Note: Descriptions are shown in the official language in which they were submitted.
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SUSTAINED-RELEASE FORMULATIONS FOR TREATING CNS
MEDIATED DISORDERS
FIELD OF THE INVENTION
This invention relates to the effective treatment of pathological
conditions, such as convulsions, bipolar affective disorder, migraine, anxiety
and spasticity, the symptoms of which are alleviated by a modulation of
activity in the central nervous system (CNS), without producing undesirable
excessive sedation or muscle weakness. More particularly, the invention
relates to the preparation and use of sustained-release formulations of
isovaleramide, isovaleric acid, and related compounds for treatment of
patients
suffering from such conditions.
BACKGROUND OF THE INVENTION
A number of pathological conditions are characterized by a profound
aberration in the normal function of the CNS. Such conditions include, for
example, epilepsy, stroke, bipolar affective disorder, migraine, anxiety,
spasticity, spinal cord injury, chronic neurodegenerative disorder and
diseases
such as Parkinson's disease, Huntington's disease, and Alzheimer's disease.
At the clinical level, these conditions usually respond only to pharmacologic
intervention with compounds or substances that possess significant activity at
the level of the CNS.
Isovaleramide, isovaleric acid and related compounds have been
described for treating abnormalities of the CNS, such as epilepsy. These
compounds provide a therapeutic approach by effecting a modulation of CNS
activity without producing excessive sedation, muscle weakness, fatigue,
teratogenicity or hepatotoxicity.
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It has been discovered herein that orally administered isovaleramide
has a short half life in humans. In the absence of an approach to reduce the
rate of uptake of drug following administration, the short half life requires
that
isovaleramide be administered frequently to sustain a therapeutic
concentration
of the drug without adverse effects. Frequent dosing schedules increase costs
and raise concerns of patient compliance. Thus, it would be desirable to have
a sustained-release formulation of isovaleramide, isovaleric acid and related
compounds that can be administered on a once or twice per day schedule for
the effective treatment of epilepsy and other pathological conditions of the
CNS.
SUMMARY OF THE INVENTION
Accordingly, it is an object of the present invention to provide a
composition comprising a sustained-release drug formulation for sustained
delivery of isovaleramide, isovaleric acid, and related compounds for the
treatment of various pathologies by effecting a modulation of CNS activity
without producing excessive sedation, muscle weakness, fatigue, teratogenicity
or hepatotoxicity. Such composition is useful for treatment of convulsions,
spasticity, affective mood disorder, neuropathic pain syndrome, migraine and
other headache pathologies, restlessness syndrome, movement disorder,
substance abuse/craving, cerebral trauma and anxiety-related disorders such as
restlessness, nervousness, inability to concentrate, over-aggressiveness,
irritability, and insomnia as well as symptoms of smoking cessation, treatment
of alcoholism and other substance abuse, premenstrual syndrome, menstrual
discomfort, and hyperexcitability in children.
In accomplishing these and other objectives, there has been provided,
according to one aspect of the present invention, a pharmaceutical composition
comprising a sustained-release formulation of isovaleric acid, isovaleramide
and related compounds. Upon oral administration, the sustained-release
formulation releases the active compound over a period of at least 8 to 12
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hours (h). With such a formulation, only two administrations of drug need to
be given each day.
In accordance with another embodiment of the present invention, the
sustained-release composition comprises a matrix, wherein the matrix comprises
a gelling agent that dissolves slowly and/or resists hydration. In one
embodiment, the gelling agent is xanthan gum. In another embodiment, the
active compound is dispersed in the matrix.
In accordance with another embodiment of the present invention, the
sustained-release composition comprises a film-coating that retards access of
liquids to the active compound and/or retards release of the active compound
through the film-coating.
In accordance with yet another embodiment of the present invention,
the sustained-release composition comprises one or more excipients that assist
in formulation.
In accordance with still another embodiment of the present invention,
the sustained-release composition comprises a core wherein the core comprises
a compressed mixture of the therapeutically effective unit dose of the active
compound and a matrix material, and a film-coating around the core. In another
embodiment, the matrix material dissolves slowly and/or resists hydration,
while in another embodiment, the matrix material is xanthan gum.
In accordance with another embodiment, the composition further
comprises one or more excipients to assist in formulation.
In accordance with yet another embodiment, the film coating comprises
a polymeric coating material. In a further embodiment, the polymeric material
comprises a mixture of ethyl cellulose and hydroxypropyl methylcellulose, and
in another embodiment, further comprises a plasticizer.
In accordance with still yet another embodiment, the sustained-release
composition is in the form of a tablet, capsule, or multiparticulate
composition.
In accordance with another aspect of the present invention, a process is
provided for producing the sustained-release formulations described above.
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In accordance with yet another aspect of the present invention; methods
are provided for treating CNS mediated pathologies and conditions by
administering the sustained-release compositions described above.
Other objects, features, and advantages of the present invention will
become apparent from the following detailed description. It should be
understood, however, that the detailed description and the specific examples,
while indicating preferred embodiments of the present invention, are given by
way of illustration only, since various changes and modifications within the
spirit and scope of the invention will become apparent to those skilled in the
art
from this detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
Figures la and 1b depict the structures of compounds, including
isovaleramide, capable of inducing a modulation of the central nervous system.
Figure 2 portrays a 24-hour dissolution profile of film-coated sustained-
release tablets containing 400 mg of isovaleramide (Formulation II, Example
2.1). Dissolution is performed in two stage media essentially as described in
Example 2.1 using simulated gastric fluid without enzymes (SGF) followed by
simulated intestinal fluid without enzymes (SIF). Dissolution in SGF and SIF
alone also is analyzed. Percent of drug released as determined by HPLC (%
label claim) is plotted on the Y axis versus time (hours) on the X axis. At 16
hours, over 75 % of the drug is released under the two stage analysis. Drug
release efficiency is greater in SIF as compared to SGF as shown by the
individual dissolution profiles.
Figure 3 portrays a 24-hour dissolution profile of film-coated sustained-
release tablets containing 600 mg of isovaleramide (Formulation III, Example
2.1). The dissolution assay and subsequent analysis is performed as described
in Example 3.1. At 16 hours, over 80 % of the drug is released under the two
stage media analysis. Drug release rate is similar for SIF and SGF as shown
by the individual dissolution profiles.
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Figure 4 portrays a 24-hour dissolution profile of film-coated
multiparticulate composition formulations containing isovaleramide (Example
2.2). The dissolution assay and subsequent analysis is performed as described
in Example 3.2.
Figure 5 portrays a 24-hour dissolution profile of the 6 % and 8 % film-
coated multiparticulate composition formulations containing isovaleramide. At
16 hours, approximately 80% of the drug is released. Drug release rate is
similar for SIF and SGF as shown by the individual dissolution profiles.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
1. OVERVIEW
Isovaleric acid and its pharmaceutically acceptable salts, amides such as
isovaleramide, alcohol esters and structurally related compounds effect a
modulation of CNS activity and are useful for treating epilepsy and a variety
of
other CNS disorders. As described below (Example 1), orally administered
isovaleramide is readily absorbed from the gastrointestinal tract and rapidly
eliminated in human subjects, exhibiting a half life of about 2.5 hours for
doses
ranging from 100 to 1600 mg. These characteristics are inconvenient for using
isovaleramide for oral treatment of CNS disorders because frequent dosing is
required to maintain a therapeutic drug level, which could create problems
with
patient compliance and costs.
In response to this need, the present invention provides sustained-
release compositions of isovaleramide and related compounds. The
formulations disclosed herein are designed to deliver a specific amount of
drug
over a specific course of time to achieve a therapeutic plasma drug
concentration, while minimizing peak to trough differences that occur in vivo.
This is achieved despite the fact that the drug is very water soluble.
"Sustained Release" as used herein, means the release of an active
compound whereby the level of active compound available to the host is
maintained at some level over a period of time. This is distinguished from
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"controlled release" which typically is broadly defined to include
instantaneous
release, delayed release and sustained release concepts. "Instantaneous
release" refers to immediate release to the biosystem of the host while
"delayed
release" means the active ingredient is not made available to the host until
some time delay after administration. Although the compositions of the present
invention are designed to achieve sustained release of the active compounds of
the composition, instantaneous release and delayed release properties also can
be designed into the instant compositions without departing from the spirit of
the invention.
2. PREPARATION OF SUSTAINED-RELEASE FORMULATIONS
Identification of active compounds
Active compounds for treating CNS disorders include isovaleric acid, a
pharmaceutically acceptable salt of isovaleric acid, a pharmaceutically
acceptable ester of isovaleric acid, a pharmaceutically acceptable amide of
isovaleric acid, and related compounds as described in WO 98/08498A1 and
U.S. application serial no. 09/258,882 (pending). As described therein,
isovaleric acid is available from extracts of the rhizomes and roots of
T~aleriana
spp. (common name: valerian; family Valerianaceae) and ammonium
isovalerate and isovaleramide are produced in ammoniated tinctures of the
extracts.
Generally, esters of isovaleric acid are expected to be hydrolyzed in
vivo by ubiquitous esterase enzymes, thereby releasing isovaleric acid and the
constituent alcohol. In addition to isovaleramide, various N-substituted
amides
of isovaleric acid also are described in WO 98/08498A1 and U.S. application
serial no. 09/258,882
Active compounds also include compounds structurally similarity to
isovaleramide and which share similar pharmacological activities. These
compounds generally share the common structure:
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H
B
AH2C X~Y/N~
Z
CH3
Where A = H, CH3 or OH,
B = H, OH, or CH3,
X = CHz, CHCH3, C(CHs)z, -O-, CH(OH)-, or -CHzO-,
Y = -CO-, or -SOz-, and
Z = H, CHzC02H, or CHzCONHz
The structures of these compounds are shown in Figures la and 1b and
include substituted isovaleramides such as 2-methylisovaleramide, 3-
methylisovaleramide, 2,2-dimethylisovaleramide, 2,3-dimethylisovaleramide,
4-methylisovaleramide, 2,4-dimethylisovaleramide, 3,4-dimethylisovaleramide,
2,2,4-trimethylisovaleramide, 3-hydroxyisovaleramide, 4-
hydroxyisovaleramide, 4-hydroxy-3-methyl-isovaleramide, 2-
hydroxyisovaleramide, and 2,2-dimethyl-n-butyramide. For each of these
compounds that contains one or more asymmetric centers, the present invention
specifically includes each of the possible enantiomeric or diastereomeric
forms
of the compound.
N,N Diethyl isovaleramide ("Valyl"), although purported to possess
CNS depressant (sedative) activity, recently has been shown to possess CNS
stimulant (convulsant) properties (U.S. patent No. 5,506,268 and PCT
application WO 94/28,888). An amide of isovaleric acid withp-aminophenol
also can be prepared using standard methods to provide a compound,
"isovaleraminophen, " which is related structurally to the drug acetaminophen
(Tylenol~). In a manner analogous to that of the isovalerate esters, these
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substituted amides should be hydrolyzed in vivo (in this case, via hepatic
amidase enzymes), releasing isovaleramide or isovaleric acid.
In addition to the amide compounds described above, the active
compounds useful in the sustained-release formulations of the present
invention, include the sulfonamide, sulfamate, and carbamate compounds of
isovaleric acid that, by virtue of their structural similarity to
isovaleramide,
share similar pharmacological activities. Preferred sulfonamides and
sulfamates include 2-methyl-1-propylsulfonamide, 1-methylethyl sulfamate,
and 2-methyl-1-propyl sulfamate. Preferred carbamates include
isobutylcarbamate (CHs)zCHCHzOCONHz) and isopropylcarbamate
(CHs)zCHOCONHz).
Preparation of active compounds
The compounds of the present invention may be prepared using
synthetic methods that are well known in the art. For example, many of the
carboxylic acid precursors of the amide compounds are commercially available
(e.g., Aldrich Chemical Co., Milwaukee, WI) and can be converted into the
corresponding amide by preparation of the acid chloride with thionyl chloride
or oxalyl chloride, followed by reaction with ammonia or an amine. For
compounds containing a hydroxyl group distal to the carboxyl group, the
hydroxyl group first is protected using a suitable protecting group as
described,
for example, in Green, "Protective Groups in Organic Synthesis," Wiley Press
(1981), prior to preparation of the acid chloride. 2-hydroxy and 3-hydroxy
isovaleramide are metabolites of isovaleramide in vivo, and can be isolated in
high yield from the urine of a patient being treated with isovaleramide.
For compounds where the starting acid is not commercially available,
the required acid can be prepared by straightforward methods of organic
synthesis known to the skilled chemist. For example, carboxylic acid esters
may be deprotonated with a strong non-nucleophilic base, such as lithium
diisopropylamide, followed by alkylation with methyl iodide or methyl
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trifluoromethanesulfonate. The alkylated ester is hydrolyzed and converted to
the amide by the methods described above.
When the compounds contain one or more asymmetric centers, the
individual enantiomers may be prepared from optically active starting
materials, or separated by traditional methods of resolution, such as
fractional
crystallization of salts with chiral amines, or by preparation of amides with
chiral amides, chromatographic separation, and hydrolysis of the amides.
Alternatively, the amides can be prepared by well known methods of
asymmetric synthesis, such as alkylation of an ester or amide of the acid
prepared using a chiral auxiliary. For example, see Evans et al., Tetrahedron,
44:5525 (1988), and Fadel et al., Asymmetry 1994:531.
The present invention thus contemplates a variety of pharmaceutical
compositions containing the active compounds described above (including
isovaleramide, isovaleric acid, and/or its pharmaceutically acceptable salts,
substituted amides, alcohol esters, sulfonamide, sulfamate, and carbamate
analogs) as active ingredients in a sustained-release formulation that is
suitable
for oral, IV, parenteral, transdermal, transmucosal, intranasal, buccal, or
rectal administration. Although such compounds may be present as incidental
by-products in certain pharmaceutical formulations which are outside the scope
of the present invention, the common feature of the present formulations is
that
isovaleramide, isovaleric acid, and/or its pharmaceutically acceptable salts,
substituted amides, alcohol esters, and sulfonate, sulfamate, and carbamate
analogs, are present in a standardized amount. That is, the pharmaceutical
formulations contain a predetermined, chemically-defined, and quantifiable
amount of at least one of such compounds to enable the determination of the
quantity of a particular composition required to achieve the dosage levels
described herein.
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Sustained-release compositions
The present invention provides sustained-release pharmaceutical
compositions comprising the active compounds described above. The
pharmaceutical compositions can contain a single active compound or a
combination of two or more of the active compounds. Also, isovaleramide
and/or related compounds can be used in combination with other
pharmaceutically active ingredients.
A "unit" of drug herein refers to an individual item containing drug,
such as a capsule or tablet. "Unit dose" denotes the amount of drug contained
in a unit of the drug. The term "dose" or "dosage" refers to the amount of
drug administered at a single point in time. For example, oral administration
of two units (e.g., tablets) at a single point in time, each having a unit
dose of
100 mg of drug, results in a drug dose of 200 mg. "Daily dose" means the
amount of drug administered over a one day (24-hour) period.
The sustained-release composition of the present invention can comprise
any unit dose of active compound, generally between about 100 to 1200 mg.
Preferable unit doses of 300 mg and 600 mg can be administered in a variety
of combinations to obtain doses of 300, 600, 900, 1200 and 1500, 1800, 2100,
and 2400 mg. Smaller unit doses can be produced for pediatric administration,
generally from about 50 to 300 mg in amount. A daily dose of drug could
range between about 100 to 4800 mg, but more typically, would range between
about 300 to 2400 mg.
The approach to determine drug treatment parameters, such as the total
daily dosage, unit dose and schedule of administration, is well known and
depends on a number of factors, including, for example, mode of
administration, safety, tolerability, effectiveness, bioavailability and
pharmacokinetic properties of the composition. Drug compositions with
sustained-release properties can initially be screened for resistance to
dissolution in an in vitro simulated gastric and intestinal environment
(Example
3). Promising sustained-release compositions are then tested in vivo for
safety,
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tolerability, effectiveness, bioavailability and pharmacokinetic properties
(Examples 1 and 3).
Sustained-release formulations are designed to achieve a stable serum
concentration of the drug over a convenient period of time (e.g., 12 hours)
even though the drug has a short half life. A stable drug level is achieved by
releasing drug into the system at a sustained rate that approximates its rate
of
clearance. The amount of drug in each dose of the formulation depends on
several factors including, for example, the effective therapeutic serum
concentration of the drug as well as the bioavailability and pharmacokinetic
properties of the drug in the sustained-release formulation. For example, the
amount of isovaleramide active compound represents about 40-70 % by weight
of a sustained-release tablet, with the remainder of the composition providing
sustained-release characteristics and/or assisting in formulation. Methods for
determining and evaluating these characteristics are well known in the art.
An extensive variety of sustained-release compositions and devices have
been described for sustained and controlled release of pharmaceutical
compositions. For example, see Baker, CONTROLLED RELEASE OF
BIOLOGICALLY ACTIVE AGENTS 73 (Whey-Interscience, 1987); Heller,
"Biodegradable Polymers in Controlled Drug Delivery," in 1 CRC CRITICAL
REVIEWS IN THERAPEUTIC DRUG CARRIER SYSTEMS 39-90 (1987); Dl COlO,
"Controlled Drug Release From Implantable Matrices Based On Hydrophobic
Polymers," Biomaterials 13: 850-56 (1992); CONTROLLED RELEASE
TECHNOLOGIES: METHODS, THEORY, AND APPLICATIONS, Agis F. Kydonieus,
ed. (CRC Press Inc., 1985). Many of the previously described approaches for
sustained-release formulations can be adapted for sustained release of the
active
compounds described herein. One skilled in the art can manipulate the
individual formulations to achieve a desired release rate of drug release in
both
in vitro and in vivo testing formats following the principles of sustained
drug
delivery discussed above. In addition, a variety of pharmaceutically
acceptable
carrier materials are known in the art (see, e.g., "Remington's Pharmaceutical
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Sciences," 18th ed., Gennaro, ed., Mack Publishing Company, Easton, Pa.,
1990; and "The Pharmacological Basis of Therapeutics," Goodman and
Gilman, eds., 8th Edition, Pergamon Press, 1990) and these can be included in
sustained release formulations of the present invention.
The sustained-release composition of the present invention can be
provided in solid unit form. It may be formed into any desired solid drug
unit,
including, for example, capsules, tablets, multiparticulate compositions,
caplets,
gelcaps, lozenges, suppositories, pessaries or implants.
The inventive compositions can be administered orally using solid oral
drug units such as, tablets, caplets, gelcaps, capsules, granules,
multiparticulate
compositions, or using a liquid-based drug unit. These compounds also can be
added to foods and beverages for oral administration, particularly in the case
of
drug granules which can be sprinkled on food. In addition, the sustained-
release compositions can be formulated in chewable form (e.g., chewing gum)
to facilitate oral delivery and absorption, particularly in pediatric
applications.
The inventive compositions also can be administered by injection or other
systemic routes, such as transdermal or transmucosal administration, for
example, nasally, buccally, or rectally, via suppositories. Oral
administration
is more convenient and, hence, is preferred.
Following oral administration, the sustained-release composition slowly
releases the pharmacologically active ingredient within the body as the
formulation progresses along the gastro-intestinal tract. In this regard, the
gastro-intestinal tract is considered to be the abdominal portion of the
alimentary canal, i.e. the lower end of the esophagus, the stomach and the
intestines.
A typical sustained-release formulation of the present invention
comprises the active compound and a matrix, where the matrix comprises a
gelling agent that swells upon contact with aqueous fluid. The drug entrapped
within the gel is released from the formulation slowly, upon dissolution of
the
gel, and then is available for uptake into the body at a sustained rate. The
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active compound can be evenly dispersed within the matrix or can be present
as pockets of drug in.the matrix. For example, the drug can be formulated into
small granules which are dispersed within the matrix. In addition, the
granules
of drug also can include a matrix, providing a primary and a secondary matrix,
as described in U.S. Patent No. 4,880,830.
The gelling agent and film forming/gelling polymers are preferably a
polymeric material, which can include, for example, any pharmaceutically
acceptable water soluble or water insoluble slow releasing polymer such as
xanthan gum, gelatin, cellulose ethers, gum Arabic, locust bean gum, guar
gum, carboxyvinyl polymer, agar, acacia gum, tragacanth, veegum, sodium
alginate or alginic acid, polyvinylpyrrolidone, polyvinyl alcohol, methyl
cellulose (MC), carboxymethyl cellulose (CMC), hydroxypropyl
methylcellulose, hydroxypropyl methyl cellulose (HPMC), hydroxypropyl
cellulose (HPC), hydroxyethyl cellulose (HEC), ethylcellulose (EC), acrylic
resins or mixtures of the above (e.g., U.S. Patent No. 5,415,871). A
particularly preferred polymer is xanthan gum.
The gelling agent of the matrix also can be a heterodisperse gum
comprising a heteropolysaccharide component and a homopolysaccharide
component which produces a fast-forming and rigid gel, as described, for
example, in U.S. Patent No. 5,399,359. The matrix also can include a
crosslinking agent such as a monovalent or multivalent metal cations to add
rigidity and decrease dissolution of the matrix, further slowing release of
drug
(id.). The amount of cross-linking agent to be added can be determined using
methods routine to the ordinary skilled artisan.
The choice of gelling agent depends upon the active compound and the
overall configuration of the sustained-release composition, although use
within
a range of 10 to 70 parts per 100 parts by weight of the active compound is
generally preferred. In the case of an oral sustained release formulation, the
amount of xanthan gum generally between 5 % to 20 % of the weight of the
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composition is preferred, an amount between 5 to 10 % is more preferred and
an amount of about 6 % is most preferred.
Although in some situations, the active compound and matrix can
together represent virtually a complete sustained-release formulation, in
general, additional components that are necessary to further retard release of
active compound or to assist in formulation (i.e., excipients) will be
required.
For example, in tablets and multiparticulate composition formulations
containing 400 mg isovaleramide, the amount of gelling agent and drug is
preferably about 30 to 70 % of the formulation, more preferably about 40-60 %
of the formulation and most preferably about 50 % of the formulation. In
tablets with unit drug doses of 600 mg, the amount of gelling agent and drug
is
preferably about 50-90 % of the formulation, more preferably about 65-75 % of
the formulation and, most preferably, about 72 % of the formulation.
In multiparticulate composition formulations with unit drug doses of
600 mg, the amount of gelling agent and drug is preferably about 40-85 % of
the formulation, more preferably about 50-70 % of the formulation and, most
preferably, about 60 % of the formulation.
The matrix of the sustained-release composition also can include one or
more pharmaceutically acceptable excipients recognized by those skilled in the
art, i.e. formulation excipients. Such excipients include, for example,
binders:
polyvinylpyrrolidone, gelatin, starch paste, microcrystalline cellulose (such
as
AVICEL PH 101~, available from FMC Pharmaceutical Division,
Philadelphia, PA); diluents (or fillers): starch, pregelatinized cornstarch
(such
as STARCH 1500~, available from Colorcon, West Point, PA.), sucrose,
dextrose, lactose, fructose, xylitol, sorbitol, sodium chloride, dextrins,
calcium
phosphate, calcium sulphate; and lubricants: stearic acid, magnesium stearate,
calcium stearate, Precirol (mixture of mono-, di- and triesters of palmitic
and
stearic acid with glycerol) and flow aids for example talc or colloidal
silicon
dioxide. Pregelatinized cornstarch, microcrystalline cellulose, and a mixture
of lactose and magnesium stearate are preferred as a formulation excipient.
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If necessary, such formulation excipients can be present in large
quantities, particularly where the composition comprises a small amount of
pharmacologically active ingredient. The relative amounts of excipient to drug
and gelling agent (and/or other matrix components) or excipient to gelling
agent depend on a number of factors. In general, with a unit drug dose of
about 400 mg, the amount of excipient relative to gelling agent (andlor other
matrix components) and drug in tablet formulations is preferably 30 to 60 % by
weight of the composition, more preferably about 30 to SO % by weight of the
composition, and most preferably about 39 % , by weight of the composition.
With unit drug doses of 600 mg, the amount of excipient relative to gelling
agent (and/or other matrix components) and drug is preferably about 10 to
30 % by weight of the composition, more preferably about 15 to 20 % by
weight of the composition, and most preferably about 16 % by weight of the
composition. Thus, a preferred range of excipient is about 16-39 % by weight
of the composition.
The matrix of the sustained-release composition of the present invention
can further include a hydrophobic material which slows hydration of the
gelling agent without disrupting the hydrophilic nature of the matrix, as
described in U.S. Patent No. 5,399,359. In certain preferred embodiments of
the present invention, the hydrophobic material is included in the matrix in
an
amount from about 1 to about 20 percent by weight and replaces a
corresponding amount of the formulation excipient. A solvent for the
hydrophobic material may be an aqueous or organic solvent, or mixtures
thereof.
The hydrophobic polymer can include, for example, a hydrophobic
cellulosic material such as alkylcellulose or ethylcellulose, polymers or
copolymers derived from acrylic or methacrylic acid esters, zero, waxes,
shellac, hydrogenated vegetable oils, waxes and waxy substances such as
carnauba wax, spermaceti wax, candellila wax, cocoa butter, cetosteryl
alcohol, beeswax, ceresin, paraffin, myristyl alcohol, stearyl alcohol,
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cetylalcohol and stearic acid. Other pharmaceutically acceptable hydrophobic
materials are known to those skilled in the art.
Examples of commercially available alkylcelluloses are AQUACOAT~
(aqueous dispersion of ethylcellulose available from FMC Pharmaceutical
Division, Philadelphia, PA) and SURELEASE~ (aqueous dispersion of
ethylcellulose available from Colorcon, West Point, PA). Examples of
commercially available acrylic polymers suitable for use as the hydrophobic
material include EUDRAGIT~ RS and RL (copolymers of acrylic and
methacrylic acid esters having a low content (e.g., 1:20 or 1:40) of
quaternary
ammonium compounds) (Rohm America Inc., Piscataway, NJ).
The sustained-release composition of the present invention also can
include a film-coating that surrounds the active compound or a combination of
the active with matrix to retard access of liquids to the active compound
and/or
retard release of the active compound through the film-coating. The film-
coating can provide characteristics of gastroresistance and enterosolubility
by
resisting rapid dissolution of the composition in the digestive tract. Such
film-
coating can comprise gels, waxes, fats, emulsifiers, combination of fats and
emulsifiers, polymers, starch, and the like.
Filin-coatings for sustain release compositions preferably comprises a
polymeric coating material such as a hydrophobic polymer, e.g.,
ethylcellulose, which is applied together with a plasticizer. The rate of drug
release is effected by adjusting the amount of film-coating applied, the
plasticizer type, the amount of plasticizer added, and by including release
modifying agents such as aqueous polymers to the coating formulation.
In a tablet composition of the present invention, the film-coating
generally represents about 5-15 % by weight of the sustained-release
composition. Preferably, the core by weight represents about between 88-91
(or about 90 % ) of the composition with the remaining 9 % to 12 % (or about
10%) provided by the coating.
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In a multiparticulate composition formulation of the present invention,
the film-coating generally represents about 1-10 % by weight of the sustained-
release composition. Preferably, the core by weight represents about between
92-96 % of the composition with the remaining 4 % to 8 % (or about 6 % )
provided by the coating.
Coating can be applied from a solution, suspension or as dry powder.
A solution formulation can be in organic solvent or aqueous solvent. Aqueous
solvent systems are preferred for general safety reasons. The active compound
can be coated, either alone or combined with a matrix. The coating preferably
is applied to the drug or drug and matrix combination as a solid core of
material as is well known in the art.
Polymers useful for coating compositions of the present invention
include a cellulosic derivative, for example, methylcellulose (METHOCEL~
A: Dow Chemical Co., Midland, Michigan), HPMC with a molecular weight
between 1,000 and 4,000,000 (METHOCEL~ E: Dow Chemical; or
PHARMACOAT~: Shin-Etsu Chemical Co., Tokyo, Japan), hydroxypropyl
cellulose with a molecular weight between 2,000 and 2,000,000, ethyl
cellulose, cellulose acetate, cellulose triacetate, cellulose acetate
butyrate,
cellulose acetate phthalate, cellulose acetate trimellitate (Eastman Kodak),
carboxymethylethyl cellulose (DUODCEL~: Lehmann & Voss, Hamburg,
Germany), HPMC phthalate, ethylcellulose, methylcellulose. Other polymers
useful in a coating composition include acrylic polymers such as
polymethacrylic acid-methacrylic acid copolymer (Type A 1:1 EUDRAGIT~
L100; Rohm Pharma Gmbh, Weiterstadt, Germany; Type B 1:2 EUDRAGIT~
5100; and Type C 1:1 EUDRAGIT~ L100-S5, aqueous dispersion 30%
solids, EUDRAGIT~ L30D), poly(meth)acryl ester: poly(ethyl acrylate,
methyl methacrylate 2:1), EUDRAGIT~ NE30D aqueous dispersion 30%
solids, polyaminomethacrylate EUDRAGIT~ E100,
poly(trimethylammonioethyl methacrylate chloride)ammoniomethacrylate
copolymer, EUDRAGIT~ RL30D and EUDRAGIT~ RS30D, as well as
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carboxyvinyl polymers, polyvinylalcohols, glucans scleroglucans, mannans,
and xanthans .
Aqueous polymeric dispersions useful for coating the present invention
include EUDRAGIT~ L30D and RS/RL30D, and NE30D, SURELEASE~
(Colorcon, Orpington Kent, United Kingdom) brand ethyl cellulose, EC brand
N-lOF ethyl cellulose, AQUATERIC~ (FMC, Philadelphia, PA) brand
cellulose acetate phthalate, COATERIC~ (Colorcon Inc., West Point, PA)
brand Polyvinyl acetate phthalate), and AQUACOAT~-brand hydroxypropyl
methylcellulose acetate succinate. Most of these dispersions are latex,
pseudolatex powder, or micronized powder mediums.
A plasticizing agent preferably is included in the coating to improve the
elasticity and the stability of the polymer film and to prevent changes in the
polymer permeability over prolonged storage. Suitable conventional
plasticizing agents include, for example, diethyl phthalate, glycerol
triacetate,
acetylated monoglycerides, acetyltributylcitrate, acetyltriethyl citrate,
castor
oil, citric acid esters, dibutyl phthalate, dibutyl sebacate, diethyloxalate,
diethyl
malate, diethylfumarate, diethylphthalate, diethylsuccinate, diethylmalonate,
diethyltartrate, dimethylphthalate, glycerin, glycerol, glyceryl triacetate,
glyceryltributyrate, mineral oil and lanolin alcohols, petrolatum and lanolin
alcohols, phthalic acid esters, polyethylene glycols, propylene glycol, rape
oil,
sesame oil, triacetin, tributyl citrate, triethyl citrate, and triethyl acetyl
citrate,
or a mixture of any two or more of the foregoing. Plasticizers which can be
used for aqueous coatings include, for example, propylene glycol, polyethylene
glycol (PEG 400), triacetin, polysorbate 80, triethyl citrate, diethyl d-
tartrate.
A coating solution comprising a mixture of HPMC and aqueous
ethylcellulose (e.g., AQUACOAT~ brand) as the polymer and dibutyl
sebacate as plasticizer is preferred for coating the tablet compositions of
the
present invention (AQUACOAT~ ECD is an aqueous dispersion of
ethylcellulose polymer comprising total solids (29-32 % ), ethylcellulose
(24.5-
29.5 % ) sodium lauryl sulfate (0.9-1.7 % ) cetyl alcohol ( 1.7-3.3 % ),
hydrogen
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peroxide ( < 50 ppm), heavy metals ( < 10 ppm), total aerobic microbial count
( < 100 cfu/g), total yeast and mold count ( < 20 cfu/g) with a pH of 4.0-7.0
and a viscosity of 150 cps). Preferably, the plasticizer represents about 1-2%
of the composition.
In addition to the polymers, the coating layer can include an excipient
to assist in formulation of the coating solution. Such excipients may include
a
lubricant or a wetting agent. Suitable lubricants as excipients for the film
coating include, for example, talc, calcium stearate, colloidal silicon
dioxide,
glycerin, magnesium stearate, mineral oil, polyethylene glycol, and zinc
stearate, aluminum stearate or a mixture of any two or more of the foregoing.
Suitable wetting agents include, for example, sodium lauryl sulfate, acacia,
benzalkonium chloride, cetomacrogol emulsifying wax, cetostearyl alcohol,
cetyl alcohol, cholesterol, diethanolamine, docusate sodium, sodium stearate,
emulsifying wax, glyceryl monostearate, hydroxypropyl cellulose, lanolin
alcohols, lecithin, mineral oil, onoethanolamine, poloxamer, polyoxyethylene
alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan
fatty acid esters, polyoxyethylene stearates, propylene glycol alginate,
sorbitan
esters, stearyl alcohol and triethanolamine, or a mixture of any two or more
of
the foregoing.
In another aspect of the present invention, the sustained-release
composition of the present invention comprises a semi-permeable wall
surrounding the active compound, the semi-permeable wall being permeable to
the passage of fluid but impermeable to the passage of said active compound.
The composition includes one or more exits through the semi-permeable wall
for sustained release of the active compound, in accordance with the method of
disclosed in U.S. Patent No. 5,674,895. In such cases, the active compound
can be placed inside the semi-permeable wall alone or as a sustained-release
formulation such as with a matrix and/or film-coating.
In another embodiment, an intact film coat with pores for releasing
drug through osmotic action can be produced as described in U.S. Patent
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No. 5,256,440. According to this approach, a sustained-release drug core is
coated with a film that comprises a detachable zone and a fixed zone, wherein
the detachable zone, when exposed to an environment of use, detaches from
the device to expose a portion of the surface of the compressed core beneath
the detachable zone of the film coating, and the fixed zone remains attached
to
the compressed core. The pores are produced by inscribing (i.e., intagliation)
one or more areas on the surface of a drug core prior to coating. An aqueous
dispersion of a polymeric coating, i.e., latex, is then applied to the
intagliated
dosage form core. When placed in an aqueous environment of use, the film
coating within the circumscribed region of the dosage form surface is
reproducibly detached, leaving a coated core tablet with a predefined discrete
portion of the core surface exposed to the environment of use.
In another approach, an intact film coat with pores can be formulated
by preparing a film coating where an insoluble polymer such as cellulose
acetate is mixed with a soluble material such urea or sucrose. Appel et al.,
Pharm. Res., 8:600 (1991). After coating, the soluble material becomes
detached from the film coat, leaving small pores for releasing drug. Rates of
release varying from 1 to 100 % can be achieved by varying the coating
thickness, pore-former level, and plasticizer type and concentration (id. ).
The compression tablet described above also can include multiple
layers, each compressed in succession (i.e., a multiple-compression tablet),
each layer having a discrete zone, e.g., one for rapid release and one for
delayed release, both of which combine to produce sustained release. See U.S.
Patent No. 4,996,061. Such tablets include a fully encased tablet with the
outer material completely surrounding the inner material, a layered tablet,
which is made up of two or more distinct layers or discrete zones of
granulation compressed together with the individual layers lying one on top of
another, and the inlay tablet, also referred to as a dot, or bull's-eye
tablet,
where one surface of the zone corresponding to an inner core zone is exposed
(id. ).
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To obtain the gastroresistance, cellulose, acetophthalate, cellulose
acetopropionate, cellulose trimellitate, acrylic and methacrylic polymers and
copolymers with different molecular weight and solubility dependent on
different pH values may be applied as a polymer coating. See U.S. Patent
No. 5,399,359. The materials may be applied on the finished pharmaceutical
form (core+external layer) by the classic film-coating process using solutions
in organic solvents or aqueous dispersions and operating by nebulization in
basin or in fluidized bed. The gastroresistant and enterosoluble materials may
also be used in association with retarding polymers.
A compressed core containing the active compound and a film-coating
around the core also can comprise a sugar coating containing a further dose of
active drug around the seal coated core as described in U.S. Patent No.
4,428,858. Sustained-release compositions of the present invention also can
comprise multiple compartments as described for capsules in U.S. Patent
No. 5,672,359. In a three compartment design, the outer compartment may
incorporate the active compound or an odoriferous agent and excipients into a
layer which coats and thus surrounds the intermediate component of the
capsule. This outer component represents the rapid or instantaneous release
portion of the delivery system. The intermediate compartment comprises a
powder formulation which represents the intermediate rate of release portion
of
the delivery system. The innermost compartment incorporates the active
compound in a slow release formulation as described above or as
multiparticulate form, such as small pellets which may be coated or uncoated.
Methods of preparation
A sustained-release composition according to the invention may be
formed into a solid dosage presentation according to conventional processes.
The pharmacologically active compound and matrix, together with other
optional pharmaceutically acceptable excipients, are mixed and then
compressed to produce a solid formulation (Example 2). In one such method
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the pharmacologically active compound is mixed with a minor proportion of
the matrix material of the present invention to form a dry mixture of powders.
The mixture is then granulated using a binder material in a solvent such as an
alcoholic solvent e.g. isopropyl alcohol or a mixture of a miscible organic
solvent and an aqueous solvent. The wet granular mass is then dried. Other
ingredients can then be added to the granules and compressed into tablets.
Alternatively, if the nature of the active compound permits, all the
ingredients
may be dry mixed, including excipients, to form a homogeneous blend which
is then compressed to give a tablet of the correct weight.
The solid formulations according to the invention should be compressed
to a sufficient hardness to prevent the premature ingress of the aqueous
medium into the core and prevention of surface pitting and breakage during
coating of the core. When the final product to be manufactured is tablets, the
complete mixture, in an amount sufficient to make a uniform batch of tablets,
is subjected to tableting in a conventional production scale tableting machine
at
an appropriate pressure. Typical compression forces are about 1,000 to about
8,000 pounds.
The application of specialized coatings can be by known methods such
as film coating in conventional pans or film coating in a fluidized bed
suspension coating apparatus. The conventional pan coating process involves
application of the coating as a film using the coating material in a solution
or
suspension, which is applied to the incipient beads while they are in constant
motion. Heat is generally applied to dry the coating.
The fluidized bed coating process involves the application of the coating
material in a solution or suspension using a spray nozzle to atomize the
coating
solution or suspension for application to the incipient beads, which are in
motion in the fluidized bed apparatus. Generally, in beads that are to be
coated, the incipient beads move up a column where the coating is applied and
are dried in an expansion chamber. If tablets are to be coated, the process is
the same, except that no column is used. This process is cyclic in nature,
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occurring repeatedly until the desired amount of coating is applied. For
example, see IZEMINGTON'S PHARMACEUTICAL SCIENCES, supra, and THE
THEORY AND PRACTICE OF INDUSTRIAL PHARMACY, Lackman, Liberman and
King, eds. (Lea and Febiger, Philadelphia, 1970).
Active Compound Dosage
The sustained-release compositions of the present invention are
administered in a "therapeutically effective amount" if the amount
administered
produces a physiologically significant effect. A physiologically significant
effect
results in a detectable change in the physiology of a recipient patient. In
the
present context, for example, a physiologically significant effect for an
antispasticity agent results in the alleviation of one or more symptoms of
spasticity, while the effect of an anticonvulsant agent is physiologically
significant
if the presence of the agent results in the reduction of the severity, number,
or
duration of convulsions. Similarly, for each of the pathologies recited above,
the
effect of a compound is physiologically significant if, upon administration to
a
patient, it can alleviate or reduce a clinically recognized symptom of that
pathology.
The indicated dosage of isovaleramide and related compounds in
treating CNS-effected disorders such as epilepsy or spasticity is on the order
of
50 to 2400 mg per dose or 1-40 mg/kg body weight. The precise dose depends
several factors including the nature and dose of the active compound, the
particular sustained-release formulation, and the potential for inter-subject
variability.
For use as an anti-convulsant, an effective concentration of
isovaleramide in the serum is expected to be about 5 to 15 p,g/ml with a
target
concentration of about 10 ~g/ml. Thus, for a 70 kg patient with a plasma
clearance of about 150 ml/h for isovaleramide (NPS 1776), a 1200 mg dose of
isovaleramide administered twice daily (2400 mg daily dose) should achieve
the target therapeutic steady state plasma concentration of about 10 pg/ml.
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The sustained-release formulations of the present invention provide a steady
rate of drug release for at least about 8 hours and more preferably for at
least
about 12 hours. However, drug release rates exceeding 12 hours also are
contemplated
In addition to use in humans, isovaleramide and related compounds can
be used to treat disorders of the CNS (e.g., convulsions, spasticity or
anxiety)
in animals such as cats, dogs, birds, horses, cattle, mink, poultry, and fish.
In
such cases the active compound may be administered by injection or other
systemic routes, such as transdermal or transmucosal administration (for
example, rectal administration via suppositories), or orally, including by
addition to food or drink. The indicated oral dosage of isovaleramide and/or
related compounds per kilogram of body weight for convulsions or spasticity in
non-human animals is about 50-1200 mg/kg, depending upon the species of
animal and the route of administration.
3. EXEMPLARY PATHOLOGIES AMELIORATED BY A
MODULATION OF CNS ACTIVIZ'y
A description of various CNS-related conditions and their treatment by
active compounds used in sustained-release formulations of the present
invention including, for example, epilepsy, spasticity, convulsive disorders,
affective mood disorders, neuropathic pain syndromes, headaches, restlessness
syndrome, movement disorders, have been described in WO 98/08498A1 and
U.S. application serial no. 09/258,882. CNS-related conditions and treatment
by the above active compounds also has been described previously for anxiety,
sedation and hypnotic activity in U.S. Patent No. 5,506,268. Additional
conditions for application of the sustained-release compositions of the
invention
include cerebral insult and neuroprotection and substance abuse/craving states
as described below.
CEREBRAL INSULT AND NEUROPROTECTION: Excitatory
neurotransmitters such as glutamate and aspartate, as well as a variety of
voltage-gated ion channels, are thought to play a central role in mediating
cell
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death after a variety of cerebral insults including, but not limited to,
ischemia,
trauma, seizure and hypoglycemia. Many studies have shown that compounds
or therapeutic strategies that decrease excitatory neurotransmission, for
example, glutamate antagonists, ion channel blockers, and the like, elicit a
S neuroprotective effect in animal models of cerebral insults.
Recent studies have shown that compounds such as GABAergic agents
(chlormethiazole, valproate or muscimol) that enhance inhibitory
neurotransmission, also can elicit a neuroprotective effect following the same
type of cerebral insults described above (Lyden, in "Neuroprotective Agents
and Cerebral Ischaemia," IRN 40, Academic Press Limited, Chapter 10,
(1997)). GABA and glycine are the primary inhibitory neurotransmitters in the
mammalian central nervous system and, therefore, it is expected that
enhancement of inhibitory neurotransmission via GABA or glycine agonists as
well as via other agents that have been shown to increase GABA or glycine
inhibitory neurotransmission (GABA/glycine re-uptake inhibitors,
GABA/glycine metabolic inhibitors, GABA/glycine synthesis enhancers,
GABA/glycine receptor modulators, etc.) also will produce a neuroprotective
effect. Studies have shown that the combination of the GABA agonist
muscimol and the glutamate antagonist, MK-801 appeared to confer an added
neuroprotective effect over either agent alone, although the effect was modest
(Lyden, supra, (1997)).
Kindling has been proposed as a model to search for drugs with
antiepileptogenic efficacy (Wada, Epilepsia, 19: 217-227, (1974); Sato et al.,
Epilepsy Res., 5: 117-124, (1990)); Silver et al., Ann. Neurol., 29: 356-363,
(1991)). The term "antiepileptogenic" refers to the idea of inhibiting the
processes that underly the development of epilepsy. "Anticonvulsant", on the
other hand, refers to the actual inhibition of seizures in an epileptic model.
Various anticonvulsants that have been shown to delay the acquisition
of seizures in animal models of kindling have been proposed to be
antiepileptic
versus anticonvulsant i.e., the compounds are neuroprotective and block the
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development of seizures rather than merely blocking the seizure once the
disorder is in place (White et al. , "Experimental Selection, Quantification,
and
Evaluation of Antiepileptic Drugs (99-110) in Antiepileptic Drugs, Fourth
Edition, R.H. Levy, R.H. Matson, and B.S. Meldrum, eds., Raven Press Ltd.,
Chapter 7, (1995)). Seizure kindling models are characterized by giving a sub-
seizure eliciting electrical or chemical stimulus (i.e., sub-threshold) over a
period of time (Goddard et al., Exp. Neurol., 25: 295-330, (1969)). The
majority of initially non-convulsive animals that are exposed to such stimuli
over a number of days, eventually exhibit seizure activity to these stimuli,
have
a permanently lowered threshold, exhibit altered manifestations of normal
behavior and, therefore, are considered "kindled. " The kindling phenomenon
has been proposed to underlie the development of disorders such as certain
types of epilepsy syndromes. Several kindling models of seizure development
have been characterized.
Compounds that have been shown to delay or block acquisitions of
seizures in these kindling models have been suggested to be a possible
effective
therapy following cerebral insults including, but not limited to, ischemia,
haemorrhagic stoke, trauma, infection, seizure and hypoglycemia that can lead
to an elevated incidence of seizure disorders ("The Epilepsies: Etiologies and
Prevention," Kotagal and Luders, Eds., (1999)).
SUBSTANCE ABUSElCRAVING: Anticonvulsants such as
carbamazepine, that have shown efficacy in kindled models of epilepsy, have
also demonstrated efficacy in reducing the symptoms of affective mood
disorders and substance abuse/craving in patients (Post, et al., Ann. N. Y.
Acad.
Sci., 537:292-308, (1988); Post, et al., Epilepsia, 25: 234-239, (1984); Post,
et al., Psychopharmacol., 72: 189-196, (1981); Halikas et al., Lancet,
8638:623-624 (1989); Blumer et al., Compr. Psychiatry, 29(2):108-22 (1988)).
Post et al., Biol. Psychiatry, 11(4):403-419 (1976) have demonstrated a
pharmacologic (chemical) kindling model employing subconvulsive doses of
cocaine as the stimulus. The progressive human response to high cocaine
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usage such as irritability, restlessness, hypervigilance, and paranoia may be
a
human equivalent of the kindling phenomenon observed in animals.
Several kindling models of seizure development have been
characterized. Seizure kindling models are characterized by administration of
a
sub-seizure eliciting electrical or chemical stimulus (i. e. , sub-threshold)
over a
period of time (Goddard et al., supra, (1969)). The majority of initially non-
convulsive animals that are exposed to such stimuli over a number of days
eventually exhibit seizure activity to these stimuli, have a permanently
lowered
threshold, exhibit altered manifestations of normal behavior and therefore are
considered "kindled. " A kindling phenomenon has been proposed to underlie
the development of disorders such as certain types of epilepsy syndromes,
substance abuse/craving and affective mood disorders such as bipolar (Post et
al., supra, (1981, 1984, and 1988); and Ballenger, et al., Br. J. Psychiatry,
133:1-14, (1978).
The pharmaceutical compositions of the invention display
anticonvulsant activity and efficacy in animal models of kindling and,
accordingly, the inventive pharmaceutical compositions should be useful in
treating conditions associated with substance abuse/craving.
4. DEMONSTRATING THERAPY-IMPLICATING ACTIVITY
The suitability and effectiveness of a given sustained-release
pharmaceutical formulation for the alleviation of a pathology, as discussed
above, can be demonstrated using animal models such as (but not limited to)
those described below.
(a) The Mutant Spastic Mouse
The mutant spastic mouse is a homozygous mouse that carries an
autosomal recessive trait of genetic spasticity due to a deficit of glycine
receptors throughout the central nervous system. This application of this
animal model to spasticity drug testing has been described previously in WO
98/08498A1.
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(b) The Acute/Chronic Spinally Transected Rat And The
Acute Decerebrate Rat
There are several models of spasticity including the acute decerebrate
rat, the acute or chronic spinally transected rat, and the chronically spinal
cord-
s lesioned rat. Wright, J., et al., Clin. Orthop., 253:12 (1990). These models
have also provided methods to test various treatment paradigms that have led
to
similar treatments being tested in humans and are described in greater detail
in
WO 98/08498A1.
(c) Primary Observation Irwin Test In The Rat
This method is based on that described by Irwin, Psychopharmacologia
13: 222-57 (1968). It is used to detect physiological, behavioral, and toxic
effects of a test substance, and indicates a range of dosages that can be used
for
later experiments. This method is described in greater detail in WO
98/08498A1.
(d) Rotarod Test In The Rat and Mouse
This is a test of neurological deficits using the method described by
Dunham et al. , J. Am. Pharm. Assoc. , 46: 208-209 (1957), involving
placement of rats or mice on rotating rod. This model is described in greater
detail in WO 98/08498A1.
(e) Anticonvulsant Activity
There are numerous in vivo models involving different kinds of seizures
and behavioral effects that are relevant for clinically distinct forms of
epilepsy.
These include , for example, the Frings audiogenic seizure-susceptible mouse
for reflex epilepsy, which has been described in greater detail in WO
98/08498A1.
(fj Anti-Manic Activity
The amphetamine-induced hyperactivity model in rats can be used to
assess the possible use of compounds in the treatment of affective mood
disorders. In addition to being a test for classical and atypical
antipsychotic
activity, this procedure has also been proposed as a simple animal model of
manic behavior. Costall et al. , Brain Res. , 123: 89-111 (1977).
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(g) Neurogenic Inflammation Of The Meninges
Neurogenic inflammation within the meninges has been proposed as an
event in the underlying pathology of migraine headaches. Lee et al. , Brit. J.
Pjtarmacol. , 116:1661-67 (1995). Compounds are tested for their ability to
block the leakage of radiolabeled bovine serum albumin within the dura mater
post trigeminal stimulation.
(h) Analgesic Properties
There are many whole-animal assays for determining analgesic
properties, such as writhing, hotplate, tail flick, arthritic pain, paw
pressure
tests, and the Bennet or Chung models of neuropathic pain. Albe-Fessard et
al., in ADVANCES IN PAIN RESEARCH AND THERAPY, Chapter 13, pages 11-27,
(Raven Press, 1990).
(i) Movement Disorders and Restlessness Syndromes
Animal models exist for the study of movement disorders and
restlessness syndromes, for example, drug-induced akathisias, serotonin
syndrome, rotation induced by unilateral nigral lesions (Lloyd et al. , Med.
Biol., 65(2-3):159-65 (1987)). Additionally, individual case reports of
anecdotal efficacy of compounds in humans have been a source for support for
these indications. Mellick et al., Am. J. Emerg. Med., 13(1):96 (1995); and
Olson et al. , Am. J. Med. , 102:60-66 (1997).
(j) Neuroprotection
Kindling has been proposed as a model that can be used to identify
drugs with antiepileptogenic efficacy (Wads, supra, (1974); Sato et al.,
suprai,
(1990); and Silver et al., supra, (1991). The term "antiepileptogenic" refers
to
the idea of inhibiting the processes that underly the development of epilepsy
thereby providing a "neuroprotective" effect. "Anticonvulsant," on the other
hand, refers to the acutal inhibition of seizures in an epileptic model.
Several
models of kindling are useful. The amygdala-kindled rat is such a model
(Tober, Eur. J. Pharmacol. , 15:163-169, (1996)). Seizure kindling models are
characterized by giving a sub-seizure eliciting electrical or chemical
stimulus
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(i.e., sub-threshold) over a period of time (Goddard et al., supra, (1969)).
The majority of initially non-convulsive animals that are exposed to such
stimuli over a number of days, eventually exhibit seizure activity to these
stimuli, have a permanently lowered threshold, exhibit altered manifestations
of normal behavior and therefore are considered "kindled."
Acute cerebral insults such as status epilepticus, traumatic injury and
stroke induce damage to selective neuronal populations in the hippocampus
(Matsuyama et al., J. Cereb. Blood Flow Metab., 13: 229-234, (1993)); and
Sloviter, Science, 235: 73-76, (1987)) suggesting that substances designed to
prevent the neuronal damage that occurs in a variety of human neurological
diseases would be therapeutically useful. In Jolkkonen et al. , Neuroreport,
7:
2031-2035, (1996) it was found that augmentation of GABAergic inhibition by
chronic infusion of the GABA transaminase inhibitor, vigabatrin, prevented the
delayed seizure-induced damage following kainate-induced status epilepticus.
Stroke in humans is a highly variable clinical condition, dependent upon
pre-existing disease in a patient, the site and severity of the stroke, the
type of
stroke (ischemic or hemorrhagic), and the time from onset to presentation for
treatment. A number of animal models of stroke have been developed over the
past several years to aid in our understanding of the pathophysiological
mechanisms of neuronal injury and to allow for the evaluation of potential
neuroprotective agents (Ginsberg et al., Stroke, 20: 1627-1642 (1989); and
Hunter et al., Trends. Pharmacol. Sci. 16:123-128 (1996)). A major goal of
these animal models has been to reduce the biological variability, by
controlling or eliminating the variables mentioned above, to facilitate data
analysis and interpretation. In doing so, however, these animal models do not
perfectly mimic the human condition.
(k) Substance Abuse/Craving
Kindling phenomenon has been proposed to underlie the development of
disorders such as epilepsy substance abuse/craving and affective mood
disorders such as bipolar (Post et al. 1981: Post et al. , 1984; Ballenger et
al. ,
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1978; Post et al., 1988). Anticonvulsants, such as cambamazepine, that have
shown efficacy in kindled models of epilepsy, have also demonstrated efficacy
in reducing the symptoms of affective mood disorders and substance
abuse/craving in patients (Post and Weiss, supra (1989), Halikas et al.,
supra,
(1989); and Blumer et al., supra, (1988)). Post et al., Biol. Psychiatry 11:
403-
419, (1976)) have demonstrated a pharmacologic (chemical) kindling model
employing subconvulsive doses of cocaine as the stimulus. The progressive
human response to high cocaine usage such as irritability, restlessness,
hypervigilance, and paranoia may be a human equivalent of the kindling
phenomenon observed in animals. Recently, the anticonvulsant drug,
vigabatrin, was proposed as a possible treatment for cocaine or nicotine
craving (Dewey, et al., Synapse, 31:76, (1999)).
**************************
The therapeutic effects of isovaleramide, isovaleric acid, and related
compounds, as illustrated in various of the assays described above , are
exploited to unexpected advantage in sustained-release formulations of the
present invention. These formulation can be used to treat the pathologies
described above, including, for example, spasticity, bipolar affective
disorder
and convulsions/seizures. With this background, the present invention will be
understood more readily by reference to the following examples, which are
provided for purposes of illustration and are not intended to be limiting of
the
invention.
Example 1
Pharmacokinetic Properties of Isovaleramide Orally Administered in Humans
Isovaleramide (NPS 1776) was orally administered in a double-blind,
placebo-controlled, ascending single dose study conducted in two groups of
healthy young male Caucasian subjects and one group of healthy young female
Caucasian subjects to investigate the safety, tolerability, pharmacodynamics
and pharmacokinetics of the drug. Various amounts of the drug were dissolved
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in 250 mL of a flavored soft drink (powdered soft drink diluted in mineral
water) and administered as an oral solution.
Safety and tolerability:
Isovaleramide was well tolerated following oral administration of 100 to
1600 mg to healthy male subjects. There were few drug-related adverse events
during the study, and all were mild in severity. The most common adverse
events were polyuria and headache. There were no dose-related trends in the
incidence or severity of adverse events, or any difference in the incidence or
severity of adverse events reported. Similar results were obtained in a 1200
mg dose level female group administered the drug for gender comparison. For
all dose levels, there were no clinically significant drug-or dose-related
changes
in vital signs (body temperature, supine and standing blood pressure and heart
rate), 12-lead ECG, clinical laboratory assessments or physical examination.
Pharmacokinetics:
Isovaleramide administered orally in the absence of a sustained-release
formulation was rapidly absorbed and rapidly eliminated in human subjects
(Table 1). Systemic exposure to the drug increased with increasing oral doses
from 100 to 1600 mg in male subjects. The increase in C~x and AUC was
slightly greater than proportional to the increase in the dose level. Values
for
t"~ax and t'/z did not markedly vary with the dose, while the plasma clearance
and volume of distribution decreased with increasing dose. Pharmacokinetic
parameters of NPS 1776 (1200 mg dose) in females were not markedly
different to those in males with the exception of t'/z, which was slightly
lower
in females (1.89 h) than in males (2.43 h).
Table l: Pharmacokinetic Parameters for Oral Isovaleramide in Male Humans
ParameterDose
of isovaleramide
100 mg 200 mg 400 mg 800 mg 1200 mg 1600 mg
C~* 1.51 3.32 6.84 16.4 27.9 39.3
(~g/mL) (1.30-1.76)(2.82-3.89)(6.37-7.34)(13.7-19.5)(23.3-33.1)(36.8-42.1)
t1/2$ 2.70 2.61 2.50 2.35 2.43 2.65
(h) (2.16-3.22)(1.93-3.25)(2.08-2.92)(2.13-2.96)(1.92-2.80)(2.12-3.36)
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CL/F~ 230 185 188 164 148 130
(mL/h) I (37.7) I (18.8) (29.8) l23 71 (~~ u) (17 5)
*Geometrtc mean (95 % confidence intervals)
~Arithmetic mean (SD)
$Harmonic mean (min-max)
The results show that isovaleramide has a short half life of about 2.5
hours in humans when orally administered in the absence of a sustained-release
formulation. For all doses, the maximum drug concentration was achieved in
less than one hour and typically in about 30 minutes following administration.
For a 2.5-hour half life, a single dose of drug results in about a 10-fold
change in the drug concentration in the blood over a 12-hour period. If one
assumes an effective target blood concentration of the drug of about 10
p.g/mL,
then administration of a 1200 mg dose of the drug falls below the effective
concentration at about 5 hours after administration. That is, 1200 mg results
in
an initial maximum blood concentration of about 27 mg (CmaX), which
decreases four fold - two half lives - to about 6-7 mg at five hours after
injection.
Thus, use of a sustained-release formulation could avoid having to
administer, say, a 1200 mg dose every 4 to 6 hours, in order to maintain a
therapeutic concentration of drug in the serum.
Exam In a 2
Preparation of Sustained-release Pharmaceutical Formulation of Isovaleramide
Example 2.1
This example describes the preparation of film coated tablets of
isovaleramide (NPS 1776) which were designed to release drug in a sustained
manner. The formulations were designed to deliver a specific amount of drug
over a specific course of time to achieve a specific plasma drug
concentration,
while minimizing peak to trough differences that occur in vivo. This was
achieved despite the fact that the tablet contains a very high drug load and
the
drug is very water soluble.
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Sustained release was achieved with two barriers. An outside barrier
is an ethyl cellulose/hydroxypropyl methyl cellulose film coat that retards
diffusion of water into the tablet core and acts as a barrier against drug
diffusion out from the inner core of the tablet. An inside barrier comprises
xanthan gum in the tablet core matrix, which hydrates and swells to form a
viscous gel
A. Manufacturing Procedure for dual barrier tablet
Preparation of the tablet core
1. Active drug (e.g., Isovaleramide; NPS 1776; Dread, Lawrence,
Kansas; cGMP grade) was dispersed by passage through a #30 mesh screen.
2. Drug, xanthan gum (e.g., XANTURAL~; Monsanto, St Louis,
Missouri; grade NF) and lactose (e.g. monohydrate form, spray dried,: Dread,
Palo Alto, CA; NF grade) were mixed into a 1-L glass jar and blended in a
Turbula mixer for four minutes at 96 rpm.
3. Magnesium stearate (e.g. Dread, Palo Alto, CA; NF grade) was
added and the mixture blended for one minute.
4. The final blend was compressed into caplets using 0.32-inch x 0.75-
inch x 0.060-inch tooling to a target weight of 800 mg and a target hardness
of
8 kP, and target thickness of 0.25 inch.
Coating of the tablet cores
1. Hydroxypropyl methylcellulose (HPMC; e.g., Dow Chemical Co.,
Midland, Michigan; NF grade) solution was prepared by adding HMPC slowly
to purified water heated to approximately 80°C. The solution was
allowed to
cool to room temperature by placing vessel in a cold water bath. Additional
water was added to prepare the final requisite amount of HPMC solution.
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2. AQUACOAT~ ECD /dibutyl sebecate mixture was prepared by
adding dibutyl sebacate (DBS: e.g., Morflex Inc., Greenboro, North Carolina;
NF grade) to AQUACOAT~ ECD (e.g., FMC Pharmaceutical Division,
Philadelphia, PA) while mixing. Mixing was continued for a minimum of 30
minutes.
3. The HPMC solution was added slowly to the AQUACOAT~
ECD/DBS mixture.
4. The core tablets were loaded into a coating apparatus (Vector LCDS
3 coater) fitted with a 1.3 liter coating pan and warmed until an outlet
temperature of 40°C was reached.
5. The tablets were spray coated until the planned theoretical weight
gain (based on core tablet weight) was achieved, however, after curing, the
actual coating solids applied were less than the theoretical value (e.g., 8%
or
% theoretical can be 5 % and 12 % coat, respectively after curing). Thus,
15 extra spray may need to be added to account for the loss upon curing.
Conditions for coating were as follows:
Inlet temperature 70C
Outlet temperature 40-43C
Spray rate 4-5g/min
Pan speed 14 rpm
Fluidizing air 30-40 scfm
Atomization air pressure26 psi
6. Spraying was stopped when the requisite amount of coating
suspension was applied. The tablets were dried for approximately 5 minutes in
the coating pan. The inlet temperature was adjusted during drying to keep
outlet temperature below 45°C.
7. The tablets were cured in an oven at 60°C for 18 hours.
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B. Composition Analysis Of Sustained-release Tablets
The composition of a variety of sustained release tablets are provided in
tables 7-9 below.
Table 7
Formulation Composition for a 5% Film-Coated Tablet Containing 400
Mg Isovaleramide (NPS 1776)
Component Tablet Batch (g) Percent
(mg) (% w/w)
Isovaleramide (NPS 1776) 400.0 200.0 47.6
Xantham Gum 56.0 28.0 6.7
Lactose Monohydrate, Spray-dried340.0 170.0 40.5
Magnesium Stereate 4.0 2.0 0.5
Core Tablet Total Weight 800.0 400.0 95.3
AQUACOAT~ ECD (solids wt. 24.41 24.42 2.9
)
Hydroxypropyl methylcellulose9.8 9.8 1.1
Dibutyl sebacate 5.8 5.8 0.7
Purified water3 (63.1 (63.1 ) N/A
)
Coated Tablet Total Weight 840.0 840.0 100.0
N/A = Not Applicable, I Solids content provided by 81. 3 mg of suspension,
2Solids content provided by 81.3 g of suspension, 3Removed during
processing.
25
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Table 8
Formulation Composition for a 12% Film-Coated Tablet Containing 400
Mg Isovaleramide (NPS 1776)
Component Tablet Batch (g) Percent
(mg) (% w/w)
Isovaleramide (NPS 1776) 400.0 200.0 44.6
Xantham Gum 56.0 28.0 6.3
Lactose Monohydrate, Spray-dried340.0 170.0 37.9
Magnesium Stereate 4.0 2.0 0.4
Core Tablet Total Weight 800.0 800.0 89.2
AQUACOAT~ ECD (solids wt.) 58.8' 58.52 6.5
Hydroxypropyl methylcellulose23.4 23.4 2.6
Dibutyl sebacate 14.1 14.1 1.6
Purified water3 (151.4) (151.4) N/A
Coated Tablet Total Weight 896.0 896.0 100.0%
N/A = Not Applicable, ' Solids content provided by 195.1 mg of suspension. ,
2Solids content provided by 195.1 g of suspension, 3Removed during
processing.
Table 9
Formulation II: Composition of a 9% Film-Coated Tablet Containing 400
Mg Isovaleramide
Component Tablet Batch Percent
(mg) (g) % w/w
Isovaleramide (NPS 1776) 400.0 400.0 45.5
Xanthan Gum 56.0 56.0 6.4
Lactose Monohydrate, Spray-dried340.0 340.0 38.6
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Magnesium Stearate 4.0 4.0 0.5
Core Tablet Total Weight 800.0 800.0 91.0
mg mg
AQUACOAT~ ECD (solids wt.) 48.81 48.82 5.5
Hydroxypropyl methylcellulose19.5 19.5 2.2
Dibutyl sebacate 11.7 11.7 1.3
Purified water3 (126.2) (126.2) N/A
Coated Tablet Total Weight 880.0 880.0 100.0%
mg g
N/A = Not Applicable, 1 Solids content provided by 162.6 mg of suspension,
ZSolids content provided by 162.6 g of suspension, 3Removed during
processing.
Table 10
Formulation III: Composition of a 12% Fihn-Coated Tablet Containing
600 Mg Isovaleramide
Component Tablet Percent
(mg) (% w/w)
NPS 1776 600.0 66.0
xanthan Gum 56.0 6.2
Lactose Monohydrate, Spray-dried140.0 15.4
Magnesium Stearate 4.0 0.4
Core Tablet Total Weight 800.0 gg,0
AQUACOAT~ ECD (solids wt.) 48.71 5.4
Hydroxypropyl methylcellulose 48.7 5.4
Dibutyl sebacate 11.7 1.2
Purified Water2 USP (213.6) N/A
Coated Tablet Total Weight 909.1 mg 100.0
N/A = Not Applicable, 1 Solids content provided by 162.4 mg of suspension,
2Removed during processing.
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Example 2.2
This example describes the preparation of multiparticulate compositions of
isovaleramide (NPS 1776) which were designed to release drug in a sustained
manner. These formulations were designed to deliver a specific amount of
drug over a specific course of time to achieve a specific plasma drug
concentration, while minimizing peak to trough differences that occur in vivo.
C. Manufacturing Procedure for Multiparticulate Compositions (MPC)
Preparation of the tablet core
1. NPS 1776 (200-300 gm) was mixed with microcrystalline cellulose
(AVICEL PH 101~) and pregelatinized cornstarch (STARCH 1500~)in a
small high shear mixer. Water was added such that small agglomerates were
formed.
2. The material was extruded through 1.7-mm holes with a small extruder.
The extrudate was spheronized with a maurumerizer (available from Luwa,
Charlotte NC) with a plate speed of 1,000 rpm. Beads were formed within 2
minutes and were tray dried in a 50 °C oven overnight.
3. One 700-gm batch of beads (approximately 60 % drug loading) was
prepared and coated. Materials were screened though an #8 mesh screen to
break up large lumps and added to a KGS~ high shear mixer (available from
Key International, Englishtown, NJ). The materials were mixed for 2 minutes
with an impeller speed of 200 rpm and chopper speed of 2,000 rpm. Water
was added at approximately 25 mL/minute and impeller speed was gradually
increased to 350 rpm. A total of 375 mL of water was added over 20 minutes.
The energy input increased from 36 watts to 460 watts. The material was
extruded and spheronized as above.
Coating of the tablet cores
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4. The beads were coated in a UNIGLATT~ coater (available from Glatt
Air Technologies, Ramsey, NJ) with a cellulose acetate butyrate solution.
Dissolution of multiparticulate compositions were performed using USP
Apparatus 1 (rotating basket) instead of USP Apparatus 2. Conditions for
coating were as follows:
Inlet air temperature 48-52°C
Outlet air temperature 42-44.°C
Spray rate lOg/min
Atomization air pressure 15 psi
Table 11
700 gram Batch Preparation for Multiparticulate Compositions (MPC)
Containing 420 gram Isovaleramide (NPS 1776) and Batch Preparation for
Film Coating Solution
MPC Components Batch (g)
Isovaleramide (NPS 1776) 420
AVICEL PH 101 224
STARCH 1500 56
MPC Total Weight 700
Coating Solution ComponentsBatch (g)
Cellulose Acetate Butyrate 63.0
Triethyl Citrate 18.9
Sucrose 22.0
Acetone' (1750 mL)
Ethanol' (350 mL)
Water' (350 mL)
Film Coat Total Weight 103.9
'Removed during processing.
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Table 12
Film Coated Multiparticulate Composition (MPC) Formulations
Containing Isovaleramide (NPS 1776)
Component 1% Film 4% FiLn 6% Film 8% Film
Coat Coat Coat Coat
(% w/w) (% w/w) (% w/w) (% w/w)
Isovaleramide (NPS 59.4 57.6 56.4 55.2
1776)
AVICEL PH 101 31.7 30.7 30 29.4
STARCH 1500 7.9 7.7 7.6 7.4
MPC Percent Total 99 96 94 92
Cellulose Acetate 0.61 2.44 3.66 4.88
Butyrate
Triethyl Citrate 0.18 0.72 1.08 1.44
Sucrose 0.21 0.84 1.26 1.68
Acetone' N/A N/A N/A N/A
Ethanol' N/A N/A N/A N/A
Water' N/A N/A N/A N/A
Coated MPC Total 707.1 729.2 744.7 760.9
Wt.
Coated MPC Total 100.0 100.0 100.0 100.0
%
Example 3
In Vitro Release and In Vivo Pharmacokinetic Analvsis of Sustained-release
Pharmaceutical Formulation of Isovaleramide
Example 3.1: Formulation I. Formulation II, and Formulation III
This example describes methods to evaluate the efficacy of sustained-
release formulations of isovaleramide (Formulation I, Formulation II, and
Formulation III) and related compounds. Sustained-release formulations were
tested in a standard, 24-hour dissolution assay essentially as described in
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UNITED STATES PHARMACOPEIA (USP), edition XXIV (Apparatus 2; United
States Pharmacopeia, 24, U.S. Pharmacopeial Convention, Inc., Rockville,
Md., pages 1941-1947 (2000)). Dissolution of drug was determined in
simulated gastric fluid (SGF) without enzymes or in simulated intestinal fluid
(SIF) without enzymes as described previously (id. , pages 2235-2236). A two-
stage media dissolution model, involving two-hour incubation in SGF followed
by 22-hour incubation in SIF (id. at 1947: entitled "Delayed-release (Enteric
Coated) Article- General Drug Release Standard"), was used to project in vivo
drug dissolution and to determine if a formulation has delayed release
properties. The amount of drug released into SGF or SIF was determined by
C18 reverse-phase high pressure liquid chromatography.
Sustained-release Formulation I was produced as a tablet with a single
barrier to retard drug release. Formulation I is the "core" tablet portion of
Formulation II, shown in Table 9. Thus, Formulation I contains 400 mg of
isovaleramide, xanthan gum and lactose. Oral administration of Formulation I
to humans resulted in a peak serum drug concentration of about 4 hours, which
is about four times that with isovaleramide itself (Example 1).
Sustained-release Formulation II, containing 400 mg isovaleramide,
was produced as a tablet with two barriers, to retard drug release as
described
in Example 2.1, Table 9. In the in vitro drug dissolution assays, Formulation
II showed significant delay in dissolution, with greater than 75 % of the drug
released into the medium after 16 hours in the two stage assay (Figure 3.1).
Pharmacokinetic analysis of Formulation I and II were performed in
two groups of eight human volunteers administered orally either one sustained-
release tablet (400 mg dose) or two tablets (800 mg dose). All 800 mg doses
and 6/8 of the 400 mg doses of Formulation II had peak serum concentrations
occurring between 8-12 hours post administration. This compares with a mean
peak concentration occurring at about 3 hours for Formulation I. Formulation
II was about 85 % orally bioavailable, while Formulation I was about 100
bioavailable.
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These results indicated that administering 1200 mg of isovaleramide
twice daily (2400 mg daily dose) as Formulation II, with dosing at 12-hour
intervals, achieves a target therapeutic steady-state plasma drug
concentration
of 10 ~g/ml. Inter-subject variability was higher than for individuals taking
Formulation I. Also, the dissolution rate of Formulation II in the in vitro
assay
was greater in SIF than SGF, indicating that dissolution probably is pH-
dependent for Formulation II. The variability observed in vivo may result
from variation in gastric residence times between individuals.
Formulation III differs from Formulation II in that the former has a
decreased ratio of AQUACOAT~ ECD to hydroxypropyl methylcellulose in
the coat. In the two-stage dissolution in vitro assay, over 80% of the drug in
Formulation III is released at 16 hours, with little apparent pH-dependency
(Figure 3.1: compare SGF with SIF). These results indicate that a therapeutic
steady-state plasma concentration of about 5 to 15 pg/ml (target of about 10
pg/ml) should be achieved in humans who receive two units of Formulation III
(i.e., a 1200 mg dose of isovaleramide) at about 12-hour intervals (2400 mg
daily dose). The reduction in pH dependency suggests that Formulation III has
improved inter-subject variability, relative to Formulation II.
Example 3 .2: Film Coated MPC Formulations' 1 % 4 % 6 % and 8 % MPC
Formulations
This example describes methods to evaluate the efficacy of the sustained
release, film coated multiparticulate composition formulations (1 % , 4 % , 6
% ,
and 8% Film Coated MPCs) of isovaleramide and related compounds.
Sustained-release, film coated multiparticulate composition formulations were
tested in a standard, 24-hour dissolution assay essentially as described in
UNITED STATES PHARMACOPEIA (USP), edition XXIV(Apparatus 1; United
States Pharmacopeia, 24, U.S. Pharmacopeial Convention, Inc., Rockville,
Md., pages 1941-1947 (2000)). Dissolution of drug was determined in
simulated gastric fluid without enzymes (SGF) or in simulated intestinal fluid
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without enzymes (SIF) as described previously (id. , pages 2053, 4082 and
4680). The amount of drug released into SGF or SIF was determined by C18
reverse-phase high pressure liquid chromatography.
The 1 % , 4 % , 6 % , and 8 % Film Coated MPCs demonstrated little
difference in drug release in SGF or SIF (Figure 4). The isovaleramide release
profile of the 6 % , and 8 % Film Coated MPCs were similar to the Formulation
II release profile of 80% isovaleramide released in 16 hours (Figure 5).
Although the foregoing refers to particular preferred embodiments, it
will be understood that the present invention is not so limited. It will occur
to
those of ordinary skill in the art that various modifications may be made to
the
disclosed embodiments and that such modifications are intended to be within
the scope of the present invention, which is defined by the claims below.
q._
