Note: Descriptions are shown in the official language in which they were submitted.
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METHODS AND COMPOSITIONS
EMPLOYING OPTICALLY PURE S(+) VIGABATRIN
5. 1. FIELD OF THE INVENTION
The invention relates to methods of prevention, treatment, and/or
management of peripheral neuropathy or the symptoms thereof, drug addiction or
the
symptoms thereof, and symptoms associated with drug withdrawal.
2. BACKGROUND OF THE INVENTION
Peripheral neuropathy ("PN") in general is a syndrome that can occur upon
the disease or damage of nervous tissue. It is characterized, alone or in
combination, by
sensory loss, muscle weakness and atrophy, decreased deep tendon reflexes, and
vasomotor
symptoms.
Peripheral neuropathies are classified as those that occur upon disease or
damage of a single nerve (mononeuropathy), upon disease or damage of two or
more nerves
in separate areas (multiple mononeuropathy), and upon disease or damage of
many nerves
simultaneously (polyneuropathy). lPeripheral neuropathies may also be
classified by the
general type of nerves) affected. for example, some neuropathies involve motor
fibers,
2 0 whereas others mainly affect sensory fibers (dorsal root ganglia) or
cranial nerves. Some
relatively common peripheral neuropathies have also been given specific names:
carpal
tunnel syndrome is one example; Guillain-Barre syndrome is another.
Carpal tunnel syndrome (CTS) is an affliction endured by millions.
Occurring most often in women, it is particularly associated with occupations
that require
repeated forceful wrist flexion, as well as with acromegaly, myxedema, and
fluid changes of
pregnancy. CTS results from compression of the median nerve in the volar
aspect of the
wrist between the longitudinal tendons of forearm muscles that flex the hand
and the
transverse superficial carpal ligament. This compression causes pain, sensory
deficit in the
palmar aspect of the first three digits, and/or weakness and atrophy in
muscles controlling
3 0 thumb movement. The Merck Manual, 16th ed., 1519 ( 1992).
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Guillain-Barre syndrome (GBS) is another specific kind of peripheral
neuropathy. GBS is an acute, usually rapidly progressive form of inflammatory
polyneuropathy characterized by rrmscular weakness and mild distal sensory
loss. It
typically occurs between about 5 days to 3 weeks after a banal infectious
disorder, surgery,
f~ or an immunization, and is thus believed to be caused by an autoimmune
reaction of some
kind. The most frequently identifiE;d cause of GBS is Campylobacter jejuni
infection.
Hughes, R. A. C., et al., J. Infect. L)iseases, 176(Suppl. 2):592-8 (1997).
The diseases and injuries that can lead to peripheral neuropathies generally
are numerous and varied. They include, but are not limited to: trauma caused
by injury or
surgical operation; tumors; bony hyperostosis; casts; crutches; prolonged
cramped postures;
hemorrhage into a nerve; exposure to cold or radiation; collagen-vascular
disorders;
metabolic diseases such as diabetes; infectious diseases such as Lyme disease
and HIV;
toxins such as emetine, hexobarbital, barbital, chlorobutanol, sulfonamides,
phenytoin,
nitrofurantoin, the vinca alkaloids, heavy metals, carbon monoxide,
triorthocresylphosphate,
orthodinitrophenol, and other solvents and industrial poisons; autoimmune
reactions;
nutritional deficiency and vitamin I3 deficiency in particular; and metabolic
disorders such
as hypothyroidism, porphyria, sarcoidosis, amyloidosis, uremia and diabetes.
The Merck
Manual, 16th ed., 1518 (1992).
The nature and effectiveness of conventional treatments of peripheral
2 0 neuropathy vary with the underlying disorder. For example, successful
renal transplantation
usually diminishes the uremic polyneuropathy that occurs in about half of
patients
undergoing dialysis. Pirzada, N. A., et al., Postgrad Med, 102:249-261 (1997).
Similarly,
immunologically mediated neuropathy may be treated with immunosuppression or
immunomodulation therapy. Openshaw, H., Biol. Blood and Marrow Trans., 3:202-
209
(1997). Because the etiology of peripheral neuropathy is often difficult to
determine,
however, its treatment is often slow and ineffective. See, e.g., Hughes, R. A.
C., et al., J.
Infect. Diseases, 176(Suppl 2):S92-.8 (1997). There is thus a need for a safe
and effective
treatment of peripheral neuropathy.
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Vigabatrin, chemically named 4-amino-5-hexanoic acid, is an irreversible
inhibitor of the gamma-aminobutyric acid-transaminase (GABA-T) enzyme. GABA-T
inactivates the inhibitory neurotransmitter 4-aminobutyric acid (GABA), which
acts at the
brain's GABA/benzodiazepine receptor to increase membrane conductance of
chloride ions,
5. stabilizing the membrane potential, and consequently dampening excitatory
input.
Meldrum, B.S., Brit. J. Clin. Pharm., 27:3S-l IS (1989). By inhibiting the
metabolism of
GABA, vigabatrin can increase GABA concentrations in the central nervous
system to
levels which suppress or diminish the intensity of a variety of seizures.
Because vigabatrin
is not degraded by the GABA-T enzyme, only new enzyme synthesis can restore
GABA-T
activity. Thus, even a single dose produces a lasting, dose-dependent
inhibition of brain
GABA-T in experimental animals, and elevated GABA levels are seen for at least
24 hours.
Shields, W. D., and Sankar, R., Sem. Ped. Neur., 4(1):43-50 (1997).
Although not yet approved for use in the United States, vigabatrin is
currently,used in other countries as an anti-epileptic agent. Shields, W. D.,
and Sankar, R.,
Sem. Ped. Neur., 4(1 ):43-50 ( 1997). It is commonly available as a racemic
mixture of the
R(-) and S(+) stereoisomers. Further, the S(+) stereoisomer is reported to be
active as a
GABA-T inhibitor, and in in viva animal studies of anti-convulsant activity.
Gram, L., et
al., Brit. J. Clinical Pharmacol., 27:135-185, (1989).
Thus, it is desired to find a compound with the advantages of vigabatrin for
the treatment of a variety of conditions and disorders, particularly in a
dosage form that is
convenient for administration to a patient, without any of the known
disadvantages of
vigabatrin.
3. SUMMARY OF THE INVENTION
The use of the optically pure S(+) stereoisomer of vigabatrin in treating
peripheral neuropathy, its symptoms, and conditions or disorders related
thereto is
encompassed by the present invention. Such conditions and disorders include,
but are not
limited to, carpal tunnel syndrome, Guillain-Barre syndrome, and other
peripheral
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neuropathv disorders such as those resulting from trauma caused by injury or
surgical
operation: tumors; bony hyperostosis; casts; crutches; prolonged cramped
postures;
hemorrhage into a nerve; exposure to cold or radiation; collagen-vascular
disorders;
metabolic diseases such as diabetes; infectious diseases such as Lyme disease
and HIV;
!i toxins such as emetine, hexobarbital, barbital, chlorobutanol,
sulfonamides, phenytoi.n,
nitrofurantoin, the vinca alkaloids, heavy metals, carbon monoxide,
triorthocresylphosphate,
orthodinitrophenol, and other solvents and industrial poisons; autoimmune
reactions;
nutritional deficiency and vitamin B deficiency in particular; and metabolic
disorders such
as hypothyoidism, porphyria, sarcoidosis, amyloidosis, uremia and diabetes.
1c1 This invention further encompasses a method of treating or preventing
peripheral neuropathy which comprises administering to a mammal, preferably a
human, in
need of such treatment a therapeutically effective amount of S(+) vigabatrin,
or a
pharmaceutically acceptable salt thereof, substantially free of its R(-)
stereoisomer.
In another embodirrAent, the invention encompasses a method of treating or
lEC preventing carpal tunnel syndrome which comprises administering to a
mammal, preferably
a human, in need of such treatment a therapeutically effective amount of S(+)
vigabatrin, or
a pharmaceutically acceptable Bait thereof, substantially free of its R(-)
stereoisomer.
This invention further encompasses a method of treating or preventing
Guillain-Barre syndrome which comprises administering to a mammal, preferably
a human,
2 Ci in need of such treatment a therapeutically effective amount of S(+)
vigabatrin, or a
pharmaceutically acceptable salt thereof substantially free of its R(-)
stereoisomer.
This invention also encompasses a method of preventing, treating, or
managing drug or alcohol addiction, or the symptoms thereof, which comprises
administering to a mammal, preferably a human, in need of such treatment a
therapeutically
2 f~ effective amount of S(+) vigabatrin, or a pharmaceutically acceptable
salt thereof,
substantially free of its R(-) stereoisomer.
The invention further encompasses a method of alleviating, treating, or
managing the pain and other symptoms associated with the termination of drug
use (f.e.,
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withdrawal conditions) which corr~prises administering to a mammal, preferably
a human,
in need of such treatment a therapeutically effective amount of S(+)
vigabatrin, or a
pharmaceutically acceptable salt thereof, substantially free of its R(-)
stereoisomer.
In another embodiment, this invention relates to a composition adapted for
!i the treatment of a mammal, preferably a human, suffering from peripheral
neuropathy
which comprises an amount of S(+) vigabatrin, or a pharmaceutically acceptable
salt or
solvate thereof, substantially free of its R{-) stereoisomer, said amount
being sufficient to
alleviate the symptoms of peripheral neuropathy.
This invention further encompasses a pharmaceutical composition
ll) employing S(+) vigabatrin, or a pharmaceutically acceptable salt thereof,
substantially free
of its R(-) stereoisomer, said composition being formulated for controlled-
release of the
active ingredients) therein. Preferably, the composition is adapted for the
prevention,
treatment, or management of peripheral neuropathy, drug addiction, and
alleviation of
withdrawal symptoms. This controlled-release formulation is particularly
useful within the
1!i methods described herein.
The invention encompasses single unit dosage forms of optically pure S(+)
vigabatrin, or a pharmaceutically acceptable salt thereof, substantially free
of its R{-)
stereoisomer, which comprises from about 0.01 g to 1 g of active ingredient in
a tablet,
capsule, or other single unit dosagf; form suitable for oral administration.
The single unit
2I) dosage forms of the invention may also be controlled-release forns as
described below.
4. DETAILED DESCRIPTION OF THE INVENTION
Unexpectedly, substantially optically pure S(+) vigabatrin, or a
pharmaceutically acceptable salt thereof, is effective in the prevention,
treatment,
2!i mitigation, and/or management of peripheral neuropathy ("PN'), alcohol and
drug addiction
or the symptoms thereof, or conditions associated with alcohol or drug
withdrawal. In
addition, optically pure S(+) vigabatrin can be used for the treatment,
prevention and/or
management of these disorders while reducing or avoiding adverse effects,
including
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undesirable side-effects associated with the administration of racemic
vigabatrin.
Therefore, in one aspect, the present invention relates to a method of
treating
peripheral neuropathy which comprises administering to a mammal a
therapeutically
effective amount of S(+) vigabatrin, or a pharmaceutically acceptable salt or
solvate thereof,
substantially free of its R(-) stereoisomer.
In another embodiment, this invention encompasses single unit dosage forms
of optically pure S(+) vigabatrin, or a pharmaceutically acceptable salt,
solvate, hydrate or
ciatherate, thereof, substantially fcec; of its R(-) stereoisomer, which
comprises from about
0.1 to about 1 g of active ingredient in a compressed tablet. This dosage form
is particularly
suitable for the treatment of peripheral neuropathies, such as carpal tunnel
syndrome and
Guillain-Barre syndrome, and addiction and withdrawal symptoms of alcohol and
drug use.
The methods and compositions of this invention include the benefit of
reducing or avoiding adverse effects associated with racemic vigabatrin. The
invention also
allows the concurrent or sequential use of conventional PN therapies, and
drugs such as
corticosteroids and antibiotics. The invention further allows the concurrent
or sequential
use of S(+) vigabatrin and anticonvulsants including, but not limited to,
felbamate,
gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, zonisamide,
carbamazepine,
phenobarbital, phenytoin, and valproic acid.
The pharmaceutical compositions of the present invention may also be
2 0 formulated to provide slow or controlled-release of the active ingredient
therein using, for
example, hydropropyimethyl cellulose in varying proportions to provide the
desired release
profile, other polymer matrices, gels, permeable membranes, osmotic systems,
multilayer
coatings, microparticles, liposomes, :microspheres, or the like, or a
combination thereof.
Suitable controlled-release formulations known to those of ordinary skill in
the art,
including those described herein, may be readily selected for use with the
S(+) vigabatrin
compositions of the invention. Thus, single unit dosage forms suitable for
oral
administration, such as tablets, capsules, gelcaps, and the like that are
adapted for
controlled-release, are encompassed 'by the present invention.
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All controlled-release pharmaceutical products have a common goal of
improving drug therapy over that achieved by their non-controlled
counterparts. Ideally, the
use of an optimally designed controlled-release preparation in medical
treatment is
characterized by a minimum of drug substance being employed to cure or control
the
condition in a minimum amount of time. Advantages of controlled-release
formulations
may include: 1 ) extended activity of the drug; 2) reduced dosage frequency;
and 3)
increased patient compliance.
Most controlled-release formulations are designed to initially release an
amount of drug that promptly produces the desired therapeutic effect, and
gradual and
continual release of other amounts of drug to maintain this level of
therapeutic effect over
an extended period of time. In order to maintain this constant level of drug
in the body, the
drug must be released from the dosage form at a rate that will replace the
amount of drug
being metabolized and excreted from the body.
The controlled-release of the active ingredient may be stimulated by various
1'5 inducers, for example pH, temperature, enzymes, water, or other
physiological conditions or
compounds. The term "controlled-release component" in the context of the
present
invention is defined herein as a compound or compounds, including polymers,
polymer
matrices, gels, permeable membranes, liposomes, microspheres, or the like, or
a
combination thereof, that facilitates the controlled-release of the active
ingredient (e.g., S(+)
2 iD vigabatrin) in the pharmaceutical composition.
The present invention further encompasses the use of S(+) vigabatrin in the
prevention and treatment of the symptoms associated with withdrawal from the
use of
central nervous system ("CNS") stimulants and depressants, such as alcohol and
sedatives,
and other drugs that act on the C'.NS which are not considered pure stimulants
or
2!5 depressants, such as barbiturates, psychedelic agents, and marijuana. One
embodiment of
the present invention relates to the administration of a therapeutically
effective amount of
S(+) vigabatrin, or a pharmaceutically acceptable salt thereof, substantially
free of its R(-)
stereoisomer to a mammal for the treatment of such withdrawal symptoms.
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The invention also encompasses the use of S(+) vigabatrin to prevent, treat,
or manage the development of physical dependence on drugs and alcohol. In one
embodiment, a therapeutically effective amount of S(+) vigabatrin, or a
phanmaceutically
acceptable salt thereof, substantially free of its R(-) stereoisomer, is
administered to a
patient for the treatment of one or :more such dependencies.
The present invention further encompasses the use of S(+) vigabatrin in
combination with standard detoxification methods to prevent or treat drug
withdrawal
symptoms in a mammal. In an embodiment of this invention, S(+) vigabatrin, or
a
pharmaceutically acceptable salt thereof, substantially free of its R(-)
stereoisomer, is
11) administered before, during, and/or after the detoxification methods.
Symptoms of drug
withdrawal include, but are not limited to, depression; pain; fever;
restlessness; lacrimation;
rhinorrhea; uncontrollable yawning; perspiration; piloerection; restless
sleep; mydriasis;
twitching and muscle spasms; severe aches in the back, abdomen and legs;
abdominal and
muscle cramps; hot and cold flashes; insomnia; nausea, vomiting, diarrhea;
coryza and
1!s severe sneezing; and increases in body temperature, blood pressure,
respiratory rate, and
heart rate (referred to hereinafter, either singly or in combination, as
"withdrawal
conditions", "withdrawal symptorr~s", "conditions associated with drug
withdrawal", or
"withdrawal").
The terms "withdrawal conditions", "withdrawal symptoms", "conditions
2 0 associated with drug withdrawal", and "withdrawal" as used herein, mean
the symptoms
and disorders, as listed above, that occur during withdrawal from any alcohol
or drug
addiction.
The present invention further encompasses the use of S(+) vigabatrin in
combination with standard detoxification methods to prevent or treat alcohol
withdrawal
2!5 symptoms in a mammal. In an embodiment of this invention, S(+) vigabatrin,
or a
pharmaceutically acceptable salt thereof, substantially free of its R(-)
stereoisomer, is
administered before, during, and/or after the detoxification methods. Heavy
consumers of
alcohol acquire a tolerance and a state of dependence to alcohol. Alcohol
withdrawal is not
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as severe as drug withdrawal, but includes many of the same symptoms. Symptoms
of
alcohol withdrawal include, but arc; not limited to, drug craving, tremors,
irntability, nausea,
sleep disturbance, tachycardia, hypertension, sweating, perceptual distortion,
and seizures.
Moreover, in combination with other health problems, such as malnutrition,
infection, or
electrolyte imbalance, the syndrome of delirium tremens becomes likely.
Delirium tremens
is characterized by severe agitation., confusion, visual hallucinations,
fever, profuse
sweating, tachycardia, nausea, diarrhea, and dilated pupils.
The present invention also encompasses the use of S(+) vigabatrin in
combination with other pharmacologically active compounds, such as
antidepressants,
preferably tricyclic antidepressants. Examples of antidepressant compounds
include, but
are not limited to, tricyclic antidepressants, such as amitriptyline,
clomipramine, doxepin,
imipramine, trimiprimane, amoxapine, desipramine, maprotiline, nortriptyline,
and
protryptiline; serotonin-reupake inhibitors, such as fluoxetine, fluvoxamine,
paroxetine,
sertraline, and venlafaxine; atypical antidepressants, such as bupropion,
nefazodone, and
15~ trazodone; and other monoamine o:xidase inhibitors, such as phenelzine,
tranylcypromine,
and selgiline, or an isomer of any of the above compounds, either singly or in
combination.
As used herein, the terms "adverse effects" and "adverse side effects"
include, but are not limited to, hyperactivity, agitation, drowsiness,
somnolence, fatigue,
dizziness, irritability, sedation, weight gain, increased appetite, insomnia,
nausea and
2 a~ vomiting, ataxia, decreased appetite, headache, vertigo, and psychosis.
The terms "pharmaceutically acceptable salts" or "a pharmaceutically
acceptable salt thereof ' refer to salty prepared from pharmaceutically
acceptable nontoxic
acids or bases, including inorganic acids and bases; organic acids and bases;
solvates;
hydrates; and clatherates thereof. Since the compound of the present invention
has both
25~ acidic and basic moieties, salts rnay be prepared from pharmaceutically
acceptable nontoxic
acids or bases. Examples of suitable inorganic bases include metallic salts
made from
aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc.
Appropriate organic
bases may be selected, for example, from N,N-dibenzylethylenediamine,
chloroprocaine,
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choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine),
lysine and
procaine. In another embodiment, S(+) vigabatrin is administered as the free
acid or free
base.
The term "racemic", as used herein, means a mixture of the S(+) and R(-)
!i stereoisomers of a compound wherein the S(+) and R(-) stereoisomers are
present in
approximately a 1:1 ratio.
The terms "substantially optically pure," "optically pure," and "optically
pure stereoisomers", as used herein, mean that the composition contains
greater than about
90% of the desired stereoisomer by weight, preferably greater than about 95%
of the desired
lt) stereoisomer by weight, and most preferably greater than about 99% of the
desired
stereoisomer by weight, said percent based upon the total weight of
vigabatrin. In other
words, the term "substantially free" means less than about 10 weight percent,
preferably
less than about 5 weight percent, and more preferably less than about 1 weight
percent of
the undesired stereoisomer.
l:i The term "peripheral neuropathy", as used herein, is defined as a disorder
characterized by sensory loss, muscle weakness and atrophy, decreased deep
tendon
reflexes, vasomotor symptoms or any combinations thereof resulting from damage
or
disease of at least one nerve. As used herein, the peripheral neuropathy
includes carpal
tunnel syndrome, Guillain-Barre s~mdrome, and related disorders.
2 0 The phrase "therapeutically effective amount of S(+) vigabatrin", as used
herein, means that amount of optically pure S(+) vigabatrin, or a
pharmaceutically
acceptable salt thereof, substantially free of its R(-) stereoisomer, which
provides a
therapeutic benefit in the treatment, management, or prevention of a
peripheral neuropathy,
alcohol addiction, drug addiction, alcohol withdrawal, drug withdrawal, or
related disorders.
2:~ Substantially pure S(+) vigabatrin may be obtained from a racemic mixture
of vigabatrin, the chemical synthesis of which can be performed by the methods
described
in U.S. Patent Nos. 3,960,927 and :1,380,936, the disclosures of which are
incorporated
herein by express reference thereto.
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The S(+) stereoisomer of vigabatrin may be obtained from its racemic
mixture by chiral separation, such as by gas chromatography, column
chromatography, or
HPLC. The S(+) stereoisomer of vigabatrin may also be obtained from its
racemic mixture
by resolution of the stereoisomers using conventional means such as from an
optically
active resolving acid. See, e.g., Jacques, J., et al., Enantiomers, Racemates
and Resolutions,
(Wiley-Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron
33:2725 (1977);
Eliel, E. L. Stereochemistrv of Carbon Compounds (McGraw-Hill, NY, 1962);
Wilen, S. H.
Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed.
Univ. of Notre
Dame Press, Notre Dame, IN, 1972). Furthermore, optically pure S(+) vigabatrin
can be
10~ prepared from the racemic mixture by enzymatic biocatalytic resolution.
See, e.g., U.S.
Patent No. 5,316,944, the disclosure of which is incorporated herein by
express reference
thereto.
In addition to separation techniques such as those described above, S(+)
vigabatrin can be synthesized by stereospecific synthesis using methodology
well known to
15 those skilled in the art. Chiral synthesis can result in products of high
enantiomeric purity.
However, in some cases, the enantiomeric purity of the product is not
sufficiently high. The
skilled artisan will appreciate that the separation methods described above
can be used to
further enhance the enantiomeric purity of S(+) vigabatrin obtained by chiral
synthesis.
The magnitude of a prophylactic or therapeutic dose of S(+) vigabatrin in the
2 0 acute or chronic management of peripheral neuropathy, drug addiction,
alcohol addiction,
drug withdrawal, and alcohol withdrawal, as described herein, will vary with
the severity of
the condition to be treated, and the route of administration. The dose, and
perhaps the dose
frequency, will also vary according to the age, body weight, and response of
the individual
patient. Suitable dosing regimens can be readily selected by those skilled in
the art with due
2 5 consideration of such factors. In general, the total daily dose range for
S(+) vigabatrin, for
the conditions described herein, is from about 0.01 g to about 4.5 g, in
single or divided
doses. Preferably, a daily dose range should be between about 0.05 g to about
4.0 g, in
single or divided doses, while most preferably, a daily dose range should be
between about
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0.1 g to about 3.0 g, in single or divided doses. The maximum daily dosage for
children is
preferably about 150 mg/kg. It is preferred that the doses for both adults and
children be
administered from one to four times daily.
In managing an adult patient, the therapy may be initiated at a lower dose,
e.g., preferably about 0.1 g to about 1 g per day, and increased by about 0.01
g per day up to
the recommended daily dose or higher depending on the patient's global
response. When
the methods of the present invention are used to treat children, a starting
daily dose of no
more than about 40 mg/kg is recommended. This may be increased at appropriate
intervals
up to the daily recommended dose. It is further recommended that patients over
65 years
initially receive low doses, and that their dose be titrated based on
individual responses)
and blood level(s). It may be necessary to use dosages outside these ranges in
some cases
as will be apparent to those skilled in the art. Further, it is noted that the
clinician or
treating physician will know how and when to interrupt, adjust, or terminate
therapy in
conjunction with individual patient response.
Any suitable route of administration may be employed for providing the
patient with an effective dosage of S(+) vigabatrin. For example, oral,
rectal, nasal,
parenteral (subcutaneous, intramuscular, intravenous), sublingual, buccal,
mucosal,
transdermal, and like forms of administration may be employed. Dosage forms
include
tablets, troches, lozenges, dispersions, suspensions, suppositories,
solutions, capsules, soft
2 0 elastic gelatin capsules, patches, and the like. In one aspect of the
present invention, orally
administered compositions of S(+) vigabatrin may be prepared in a controlled-
release
formulation.
The pharmaceutical compositions for use in the present invention comprise
optically pure S(+) vigabatrin as the active ingredient, or a pharmaceutically
acceptable salt
2 5 or solvate thereof, and may also contain a pharmaceutically acceptable
carrier, and
optionally, other therapeutic ingredients.
The compositions of the present invention can be prepared in the form of
suspensions, solutions and elixirs; aerosols; and can include carriers such as
starches,
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sugars, microcrystalline cellulose" diluents, granulating agents, lubricants,
binders,
disintegrating agents, and the like, in the case of oral solid preparations
(such as powders,
capsules, and tablets) with the oral solid preparations being preferred over
the oral liquid
preparations. A preferred oral solid preparation is capsules. The most
preferred oral solid
preparation is tablets.
Because of their ease of administration, tablets and capsules represent the
most advantageous oral dosage unit form, in which case solid pharmaceutical
carriers are
employed. If desired, tablets may be coated by standard aqueous or non-aqueous
techniques, and may be formulated for controlled-release using techniques well
known in
the art. Preferred controlled-release formulations are capsules and tablets.
Pharmaceutical compositions of the present invention suitable for oral
administration may be presented as discrete pharmaceutical unit dosage forms,
such as
capsules, cachets, soft elastic gelatin capsules, tablets, or aerosols sprays,
each containing a
predetermined amount of the active ingredient, as a powder or granules, or as
a solution or a
suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water
emulsion, or a water-
in-oil liquid emulsion. Such compositions may be prepared by any of the
methods of
pharmacy, but all methods include the step of bringing into association the
active ingredient
with the carrier which constitutes one or more necessary ingredients. In
general, the
compositions are prepared by unifbrmly and intimately admixing the active
ingredient with
2 0 liquid earners or finely divided solid carriers or both, and then, if
necessary, shaping the
product into the desired presentation.
For example, a tablet may be prepared by compression or molding,
optionally, with one or more accessory ingredients. Compressed tablets may be
prepared by
compressing in a suitable machine the active ingredient in a free-flowing form
such as
2.5 powder or granules, optionally mixed with one or more of a binder, filler,
lubricant, inert
diluent, or surface active or dispersing agent. Molded tablets may be made by
molding, in a
suitable machine, a mixture of the powdered compound moistened with an inert
liquid
diluent and optionally one or more; of a binder, filler, lubricant, inert
diluent, or surface
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active or dispersing agent.
Optically pure S(+) vigabatrin for use in the present invention may be
formulated as a pharmaceutical composition in a soft elastic gelatin capsule
unit dosage
form by using conventional methods well known in the art. See, e.g., Ebert,
Pharm. Tech,
!i 1 (5):44-50 ( 1977). Soft elastic gelatin capsules have a soft, globular
gelating shell
somewhat thicker than that of hard gelatin capsules, wherein a gelatin is
plasticized by the
addition of plasticizing agent, e.g., glycerin, sorbitol, or a similar polyol.
The hardness of
the capsule shell may be changed by varying the type of gelatin used and the
amounts of
plasticizer and water. The soft gelatin shells may contain a preservative,
such as methyl-
1I) and propylparabens and sorbic acid, to prevent the growth of fungi. The
active ingredient
may be dissolved or suspended in a liquid vehicle or carrier, such as
vegetable or mineral
oils, glycols such as polyethylene s,;lycol and propylene glycol,
triglycerides, surfactants
such as polysorbates, or a combination thereof.
Desirably, each unit dosage form, such as a tablet, capsule, cachet, or soft
1!s elastic gelatin capsule, contains from about 0.01 g to about 1 g of the
active ingredient, and
preferably from about 0.025 g to about 0.9 g of the active ingredient, and
more preferably
about 0.5 g to about 0.8 g of the active ingredient.
Optically pure S(+) vigabatrin for use in the present invention may also be
formulated for parenteral administration by injection (subcutaneous,
intramuscular, or
2 0 intravenous), and may be dispensed in a unit dosage form, such as a
multidose container or
an ampule. Compositions of S(+) vigabatrin for parenteral administration may
be in the
form of suspensions, solutions, emulsions, or the like in aqueous or oily
vehicles, and in
addition to the active ingredient may contain one or more formulary agents,
such as
dispersing agents, suspending agents, stabilizing agents, preservatives, and
the like.
2!i In addition to the common dosage forms set out above, the compounds of the
present invention may also be administered by controlled-release means and/or
delivery
devices such as those described in U.S. Patent Nos.: 3,845,770; 3,916,899;
3,536,809;
3,598,123; 4,008,719; 5,674,533; '1,059,595; 5,591,767; 5,120,548; 5,073,543;
5,639,476;
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5,354,556; and 5,733,566 the disclosures of which are incorporated herein by
express
reference thereto.
The controlled-release formulations of the present invention are capable of
releasing the S(+) vigabatrin at the required rate to maintain substantially
constant
pharmacological activity for a period of time sufficient to provide
therapeutic benefits. The
S(+) vigabatrin may be prepared in a variety of controlled-release
formulations, including,
but not limited to, controlled-release pharmaceutical compositions in liquid
dosage forns
(U.S. Patent No. 5,674,533); conta-olled-release of active agents by the use
of a gastro-
resistant tablet (U.S. Patent No. 5,059,595); a liquid reservoir transdermal
patch (iJ.S.
Patent No. 5,591,767); a controlled-release drug delivery device comprised of
swellable
polymers (U.S. Patent No. S,i20,548); controlled-release formulations
containing a trophic
factor entrapped by a ganglioside-liposome vehicle (U.S. Patent No.
5,073,543); a stable
solid controlled-release formulation having a coating derived from an aqueous
dispersion of
a hydrophobic acrylic polymer I;U..S. Patent No. 5,639,476); a controlled-
release powder
1!5 that contains the active ingredient (U.S. Patent No. 5,354,566); and
polymeric
microparticles that release antiparasitic compositions (U.S. Patent No.
5,733,566).
In one embodiment, the controlled-release component is biodegradable,
induced by exposure to the aqueous environment, pH, temperature, or enzymes in
the body.
In another embodiment, the controlled-release component may swell and
2 0 fore porous openings large enough to release S(+) vigabatrin after
administration to a
patient.
In another embodiment, controlled-release is achieved by the use of coated
beads or granules. A solution of S(+) vigabatrin in a non-aqueous solvent,
such as a
mixture of acetone and alcohol, is coated onto granules, such as small inert
seeds or beads,
2Ei made of a combination of sugar and starch. These granules may be coated
with a lipid
material, such as beeswax, or a cel';lulosic material, such as ethylcellulose.
The variation in
the thickness of the coats and the type of material used in the coating is
reflected by the
speed the bodily fluids are capable of penetrating the coating and dissolving
the S(+)
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vigabatrin. Preferably, various coating thicknesses of drug granules are
present to produce a
sustained and controlled-release of S(+) vigabatrin. In another embodiment, a
portion of the
drug granules is coated only with S(+) vigabatrin, while the remaining portion
of the drug
granules is coated with S(+) vigabatrin and the lipid material. The drug
granules without
the lipid material coating provide m initial dose of the drug, while the drug
granules coated
with the lipid material provide a controlled-release of S(+) vigabatrin.
In another embodiment, microencapsulation of S(+) vigabatrin is used in
controlled-release applications. Microscopic size particles can form thin
coatings of "wall"
material around S(+) vigabatrin. Wall-forming materials include, but are not
limited to,
gelatin and synthetic polymers, such as polyvinyl alcohol, ethylcellulose,
polyvinyl
chloride, or a mixture thereof. Preferably, an additive, such as acacia, is
used for its ability
to concentrate wall-forming material into tiny liquid droplets that form a
film or coat around
the drug or drugs to be encapsulated.
In another embodiment, sol-gels may be used, wherein S(+) vigabatrin is
incorporated into a sol-gel matrix that is a solid at room temperature. This
matrix is
implanted into a patient, preferably a mammal, and more preferably a human,
having a body
temperature high enough to induce l;el formation of the sol-gel matrix,
thereby releasing
S(+) vigabatrin into the patient.
In another embodiment, the drug may be embedded in an inert plastic matrix.
S(+) vigabatrin is granulated with an inert plastic material, such as
polyethylene, polyvinyl
acetate, polymethacrylate, or a mixture thereof, and the granulation is
compressed into
tablets. S(+) vigabatrin is slowly released from the inert plastic matrix by
leaching via
bodily fluids.
In another embodiment, repeat action formulations release two full doses of
S(+) vigabatrin sequentially. This method utilizes specialized tablets that
release an initial
dose of S(+) vigabatrin from the tablet shell, and a second dose is released
from an inner
core of the tablet, separated from the; outer shell by a slowly permeable
baffler coating.
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Moreover, any suitable method known to those of ordinary skill in the art for
formulating controlled-release dosage forms rnay be employed according to the
invention.
The invention is further defined by reference to the following examples,
describing in detail the preparation of the compound and the compositions of
the present
invention, as well as their utility. It will be apparent to those skilled in
the art that many
modifications, both to materials and methods, may be practiced without
departing from the
purpose and interest of this invention.
EXAMPLES
5.1 EXAMPLE 1: Potency and Specificity
The relative potency and specificity of optically pure S(+)vigabatrin, as
compared to R(-)vigabatrin and racemic vigabatrin, as a potent irreversible
inhibitor of
GABA-T may be determined by pharmacological study. As a consequence of this
enzyme's inhibition activity, the compounds will produce proportional
increases in
concentration ofthe inhibitory neurotransmitter GABA. The relative specificity
of the
compounds may be determined against cerebral neuronal and filial cell GABA-T.
Because transamination by GABA-T otherwise represents the significant
catabolic pathway of cerebral GABA, the irreversible inhibition of GABA-T by
S(+)
vigabatrin results in an elevation of brain GABA levels throughout the brain.
However,
2 0 filial GABA-T is less sensitive to S(+) vigabatrin, presumably for the
lack of an uptake
system for the drug into filial cells. Thus the drug may preferentially
influence amounts of
cerebral neuronal, synaptically-released GABA. Rogawski, M.A., et al., Pharm.
Rev.,
42(3):223-286 (1990); Jung, M.T, en al., J. Neurochem. 29:797-802 (1977);
Abdul-Ghani,
A.S., et al., Biochem. Pharm. 30:1203-1209 (1981); Larsson, O.M., et al.,
Neuropharm.
Z 5 25:617-625 ( 1986).
The test systems are based on tissue culture techniques with two distinct
cerebral cell types: a) cerebral neurons with characteristics of GABAergic
neurons derived
from cultured cerebral cortex of 15 clay mouse embryos, and b) astrocytes
obtained by
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culture of cortical tissue of newborn mice. See Gram, L., et al., Brit. J.
Clin. Pharm. 27,
(Suppl. 1):13S-18S (1989). Racetr~ic vigabatrin and its stereoisomers may be
incubated
with the tissue cultures of 10 minutes at 37°C, or alternatively the
compounds may be
present throughout the full incubation period with the cell cultures. As a
function of their
molar concentration, S(+)vigabatrin, R(-)vigabatrin and racemic vigabatrin may
be
compared for their ability to inhibivt both preparations of neuronal GABA-T
and glial cell
GABA-T. The drugs may be compared at the concentrations that inhibit by 50%
the
enzyme activity of the appropriate GABA-T (ICS°). Further, the
concentrations of the drugs
may be compared for their ability to increase both the cell content, and the
neurotransmitter,
GABA. (See aforementioned references, and Gram, L., et al., Brit. J. Clin.,
Pharm. 27,
(Suppl. 1):13S-18S (1989)).
5.2 EXAMPLE 2: Oral Formulation
Table 1: Compressed Tablets
1.i Formula Quantity
per
Tablet
in
mg
A B C D E
Active Ingredient S(+) 10.0 25.0 100.0 250.0 500.0
Vigabatrin
Lactose BP 57.0 42.0 67.0 I 17.0 117.0
Starch BP 20.0 20.0 20.0 20.0 20.0
2 Microcrystalline Cellulose10.0 10.0 10.0 10.0 10.0
0
Hydrogenate Vegetable 1.5 1.5 1.5 1.5 1.5
Oil
Polyvinylpyrrolidinone 1.5 1.5 1.5 1.5 1.5
Compressed Weight 100.0 100.0 200.0 400.0 650.0
The active ingredient, S(+) vigabatrin, is sieved through a suitable sieve and
blended with the lactose until a uniform blend is formed. Suitable volumes of
water are
added and the powders are granulated. After drying, the granules are then
screened and
blended with the remaining excipients. The resulting granules are then
compressed into
tablets of desired shape. Tablets of other strengths may be prepared by
altering the ratio of
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active ingredient to the excipient(s) or the compression weight.
S.3 EXAMPLE 3~ Controlled-Release Formulation- S(+) Vieabatrin Coated Beads
A suspension of S(+) vigabatrin and HPMC (Opadry'~Clear Y-5-7095) may
be applied onto 18/20 mesh Nupariel beads in a fluid bed dryer with a Wurster
insert at an
inlet temperature of 60°C. An Opadry~ Lavender YS-1-4729 HMPC Base
filmcoating
suspension is then applied after dmg loading as a protective coat at a 5%
weight gain.
After the overcoating process is complete, the S(+) vigabatrin beads are then
overcoated with a retardant coating mixture of Eudragit~ RS 30D and Eudragit~
RL 30D at
1.0 a ratio of 90:10, RS to RL, at a 5°,% weight gain level. The
application of this mixture of
Eudragit'~ RS 30D and Eudragit'~ RL 30D along with talc (included as an
antitacking agent)
and triethyl citrate (plasticizer) is done at an inlet temperature of
35°C in a Wurster insert.
The resulting S(+) vigabatrin beads are given a final overcoat of Opadry~
Lavender YS 1-4729 at a 5% weight gain level, and cured on paper-lined trays
in a 45°C dry
7.5 oven for 2 days. After the curing vprocess is complete, the S(+)
vigabatrin beads are filled
into gelatin capsules at 0.5 g SI+) vigabatrin strength. All Opadry'~ products
used in this
example and the following examples are available from Colorcon, West Point,
PA. All
Eudragit~ products used in this example and the following examples are
available from
Rohm Pharma. The final formula is provided in Table 2 below:
:! 0
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Table 2 - Final Formulation of ~+"),~ViQabatrin Gelatin Capsules
Processing Step~lngredient % mglCapsule
Drug Load S(+) Vigabatrin 60.3 S00
Nupariel F'G 18/20 30.8 2SS
Opadry'~ (:lear Y-S-70951.8 1 S
First Overcoat Opadry'~ i.avender 1.9 15.8
YS 1-4729
Retardant Eudragit~ RS 30D 1.7 14.2
Overcoat Eudragit~~ RL 30D 0.2 l.fi
Triethyl Citrate 0.4 3.2
iy Talc 0.8 6.3
Opadry~ Lavender YS 18
1- 2.1
4729
Total: 100 829.1
1.5
5.4 EXAMPLE 4' Controlled-Release Formulation .S(+) ViEabatrin and Acrylic
Polymer Coating
S(+) vigabatrin beads are prepared by dissolving S(+) vigabatrin in water,
2 0 adding Opadry~ ~'-S-1442, light pink and mixing for about 1 hour to obtain
a 20% w/w
suspension. This suspension is sprayed onto Nupareil 18/20 mesh beads using a
Wurster
insert.
The loaded S{+) vigabatrin beads are overcoated to form a protective coating
with a S% w/w gain of Opadry~' Light Pink using a Wurster insert. A retardant
coating is
25 then applied to the S(+) vigabatrin beads by coating them with a S% weight
gain of a
mixture of Eudragit~ RS 30D and Eudragit~ RL 30D at a ratio of 90:10, RS to
RL. The
addition of triethyl citrate (plasticizer) and talc (anti-tacking agent) is
also included in the
Eudragit suspension. A Wurster insert is used to apply the coating suspension.
After the retardant coating is applied, the S(+) vigabatrin beads are given a
3 0 final overcoat of Opadry~ Light Pink to a S% weight gain using a Wurster
insert, and cured
in a4S°C oven for two days. The cured beads are then filled into
gelatin capsules at a O.OS g
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S(+) vigabatrin strength. The complete formula is shown in Table 3 below:
Table 3 - Final Formulation of S(+ZVigabatrin Gelatin Capsules
Processing StepIngr~rdient % mglunit
!i Drug Loading S(+) vigabatrin35.3 50
Nupareil 18/20 52.2 74.0
Opadry~ Fight 1.4 2.0
Pink
First Overcoat Opadry~ Eight 3.0 4.2
Pink
Retardant CoatingEudragit~ RS 2.7 3.8
30D
Eudragit~ RL 0.3 0.4
30D
Triethyl Citrate0.6 0.8
Talc 1.2 1.7
Second OvercoatOpadry~ Light 3.4 4.8
Pink
'Total ~ 100 ~ 141.7
1 ~i
5.5 EXAMPLE 5: Preparation of Sl+1 Vi~gabatrin Microgranulate
A mixture of 80% (~w/w) S(+) vigabatrin, 10% (w/w) polyvinylpyrrolidone
(PVP K30), and 10% (w/w) 450-mesh lactose may be wetted with 500 mL water and
mixed
in a mixer-granulator for 10 minutE;s. A 5% (w/w) solution of polyethylene
glycol (PEG
6000) is added as an aqueous solution to the stirred mixture at a rate of 25
mL/min using a
0.8 mm nozzle at a pressure of 2 b~~rs. During the wetting step, the mixer
speed is 175 rpm
and the speed of the mill is 3000 rlrm. After wetting, the kneading and
rounding step is
done by maintaining mixer and mill speeds at a constant rate for 15 minutes.
The resulting
2:. microgranulate is dried in an artificial ventilation incubator and sieved
through a 225-
mesh/cm2 screen until a microgranulate with a granule size distribution
ranging from 90 ~m
and a spheroidal shape was obtained.
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5.6 EXAMPLE 6: Coating of Microgranulates
A. First Film Layer
Two kilograms of the microgranulate prepared in accordance with
Example 5 are stirred for 1 minute in a Glatt GPCG3 (Glad, GmbH, Buizen
Lorrach,
_°. Germany) fluidizer into which air_heated to a temperature of
40°C to 4S°C was blown at a
rate of 40 m'/hour. The granulate was sprayed at a pressure of 2 bars and a
rate of 10 to 13
g/min with 400 mL of a solution h<~ving the following weight percent
composition:
Cellulose acetate phthalate 4%
Diethyl phthalate 1
10i Acetone 71
Isopropyl alcohol 24%
B. Second Film Laver 'Waxes
A solution having the following weight percent composition was prepared:
15 Glyceryl monostearate 4.S%
White beeswax 0.4%
Cetyl alcohol O.OS%
Stearyl alcohol O.OS%
Chloroform 90.6%
2 Methanol 4.4%
0
1.1 S g of this solution may be applied to 2 kg of the microgranulate
previously coated with a first layer as described in Section A of Example 6.
The identical
operating conditions as in Section A of Example 6 are used in this case.
Additional layers
25 may optionally be coated on the beads as described in Section A of Example
6.
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5.7 EXAMPLE 7- Oral Liquid Formulation of S(+) Vigabatrin
A microgranulate, prepared as described in Example S and coated with three
successive layers as described in Example 6, may be added to a final
proportion of 12.5%
(w/w), to a mixture containing 6.2'% (w/w) microcrystalline cellulose, 0.8%
(w/w) sodium
carboxyrnethylcellulose, 0.5% (w/w) sodium citrate, 0.8% (w/w) citric acid,
0.2 % (w/w)
methylparaben. 0.05% (w/w) prop;ylparaben, 2% (w/w) tragacanth, 0.05% (w/w)
Span 20
surfactant, 0.2% (w/w) dimethylp0lysiloxane, 0.0 1% (w/w) glycamil, 0.25%
(w/w) orange-
grapefruit flavor, and powdered sugar to 140%. Adding 80 g water to 33 g of
this
suspension gives a suspension containing 30 mg/mL S(+) vigabatrin.
While the present invention has been described with respect to the particular
embodiments, it will be apparent t0 those skilled in the art that various
changes and
modifications may be made without departing from the spirit and scope of the
invention as
defined in the claims. Such modifications are also intended to fall within the
scope of the
appended claims.
1!S
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