Title of Invention

A METHOD OF PREPARING A COMPOSITION OF PARTICLES, AND THE COMPOSITION THEREOF

Abstract A method of preparing a composition of particles, wherein the particles comprise a modafinil compound, comprising a contacting particle-forming composition of modafinil with an aqueous medium, and an aqueous composition comprising the same.
Full Text FIELD OF THE INVENTION
The invention relates to particle-forming compositions comprising a
modafinil compound. The inventionis also directed to compositions of suspended
particles which are formed when the particle-forming compositions are contacted
with an aqueous medium. The invention is further directed to methods of
preparation of the compositions, and the use of the compositions in the treatment of
diseases to a subject in need thereof.
BACKGROUND OF THE INVENTION
Modafinil (C15H15NO2S), is 2-(benzhydryl-sulfinyl)acetamide, and is also
known as 2-[(diphenylmethyl) sulfinyl] acetamide.
Modafinil has been described-as presenting a "neuropsychopharmacologica!
spectrum characterized by the presence of excitation with hyperactivity and of
hypermotility; and by the absence of stereotypy (except in high doses) and of
potentialization of the effects of apomorphine and amphetamine" (U.S. Patent
4,177,290; hereinafter the " '290 patent," which is incorporated in its entirety 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)). Modafinil has been successfully tested in humans for
treatment of idiopathic hypersomnia and narcolepsy (Bastuji et al., Prog. Neuro-
Psych. Biol. Psych. 12:695 (1988)).
Other uses of modafinil have been presented. U.S. Patent 5,180,745,
incorporated in its entirety herein by reference, 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. Patent 4,927,855,

incorporated in its entirety herein by reference). European Published Application
547952 (published June 23, 1993) discloses the use of modafinil as an anli-ischemic
agent. European-Published Application 594507 (published April 27, 1994) discloses
the use of modafinil to treat urinary incontinence.
Preparations of modafinil having a defined solid particle size have been ■ ■ :
described in U.S. Pat. No. 5,618,845, incorporated in its entirety herein by reference,
and preparations of a levorotatory isomer of modafinil was described in U.S. Patent
No. 4,927,855. Heterocyclic derivatives of modafinil are disclosed in U.S. Patent
Application No. 60/204,789, incorporated its entirety herein by reference.
Modafinil has been approved for use in humans in 100 mg and 200 mg solid
unit dose forms in the U.S. It is also desirable to formulate modafinil in liquid
compositions. It has been observed that modafinil has very poor water and lipid
solubility and it is therefore difficult to solubilize modafinil in pharmaceutically-
acceptable compositions. Conventional solid and liquid formulations that include
modafinil are described in the '290 patent. Liquid suspensions or emulsions of
modafinil were mentioned in U.S. Pat. No. 5,618,845. A suspension of modafinil
was reported in U.S. Pat. No. 5,180,745. An aqueous cyclodextrin solution of
modafinil was described in Rambert, F.A., et al. Neuropsvchopharmacologv, 10(3S),
Part 2 (May 1994).
A technique recently developed to formulate liquid pharmaceutical
compositions for agents that display very low water solubility involves a self-
emulsifying drug delivery system, known as "SEDDS". These drug delivery systems
are isotropic mixtures of lipids or lipid-soluble compounds and a surfactant that
rapidly form thermodynamically stable microparticles upon contact with water. See,
e.g., Shah et al., International Journal of Pharmaceutics (Netherlands), 106:15-23,
(1994), which is incorporated in its entirety herein by reference.
Despite the low lipid solubility of modafinil, it has been discovered that
modafinil can be formulated to produce particle-forming compositions, wherein the
compositions are capable of forming particles comprising a modafinil compound
upon contact with water. These compositions have been found to effectively
solubilize modafinil in an aqueous component and to provide for effective
bioavailable delivery of modafinil to a subject in need thereof.

SUMMARY OF THE INVENTION
Accordingly, one object of the present invention is to provide particle-
forming compositions comprising a modafinil compound. Particularly, the particle-
forming compositions of the present invention are non-aqueous and optionally
comprise an amount of at least one surfactant sufficient to allow for the formation of
a composition of particles upon contact of the particle-forming composition with an
aqueous medium.
It is another object of the invention to provide for compositions of
particles in an aqueous medium, wherein the particles comprise a modafinil
compound. Preferably the compositions of particles comprises a stable suspension,
wherein the suspendedparticles comprise a modafinil compound.
Preferably, both the particle-forming compositions and the compositions
of particles, wherein the particles comprise a modafinil compound, are.
pharmaceutically acceptable^compositions and.allow for bioavailable delivery of a
modafinil compound uponoral administration to a subject in need thereof.
It is another object of the invention to provide a method of forming a
composition of particles in an aqueous medium which comprises contacting the
particle-forming compositions comprising a modafinil compound with an aqueous
medium.
It is another object of the inventioirto provide a method of treating a
disease or disorder in a subject which comprises administering to the subject a
therapeutically effective amount of either of the compositions of the present
invention.
These and other objects, which will become apparent during the
following detailed description, have been achieved by the inventors' discovery that
despite its poor aqueous and lipid solubility, a modafinil compound can be
formulated to provide effective bioavailability upon administration to a subject in
need thereof.
DETAILED DESCRIPTION OF THE INVENTION
Thus, in a first embodiment, the present invention provides a particle-forming

composition comprising a modafinil compound. Preferably the particle-forming
composition is non-aqueous. Preferably the particle-forming composition comprises
at least one surfactant. Preferably the particle-forming composition comprises .
modafinil.. ....
In a second embodiment, the present invention provides for a composition of
particles in an aqueous medium, wherein the.particles comprise a modafinil
compound.. Preferably the composition of particles comprises at least one surfactant.
Preferably the particles comprise modafinil. Preferably the composition of particles
is a stable suspension.; •
In certain preferred embodiments, the compositions are pharmaceutically
acceptable.
As used hereini "the compositions" refers collectively to the particle-forming
compositions and the compositions of particles wherein the particles comprise a
modafinil compound..
As used herein, a "non-aqueous" composition refers to a composition that
contains from 0-10 % water by weight.'
As used herein"; "aqueous medium" refers to any medium comprised of
greater than 10% water.
As used herein, a "particle-forming composition" refers to a composition that
is capable of forming particles upon contact with an aqueous medium. Preferably
the particle-forming composition is a liquid or solid solution.
As used herein, "particle" or "particles" refers to substantially non-crystalline
structures, preferably an aggregation of molecules in a discrete non-crystalline
structure, such as a micelle, microsphere, droplet, colloid, or globule. Preferably the
particles comprise a modafinil compound, and more preferably, comprise modafinil.
As used herein, "composition of particles" refers to a composition comprising
a particle wherein the particle comprises a modafinil compound.
As used herein, "stable suspension" refers to a mixture of particles that
remain intact and dispersed in a liquid medium such that the suspension can be
stored and administered in a pharmaceutically acceptable manner.
As used herein, "a modafinil compound" or "modafinil compound" and the
like, refers to modafinil, its racemic mixtures, individual isomers, 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 (a modafinil compound) in the body of a subject. In certain
preferred embodiments, the modafinil compound is modafinil.
As used herein, "bioavailablel:' is intended to mean a portion of the
administered dose that is absorbed in the blood stream and can readily be determined
by techniques known in the art, such as, for example, by measuring the blood serum
level of a compound.
As used herein, the term "pharmaceutically acceptable" refers to those
compounds, materials, compositions, and/or dosage forms which are, within the
scope of sound medical judgment, suitable for contact with the tissues of human
beings and animals without excessive toxicity, irritation, allergic response, or other
problem complications commensurate with a reasonable benefit/risk ratio.
As used herein, the term "subject" refers to a warm blooded animal such as a
mammal, preferably a human or a humarr child, which is afflicted with, or has the
potential to be afflicted with one or more diseases andxonditions described herein.
As used herein, "therapeutically effective amount" refers to an amount which
is effective in reducing, eliminating; treating, preventing or controlling the symptoms
of the herein-described diseases and conditions. The term "controlling" is intended
to refer to all processes wherein there may be a slowing, interrupting, arresting, or
stopping of the progression of the diseases and conditions described herein, but does
not necessarily indicate a total elimination of all disease and condition symptoms,
and is intended to include prophylactic treatment.
As used herein, "unit dose" 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 a modafinil
compound, or a pharmaceutical^ acceptable composition comprising a modafinil
compound.
As used herein, a "lower alkyl alcohol" refers to a branched or straight-
chained alkyl alcohol containing from 1 to 6 carbon atoms, such as methanol,
ethanol, n-propanol, isopropanol, n-butanol, isobutyl alcohol, sec-butyl alcohol.

l-buly) alcohol, pentanol, hexanol, etc; with preferred lower alkyl alcohols including
cihanol, propanol and isopropanol.
As used herein, the term "arylalkyl alcohol" refers to aryl-substituted Ci-Q
;i!kyl aicohoJs such as benzyl alcohol, phenethyl alcohol, diphenylmethyl alcohol
(benzhydrol), etc.; with preferred arylalkyl alcohols including ben^yl alcohol, a-
phenerhyl alcohol and fi-phenethyl alcohol.
As used herein, "antioxidant" is intended to indicate any substance useful to
retard deterioration by oxidation or to inhibit reactions promoted by oxygen or
peroxides..
As used herein, "lipid", is intended to indicate a fat, oil, wax, sterol, glycerol
ether, triglyceride, or combination thereof.
As used herein, the term "about" refers to a range of values ± 10% of a
specified value. For example, the phrase "about 50%" includes ± 10% of 50, or from
45 to 55%.
In certain preferred embodiments, the compositions comprise a modafinil
compounds a concentration of about 1 to about 500 mg/ml. In certain more
preferred embodiments, a modafinil compound is present from about 1 to about 200
mg/ml, and most preferably from about 20 to about 80 mg/ml.
In certain embodiments, the compositions comprise at least one surfactant. In
other preferred embodiments, there are three surfactants, and other more preferred ,
embodiments include one or two surfactants. In certain embodiments, the surfactant
acts-as the primary solubilizing agent. In other embodiments, the compositions
comprise from about 0.5% to about 50% total surfactant. The amount of total
surfactant is more preferably at least 5%, and less than about 40%, depending upon
the surfactant and the additional components of the composition. Preferably,
appropriate surfactants are those, when admixed with a modafinil compound, result
in particle-forming compositions and compositions of particles, and more
preferably, in stable suspensions. One skilled in the art can readily determine the
appropriate surfactant or combination of surfactants, and their relative amounts, by
use of conventional techniques and observing the characteristics of the resultant
composition. Several factors can be considered, including for example, the
solubility of the modafinil compound in the solution, the degree of precipitation of

the modafinil compound, the degree of solubilization or emulsification of the'
solution and the stability of the solution over a period of time.
The surfactants include; but are not limited to, polyoxyethylene sorbitan fatty
acid esters, polyethylene glycol ethers, saturated polyglycolized glycerides, fatty acid
esters of polyethylene glycols, medium chain monogiycerides, medium chain fatty
acid esters, d-ct-tocopheryl polyethylene glycol succinate,polyethylene/propylene
glycol copolymers, block copolymers of ethylene oxide and propylene oxide,
polyoxyl stearates, ethoxylated castor oils, and ethoxylated hydroxystearic acids.
Additional surfactants can be foundJn The Handbook of Pharmaceutical Excipients,
2nd Ed., (The Pharmaceutical Press, London and American Pharmaceutical
Association (1994)), a common text in the field, which is hereby incorporated by
reference in its entirety.
The polyoxyethylene sorbitan fatty acid esters (polysorbates) are non-ionic
surfactants (detergents) that may comprise a mixture;of fatty acids. Commercially
available examples are polyoxyethylene (20) sorbitan monolaurate (such as Tween®
20), polyoxyethylene (40) sorbitan monopalmitate_(such as Tween® 40),
polyoxyethylene (80) sorbitan monooleate (such as Tween® 80) and sorbitan
monolaurate (such as Span® 20). Preferred polyoxyethylene sorbitan fatty acid
esters are polyoxyethylene (80) sorbitan monooleate (in particular, Tween® 80) and
sorbitan monolaurate (in particular, Span® 20). The saturated polyglycolized
glycerides include, for example, mono-, di-, or triglycerides. The di-fatty acid esters
of polyethylene glycols include, for example, Gelucire® 44/14 (primarily a fatty acid
ester of PEG-1500, available from Gattefosse, Saint-Priest, France). The medium .
chain monogiycerides, wherein the chain length is from 6 to 10 carbon atoms,
include for example, glyceryl monocaprylate (Imwitor® 308), glyceryl monocaproate
(Capmul® MCM C-8), glyceryl caprylate/caprate (Capmul® MCM) and a mixture of
polyoxyethylene glyceryl caprylate and polyoxyethylene glyceryl caproate
(Labrasol®). The medium chain fatty acid esters include medium chain length
triglycerides, such as a mixture of glyceryl tricaprate and glyceryl tricaprilate
(Miglyol® 612). The block copolymers of ethylene oxide and propylene oxide
include, for example, polyoxyethylene-polyoxypropylene block co-polymer
(Pluronic® F-68). The polyoxyl stearates include polyethoxylated (40) stearic acid

(Myrj® 52), The ethoxylated castor oils include, for example, polyethoxylated (60)
hydrogenated castor oil (Cremophor® EL). The ethoxylated hydroxystearic acids
include, for example, polyethylene glycol 660 hydroxystearate (Solutol® HS 15).
Some surfactants are solid or semisolid at room temperature, e.g., glyceryl
monoeaprylate, and Gelucire® 44/14.
Examples of surfactants which are particularly effective as the primary
solubilizingagent, such as those compositions where the surfactant comprises more
than 50% of the composition, include polyethoxylated (60) hydrogenated castor oil
(such as Cremophor® EL), polyethylene glycol 660 hydroxystearate .(such.as,.
Solutol® HS 15), polyethoxylated (40) stearic acid, (such as Myrj® 52) and _..
polyoxyethylene (80) sorbitan monooleate (such as Tween® 80).
In other preferred embodiments, the compositions comprise more than one
surfactant. In certain embodiments, the additional surfactants may be selected from
any of the.aforementioned surfactants. Preferably, an additional, or second
surfactant,- is a polyoxyethylene sorbitan fatty acid ester, and more preferably is
polyoxyethylene (80) sorbitan monooleate (in particular, Tween® 80) and sorbitan:
monolaurate (in particular, Span® 20).
In other embodiments, the compositions comprise a polyoxyethylene sorbitan
fatty acid ester, preferably polyoxyethylene (80) sorbitan monooleate (in particular,
Tween® 80); medium chain monoglycerides, in particular, glyceryl
caprylate/caprateXCapmul® MCM); and medium chain length triglycerides, such as
a mixture of glyceryl tricaprate and glyceryl tricaprilate (in particular* Miglyol®
612)." A preferred composition comprises Tween® 80, Capmul® MCM, and
Miglyol® 612.
In certain embodiments of the invention, the compositions comprise at least
one organic solvent. In certain preferred embodiments, there are three solvents, and
other more preferred embodiments include one or two solvents. In certain preferred
embodiments, the amounts of any additional solvents comprise from about 0.5% to
about 50% (v/v) of the composition, with a more preferred amount of about 1% to
about 50% (v/v), and a most preferred amount about 5% to about 20% (v/v).
Preferably, an appropriate organic solvent is one which increases the
solubility of a modafinil compound in a particle-forming composition and does not

adversely impact upon the formation of suspended particles.
In certain preferred embodiments, the compositions comprise at least one
organic solvent including glycerin;propylene glycol, diethylene glycol ethyl ether,
propylene carbonate, tetraglycol (also known as glycofurol), mediumchain length
monoglycerides, or polyethyleneglycols. Medium chain length monoglycerides
include glyceryl monocaprylate (Imwitor®), glyceryl caprylate/caprate (such as
Capmul®) and polyoxyethylene glyceryl caproate (such as Labrasol®). Preferred
organic solvents include polyethylene glycols or "PEG", which refer to a liquid or
solid polymer of the general formula H(OCH7CH2)nOH, wherein n is at least 4. The
preferred PEG has an average molecular weight of from about 200 to about 1500,
and commercially available PEG"materials include PEG-200, PEG-300, PEG-400,
PEG-540, PEG-600, PEG-800, PEG-1000 and PEG-1450. All are commercially
available from, for example, from Union Carbide Corporation in both food or
pharmaceutical grades. Preferred PEG solvents for use in the present composition
include PEG-300, PEG-400 and PEG 1450, with PEG-300 and PEG-400 being morer
preferredr
In certain embodiments, the compositions comprise glycol and a surfactant.
Preferably the surfactant is an ethoxylated hydroxystearic acid, and in particular is
polyethylene glycol 660 hydroxystearate. In certain preferred embodiments, the
ratio of glycol to surfactant is 1:1.
In other preferred embodiments, the compositions comprise an additional, or
second solvent, which is preferably a lower alkyl alcohol or an alkylaryl alcohol, and
more preferably benzyl alcohol, a-phenethyl alcohol or (3-phenethyl alcohol. In
more preferred embodiments, the solvent system includes mixtures of a polyethylene
glycol and an arylalkyl alcohol. More preferred embodiments include mixtures of
PEG-400 and benzyl alcohol, PEG-400 and a-phenethyl alcohol, and PEG-400 and
(3-phenethyI alcohol. A most preferred embodiment includes a mixture of 95:5 (v/v)
PEG-400:benzyl alcohol.
In certain preferred embodiments, the compositions comprise a modafinil
compound, or preferably modafinil, at a concentration of about 1 to about 100
mg/ml, preferably from about 1 to about 60 mg/ml and more preferably from about
20 to about 50 mg/ml; a first surfactant selected from a polyoxyethylene sorbitan

fatty acid ester, a polyethylene glycol ether, a saturated polyglycolized^glyceride, a
fatty acid ester of a polyethylene glycol, a medium chain monoglyceride, a medium
chain fatty acid ester, d-a-tocopheryl polyethylene glycol succinate, a
polyethylene/propylene glycol copolymer, block copolymers of ethylene oxide and
propylene oxide, a polyoxyl stearate, an ethoxylated castor oil, and an ethoxylated
hydroxystearic acid; and may additionally comprise a second surfactant selected .
from a polyoxyethylene sorbitan fatty acid ester; and may further additionally
comprise an organic solvent selected from glycerin, propylene glycol, diethylene
glycol ethyl ether, propylene carbonate, a medium chain length monoglyceride, and a^
polyethyleneglycol. In a more preferred embodiment, the compositions are
pharmaceutically acceptable.
In certain further preferred embodiments, the first surfactant is a saturated
poiygiycolized glyceride, a fatty acid ester of a polyethylene glycol, or a medium
chain monoglyceride; the second surfactant is a polyoxyethylene sorbitan fatty acid
ester; and the.organic solvent is a polyethyleneglycol. In more preferred
embodiments, the first surfactant is glyceryl caprylate/caprate; glyceryl
rnonocaprylate or polyethoxylated (40) stearic acid; the second surfactant is sorbitan
monolaurate; and the organic solvent is PEG-300 or PEG-400.
In certain most preferred embodiments, the compositions comprise 90%
PEG-400, 5% sorbitan monolaurate, 5% glyceryl caprylate/caprate (w/w/w), or in
particular, 90% PEG-400,5% Span® 20, 5% Capmul® MCM (w/w/w). In other most
preferred embodiments, the compositions comprise 90% PEG-400, 5% sorbitan
monolaurate, 5% glyceryl rnonocaprylate (w/w/w), or in particular, 90% PEG-400,
5% Span® 20, 5% Imwitor® 308 (w/w/w). In anothermostr preferred embodiment,
the compositions comprise 90% PEG-400,5% sorbitan monolaurate, 5%
polyethoxylated (40) stearic acid (w/w/w), or in particular, 90% PEG-400, 5% Span®
20, 5% Myrj® 52 (w/w/w).
In other more preferred embodiments, the first surfactant is glyceryl
caprylate/caprate, glyceryl rnonocaprylate, polyethoxylated (40) stearic acid or a
mixture of polyoxyethylene glyceryl caprylate and polyoxyethylene glyceryl
caproate; the second surfactant is polyoxyethylene (80) sorbitan monooleate; and the
organic solvent is PEG-300 or PEG-400.

In other most preferred embodiments, the compositions comprise 70% PEG-
400. 15% polyoxyethylene (80) sorbitan monooleate, 15% glyceryl caprylate/caprate
(w/w/w), in particular, 70% PEG-400,15% Tween6" 80, 15% Capmui® MCM
(w/w/w). In another most preferred embodiment, the compositions comprise 70%
PEG-400,15% polyoxyethylene (80) sorbitan monooleate, 15% glyceryl
monocaprylate (w/w/w), in particular 70% PEG-400, 15% Tween® 80,15%
Imwitor® 308 (w/w/w). In a furthermost preferred.embodiment, the compositions
comprise 70% PEG-400,-15% polyoxyethylene (80) sorbitan monooleate, 15%
polyethoxylated (40) stearic acid (w/w/w), in particular, 70% PEG-400,15% Tween®
80,15% Myrj® 52 (w/w/w). In an additional most preferred embodiment, the
compositions comprise 70% PEG-400,15% polyoxyethylene (80) sorbitan
monooleate, 15% of a mixture of polyoxyethylene glyceryl caprylate and
polyoxyethylene glyceryl caproate~(w/w/w), in particular, 70% PEG-400,15%
Tween® 80,15% Labrasol® (w/w/w),
In another embodiment, the present invention provides for a method of
preparing a composition of particles, wherein the particles comprise a modafinil
compound, comprising contacting a particle-forming composition of a modafinil
compound with an aqueous medium. Preferably, the modafinil compound is
modafinil.
In yet another embodiment, the present invention provides a method of
preparing a composition of particles, wherein, the particles comprise a modafinil
compound, comprising:
(a) dissolving a modafinil compound in a liquid comprising at least one surfactant to
form the particle-forming composition; and
(b) contacting the particle-forming composition with an aqueous medium to form a
composition of particles. In a preferred embodiment, the amount of surfactant is
from about 1% to about 50% by weight of the composition. In a preferred
embodiment, the modafinil compound is modafinil. In another preferred
embodiment, the composition of particles is formed by contacting the particle-
forming composition with the aqueous medium in vitro. In yet another preferred
embodiment, the composition of particles is formed by contacting the particle-
forming composition with the aqueous medium in vivo.

In a further embodiment of the present invention, there is provided a method
of treating a disease or disorder in a subject, comprising administering a
therapeutically effective amount of a modafinii compound, or preferably modafinil in
a particle-forming composition comprising at least one surfactant to the subject. In a
preferred embodiment, the particle-forming composition contacts with aqueous
medium in vivo, thereby forming a composition which is therapeutically effective.
In yet another embodiment, the present invention provides for a method of
treating a disease or disorder in a subject, comprising:
(a) contacting a modafinil compound in a particle-formingcomposition comprising
at least one surfactant with an aqueous medium, thereby forming a composition of
particles, wherein the particles comprise a modafinil compound; and.
(b) administering a therapeutically effective amount of the composition of particles
to a subject. In a preferred embodiment, the modafinil compound is modafinil.
In another embodiment, the presenHnventibn provides for the use of a
modafinil.compound, or preferably modafinil for the preparatioirof pharmaceutical
compositions useful in the treatment of a disease or disorder^/
In certain preferred embodiments, the pharmaceutical.compositions are useful
for treatment of sleepiness, such as excessive daytime sleepiness associated with
narcolepsy, or sleepiness associated with sleep apneas, tiredness, Parkinson's disease,
cerebral ischemia, stroke, sleep apneas, eating disorders, attention deficit
hyperactivity disorder, cognitive dysfunction or fatigue, such as fatigue resulting
from multiple sclerosis ("MS fatigue"); and for promotion of wakefulness,
stimulation of appetite, or stimulation of weight gain.
In certain embodiments, administration of a therapeutically effective amount
of the composition can be readily determined by the attending diagnostician, as one
skilled in the art, by the use of conventional techniques and by observing results
obtained under analogous circumstances. In determining the therapeutically effective
amount, a number of factors are considered by the attending diagnostician, including,
but not limited to: the species of subject; its size, age, and general health: the specific
disease involved; the degree of involvement or the severity of the disease; the
response of the individual subject; the particular compound administered; the mode
of administration; the bioavailability characteristic of the preparation administered;

the dose regimen selected; the use of concomitant medication; and other relevant
circumstances.
A therapeutically effective amount of a modafinil compound will vary
depending upon a number of factors, including the dosage of the drug to be
administered, the chemical characteristics (e.g., hydrophobicity) of the compounds
employed, the potency of the compounds, the type of disease, the diseased state of
the patient, and the route of administration. Generally, treatment is initiated with
small dosages, which can then be increased by small increments until the optimum
desired effect under the circumstances.is achieved.
In certain preferred embodiments, the compositions comprise at least one unit
dose of a modafinil compound. In certain more preferred embodiments, the
compositions comprise one unit dose of modafinil. Preferable daily doses of
modafinil range from about 0.01 to 100 mg/kg of body weight. By way of general
guidance, daily doses for humans range from about 0.1 mg to about 2000 mg.
Preferably the unit dose range is from about 1 to about 500 mg administered one to
four times a day, and even~moye~prefeTably from about 10 mg to about 400 mg, one
to two times a day. In certain preferred embodiments, the unit dose is 100 or 200
mg. In other preferred embodiments, a unit dose is one that is necessary to achieve a
blood serum level of about 0.05 to 30 ng/ml, and more preferably, of about 1 to
about 20 f^g/ml in a subject.
In a further embodiment, the present invention provides for the compositions
comprising a modafinil compound and at least one surfactant, wherein upon
administration of either of the compositions to a subject, the modafinil compound
has a blood serum level of about 0.05 to about 30 u.g/ml in said subject. In a
preferred embodiment, the modafinil compound has a blood serum level of about 1
to about 20 u.g/ml in said subject. In another preferred embodiment, the composition
being administered to achieve the desired blood serum levels is a particle-forming
composition comprising a modafinil compound. In a further preferred embodiment,
the composition being administered to achieve the desired blood serum levels is an
aqueous composition of particles, wherein the particles comprise a modafinil
compound. In more preferred embodiments, the modafinil compound is modafinil.
In a further embodiment, the present invention provides for compositions that

are suitable for oral administration to a subject. Oral administration includes
ingestion in the form of a liquid composition, such as a syrup, elixir, emulsion; or a
capsule. A preferred embodiment is in the form of a capsule, and more preferably as
hard capsules, comprising gelatin, hydroxypropylmethylcellulose ("cellulose"), or
starch. Another more preferred embodiment is in the form of soft gelatin capsules.
In particular, the soft gel capsules comprise a non-aqueous composition. In
additional preferred embodiments, the composition being used for oral
administration is a particle-forming composition comprising a modafinil compound.
In further preferred embodiment, the composition being used for oral administration
is an aqueous composition of particles, wherein"the particles comprise a modafinil
compound.
In other embodiments of the invention, the compositions may also be
prepared in admixture with additional pharmaceutically-acceptable excipients or
components to further promote effective therapeutic use. The excipients may
include lipids, for example, those which are useful to change particle size;
antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as
ascorbic acid, sodium bisulfite, and fatty acid.esters of ascorbic acid, such as
ascorbyl palmitate; chelating agents such as ethylene diaminetetraacetic acid; buffers
such as acetates, citrates or phosphates and agents.for the adjustment of toxicity
such as sodium chloride or dextrose; and other excipients such as flavorings,
sweetening agents and coloring agents. Other appropriate excipients can readily be
determined by one skilled in the art, and may further include those found in The
Handbook of Pharmaceutical Excipients,,_2rid Ed.^("The Pharmaceutical Press,
London and American Pharmaceutical Association (1994)).
The compositions of the present invention comprise modafinil compounds,
which may be readily prepared by one skilled in the art using conventional methods.
Methods for preparing modafinil and various derivatives appear in U.S. Pat. No.
4,177,290, and methods for preparing other modafinil compounds appear in U.S.
Pat. No. 4,927,855, 5,719,168 and in U.S. Patent Application No. 60/204,789.
There is wide latitude in formulation of the compositions of the present
invention. The compositions of particles may be formed by contacting the particle-
forming compositions comprising a modafinil compound with an aqueous medium

in vitro, i.e., subjected to predilution, prior to ingestion by the subject, or in vivo, e.g.
contact with aqueous contents of the gastrointestinal composition of the subject. If
the composition is prediiuted.-a preferable dilution ratio is from about 1:1000 (1 part
formulation to 999 parts aqueous medium) to about 1:2 (1 part formulation to 1 part
aqueous medium). More preferably, the dilution ratio is from about 1:500 (1 part
formulation to 499 parts-aqueous medium) to about 1:3 (1 part formulation to 2 parts
aqueous medium). By way of general guidance, for administration to humans a
convenient ratio is aboutl :250, which is a rough correspondence to a 1 ml unit dose
dispersed in an 8-ounce glass of an aqueous liquid. .
In certain preferred embodiments, when the particle-forming composition is
contacted with an aqueous mediunTT a homogeneous, stable composition comprising
suspended particles is formed. Preferably, the particles comprise a modafinil
compound. Typically, the particles are thermodynamically stable, and are formed
spontaneously upon mixing, without external mechanical agitation. The particles are
preferably in the microparticle sizejange, with a diameter of about 1 to about 1000
nm. More preferably, the particles have a diameter of about 1 to about 400 nm, and
most preferably about 1 to about 100 nm;
A feature of these preferred compositions is that they are translucent and
optically isotropic. A useful indication of the particle size is the degree of optical
transparency of a given volume of water comprising a given amount of formulation.
This is due to the scattering of visible light by the particles, with the larger particles
causing greater scatteringr In general, the greater the optical transparency, the
smaller the particle size. High optical transparency, i.e., bluish haze invisible or
nearly invisible, generally indicates a particle size of less than 100 nm. A distinct
bluish haze generally indicates a particle size from about 100 nm to about 400 nm.
Without intending to be bound by theory, it is noted that particle size tends to be
essentially constant for a given formulation, regardless of the dilution ratio. If
particles fail to form, an increase in dilution ratio, or an adjustment of the amount
and type of surfactant may be used to promote particle formation.
An additional feature of these preferred compositions is that they remain
physically stable, which allows for desirable and effective use of the compositions as
pharmaceutically acceptable formulations. An indication of a stable compositions is

retention of the same outward appearance and_properties over an extended period of
time, sufficient to retain pharmaceutical acceptability. In stable compositions, the
particles generally remain intact and sufficiently dispersed-or suspended in the liquid
medium. Typically, creaming or sedimentation is minimal, or otherwise, the
particles can be redispersed upon mild agitation. Additionally, the particles do not
readily or irreversibly aggregate, coalesce, or otherwise;revert back to two separate
bulk phases.
The compositions of the present invention may be a liquid, semi-solid, or
solid at room temperature. If liquid, the compositions may be contained in a
capsule. If semi-solid or solid, the compositions can.be in the form of a capsule or
tablet.
Whether a composition according to the invention is a liquid, semi-solid, or
solid at room temperature, may depend upon the selection of components, or other
concerns such as commercial viability, administration and the like. For example, a
semi-solid or solid formulation is convenientfor manufacturing unit doses of
modafinil compound in the fornrof a capsule,=including both hard gelatin and soft
gelatin capsules, and tablets. When the liquid or solid formulation contacts an
aqueous medium, e.g., gastrointestinal liquids, the formulation disperses into
suspended particles in which modafinil compound is biologically available.
Compositions whose inert or non-active components (i.e., components other
than modafinil) are all liquid at room temperature can be prepared by simply mixing
the components without heating. The desired amount of a modafinil compound can
be weighed out and dissolved in the mixture of inert components, without heating.
Moderate heating, preferably less than 60° C, can be applied to hasten complete
mixing of the inert components, to hasten dissolution of a modafinil compound, or
both.
Preparation of compositions comprising one or more components that are
solid at room temperature is carried out at a moderately elevated temperature,
preferably less than 60° C. While moderate heating can be useful, excessive heating
can cause decomposition of one or more components of the formulation. For
example, decomposition of Polysorbate 80 can occur at temperatures above 60° C.
Decomposition of Polysorbate 80 may occur if maintained at 90° C for more than

one hour. As will be appreciated by one of ordinary skill in the art, any deleterious .
effects of heat accumulate with time. Therefore, when heat is applied, time and
temperature .will typically be balanced against one another.
The materials, methods, and examples presented herein are intended to be
illustrative, and. not to be .construed as limiting the scope or content of the invention.
Unless otherwise defined, all technical and scientific terms are intended to have
their art-recognized meanings^.
Examples^
A. Materials^
All the materials in the following examples are commercially available or can
be readily prepared.by one_skilledjn the art by known or readily available literature
methods^ The surfactants were used as supplied_with no additional purification or
dilution. Solvents of USP/NF grade or better were employed.
BfMethodsfe;
l.HPLCL.
The following HPLC method was used to measure modafinil content in the_
compositions: A lOmL serum bottle or 4mL screw cap vial containing the surfactant
solution saturated with modafinil was filtered through a 1.2 \xm syringe filter as
indicated.ia the sample preparations described hereinafter. lOuJL of the clear...
solution was dil.uted.to. lmL.with 990uJL of dimethylsulfoxide (Fischer Certified
ACS grade). 10u.L of the diluted solution was used for each injection in the HPLC
analysis for modafinil content in each mixture. The column conditions are listed
below.

Concentration was calculated by comparison to area from a modafinil

standard used at 0.4mg/mL with appropriate dilution. The results are shown in
Example 8, Table J. Each measurement of concentration was an average of two
injections.
2. H->0 Dispersion
To determine if a formulation would be suitable as a SEDDS, a 1:20 dilution
of each test formulation was prepared with water and timed for the formation of a
cloudiness or appearance of a precipitate. In most cases, the failure of the SEEDS
was noted by observing a coarse emulsion (as evidenced by cloudiness) or obvious
solid particle precipitation within about 10 minutes of mixing.
3. Method for Measurements of Blood Level in Rats Given Modafinil
Formulations
21 adult male Sprague-Dawley rats (body weight: 359±6 grams) were fasted
overnight prior to use. Each oral formulation was administered via oral gavage
(n=3/formulation). The dose of modafinil administered waslOO mg/kg using a dose
volume of 3.3 ml/kg. Blood was collected from the lateral tail vein at 0.25, 0.5,1, 2,
4 and 6 hours post dose. The blood was collected on wet ice and spun at
13,000RPMfor 10 minutes. The supernatant (plasma) was collected and frozen on
dry ice. Samples were stored at-70 °C until analysis. The blood serum levels of
modafinil in these experiments were measured by LC/MS, as shown in Example 9,
Table 2.
Example 1: Preparation of 90% PEG 400, 5% Span® 20, 5% Capmul® MCM
(w:w:w)
To 90 grams of PEG 400 were added 5 grams of Span® 20 and 5 grams of
Capmul® MCM with stirring until the solution was homogeneous. To a separate
container were added 0.1 gram of modafinil and 1 mL of the mixed
solvent/surfactant with stirring and heating to 55-60° C. The solution was allowed to
cool to room temperature and any undissolved solid was removed by filtering the
solution using a 1.2u.L syringe Filter.

Example 2;-Preparation of 90% PEG.400. 5% Span® 20. 5% Imwitor® 308 fw:w:\v)_.
A quantity of soiid Iinwiior 308 was melted and 5 grams were added to 90
grams of.PEG-400 and 5 grams of Span® 20 with stirring until the solution was
homogenous. To a separate container were added 0.1 gram of modafinil and 1 mL of
the mixed solvent/surfactant with stirring and heating to 55-60° C. The solution was
allowed to cool to room temperature. Since this mixture is semi-solid, gentle.,
warming to about 35-40° C was necessary before viscosity was low enough to allow
filtration to remove any undissolved modafinil by filtering the solution using a 1.2|iL.,
syringe filter.
Example^: Preparation of 90% PEG 400. 5% Span® 20. 5% Mvri®-52 (w:w:w)
A quantity of solid Myrj®-52 was melted and 5 grams were addedio_90
giaifurofTEG-400~a7Hf5~gTaTTrs of Span13 20 with stirring until the solution was .
homogenous; -To a separate-container were added 0.1 gram of modafinil and-1 mL of
the mixed.so! vent/surfactant with stirring and heating to 55-60° C. The solution-was-
allowed.to cool to room.temperature.. Since this mixture is semi-solid, gentle
warming to about 35-40 °C was necessary before viscosity was low enough to allow
filtration' to remove any undissolved modafinil by filtering the solution using a 1.2uL
syringe filter;"
Example4: Preparation of 70%PEG 400.15% Tween® 80.15% Labrasol® (w:w:w) .
To 70 grams of PEG-400 were added J 5 grams of Tween® SO (Polysorbate.
80) and 15 grams of Labrasol® with stirring until the solution was homogeneous. To
a separate container were added 0.1 gram of modafinil was weighed and 1 mL of the
mixed solvent/surfactant with stirring and heating to 55-60° C. The solution was
allowed to cool to room temperature and any undissolved solid was removed by
filtering the solution using a l.2pJL syringe filter.

Example 5: Preparation of 70% PEG 400,15%. Tween® 80. 15% Mvri®-52 (w:w:w)
A quantity of solid Myrj®-52 was melted and 15 grams were added to 70
grams of PEG-400 and 15 grams of Tween® 80 with stirring until the solution was
homogenous. To a separate container were added 0.1 gram of modafinil and 1 mL of
the mixed solvent/surfactant with stirring and heating to 55-60° C. The solution was
allowed to cool to room temperature:"-Since this mixture is semi-solid, gentle
warming to about 35-40° C was necessary before viscosity was low enough to allow
filtration to remove any undissolved modafinil by filtering the solution using a 1.2uX^
syringe filter. :■;.
Example-6:-Preparation-of 70%'PEG 400.15% Tween® 80.15% Capmul® MCM
(w:w:w)
To 70 grams of PEG-400 were added 15 grams of Tween®80 (Polysorbate
80) and 15 grams of Capmul® MCMwith stirring until the solution was
homogeneous. To a separate-.container were added 0.1 gram of modafinil and 1 mL
of the mixed solvent/surfactant with stilting and heating to 55-60° C. The solution
was allowed to cool to room temperature and any undissolved solid was removed by
filtering the solution using a 1.2uT, syringe filter.
Exampie.7: Preparation of 70% PEG 400,15% Tween® 80,15% Imwitor® 308,
fw:w:w)
A quantity of solid Imwitor®-308 was melted and 15 grams were added to 70
grams of PEG-400 and 15 grams of Tween® 80 with stirring until the solution was
homogenous. To a separate container were added 0.1 gram of modafinil and 1 mL of
the mixed solvent/surfactant with stirring and heating to 55-60°C. The solution was
allowed to cool to room temperature. Since this mixture is semi-solid, gentle
warming to about 35-40 °C was necessary before viscosity was low enough to allow
filtration to remove any undissolved modafinil by filtering the solution using a 1.2ui,
syringe filter.

Rxample-8: Solubility of Modafinil in Particle-forming Compositions
Tiio 6oluuility"of niudafriTil in the compositions of Examples 1-7, as measured
by HPLC, is shown below in Table 1.

Example^: BloocLSenujTi.Ijfcvels of Modafinil in Rats
The blood serum levels of modafinil in rats, upon administration of
compositions of Examples 1-7, is shown below in Table 2. The Oraplus
composition is intended to mimic the bioavailability of solid modafinil dosed in an
oral.fashion such as a tablet, but without the difficulty of administering a tablet to the
rat.- Oraplus® is an-oral suspending vehicle that is commercially available (Paddock
Laboratories, Minneapolis, MN), and is primarily composed of purified water,
microcrystalline cellulose, sodium carboxymethylcellulose, xanthan gum,
carrageenan, citric acid and sodium phosphate (as buffers), simethicone (antifoaming
agent), and potassium sorbate and methyl paraben (preservatives).


As those skilled in the artwill appreciate, numerous modifications and
variations of the present invention are possible in light of the above teachings. It is
thereforeiunderstoodihatvvithin the scope-of the appended claims, the invention may
be practiced otherwise than as specifically described herein, and the scope of the.
invention is intended to encompass all such variations.

WE CLAIM :
1. A method of preparing a composition of particles, wherein the
particles comprise a modafinil compound, comprising a contacting
particle-forming composition of modafinil with an aqueous
medium.
2. The method as claimed in claim 1, wherein the particle-forming
composition is contacted with an aqueous medium in vitro.
3. The method as claimed in claim 1, wherein the modafinil
compound is modafinil.
4. A method of preparing a composition of particles, wherein the
particles comprise a modafinil compound, comprising :

(a) dissolving a modafinil compound in a liquid comprising at
least one surfactant in an amount from about 1% to 50%, to
form a particle-forming composition; and
(b) contacting the particle-forming composition with an aqueous
medium to form the composition of particles.

5. A particle-forming composition as proposed by the method as
claimed in claim 1 comprising a modafinil compound, at least one
surfactant, and an organic solvent, characterized in that the
composition spontaneously forms a stable suspension of non-
crystalline particles comprising the modafinil compound when
contacted with an aqueous medium, wherein the non-crystalline
particles have a diameter of 1 to 1,000 nm.
6. An aqueous composition of non-crystalline particles as proposed
by the method as claimed in claim 4 comprising at least one
surfactant, an organic solvent, and a modafinil compound, wherein
the non-crystalline particles have a diameter of 1 to 1,000 nm, and
wherein the composition is liquid, homogeneous, stable,
translucent, and optically isotropic.
7. The composition as claimed in claim 5 or 6, wherein the
composition is pharmaceutically acceptable.
8. The composition as claimed in claim 5 or 6, wherein the surfactant
or surfactants comprise from 0.5% to 50% (w/w) of the
composition.
9. The composition as claimed in claim 5 or 6 wherein the surfactant or
.
surfactants comprise from 1% to 20% (w/w) of the composition.

10.The composition as claimed in claim 5 or 6, wherein the surfactant
or surfactants is a polyoxyethylene sorbitan fatty acid ester, a
polyethylene glycol ether, a saturated polyglycolized glyceride, a fatty
acid ester of polyethylene glycol, a medium chain monoglyceride, a
medium chain fatty acid ester,
d-α-tocopheryl polyethylene glycol succinate, a
polyethylene/propylene glycol copolymer, block copolymers of
ethylene oxide and propylene oxide, a polyoxyl stearate, an
ethoxylated castor oil, or an ethoxylated hydroxystearic acid.
11.The composition as claimed in claim 10, comprising a second
surfactant.
12.The composition as claimed in claim 11, wherein the second
surfactant is a polyoxyethylene sorbitan fatty acid ester.
13.The compostion as claimed in claim 12, wherein the second
surfactant is sorbitan monolaurate or Polysorbate 80.
14.The composition as claimed in claim 10, wherein the composition
comprises Polysorbate 80, glyceryl caprylate/caprate and a
mixture of glyceryl tricaprate and glyceryl tricaprilate.

15. The composition as claimed in claim 5 or 6, wherein the organic
solvent is glycerin, propylene glycol, diethylene glycol ethyl ether,
propylene carbonate, a medium chain length monoglyceride, or a
polyethyleneglycol.
16.The composition as claimed in claim 15, further comprising benzyl
alcohol, a-phenethyl alcohols or p-phenethyl alcohol.
17.The composition as claimed in claim 5 or 6, comprising one or
more unit doses of a modafinil compound.
18.The composition as claimed in claim 17, comprising one unit dose
of a modafinil compound.
19.The composiotion as claimed in claim 18, wherein the unit dose is
200 mg.
20.The composition as claimed in claim 18, wherein the unit dose is
100 mg.
21.The composition as claimed in claim 5 or 6, wherein the
composition is suitable for oral administration to a subject.

22. The composition as claimed in claim 21, wherein the composition
is encapsulated within a capsule.
23.The composition as claimed in claim 22, wherein the capsule is a
soft gelatin capsule.
24.The composition as claimed in claim 22, wherein the capsule is a
hard capsule.
25.The composition as claimed in claim 21, wherein the composition
is a syrup, elixir, or emulsion.
26.The composition as claimed in any of the preceding claims,
wherein the modafinil compound is modafinil.
27.The composition as claimed in claim 26, wherein modafinil is
present at a concentration of 1 to 500 mg/ml.
28.The composition as claimed in claim 27, wherein modafinil is
present at a concentration of 1 to 200 mg/ml.

29. The composition as claimed in claim 5 or 6, wherein a modafinil
compound is present at a concentration of 1 to 100 mg/ml a first
surfactant selected from a polyoxyethylene sorbitan fatty acid
ester, a polyethylene glycol ether, a saturated polyglycolized
glyceride, a fatty acid ester of a polyethylene glycol, a medium
chain monoglyceride, a medium chain fatty acid ester, d-α-
tocopheryl polyethylene glycol succinate, a polyethylene/propylene
glycol copolymer, block copolymers of ethylene oxide and
propylene oxide, a polyoxyl stearate, an ethoxylated castor oil, and
an ethoxylated hydroxystearic acid; a second surfactant selected
from a polyoxyethylene sorbitan fatty acid ester; and an organic
solvent selected from glycerin, propylene glycol, diethylene glycol
ethyl ether, propylene carbonate, a medium chain length
monoglyceride, or a polyethylene glycol.
30.The composition as claimed in claim 29, wherein the modafinil
compound is modafinil.
31.The composition as claimed in claim 30, wherein the first
surfactant is a saturated polyglycolized glyceride, a fatty acid ester
of a polyethylene glycol, or a medium chain monoglyceride; the
second surfactant is a polyoxyethylene sorbitan fatty acid ester;
and the organic solvent is a polyethyleneglycol.

32.The composition as claimed in claim 31, wherein the first
surfactant is glyceryl caprylate/caprate, glyceryl monocaprylate or
polyethoxylated (40) stearic acid; the second surfactant is sorbitan
monolaurate; and the organic solvent is PEG-300 or PEG-400.
34.The composition as claimed in claim 32,wherein the composition
comprises 90% PEG-400,5% sorbitan monolaurate, 5% glyceryl
caprylate/caprate (w/w/w).
35. The composition as claimed in claim 32, wherein the composition
comprises 90% PEG-400, 5% sorbitan monolaurate, 5% glyceryl
monocaprylate (w/w/w).
36.The composition as claimed in claim 32, wherein the composition
comprises 90% PEG-400, 5% sorbitan monolaurate, 5%
polyethoxylated (40) stearic acid (w/w/w).
37.The composition as claimed in claim 31, wherein the first
surfactant is glyceryl caprylate/caprate, glyceryl monocaprylate,
polyethoxylated (40) stearic acid or a mixture of polyoxyethylene
glyceryl caprylate and polyoxyethylene glyceryl caproate; the
second surfactant is polyoxyethylene (80) sorbitan monooleate;
and the organic solvent is PEG-300 or PEG400.

38.The composition as claimed in claim 36, wherein the composition
comprises 70% PEG-400, 15% polyoxyethylene (80) sorbitan
monooleate, 15% glyceryl caprylate/caprate (w/w/w)
39.The composition as claimed in claim 36, wherein the composition
comprises 70% PEG-400, 15% polyoxyethylene (80) sorbitan
monooleate, 15% polyethoxylated (40) stearic acid (w/w/w).
40.The composition as claimed in claim 36, wherein the composition
comprises 70% PEG-400, 15% polyoxyethylene (80) sorbitan
monooleate, 15% of a mixture of polyoxyethylene glyceryl
caprylate and polyoxyethylene glyceryl caproate (w/w/w).
41. The composition as claimed in any preceding claim, wherein the
modafinil compound is (-)benzhydrylsulfinyl-acetamide.
42. A composition as claimed in any of claims 5 to 41 for use as a
medicament.

43. The composition as claimed in claim 5 or 6, wherein the non-
crystalline particles have a diameter of 1 to 400 nm.
44. The composition as claimed in claim 5 or 6, wherein the non-
crystalline particles have a diameter of 1 to 100 nm.


A method of preparing a composition of particles, wherein the particles comprise a
modafinil compound, comprising a contacting particle-forming composition of
modafinil with an aqueous medium, and an aqueous composition comprising the
same.

Documents:

423-kolnp-2003-abstract.pdf

423-kolnp-2003-assignment-1.1.pdf

423-kolnp-2003-assignment.pdf

423-kolnp-2003-claims.pdf

423-kolnp-2003-correspondence-1.1.pdf

423-kolnp-2003-correspondence.pdf

423-kolnp-2003-description (complete).pdf

423-kolnp-2003-examination report-1.1.pdf

423-kolnp-2003-examination report.pdf

423-kolnp-2003-form 1.pdf

423-kolnp-2003-form 13-1.1.pdf

423-kolnp-2003-form 13.pdf

423-kolnp-2003-form 18-1.1.pdf

423-kolnp-2003-form 18.pdf

423-kolnp-2003-form 2.pdf

423-kolnp-2003-form 26.pdf

423-kolnp-2003-form 3-1.1.pdf

423-kolnp-2003-form 3.pdf

423-kolnp-2003-form 5-1.1.pdf

423-kolnp-2003-form 5.pdf

423-KOLNP-2003-FORM-27.pdf

423-kolnp-2003-granted-abstract-1.1.pdf

423-kolnp-2003-granted-abstract.pdf

423-kolnp-2003-granted-claims-1.1.pdf

423-kolnp-2003-granted-claims.pdf

423-kolnp-2003-granted-description (complete)-1.1.pdf

423-kolnp-2003-granted-description (complete).pdf

423-kolnp-2003-granted-drawings.pdf

423-kolnp-2003-granted-form 1.pdf

423-kolnp-2003-granted-form 2-1.1.pdf

423-kolnp-2003-granted-form 2.pdf

423-kolnp-2003-granted-specification-1.1.pdf

423-kolnp-2003-granted-specification.pdf

423-kolnp-2003-others.pdf

423-kolnp-2003-priority document.pdf

423-kolnp-2003-reply to examination report-1.1.pdf

423-kolnp-2003-reply to examination report.pdf

423-kolnp-2003-specification.pdf

423-kolnp-2003-translated copy of priority document.pdf


Patent Number 246771
Indian Patent Application Number 423/KOLNP/2003
PG Journal Number 11/2011
Publication Date 18-Mar-2011
Grant Date 15-Mar-2011
Date of Filing 08-Apr-2003
Name of Patentee CEPHALON INC
Applicant Address 145 BRANDY WINE PARKWAY, WEST CHESTER PA
Inventors:
# Inventor's Name Inventor's Address
1 JACOBS MARTIN J 1447 PATTERSON LANE, WEST CHESTER PA 19380
2 PATEL PIYUSH R 716 SCOTT LANE, WALLINGFORD, PA 19086
3 MCINTYRE BRADLEY T 3316 NORMA DRIVE, THORNDALE, PA 19372
PCT International Classification Number A61K 31/165
PCT International Application Number PCT/US2001/31904
PCT International Filing date 2001-10-11
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 09/640,824 2001-10-10 U.S.A.
2 60/239,490 2000-10-11 U.S.A.