include:
a) a first portion of modafinil being in the form of solid modafinil particles from a
bulk batch having a bounded particle size distribution, an average particle size (which
may or may not equal the predicted mean particle diameter); and
b) an optional second portion of modafinil being in the form of solid modafinil
particles, which may or may not be from the same bulk batch as the first portion, having
a bounded particle size distribution.
In one embodiment, the combination of the first portion and the second portion
yields a bounded particle size distribution that is different than the particle size
distribution of the bulk batch and the other bulk batch if the second portion comes from a
bulk batch which is different from the bulk batch of the first portion.
In one embodiment, the pharmaceutical composition includes two or more
portions of solid modafinil particles from a bulk batch of modafinil. In the composition,
each portion has a bounded particle size range and one or more particle size ranges
present in the bulk batch are not represented in the pharmaceutical composition.
In another embodiment, the pharmaceutical composition includes two or more
portions of solid modafinil particles. In this particular embodiment, each portion has a
bounded particle size range and there is a particle size range between the size ranges
represented in the two or more portions that is not represented in the pharmaceutical
composition.
In one embodiment of the invention, more than about 5% of the particles in the
composition are larger than about 200 microns in diameter. In another embodiment, the
composition has approximately the same dissolution profile as a modafinil composition
in which at least about 95% of the particles in an effective amount of modafinil are
smaller than about 200 microns in diameter. In yet another embodiment, the composition

has approximately the same dissolution profile as PROVIGIL® (modafinil), and
preferably at least 80% of the modafinil dissolves after 45 minutes in a 0. IN solution of
HCi.
In another embodiment, a composition of the present invention is bioequivalent to
a modafinil composition wherein at least about 95% of the particles in an effective
amount of modafinil are smaller than about 200 micronsin diameter, and is preferably the
composition of the present invention is bioequivalent to PROVIGIL® (modafinil).
In some embodiments of the blend of the present invention, fewer than about
85% of the particles can be small particles, i.e., smaller than about 200 microns in
diameter. In other embodiments, fewer than about 75% of the particles can be small
particles. In still other embodiments, fewer than about 65% of the particles can be small
particles. In yet other embodiments, fewer than about 50% of the particles can be small
particles.
In some embodiments, the small particles can be smaller than about 175 microns,
typically smaller than about 150 microns, and more typically smaller than about 125
microns in diameter. In other embodiments, the small particles can be smaller than about
100 microns, typically smaller than 75 microns in diameter. In yet other embodiments,
the small particles can be smaller than about 50 microns, typically smaller than about 25
microns and can be as small as about 10 microns or 0.01 microns or less in diameter.
A pharmaceutical composition of the present invention can include modafinil
prepared by the process of blending a first and a second portion of solid modafinil
particles wherein the first portion has a pre-determined particle size range and the second
portion has a pre-determined particle size range that is different from that of the first
portion.
Additional portions of modafinil being in the form of solid modafinil particles
can also be used and added to the first and second portions. Each additional portion also
has a bounded particle size distribution and selected from a discrete lot which is different
from the discrete lots used for the first and/or second portion. When combined, the
composition can provide a particle size distribution that is different from the particle size
distribution of one or more bulk batches
In yet another pharmaceutical composition or dosage form of the present
invention, the composition or dosage form includes an amount of modafinil effective to
alter the somnolent state of a mammal upon oral administration and is manufactured by

preparing a bulk batch and removing from the bulk batch at least one discrete lot of
particles having a bounded particle size range.
In addition to making pharmaceutical compositions of modafmil from discrete
portions, as described above, modafinil being in the form of solid modafinil particles
having a particle size distribution and selected from one or more discrete lots can be
combined with modafinil from a bulk batch to adjust the particle size distribution of the
bulk batch. In particular, one or more discrete lots can be added to a bulk batch of
modafinil having a particle size distribution, thereby enhancing the particle size
distribution of the bulk batch.
Alternatively, modafinil from a bulk batch can be processed in accordance with
the techniques described above to remove particles of a certain diameter from the batch.
Specifically, the bulk batch is first separated into discrete lots, and the lots containing
undesired particles are removed. The remaining discrete lots can be recombined to form
a blend having a particle size distribution which is different from the particle size
distribution of the original bulk batch.
In some embodiments, particles can be removed from the bulk batch in the
manner described above and then a portion from a discrete lot containing additional
particles having a different bounded diameter range than those particles which were
removed can be added to the batch. In this manner, in some embodiments
pharmaceutical compositions of the present invention contain particles which are not
present in the same proportion that existed in a bulk batch.
Once combined, analysis of the particles within the pharmaceutical composition
of the present invention can generate a cumulative particle size distribution curve, such
as the curve depicted in Fig. 2 (described in more detail below). It is because of the
mechanical separation and recombination of particles, that pharmaceutical compositions
of the current invention can exhibit particle size distribution curves that are not attainable
via normal chemical synthesis routes. This is exemplified by a comparison of the curves
set forth in Fig. 1 and Fig. 2. Further, a pharmaceutical composition of the present
invention can exhibit a particle size distribution curve that is different from at least one,
and preferably all of the particle size distribution curves attributable to any one or more
(if more than one bulk batch is used) of the bulk batches used to create the discrete lots.
EXCIPENTS AND OTHER INGREDIENTS
Although the compositions and methods disclosed herein have been described in
light of certain preferred embodiments, it is understood that the modafmil compounds
described herein may be orally administered with an inert diluent or an assimilable edible
carrier, for example. The compositions may also be enclosed in a hard or soft shell
gelatin capsule, compressed into tablets, or incorporated directly with food of the diet.
For oral therapeutic administration, the active compounds such as modafmil may be
incorporated with excipients and used in the form of ingestible tablets, buccal tablets,
troches, capsules, elixers, suspensions, syrups, wafers, and the like, although tablets are
the generally preferred method of administering modafinil. Such compositions and
preparations should contain at least 0.1% of active compound. The percentage of the
compositions and preparations may, of course, be varied and may conveniently be
between about 2 and about 60% of the weight of the unit.
The tablets, troches, pills, capsules, powders, liquid/suspensions or emulsions and
the like may also contain any of the following: a binder, such as gum tragacanth, acacia,
com starch, or gelatin; excipients, such as dicalcium phosphate; a disintegrating agent,
such as com starch, potato starch, alginic acid and the like; a lubricant, such as
magnesium stearate; and a sweetening agent, such as sucrose, lactose or saccharin may
be added or a flavoring agent, such as peppermint, oil of wintergreen, or cherry flavoring,
for example. When the dosage unit form is a capsule, it may contain, in addition to
materials of the above type, a liquid carrier. Various other materials may be present as
coatings or to otherwise modify the physical form of the dosage unit. For instance,
tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup or elixer
may contain the active compounds sucrose as a sweetening agent and methyl and
propylparabens as preservatives, a dye and flavoring, such as cherry or orange flavor. Of
course, any material used in preparing any dosage unit form should be pharmaceutically
pure and substantially non-toxic in the amounts employed. In addition, the active
compounds may be incorporated into sustained-release preparations and formulations.
In certain embodiments, the disclosed compositions may be formulated to be
administered by use of a skin patch, or transdermal delivery system, The transdermal
administration of the modafmil compositions described herein may be accomplished by
any number of systems known in the art.
These methods typically include an adhesive matrix or drug reservoir system and
may include a skin permeation enhancement agent such as ethanol, polyethylene glycol

200 dilaurate, isopropyl myristate, glycerol trioleate, linolenic acid saturated ethanol,
glycerol monooleate, glycerol monolaurate, n-decyl alcohol, capric acid, and certain
saturated and unsaturated fatty acids, and their esters, alcohols, monoglycerides, acetates,
diethanolamides and N,N-dimethylamides.
ITERATIVE TESTS OF THE PHARMACEUTICAL COMPOSITION
As described above, the optimal ratio of small to large (and optionally very large)
modafinil particles in a blend of the present invention depends upon the size of the
particles used in the final pharmaceutical composition. A pharmaceutical composition of
the present invention, once processed into a dosage form (such as a tablet), can exhibit a
similar dissolution profile to Provigil® (modafinil), and preferably a dosage form of the
present invention is bioequivalent to Provigil® (modafinil), the commercial form of
modafinil. However, one of skill in the art understands that not all combinations of
small, large and very large particles in the pharmaceutical composition will exhibit one
or both of these desirable characteristics. Accordingly, it is to be expected that routine
experimentation will be desirable to determine the optimum particle size makeup and
proportions of blend mixtures that exhibit similar dissolution profiles and/or are
bioequivalent to Provigil® (modafinil).
In some embodiments, disintegrants are added to the formulation to help the
tablet disintegrate after consumption, thereby releasing the active ingredients. Some
common disintegrants include several modified cellulose derivatives, such as
crosscarmellose sodium and other modified starch derivatives such as sodium starch
glycolate. It will also be understood by one of ordinary skill in the art that other
ingredients, binders and lubricants can further affect the dissolution profile of the dosage
form.
Further, surfactants, such as ionic, non-ionic and/or bile salt surfactants, can also
be included in the present invention. Anionic surfactants include, but are not limited to,
sodium alkyl sulfate (Sodium Lauryl Sulphate®) as well as sulfosuccinate derivatives
such as docusate sodium. Non-ionic surfactants include, but are not limited to,
polyoxyethylene sorbitan fatty acid esters (polysorbates) such as Tween 20®, Tween 80®,
Tween 40®, Span 20®, fatty acid esters of polyethylene glycols such as Gelucire 44/14®,
Gelucire 50/13®, saturated polyglycolized (including mono, di or tri) glycerides, medium
chain monoglycerides (from 6 to 10 carbon atoms long) such as glyceryl monocaprylate
(Imwitor 308®), glyceryl monocaproate (Capmul MCM C-8®), glyceryl caprylate/caprate
(Capmul MCM®), polyoxyethylene glyceryl caprylate and polyoxyethylene glyceryl

caproate (Labrasol®), medium chain fatty acid esters such as glyceryl tri caprate and
glyceryltricarilate (Miglyol 612®), block polymers of ethylene oxide and propylene
oxide, polyoxyethylene-polyoxy propylene block copolymers such as Poloxamer 188
(Pluronic F-68®), Poloxamer 237 (Pluronic F-87®), Poloxamer 338 (Pluronic F-108®),
Poloxamer 407 (Pluronic F-I27®), Poloxamer 124 (Pluronic L-44®), polyoxyl stearate-
polyethoxylated (40) stearic acid (Myrj 52®), ethoxylated castor oil-polyethoxylated (60)
hydrogenated castor oil (Cremophor EL®), ethoxylated hydrostearic acidpolyethyiene
glycol 660 hydroxystearate (Solutol® HS 15), polyoxyethylene alkyl ethers (from 12 to
18 carbon atoms long) such as polyoxyl 20 cetostearyl ether (Atlas G-3713®), polyoxyl
10 oleyl ether (Brij 96®, Brij 97®, Oleth 10®), polyethylene glycol ether (Triton X-100®,
Triton X-114®, Triton X-405®, Triton N-101®) and lecithins such as phospholipids
(dimyristoyl DL-alpha- phophatidylcholine). Bile salt surfactants include, but are not
limted to deoxycholic acid, sodium deoxycholate, cholic acid, sodium taurocholate.
FORMULATION AND ADMINISTRATION
An appropriate dosage for modafinil having a defined particle size is between
about 10 milligram and about 8(X) milligram of modafinil, more typically between about
15 milligrams and 800 milligrams of modafinil.
The pharmaceutical composition described herein is most preferably administered
orally in the form of a vehicle such as a tablet, capsule, powder, pill, liquid/suspension or
emulsion. The administration vehicle may comprise a pharmaceutically-acceptable
carrier. The carrier may comprise agents that aid solubility, absorption, flavor, color or
texture of the vehicle or its contents. Topical administration via an epidermal patch or
the like, or administration via direct injection of the drug, is also acceptable.
A vehicle of the invention can include + or - 10-15% of the modafinil particles,
due to factors such as vehicle manufacturing tolerances and expected shelf life of the
modafinil. For example, a vehicle labeled as containing 50 milligrams can be initially
prepared with, e.g., 55 or 58 milligrams of modafinil, with the expectation that after one
month to two years of storage, the active amount of modafinil therein has decreased.
Vehicles prepared with such adjustments in order to compensate for the expected
degradation of the drug fall within the scope of the invention.
SPECIFIC ILLUSTRATIVE EMBODIMENTS OF PHARMACEUTICAL
COMPOSITIONS AND DOSAGE UNITS
In order to develop modafinil based products that have similar dissolution profiles
and/or bioequivalence to FDA approved modafinil products such as Provigil®
(modafinil), and/or which include at least the least amount of modafinil effective for
treating a somnolent or somnolescent state, it is desirable to tailor the blends of
modafinil. In one embodiment, all of the portions of modafinil are taken from discrete
lots having mean particle diameters smaller than or equal to about 200 microns (small
particles). In another embodiment, at least 95% of the cumulative total of modafinil
particles in the entire pharmaceutical composition are small particles having diameters
smaller than or equal to about 200 microns. In yet another embodiment, the
pharmaceutical composition contains at least 15 milligrams of modafinil taken from a
discrete lot having an average particle size smaller than or equal to about 10 microns to
about 80 microns in diameter, with the remainder of the pharmaceutical composition (by
weight) including additional small particles and/or large and/or very large particles of
modafinil.
In another embodiment, at least 25% to 100% of the cumulative total of particles
of a first portion have diameters smaller than or equal to about 20 microns. In still
another embodiment, the first portion contains modafinil in the form of solid particles,
wherein at least 50% to 1(X)% of the particles of the first portion have diameters smaller
than or equal to about 30 microns. In another embodiment, the first portion contains
modafinil in the form of solid particles, wherein at least 70% to 100% of the particles of
the first portion have diameters smaller than or equal to about 40 microns. In other
embodiments, the first portion contains modafinil in the form of solid particles, wherein
at least 75% to 100% of the particles of the first portion have diameters smaller than or
equal to about 50 microns. In yet another embodiment, the first portion contains
modafinil in the form of solid particles, wherein at least 80% to 100% of the particles of
the first portion have diameters smaller than or equal to about 60 microns. In still
another embodiment, the first portion contains modafinil in the form of solid particles,
wherein at least 85% to 100% of the particles of the first portion have diameters smaller
than or equal to about 70 microns. In another embodiment, the first portion contains
modafinil in the form of solid particles, wherein at least 90% to 100% of the particles of
the first portion have diameters smaller than or equal to about 80 microns.
As described above, the second and/or additional portions can contain small
particles. However, the second or additional portions can also contain large particles of
modafinil, and in particular particles having diameters larger than 220 microns and
smaller than or equal to 440 microns. In other embodiments, the second portion contains
modafinil particles having diameters larger than 220 microns and smaller than about 350
microns. In still other embodiments, the second portion contains modafmil particles
having diameters larger than 220 microns and smaller than about 300 microns. In yet
another embodiment, the second portion contains modafinil particles having diameters
larger than 220 microns and smaller than about 250 microns. Further, in some
embodiments, preferably no more than 50% and more preferably no more than 20% of
the cumulative total of modafinil particles can be very large particles (particles having a
diameter larger than 440 microns).
In one embodiment of a pharmaceutical composition of the present invention, the
first portion of small particles includes less than 90% of the cumulative total of modafmil
particles in the pharmaceutical composition. In another embodiment of a pharmaceutical
composition of the present invention, the second portion (and any further portions) of
large or very large particles includes greater than 10% of the cumulative total of
modafinil particles in the pharmaceutical composition, such that the first and second
portion (and any further portions) add up to 100% of the cumulative total of modafinil
particles in the pharmaceutical composition.
In one embodiment, a pharmaceutical dosage unit of the present invention
contains an effective amount of modafinil, wherein at least about 5% to about 30% of the
cumulative total of modafinil particles are smaller than or equal to about 10 microns in
diameter and more than about 5% of the total cumulative particles are large particles,
having a diameter of more than 220 microns. In another embodiment, at least about 10%
to 30% of the cumulative total of modafinil particles are smaller than or equal to about 10
microns in diameter. In still another embodiment, at least about 15% to 30% of the
cumulative total of modafinil particles are smaller than or equal to about 10 microns in
diameter. In yet another embodiment, at least about 20% to about 30% of the cumulative
total of modafmil particles are smaller than or equal to about 10 microns in diameter.
And in another embodiment, at least about 25% to about 30% of the cumulative total of
modafinil particles are smaller than or equal to about 10 microns in diameter.
In one embodiment, a pharmaceutical dosage unit of the present invention
contains an effective amount of modafinil, wherein at least about 5% to about 30% of the

cumulative total of modafinil particles are smaller than or equal to about 15 microns in
diameter and more than about 5% of the total cumulative particles are more than 220
microns in diameter. In another embodiment, at least about 10% to 30% of the
cumulative total of modafmil particles are smaller than or equal to about 15 microns in
diameter. In still another embodiment, at least about 15% to 30% of the cumulative total
of modafmil particles are smaller than or equal to about 15 microns in diameter. In yet
another embodiment, at least about 20% to about 30% of the cumulative total of
modafmil particles are smaller than or equal to about 15 microns in diameter. In another
embodiment, at least about 25% to about 30% of the cumulative total of modafmil
particles are smaller than or equal to about 15 microns in diameter.
In yet another embodiment, a pharmaceutical dosage unit of the present invention
contains an effective amount of modafmil, wherein at least about 5% to about 30% of the
cumulative total of modafmil particles are smaller than or equal to about 20 microns in
diameter and more than about 5% of the total cumulative particles are more than 220
microns in diameter. In another embodiment, at least about 10% to 30% of the
cumulative total of modafmil particles are smaller than or equal to about 20 microns in
diameter. In still another embodiment, at least about 15% to 30% of the cumulative total
of modafmil particles are smaller than or equal to about 20 microns in diameter. In yet
another embodiment, at least about 20% to about 30% of the cumulative total of
modafmil particles are smaller than or equal to about 20 microns in diameter. An in
another embodiment, at least about 25% to about 30% of the cumulative total of
modafmil particles are smaller than or equal to about 20 microns in diameter.
In yet another embodiment, a pharmaceutical dosage unit of the present invention
contains an effective amount of modafmil, wherein at least about 5% to about 30% of the
cumulative total of modafmil particles are smaller than or equal to about 25 microns in
diameter and more than about 5% of the total cumulative particles are more than 220
microns in diameter. In another embodiment, at least about 10% to 30% of the
cumulative total of modafinil particles are smaller than or equal to about 25 microns in
diameter. In still another embodiment, at least about 15% to 30% of the cumulative total
of modafmil particles are smaller than or equal to about 25 microns in diameter. In yet
another embodiment, at least about 20% to about 30% of the cumulative total of
modafmil particles are smaller than or equal to about 25 microns in diameter. An in
another embodiment, at least about 25% to about 30% of the cumulative total of
modafmil particles are smaller.than or equal to about 25 microns in diameter.

In still another embodiment of the invention, a pharmaceutical dosage unit
(including a tablet, pill or capsule of modafinil) contains modaflnil particles wherein
about 5% to about 35% of the total cumulative number of particles are more than 220
microns in diameter. In other embodiments, typically between about 10% to 30 %, more
typically 15% to 30%, and in some embodiments between 20% to 30% and even 25% to
30% of the cumulative total of particles have diameters larger than 220 microns in
diameter. Further, in such dosage units, the total amount of modafinil can be about 10
milligrams to about 800 milligrams, more typically about 15 milligrams to about 800
milligrams, and in other embodiments the total amount of modafinil in the dosage unit
can be at least about 100 milligrams to about 200 milligrams. In preferred embodiments,
dosage units contain 100 milligrams or 200 milligrams of modafinil.
The total weight of modafinil in the pharmaceutical composition, containing at
least the first portion and optionally additional portions of modafinil from discrete lots,
as described above, can include between about 10 milligrams to about 800 milligrams of
modafinil, more typically between about 15 milligrams and about 800 milligrams,
preferably between about 50 to 400 milligrams and most preferably between about 100
milligrams to 200 milligrams of modafinil.
In embodiments wherein the modafinil is in a unit dose form, a pharmaceutical
composition of the present invention can contain between about 10 milligrams and about
800 milligrams of modafinil, more typically between about 15 milligrams and about 800
milligrams, preferably between about 50 to about 400 milligrams and most preferably
between about 100 milligrams to about 200 milligrams of modafinil. In unit dose form,
embodiments having first and at least second portions, as described above, the first
portion of solid particles can be at least 15%, typically at least 50%, more typically at
least 90% and in some embodiments at least 99% of the total weight of the total
modafinil in the unit dose form.
Although primarily described herein with respect to "cumulative total number of
particles," it is within the ability of one skilled in the art to also make blends based upon
weight of the portions used from each of the discrete lots, as detailed above. In
particular, the density of modafinil is about 0.50 grams per cubic centimeter (bulk
density) and about 0.60 grams per cubic centimeter (tap density). Using the density
information, the statistical information that is described herein, and assuming the
particles of modafinil are spherical, accurate determinations of the appropriate weight of
particles in each discrete lot can be made. Similar calculations can be made with respect
to the surface area of the particles.
Notwithstanding similar dissolution and/or bioequivalence to approved modafinii
products, compositions including more than about 5% large or very large particles should
be carefully tested, preferably in human clinical trials, in order to verify safety in
humans.
METHODS OF TREATMENT
Although the specific examples presented herein are directed to modafinii of a
defined particle size, other uses of modafinii (e.g., for treatment of Parkinson's disease,
urinary incontinence, Alzheimer's disorder, etc.) have been presented in the art, and those
utilities are appropriate in conjunction with the invention as disclosed herein.
Accordingly, the present invention also includes a method of altering the
somnolent state of a mammal, such as a human, by administering to the mammal an
effective amount of the composition of the present invention.
Furthermore, the present invention includes a method for enhancing alertness or
increasing regularity of sleep rhythms by administering an effective amount of a
composition of the present invention.
The present invention also includes within its scope a method of treating a
mammal diagnosed with a modafinil-responsive disease or condition, including, but not
limited to, narcolepsy, sleepiness, excessive sleepiness, excessive daytime sleepiness
associated with narcolepsy, Parkinson's disease, urinary incontinence, multiple sclerosis
fatigue, ADHD, Alzheimer's disorder, sleep apnea, obstructive sleep apnea, depression,
and ischemia, by administering an amount of modafinii, as one or more oral unit doses,
wherein the unit doses contain an effective amount of the composition of the present
invention.
EXAMPLES
Example 1 - Separation of a Batch of Modafinii Into Discrete Lots
A bulk batch of modafinii is prepared in a conventional manner having a particle
size distribution of between about 10 microns and 500 microns. The particles of the bulk
batch pass through a series of particle separation screens having screen opening
diameters of 440 microns, 300 microns, 220 microns, 100 microns, 30 microns, 20
microns, and 10 microns. After the 10 microns screen, there is a holding container to

contain any particles of modafinil that pass through the 10 micron screen. The modafinil
passes through the screens in order of decreasing diameter. The screens are designed to
retain a portion of modafinil that cannot pass through the screen openings.
The portions are then placed into an appropriate container. Labels on each
container indicate the particle diameter of the contents. The first container has a label
"larger than or equal to 440 microns." The second container has a "smaller than 440
microns and larger than or equal to 300 microns." The third container has a label
"smaller than 300 microns and larger than or equal to 220 microns." The fourth
container has a label "smaller than 220 microns and larger than or equal to 100 microns."
The fifth container has a label "smaller than 100 microns and larger than or equal to 30
microns." The sixth container has a label "smaller than 30 microns and larger than or
equal to 20 microns." The seventh container has a label "smaller than 20 microns and
larger than or equal to 10 microns." The eighth container has a label "smaller than 10
microns."
Example 2 - Pharmaceutical Compositions From Discrete Lots
Combining a first portion from the eighth container of Example 1, a second
portion from the sixth container of Example 1, a third portion from the fourth container
of Example 1, and a fourth portion from the second container of Example 1 forms a
pharmaceutical composition of the present invention.
The first portion contains about 40% of the total cumulative particles of modafinil
in the pharmaceutical composition. The second portion contains about 30% of the total
cumulative particles of modafinil in the pharmaceutical composition. The third portion
contains about 27% of the total cumulative particles of modafinil in the pharmaceutical
composition. The fourth portion contains about 3% of the total cumulative particles of
modafinil in the pharmaceutical composition. Accordingly, about 97% of the cumulative
total of particles in the pharmaceutical composition are smaller than or equal to about
200 microns in diameter. A particle size distribution curve of this example of the present
invention is shown in Fig. 2.
Examples 3-42:
In the present invention, preferably none, or substantially nonc, of the particles
exceed 600 to 1500 microns in diameter. Specific illustrative examples of the invention
include but are not limited to tablets comprising about 100 milligrams of modafinil
wherein the modafinil particle size distribution is as follows:

Example 43: Dissolution
Modafinil is separated into two discrete lots having particle diameters larger than
or equal to about 250 microns in one discrete lot and smaller than or equal to about 200
microns in the second discrete lot. A ponion of the second discrete lot (smaller than or
equal to 200 microns) is further separated into three discrete lots: (a) between 0 microns
and 10 microns, (b) between 10 microns and 100 microns, and (c) between 100 microns
and 200 microns in diameter. Two blends are prepared using the discrete lots, one blend
having 80% particles between 10 microns and 100 microns and 20% particles larger than
about 250 microns in diameter. The second blend contains 60% particles smaller than or
equal to about 200 microns, and 40% particles having diameters larger than or equal to
about 250 microns in diameter. Portions of the blends are further combined with SDS
(sodium dodecyl sulfate), as detailed below, and are then formed into tablets. In vitro
comparative dissolution studies are then performed on the tablets.
As shown in Fig. 3, the dissolution profile of the FDA approved 100 milligram
tablet of Provigil® (modafinil) was compared with tablets of modafinil wherein 80% of
the particles in the tablet were between about 10 microns and 100 microns in diameter,
and 20% particles were larger than about 250 microns in diameter. The three comparison
tablets contained either no SDS, 0.2% SDS or 0.5% SDS, by weight, as shown in Fig. 3.
The results of the dissolution experiment shown in Fig. 3 indicate that in some
embodiments the greater the amount of SDS in the tablet, the closer the dissolution
curves of the blends approximated the curve of the FDA approved tablet of Provigil®
(modafinil).
DEFINITIONS
"Particle," as used herein, refers to a primary physical unit or an aggregated
physical unit of the acetamide compound, i.e., a piece or a grain of acetamide.
As used herein, the term "mean," when used in reference to the size of modafinil
particles, refers to the sum of the size measurements of all measurable particles measured
divided by the total number of particles measured. For example, for five measurable
particles which could be measured, and were determined to have diameters of 20
microns, 23 microns, 20 microns, 35 microns and 20 microns, the mean diameter would
be 23.6 microns. As used herein, the statistical term "average" is synonymous with the
term "mean."
As used herein, the term "diameter" is a volumetric measurement based on the
theoretical spherical shape of a modafinil particle. Specifically, the volume of a
theoretically spherical particle of modafinil can be defined by: Volume
Therefore, the theoretical diameter can be defined by: Diameter
Similarly, the surface area of a particle can also be determined from the diameter of the
theoretically spherical particle by the equation: Surface Area (SA) =
As used herein, "about" means plus or minus ten percent of the indicated value,
such that "about 20 microns" indicates 18 to 22 microns. The size of the panicle can be
determined, e.g., by the methods provided below, and by other conventional methods
known to those of skill in the art.
As used herein, the term "small particles" refers to particles having diameters
smaller than or equal to about 200 microns. As used herein the term "large particles"
refers to particles that are larger than 220 microns in diameter and smaller than or equal
to about 400 microns. As used herein, the term "very large particles" refers to particles
having a diameter larger than 440 microns.
As used herein, "consisting essentially of refers to excluding other active
ingredients but including excipients and additional amounts of the active ingredient to
account for degradation or otherwise.
The expression "bioequivalent" or "bioequivalence" is a term of art and is
intended to be defined in accordance with Approved Drug Products with Therapeutic
Equivalence Evaluations, 22nd Edition, which is published by the U.S. Department of
Health and Human Services, and is commonly known as the "Orange Book". Generally,
bioequivalence can be defined as the absence of significant difference in the rate and
extent to which the active ingredient or active moiety in pharmaceutical equivalents or
pharmaceutical alternatives becomes available at the site of drug action when
administered at the same molar dose under similar conditions in an appropriately
designed study. Bioequivalence of different formulations of the same dmg substance
involves equivalence with respect to the rate and extent of drug absorption. The extent
and rate of absorption of the test formulation is compared to a reference formulation in

order to determine whether the two formulations are bioequivalent. The standard
bioequivalence study is conducted in crossover fashion by extensive testing which
includes administering single doses of the test and reference drugs to a number of
volunteers, usually 12 to 24 healthy normal adults, and then measuring the blood or
plasma levels of the drug over time. The pharmacokinetic characteristics of the
concentration-time curve, such as the maximum observed plasma concentration (Cmax).
the time to reach Cmax, and the area under the plasma concentration versus time curve
(AUG), are examined by statistical procedures which are well-established in the field of
pharmacokinetics. Two formulations whose rate and extent of absorption differ by -
20%/+25% or less are generally considered to be bioequivalent. Detailed guidelines for
establishing the bioequivalence of a formulation with a reference formulation have been
published by the FDA Office of Generic Drugs, Division of Bioequivalence.
An "effective amount," as used herein, is an amount of modafinil that is effective
for treating a somnolent or somnolescent state, i.e., an amount of modafinil that is able to
reduce or eliminate the symptoms of a somnolescent state. An effective amount of a
pharmaceutical composition of the invention is useful for enhancing alertness, or
increasing regularity of sleep rhythms.
A "pharmaceutical composition," as used herein, means a medicament for use in
treating a mammal that comprises modafinil prepared in a manner that is appropriate for
administration to a mammal. A pharmaceutical composition according to the invention
may also, but does not of necessity, include a non-toxic pharmaceutical I y acceptable
carrier. A pharmaceutical composition can also include bulk modafinil particles of the
present invention for use in preparing dosage units.
As used herein, the term "bounded" refers to the upper and lower limits of
modafinil particle diameters. For example, a discrete lot of modafinil panicles in which
substantially all of the particles have a diameter of 10 to 50 microns has a bounded
particle size range of 10 to 50 microns.
While this invention has been disclosed with reference to specific embodiments,
it is apparent that other embodiments and variations of this invention may be devised by
others skilled in the art without departing from the true spirit and scope of the invention.
The appended claims are intended to be construed to include all such embodiments and
equivalent variations. Further, the contents of all references cited herein are hereby
incorporated by reference.
WE CLAIM.
1. A pharmaceutical composition comprising two or more portions of solid
modafinil particles from a bulk batch of modafinil, wherein each portion has a bounded
particle size range and wherein one or more particle size ranges present in the bulk batch
are not represented in the pharmaceutical composition.
2. A pharmaceutical composition comprising two or more portions of solid
modafinil particles, wherein each portion has a bounded particle size range and wherein
there is a particle size range between the size ranges represented in the two or more
portions that is not represented in the pharmaceutical composition.
3. The pharmaceutical composition of claim 1 wherein more than about 5%
of the particles in the composition are larger than about 200 microns.
4. The pharmaceutical composition of claim 3 wherein the composition has
substantially the same dissolution profile as a modafinil composition in which at least
about 95% of the particles are smaller than about 200 microns.
5. The pharmaceutical composition of claim 3 wherein the composition has
substantially the same dissolution profile as PROVIGIL® (modafinil).
6. The pharmaceutical composition of claim 3 wherein at least about-80% of
the modafinil dissolves after about 45 minutes.
7. The pharmaceutical composition of claim 3 wherein the composition is
bioequivalent (80-125%) to a modafinil composition in which at least about 95% of the
particles are smaller than about 200 microns.
8. The pharmaceutical composition of claim 3 wherein the composition is
bioequivalent (80-125%) to PROVIGIL® (modafinil),
9. The pharmaceutical composition of claim 4, 5,6, 7, or 8 in which fewer
than about 85% of the particles are small particles, i.e., smaller than about 200 microns.
10. The pharmaceutical composition of claim 4, 5, 6, 7, or 8 in which fewer
than about 75% of the particles are small particles, i.e., smaller than about 200 microns.
11. The pharmaceutical composition of claim 4, 5,6, 7, or 8 in which fewer
than about 65% of the particles are small particles, i.e., smaller than about 200 microns.
12. The pharmaceutical composition of claim 4, 5,6, 7, or 8 in which fewer
than about 50% of the particles are small particles, i.e., smaller than about 200 microns.
13. The pharmaceutical composition of claims 9, 10, 11, or 12 in which the
small particles are smaller than about 175 microns.
14. The pharmaceutical composition of claims 9, 10, 11, or 12 in which the
small particles are smaller than about 150 microns.
15. The pharmaceutical composition of claims 9, 10, 11, or 12 in which the
small particles are smaller than about 125 microns.
16. The pharmaceutical composition of claims 9, 10, 11, or 12 in which the
small particles are smaller than about 100 microns.
17. The pharmaceutical composition of claims 9, 10, 11, or 12 in which the
small particles are smaller than about 75 microns.
18. The pharmaceutical composition of claims 9, 10, 11, or 12 in which the
small particles are smaller than about 50 microns.
19. The pharmaceutical composition of claims 9, 10, 11, or 12 in which the
small particles are smaller than about 25 microns.
20. The pharmaceutical composition of claims 9, 10, 11, or 12 in which the
small particles are smaller than about 10 microns.
21. A pharmaceutical composition comprising modaflnil prepared by the
process of blending a first and a second portion of solid modafinil particles wherein said
first portion has a pre-determined particle size range and said second portion has a pre-
determined particle size range that is different from that of the first portion.
22. A pharmaceutical composition comprising at least a first first and a second
portion of modafinil wherein:
a) the first portion of modafinil being in the form of solid modafinil particles is
from a bulk batch and has a bounded particle size distribution; and
b) the second portion of modafinil being in the form of solid modafinil particles
from a the same or another bulk batch and has a bounded particle size distribution;
wherein the combination of the first portion and the second portion yields a
bounded particle size distribution that is different than the particle size distribution of the
bulk batch and the other bulk batch if the other bulk batch is different from the first bulk
batch.
23. The pharmaceutical composition of claim 22, wherein 95% of the
cumulative total of particles in the composition are smaller than or equal to about 200
microns in diameter.
24. The pharmaceutical composition of claim 22, wherein at least one portion
comprises small particles.
25. The pharmaceutical composition of claim 24, wherein at least one other
portion comprises large particles.
26. The pharmaceutical composition of claim 24, wherein at least one other
portion comprises very large particles.
27. The pharmaceutical composition of claim 24, wherein the first portion
comprises an effective amount of modafmil.
28. The pharmaceutical composition of claim 24, wherein the first and second
portion together comprise an effective amount of modafinil.
29. The pharmaceutical composition of claim 22, wherein the first and second
portion comprise at least 15 milligrams of modafinil having particle diameters of
between about 10 microns and 80 microns.
30. The pharmaceutical composition of claim 22, wherein the composition
releases at least 80% of the modafinil in 45 minutes in a 0.1 N HCl solution.
31. A method of formulating a composition of modafinil comprising the steps
of:
a) providing a batch of modafinil, wherein the particles in the batch have a
distribution of particle diameters;
b) separating the particles in the batch of modafinil into at least two discrete
lots of modafinil particles, wherein each discrete lot contains modafinil of a defined
particle diameter, thereby forming at least a first discrete lot and a second discrete lot;
c) blending a portion of the first lot with a portion of the second lot; and
d) forming a composition of modafinil from the blend of the first lot and the
second lot.
32. The method of claim 31, further comprising the step of adjusting the
proportions of the first lot and the second lot in the composition to make a composition
which releases at least 80% of the modafinil in 45 minutes in a 0.1 N HCl solution.

33. A pharmaceutical dosage unit comprising an effective amount of
modafinil wherein at least about 10% of the total cumulative modafinil particles are
smaller than about 25 microns in diameter and more than about 5% of the total
cumulative particles are more than about 200 microns in diameter.
34. The pharmaceutical dosage unit of claim 33 wherein at least about 15% of
the total cumulative modafinil particles are smaller than or equal to about 25 microns in
diameter and more than about 5% of the total cumulative particles are more than about
200 microns.
35. The pharmaceutical dosage unit of claim 33 wherein at least about 20% of
the total cumulative modafinil particles are smaller than or equal to about 25 microns in
diameter and more than about 5% of the total cumulative particles are more than about
200 microns.
36. The pharmaceutical dosage unit of claim 33 wherein at least about 25% of
the total cumulative modafinil particles are smaller than or equal to about 25 microns in
diameter and more than about 5% of the total cumulative particles are more than about
200 microns.
37. The pharmaceutical dosage unit of any of claims 32-36 wherein at least
about 95% of the total cumulative modafinil particles are smaller than 400 microns in
diameter.
38. The pharmaceutical dosage unit of any of claims 32-37 wherein the
amount of modafinil is about 100 mg.
39. The pharmaceutical dosage unit of any of claims 32-37 wherein the
amount of modafinil is about 200 mg.
40. The pharmaceutical dosage unit of claim 37 wherein more than about 10%
of the total cumulative particles are more than about 200 microns.
41. The pharmaceutical dosage unit of claim 37 wherein more than about 15%
of the total cumulative particles are more than about 200 microns.
42. The pharmaceutical dosage unit of claim 37 wherein more than about 20%
of the total cumulative particles are more than about 200 microns.
43. The pharmaceutical dosage unit of claim 37 wherein more than about 25%
of the total cumulative particles are more than about 200 microns.
44. The pharmaceutical dosage unit of claim 37 wherein more than about 30%
of the total cumulative particles arc more than about 200 microns.
45. The pharmaceutical dosage unit of any of claims 40-44 wherein the
amount of modafmil is about 100 mg.
46. The pharmaceutical dosage unit of any of claims 40-44 wherein the
amount of modafmil is about 200 mg.
47. A method of formulating a composition of modafmil comprising the steps
of:
a) providing a first batch and a second batch of modafmil, wherein the
particles in each batch have distribution of particle diameters;
b) separating the particles of the first batch of modafinil into at least two
discrete lots of modafinil particles, wherein each discrete lot contains modafinil of a
defined particle diameter, thereby forming at least a first discrete lot and a second
discrete lot;
c) recombining at least one of the discrete lots with the second batch; and
d) altering the distribution of particle diameters of the particles in the second
batch.
48. A pharmaceutical composition comprising at least a first and second
portion of modafinil wherein:
a) the first portion of modafinil being in the form of solid modafinil particles is
from a bulk batch and has a bounded particle size distribution; and
b) a second portion of modafinil being in the form of solid modafinil particles
from the same or another bulk batch and has a bounded particle size distribution;
wherein the combination of the first portion and the second portion yields a
bounded particle size distribution that is different than the particle size distribution of the
bulk batch and the other bulk batch if the other bulk batch is different from the first bulk
batch, and
wherein the particle size distribution of the first batch is at least one particle size

distribution selected from the group consisting of 0.01 80, 80

30 100, 100 49. The pharmaceutical composition of claim 48, wherein the particle size
distribution of the second batch is at least one particle size distribution selected from the
group consisting of 220 290 360, 360 50. A pharmaceutical composition manufactured by the steps comprising:
a) preparing a bulk batch; and
b) removing at least one discrete lot of particles having a bounded particle
size range from the bulk batch.
51. A pharmaceutical composition obtained from a bulk batch of modafinil,
wherein the pharmaceutical composition has a particle size distribution that is different
from the particle size distribution of the bulk batch.
52. The pharmaceutical composition of claim 48, further comprising a
surfactant.
53. The pharmaceutical composition of claim 52, wherein the surfactant is
selected from the group consisting of non-ionic, ionic, and bile salt surfactants.
54. The pharmaceutical composition of claim 52, wherein the surfactant is the
ionic surfactant sodium dodecyl sulfate.
55. The pharmaceutical composition of claim 52, wherein the surfactant is a
non-ionic surfactant selected from the group consisting of polyoxethylene stearates and
block copolymers of etheylene oxide and propylene oxide.
56. The pharmaceutical composition of claim 52, wherein the surfactant is a
bile salt surfactant selected from the group consisting of sodium cholate, sodium
taurocholate and sodium deoxycholate.
57. Use of modafinil for the preparation of a composition
'as claimed in claims 1,2,21,22 or 33 for altering the
somnolent state of a mammal.
58. Use of modafinil for the preparation of a composition
as claimed in claims 1,2,21,22 or 33 for enhancing
alertness or increasing regularity of sleep rhythms in a
mammal.
59 Use of modafinil for the preparation of a composition
as claimed in claims 1,2,21,22 or 33 for treating a mammal
diagnosed with a modafinil-responsive disease or condition
selected from the group consisting of narcolepsy, sleepiness,
excessive sleepiness, excessive daytime sleepiness associated
with narcolepsy, Parkinson's disease, urinary
incontinence, multiple sclerosis fatigue ADHD, Alzheimer's
disorder, sleep apnea, obstructive sleep apnea, depression,
and ischemia, said method comprising administering an
amount of modafinil, as one or more oral unit doses, to
said mammal.
60. A composition comprising two or more portions of solid modafinil particles
from a bulk batch of modafinil, wherein each portion has a bounded particle size
range and wherein one or more particle size ranges present In the bulc batch are
not represented in the pharmaceutical composition.
61. A composition comprising two or more portions of solid modafinil particles,
wherein each portion has a bounded particle size range and wherein there is a
particle size range between the size ranges represented in the two or more
portions that is not represented in the pharmaceutical composition.
62. The composition as claimed in claim 60 wherein more than about 5% of the
particles in the composition are larger than about 200 microns.
63. The composition as claimed in claim 62 wherein the composition has
substantially the same dissolution profile as a modafinil composition in which at
least about 95% of the particles are smaller has about 200 microns.
64. The composition as claimed in claim 62 wherein the composition has
substantially the same dissolution profile as PROVIGIL® (modafinil).
65. The composition as claimed in claims 1, 2, 3, 60 or 61 wherein the
modafinil is R-(-)-2-[(diphenylmethyl)sutfinyl]acetamide.
66. The composition as claimed in claims 1, 2, 3, 60 or 61, wherein the
modafinil compound is (-)benzhydrylsulfinyl-acetamide.
67. The method as claimed in claims 31 or 47 further comprising the step of
adjusting the proportions of the first lot and the second lot in the composition so
that more than about 5% of the total cumulative number of modafinll particles In
the composition have diameters greater than 220 microns.
68. The method as claimed in claim 67 further comprising the step of adjusting
the proportions of the first bt and the second bt in the composition so that less
than about 35% of the total cumulative number of particles area more than 220
microns.
69. The method as claimed in claim 67 further comprising the step of adjusting
the proportions of the first bt and the second bt in the compositbn so that
between about 10% to about 30% of the total cumulative number of particles
are more than 220 microns in diameter.
70. The method as claimed in claim 67 further comprising the step of forming
said composition into an oral dosage unit.
71. The method as claimed in claim 70 wherein said oral dosage unit releases at
least 80% of the modafmil in 45 minutes in a 0.1 N HCl solution.
72. The method as claimed in claim 70 wherein said oral dosage unit contains
100 mg of modafinil, and is btoequivalent to a 100 mg modafinil dosage unit in
which at least about 95% of the particles are smaller than about 200 miaons.
73. The mehod as claimed in claim 70 wherein said oral dosage unit contains
200 mg of modafinil, and it bioequivalent to a 200 mg modafinil dosage unit in
which at least about 95% of the particles are smaller than about 200 microns.

A pharmaceutical composition comprising two or more portions of solid
modafinil particles from a bulk batch of modafinil, wherein each portion has a
bounded particle size range and wherein one or more particle size ranges
present in the bulk batch are not represented in the pharmaceutical composition.

Documents:

172-kolnp-2005-abstract.pdf

172-kolnp-2005-assignment.pdf

172-kolnp-2005-claims.pdf

172-kolnp-2005-correspondence.pdf

172-kolnp-2005-description (complete).pdf

172-kolnp-2005-examination report.pdf

172-kolnp-2005-form 1.pdf

172-kolnp-2005-form 13.pdf

172-kolnp-2005-form 18.pdf

172-kolnp-2005-form 2.pdf

172-kolnp-2005-form 26.pdf

172-kolnp-2005-form 3.pdf

172-kolnp-2005-form 5.pdf

172-kolnp-2005-reply to examination report.pdf

172-kolnp-2005-specification.pdf


Patent Number 240477
Indian Patent Application Number 172/KOLNP/2005
PG Journal Number 20/2010
Publication Date 14-May-2010
Grant Date 12-May-2010
Date of Filing 11-Feb-2005
Name of Patentee CEPHALON, INC
Applicant Address 145 BRANDY-WINE PARKWAY, WEST CHESTER, PA
Inventors:
# Inventor's Name Inventor's Address
1 CRAIG HEACOCK 53 YARMOUTH LANE DOWNINGTOWN, PENNSYLVANIA PA 19335
2 PIYUSH R. PATEL 716 SCOTT LANE WALLINGFORD, PENNSYLVANIA 19086
3 ALPA PARIKH 106 GORMLEY COURT HOCKESSIN, DELAWARE 19701
PCT International Classification Number A61K 31/165
PCT International Application Number PCT/US2003/021969
PCT International Filing date 2003-07-11
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/395,537 2002-07-12 U.S.A.
2 10/616,776 2002-07-10 U.S.A.