Note: Descriptions are shown in the official language in which they were submitted.
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INTRAORALLY DISINTEGRATING VALDECOXIB COMPOSITIONS
PREPARED BY SPRAY DRYING PROCESS
FIELD OF THE INVENTION
The present invention relates to intraorally disintegrating pharmaceutical
compositions containing valdecoxib as an active ingredient, to processes for
preparing
such compositions, and to methods of treatment of cyclooxygenase-2 mediated
disorders comprising orally administering such compositions to a subject.
BACKGROUND OF THE INVENTION
The compound 4-(5-methyl-3-phenyl-4-isoxazolyl)benzenesulfonamide, also
referred to herein as valdecoxib, was disclosed in U.S. Patent No. 5,633,272
to Talley,
et al., herein incorporated by reference, together with processes for
preparing this and
related compounds. Valdecoxib has the structure:
(n
The compounds reported in above-cited U.S. Patent No. 5,633,272, including
valdecoxib, are disclosed therein as useful anti-inflammatory, analgesic and
antipyretic drugs having a high degree of selectivity for inhibition of
cyclooxygenase-
2 (COX-2) over cyclooxygenase-1 (COX-1). Above-cited U.S. Patent No. 5,633,272
also contains general references to formulations for the administration of
such
compounds, including orally deliverable dosage forms such as tablets and
capsules.
Valdecoxib has extremely low solubility in water. See for example Dionne
(1999), "COX-2 inhibitors - IBC Conference, 12-13 April 1999, Coronado, CA,
U.S.A.", Ids, 2(7), 664-666.
U.S. Patent No. 5,576,014, incorporated herein by reference, discloses an
intrabuccally dissolving compressed molding prepared by a wet granulation
process
wherein a low moldability saccharide is granulated with a high moldability
saccharide
to form a granulate, which is then compressed into a molding. The resulting
molding
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2
can incorporate a drug and is said to show quick disintegration and
dissolution in the
buccal cavity but to maintain sufficient hardness so as not break during
production
and distribution. The compressed molding of U.S. Patent No. 5,576,014 is a
type of
dosage form known as a "fast-melt tablet", exhibiting rapid disintegration,
usually
associated with the carrier materials, typically sugars, and concomitant rapid
dissolution or dispersion of the drug in the mouth, usually without need for
water
other than that contained in saliva. A drug formulated in such a tablet is
readily
swallowed.
Co-assigned International Patent Publication No. WO 01/41761 discloses
orally deliverable valdecoxib compositions having fast-onset properties. None
of the
compositions disclosed therein is an intraorally disintegrating composition.
A well-known problem with many intraorally disintegrating compositions,
even those containing sugars and/or sweetening and/or flavoring agents, is an
unpleasant taste resulting from the presence of an active drug therein.
Generally, as
the amount of active drug present in a particular intraorally disintegrating
dosage form
decreases, and/or as the aqueous solubility of a drug decreases, the less
bitter and/or
sour will be the taste of the dosage form. See for example Lieberman et al.
(1989),
Pharmaceutical Dosage Forms: Tablets Vol. l, pp. 381. Marcel Dekker, New York.
Valdecoxib, a drug with very low water solubility and with relatively low dose
requirements, would therefore be expected when formulated as an intraorally
disintegrating composition to have acceptable or, at worst, only moderately
unpleasant
organoleptic properties. Surprisingly, however, we have now discovered that
valdecoxib has an extremely unpleasant taste. Thus, there remains a need for
intraorally disintegrating valdecoxib compositions having acceptable
organoleptic
properties.
Taste-masking technologies which act by inhibiting oral dissolution of
moderately or highly water soluble drugs have been applied to pharmaceutical
dosage
forms. See for example Lieberman et al. (1989), op. cit. In such cases,
improved taste
is believed to result from a decrease in the amount of drug which dissolves in
the
mouth prior to entry into the gastrointestinal tract. Given the already
extremely low
aqueous solubility of valdecoxib, however, it was not expected that any
further
reduction in oral dissolution of valdecoxib would lead to improved
organoleptic
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properties. Further, it was expected that additional reduction in aqueous
solubility of
valdecoxib would result in unacceptable delay of therapeutic onset.
Surprisingly,
however, we have now discovered processes for preparing organoleptically
acceptable
intraorally disintegrating valdecoxib compositions, which compositions exhibit
improved organoleptic properties, yet which still exhibit rapid onset of
therapeutic
effect.
SUMMARY OF THE INVENTION
Accordingly, there is now provided a process for preparing an intraorally
disintegrating valdecoxib composition (e.g. a fast-melt tablet), the process
comprising
a step of providing valdecoxib in particulate form; a step of dissolving at
least one
pharmaceutically acceptable excipient which exhibits rapid oral dissolution in
water in
a vessel; a step of dispersing the valdecoxib in the water, and an optional
step of
heating the water. The dissolving, dispersing and optional heating steps are
performed in any order or simultaneously to result in a sprayable liquid. The
process
further comprises a step of spray drying the sprayable liquid to form a
tableting blend
and a step of compressing the tableting blend to form a tablet. In a process
of the
invention, the at least one pharmaceutically acceptable excipient which
exhibits rapid
oral dissolution is dissolved in the water in a total amount such that upon
completion
of the process, the at least one excipient which exhibits rapid oral
dissolution
comprises about 50% to about 99%, preferably about 50% to about 95% and more
preferably about 50% to about 90%, by weight, of the tablet.
The process optionally further comprises a step of adding to the vessel a
wetting agent or an aqueous solution of such wetting agent, prior to the spray
drying
step.
Compositions prepared by such a process represent an embodiment of the
present invention.
There is also now provided an intraorally disintegrating composition
comprising (a) particulate valdecoxib in a therapeutically effective amount,
and (b) at
least one pharmaceutically acceptable excipient which exhibits rapid oral
dissolution
which is in intimate association with the valdecoxib particles. The
composition is
organoleptically acceptable and the at least one pharmaceutically acceptable
excipient
which exhibits rapid oral dissolution is present in a total amount of about
50% to
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about 99%, preferably about 50% to about 95%, and more preferably about 50% to
about 90%, by weight of the composition.
An "intimate association" in the present context includes, for example,
valdecoxib admixed with the excipient which exhibits rapid oral dissolution,
valdecoxib embedded or incorporated in the excipient which exhibits rapid oral
dissolution, valdecoxib forming a coating on particles of the excipient which
exhibits
rapid oral dissolution or vice versa, and a substantially homogeneous
dispersion of
valdecoxib throughout the excipient which exhibits rapid oral dissolution.
Such an
intimate association is illustratively formed by processes disclosed
hereinabove;
alternatively or additionally, other means for forming such an intimate
association
may be employed in preparing compositions of the invention.
Valdecoxib in intimate association with an excipient which exhibits rapid oral
dissolution is also referred to herein as a "valdecoxib composite". The term
"substantially homogeneous" herein with reference to a composite or
pharmaceutical
composition that comprises multiple components means that the components are
sufficiently mixed such that individual components are not present as discrete
layers
and do not form concentration gradients within the composition. Without being
bound by theory, it is believed that the relatively high ratio of excipient
which exhibits
rapid oral dissolution to valdecoxib in processes and compositions of the
invention
and/or the intimate association of the valdecoxib with the excipient which
exhibits
rapid oral dissolution results in formation of a valdecoxib composite which
has
improved organoleptic properties.
A particularly useful intraorally disintegrating composition of the present
invention is a rapidly disintegrating oral dosage form that dissolves in the
mouth
without need for drinking water or other fluid (e.g. a fast-melt). The term
"fast-melt"
as used herein refers to a composition such as a tablet wherein an active
agent or drug
is distributed or dispersed in a matrix formed by a carrier that, upon oral
administration of the composition to a subject, disintegrates in the oral
cavity, thereby
releasing the drug, typically in particulate form, for entry to the
gastrointestinal tract
by swallowing, and subsequent absorption. The term "oral cavity" includes the
entire
interior of the mouth, including not only the buccal cavity (that part of the
oral cavity
anterior to the teeth and gums) but also the sublingual and supralingual
spaces.
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An "organoleptically acceptable" dosage form or a dosage form having
"acceptable organoleptic properties" herein is one that, upon intraoral
interaction in an
amount providing a single dose of the therapeutic agent, does not have an
excessively
unpleasant taste, smell or mouth feel, for example a pronouncedly bitter
taste, as
perceived by a majority of human subjects, or as determined by analysis of a
blind
taste evaluation study as is described hereinbelow.
Processes and compositions of the invention have been found to overcome the
unacceptable organoleptic properties of valdecoxib without unacceptably
sacrificing
rapid onset characteristics or therapeutic effectiveness. Thus, in a
significant advance
in the art, valdecoxib is now presented in an organoleptically acceptable fast-
melt
formulation. Particular advantages of compositions of the invention is that
they have
improved organoleptic properties, acceptable therapeutic onset
characteristics, and
such compositions can be efficiently prepared by processes described herein.
DETAILED DESCRIPTION OF THE INVENTION
A particular embodiment of the invention is an oral fast-melt composition
comprising (a) particulate valdecoxib in a therapeutically effective amount
and (b) at
least one pharmaceutically acceptable excipient which exhibits rapid oral
dissolution;
wherein the composition is organoleptically acceptable. The at least one
pharmaceutically acceptable excipient which exhibits rapid oral dissolution is
in
intimate association with the valdecoxib particles in the composition, and is
present in
a total amount of about 50% to about 99%, preferably about 50% to about 95%,
and
more preferably about 50% to about 90%, by weight.
A related embodiment of the invention provides an intraorally disintegrating
composition comprising (a) particulate valdecoxib in a therapeutically
effective
amount, and (b) at least one pharmaceutically acceptable excipient which
exhibits
rapid oral dissolution and which is in intimate association with said
valdecoxib
particles; wherein the composition is organoleptically acceptable; wherein the
at least
one pharmaceutically acceptable excipient which exhibits rapid oral
dissolution is
present in a total amount of about 50% to about 99%, by weight of the
composition;
and wherein the composition disintegrates within about 60 seconds, preferably
within
about 30 seconds, and more preferably within about 15 seconds, after placement
in the
oral cavity of a human subject.
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Another related embodiment of the invention provides an intraorally
disintegrating composition comprising (a) particulate valdecoxib in a
therapeutically
effective amount, and (b) at least one pharmaceutically acceptable excipient
which
exhibits rapid oral dissolution and which is in intimate association with said
valdecoxib particles; wherein the composition is organoleptically acceptable;
wherein
the at least one pharmaceutically acceptable excipient which exhibits rapid
oral
dissolution is present in a total amount of about 50% to about 99%, by weight
of the
composition; and wherein the composition, when placed in United States
Pharmacopeia 24 in vitro disintegration Test Number 701, exhibits a
disintegration
time of less than about 300 seconds, preferably less than about 200 seconds,
and more
preferably less than about 100 seconds.
Another embodiment of the invention provides an intraorally disintegrating
composition comprising (a) particulate valdecoxib in a therapeutically
effective
amount, and (b) at least one pharmaceutically acceptable excipient which
exhibits
rapid oral dissolution and which is in intimate association with said
valdecoxib
particles; wherein the composition is organoleptically acceptable; wherein the
at least
one pharmaceutically acceptable excipient which exhibits rapid oral
dissolution is
present in a total amount of about 50% to about 99%, by weight of the
composition;
and wherein administration of the composition to a human subject results in a
valdecoxib threshold concentration for therapeutic effect within about 0.5 h,
preferably within about 0.3 h, of oral administration.
By "a threshold concentration for therapeutic effect" is meant a minimum
concentration of valdecoxib in blood serum consistent with therapeutic benefit
for the
particular indication for which the valdecoxib is administered. Typically this
threshold concentration is at least about 20 ng/ml, for example about 25 ng/ml
to
about 75 ng/ml.
It will be understood that the amount of valdecoxib effective to provide a
threshold concentration for therapeutic effect is dependent, inter alia, on
the body
weight of the treated subject. Where the subject is a child or a small animal
(e.g., a
dog), for example, an amount of valdecoxib relatively low in the
therapeutically
effective range of about 1 mg to about 100 mg is likely to provide blood serum
concentrations consistent with threshold concentration and Cm~ criteria. Where
the
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subject is an adult human or a large animal (e.g., a horse), the indicated
blood serum
concentrations of valdecoxib are likely to require a relatively greater dosage
amount of
valdecoxib. For an adult human, a suitable amount of valdecoxib per dose in a
composition of the present invention to provide the indicated blood serum
concentrations is typically about 5 mg to about 40 mg.
A related embodiment of the invention provides an intraorally disintegrating
composition comprising (a) particulate valdecoxib in a therapeutically
effective
amount, and (b) at least one pharmaceutically acceptable excipient which
exhibits
rapid oral dissolution and which is intimate association with the valdecoxib
particles;
wherein the composition is organoleptically acceptable; wherein the at least
one
pharmaceutically acceptable excipient which exhibits rapid oral dissolution is
present
in a total amount of about 50% to about 99%, by weight of the composition; and
wherein administration of the composition to a human subject results in a
maximum
blood serum concentration (CI"~) not less than about 100 ng/ml.
Another related embodiment of the invention provides an intraorally
disintegrating composition comprising (a) particulate valdecoxib in a
therapeutically
effective amount, and (b) at least one pharmaceutically acceptable excipient
which
exhibits rapid oral dissolution and which is intimate association with the
valdecoxib
particles; wherein the composition is organoleptically acceptable; wherein the
at least
one pharmaceutically acceptable excipient which exhibits rapid oral
dissolution is
present in a total amount of about 50% to about 99%, by weight of the
composition;
and wherein administration of the composition to a human subject results in a
time to
reach maximum blood serum concentration (Tm~) not greater than about S h,
preferably not greater than about 4 h, and more preferably not greater than
about 3 h.
Ingredients of compositions of the invention
A composition of the invention comprises valdecoxib as active ingredient and
at least one pharmaceutically acceptable excipient which exhibits rapid oral
dissolution. Optionally, a composition of the invention can contain one or
more
additional pharmaceutically acceptable excipients including, but not limited
to, water-
soluble lubricants, water-insoluble lubricants, disintegrants, glidants,
sweeteners,
flavoring agents, colorants, etc. Such optional additional components should
be
physically and chemically compatible with the other ingredients of the
composition
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and must not be deleterious to the recipient.
Valdecoxib
Processes and compositions of the invention are particularly suitable for
valdecoxib as the active drug. Processes for preparing particulate valdecoxib
are
known per se, for example as is described in above-cited U.S. Patent No.
5,474,995,
incorporated herein by reference. Importantly, any solid state form of
valdecoxib,
illustratively that described in International Patent Publication No.
98/06708,
incorporated herein by reference, can be used in processes and compositions of
the
invention.
A valdecoxib dosage unit of the invention comprises valdecoxib in a
therapeutically effective amount of about 1 mg to about 100 mg, preferably
about 5
mg to about 50 mg. Compositions of the invention contain valdecoxib in
particulate
form. Primary valdecoxib particles, generated for example by milling or
grinding, or
by precipitation from solution, can agglomerate to form secondary aggregate
particles.
The term "particle size" as used herein refers to size, in the longest
dimension, of
primary particles, unless the context demands otherwise. Particle size is
believed to
be an important parameter affecting clinical effectiveness of valdecoxib.
Thus, in one
embodiment, a valdecoxib dosage form has a distribution of valdecoxib particle
sizes
such that the Duo particle size is less than about 75 ~,m. The "D~o particle
size" is
defined herein as a particle size such that 90% by weight of the particles are
smaller,
in their longest dimension, than that particle size.
In addition or alternatively, valdecoxib particles in a dosage form of the
invention
preferably have a weight average particle size of about 1 ~,m to about 10 Vim,
most
preferably about 5 ~n to about 7 ~,m.
Excipients which exhibit rapid oral dissolution
Suitable excipients which exhibit rapid oral dissolution are those
pharmaceutically acceptable excipients which are soluble, freely soluble, or
very
soluble in water, for example as described in Ansel et al. ( 1995)
Pharmaceutical
Dosage Forms and Drug Delivery S sty_ ems 6th Ed, pp. 228. Williams & Wilkins,
Baltimore. Preferably, such excipients have a sweet taste. A presently
preferred class
of excipients which exhibit rapid oral dissolution for use in compositions and
processes of the invention are carbohydrates. Particularly preferred
excipients which
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exhibit rapid oral dissolution are saccharides including both low moldability
and high
moldability saccharides.
Presently preferred low moldability saccharides include lactose and mannitol,
particularly mannitol in its non-direct compression or powder form as
described in
Kibbe (2000) Handbook of Pharmaceutical Excipients, 3rd Ed., Pharmaceutical
Press,
pp. 324-328. Presently preferred high moldability saccharides include maltose,
maltitol and sorbitol. Alternatively, certain oligosaccharides can be useful.
The
oligosaccharide used is not particularly limited so long as it shows rapid
dissolution in
the oral cavity and consists of two or more monosaccharide residues. Where an
oligosaccharide is used, one consisting of 2 to 6 monosaccharide residues is
preferable, and the type and combination of monosaccharide residues
constituting the
oligosaccharide are not limited. Particularly preferred high moldability
saccharides
are maltose and maltitol, more particularly maltose.
Where both a high moldability saccharide and low moldability saccharide are
present in a composition of the invention, the weight ratio of high
moldability
saccharide to low moldability saccharide is important in maintaining a
combination of
acceptable tablet hardness and rapid intraoral disintegration. A suitable
ratio is about
2 to about 20 parts by weight, preferably about 5 to about 10 parts by weight,
and
more preferably about 5 to about 7.5 parts by weight, of the high moldability
saccharide per 100 parts by weight of the low moldability saccharide.
If the ratio of high to low moldability saccharide is less than about 2:100 by
weight, tablets typically do not achieve their desired hardness, resulting in
increased
breakage during storage, transportation or handling. Alternatively, if the
ratio of high
to low moldability saccharide exceeds about 20:100 by weight, the tablets
become too
hard and desired rapid disintegration in the oral cavity is not achieved.
One or more excipients which exhibit rapid oral dissolution are typically
present in compositions of the invention in a total amount of about 45% to
about 95%,
preferably about 50% to about 87%, and. more preferably about 55% to about
80%.
Wettin a~ gents
Compositions of the present invention optionally comprise one or more
pharmaceutically acceptable wetting agents. Surfactants, hydrophilic polymers
and
certain clays can be useful as wetting agents to aid in wetting of a
hydrophobic drug,
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such as valdecoxib, during the spray dry granulation process.
Non-limiting examples of surfactants that can be used as wetting agents in
compositions of the present invention include quaternary ammonium compounds,
for
example benzalkonium chloride, benzethonium chloride and cetylpyridinium
chloride,
5 dioctyl sodium sulfosuccinate, polyoxyethylene alkylphenyl ethers, for
example
nonoxynol 9, nonoxynol 10, and octoxynol 9, poloxamers (polyoxyethylene and
polyoxypropylene block copolymers), polyoxyethylene fatty acid glycerides and
oils,
for example polyoxyethylene (8) caprylic/capric mono- and diglycerides (e.g.,
LabrasolTM of Gattefosse), polyoxyethylene (35) castor oil and polyoxyethylene
(40)
10 hydrogenated castor oil; polyoxyethylene alkyl ethers, for example
polyoxyethylene
(20) cetostearyl ether, polyoxyethylene fatty acid esters, for example
polyoxyethylene
(40) stearate, polyoxyethylene sorbitan esters, for example polysorbate 20 and
polysorbate 80 (e.g., TweenTM 80 of ICI, propylene glycol fatty acid esters,
for
example propylene glycol laurate (e.g., LauroglycolTM of Gattefosse), sodium
lauryl
sulfate, fatty acids and salts thereof, for example oleic acid, sodium oleate
and
triethanolamine oleate, glyceryl fatty acid esters, for example glyceryl
monostearate,
sorbitan esters, for example sorbitan monolaurate, sorbitan monooleate,
sorbitan
monopalmitate and sorbitan monostearate, tyloxapol, and mixtures thereof.
Sodium
lauryl sulfate is a preferred wetting agent in compositions of the present
invention.
One or more wetting agents, if desired, are typically present in compositions
of
the present invention in a total amount of about 0.05% to about 5%, preferably
about
0.075% to about 2.5%, and more preferably about 0.25% to about 1%, for example
about 0.5%, by weight of the composition.
Water-insoluble lubricants
Compositions of the present invention optionally comprise one or more
pharmaceutically acceptable water-insoluble lubricants as a Garner material.
Suitable
water-insoluble lubricants include, either individually or in combination,
glyceryl
behapate (e.g. CompritolTM 888), stearates (magnesium, calcium, and sodium),
stearic
acid, hydrogenated vegetable oils (e.g., SterotexTM), colloidal silica, talc,
waxes and
mixtures thereof. Optionally a water-insoluble lubricant can be used in
mixture with a
wetting agent, as for example in calcium stearate/sodium lauryl sulfate
mixtures (e.g.,
SterowetTM).
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Magnesium stearate, stearic acid and mixtures thereof are preferred water-
insoluble lubricants.
One or more water-insoluble lubricants optionally are present in compositions
of the present invention in a typical total amount of about 0.05% to about 5%,
preferably about 0.75% to about 2.5%, and more preferably about 1% to about
2%, for
example, about 1.5%, by weight of the composition.
Water-soluble lubricants
Compositions of the present invention optionally comprise one or more
pharmaceutically acceptable water-soluble lubricants. Water-soluble lubricants
can
help to improve tablet dissolution characteristics. Water-soluble lubricants
that can be
used in compositions of the present invention either individually or in
combination
include, for example, boric acid, sodium benzoate, sodium acetate, sodium
fumarate,
sodium chloride, DL-leucine, polyethylene glycols (e.g., CarbowaxTM 4000 and
CarbowaxTM 6000), and sodium oleate.
Disinte~rants
Compositions of the present invention optionally comprise one or more
pharmaceutically acceptable disintegrants. However, the oral fast-melt tablets
provided herein typically disintegrate rapidly in the oral cavity and have no
requirement for added disintegrant. Suitable disintegrants, if desired,
include, either
individually or in combination, starches, sodium starch glycolate, clays (such
as
VeegumTM HV), celluloses (such as purified cellulose, methylcellulose, sodium
carboxymethylcellulose and carboxymethylcellulose), croscarmellose sodium,
alginates, pregelatinized corn starches (such as NationalTM 1551 and
NationalTM
1550), crospovidone, and gums (such as agar, guar, locust bean, karaya, pectin
and
tragacanth gums). Disintegrants can be added at any suitable step during the
preparation of the composition, particularly prior to granulation or during a
blending
step prior to. tablet compression. Croscarmellose sodium and sodium starch
glycolate
are preferred disintegrants.
One or more disintegrants optionally are present in a total amount of about
0.05% to about 15%, preferably about 0.5% to about 10%, and more preferably
about
1% to about 3.5%, by weight of the composition.
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Glidants
Compositions of the present invention optionally comprise one or more
pharmaceutically acceptable glidants, for example to enhance flow of tableting
material into tablet dies., to prevent sticking of tableting material to
punches and dies,
or to produce tablets having a sheen. Glidants rnay be added at any suitable
step
during preparation of the composition, particularly prior to granulation or
during a
blending step prior to tablet compression.
Without being bound by theory, it is believed that, in some situations,
glidants,
for example talc or silicon dioxide, act to reduce interfacial tension between
drug
particles, having the effect of inhibiting and/or reducing drug agglomeration,
act to
decrease electrostatic charges on the surface of drug powders, and act to
reduce
interparticular friction and surface rugosity of drug particles. See, for
example, York
(1975) J. Pharm. Sci., 64(7}, 1216-1221.
Silicon dioxide is a preferred glidant. Suitable silicon dioxide products for
use
in preparing compositions of the invention include fumed silica or colloidal
silica
(e.g., Cab-O-SiITM of Cabot Corp. and AerosilTM of Degussa}. Silicon dioxide,
when
present in compositions of the invention, is present in a total amount of
about 0.05%
to about 5%, preferably about 0.1% to about 2%, and more preferably about
0.25% to
about 1 %, for example, about 0.5%, by weight of the composition.
Sweetening agents
Compositions of the present invention optionally comprise ane or more
pharmaceutically acceptable sweeteners. Non-limiting examples of sweeteners
that
can be used in compositions of the present invention include mannitol,
propylene
glycol, sodium saccharin, acesulfame K, neotame, aspartame, etc.
Flavoring adepts
Compositions of the present invention optionally comprise one or more
pharmaceutically acceptable flavoring agents. Non-limiting examples of
flavoring
agents that can be used in compositions of the present invention include
peppermint,
spearmint, grape, cherry, strawberry, lemon, etc.
Tablet characteristics
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Size and shape
In a preferred embodiment, compositions of the invention are in the form of
discrete solid dosage units, most preferably tablets. Tablets of the invention
can be
made to any desired size, for example 8 nim, 10 mm, 12 mm, etc.; shape, for
example
round, oval, oblong, etc.; weight; and thickness. Optionally, solid dosage
units of the
invention may have etchings or monograms on one or both sides.
Disintegrration
Preferred tablet compositions of the invention disintegrate in less than 300
seconds, preferably less than about 200 seconds, and more preferably less than
about
100 seconds, for example about 30 seconds after placement in a standard i~
vitro
disintegration assay (e.g., conducted according to U.S. Pharmacopeia 24
(2000), Test
No. 701).
Alternatively or additionally, preferred fast-melt compositions of the
invention
disintegrate within about 60 seconds, preferably within about 30 seconds, and
more
preferably within about 15 seconds after placement in the oral cavity of a
subject.
Hardness
Solid dosage forms of the invention have a hardness that cart depend on size
and shape as well as on composition, among other characteristics. Tablet
hardness
can be measured by any method known in the art, for example by a tablet
hardness
meter (e.g., Schleuniger). Preferably, compositions of the invention have a
hardness
of about 1 to about 10 kp, and more preferably of about 1 to about 6 kp.
In a presently preferred embodiment, solid dosage forms of the invention have
sufficient hardness for handling and, therefore, can be put into practical use
in the
same manner as the case of ordinary tablets. The term "sufficient hardness for
handling" as used herein means a hardness which can withstand removal from at
least
a standard type of blister packaging, or such a hardness as will withstand
other
handling such as packaging, delivery, carrying and the like.
Tablets of the invention preferably have a minimum hardness so as to resist
breakage of the tablet during removal from standard blister packaging by
pushing the
tablet through a cover sheet. A suitable hardness is about 1 kp or more for a
tablet
having a diameter of about 8 rnm, about 1.5 kp or more for a tablet having a
diameter
of about 10 mm, and about 2 kp or more when the tablet has a diameter of about
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14
12 mm.
In another presently preferred embodiment, tablets of the invention have
sufficient hardness such that a plurality of such tablets can be packaged
together, for
example in a glass or plastic bottle, without individual packaging, yet do not
exhibit
substantial breakage or sticking and/or melding together during normal
shipping and
handling. Tablets intended for such packaging preferably have a hardness of
about
3 kp or more.
Packaging
Compositions of the invention can be packaged in any suitable manner known
in the art. For example, a multiplicity of fast-melt tablets can be packaged
together,
for example in a glass or plastic bottle or container. Alternatively, fast-
melt tablets of
the invention can be individually wrapped, for example in plastic or foil, or
packaged
in known forms of blister packaging. Blister packaging with improved force
distribution properties such as is disclosed in U.S. Patent No. 5,954,204 to
Grabowski,
incorporated herein by reference, can be especially useful to package fast-
melt tablets
of the invention.
Administration of fast-melt tablets
Compositions of the present invention can be taken by a subject by any oral
administration means in accordance with the subject's choice or condition. For
example, fast-melt tablets of the invention can be taken without water. Upon
placement in the oral cavity and especially in the cheek or above the tongue,
such a
tablet is exposed to saliva and rapidly disintegrates and dissolves therein.
The rate of
disintegration andlor dissolution increases further when an intraoral
pressure, for
example a pressure between the palate and tongue or a licking or sucking
pressure, is
applied to the tablet.
Alternatively, a tablet of the present invention can be taken with the aid of
water in an amount sufficient to wet the oral cavity and to assist in
disintegration of
the tablet. Also, a tablet of the invention can be swallowed together with a
small
amount of water after complete or partial disintegration in the oral cavity.
Compositions of the invention can also be swallowed directly with water.
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Method to make fast-melt tablets
The process described below is a non-limiting, illustrative method to make
valdecoxib fast-melt tablets of the invention. Importantly, specific settings
and
parameters of the production process can be readily optimized by one of skill
in the art
in order to produce tablets with particularly desired characteristics.
In this illustrative process, maltose and mannitol are dissolved in a vessel
of
water which is heated to approximately 50 °C to about 80 °C, for
example about 70
°C. Valdecoxib is then dispersed in the vessel using a homogenizer. A
wetting agent,
for example sodium lauryl sulfate, is dissolved in a second vessel of water.
The
10 contents of the first and second vessels are then combined to form a
mixture. The
mixture is spray dried using a Niro Laboratory Mobile Minor Spray Dryer to
form a
dry granulation. The dry granulation is then optionally blended with any
desired
excipients, for example flavorants, sweeteners and lubricants, to form a
tableting
blend. The resulting tableting blend is then compressed on a rotary tablet
press to a
15 target tablet weight and hardness. The resulting tablets are then subjected
to
treatment, for example air flow treatment, in a humidity-controlled chamber
with the
effect of increasing tablet hardness.
Tablet compression
Compression is the process by which an appropriate volume of a tableting
blend of granules produced as described above is compressed between an upper
and
lower punch to consolidate material into a single solid dosage form such as a
tablet.
In processes for manufacture of fast-melt tablets of the present invention,
any suitable
means for compression can be used including, for example, a single punch
tablet
machine or a high speed rotary tablet press. The tableting pressure is not
limited, and
an appropriate pressure can be selected depending on the desired hardness and
dissolution properties of the resulting tablets. Where tablets are to undergo
temperature and humidity treatment as described immediately below, the tablets
are
preferably compressed to an initial hardness (prior to temperature and
humidity
treatment) of about 0.75 to about 1.5 kp.
Temperature and humidity treatment
Optionally, tablets of the invention can undergo heat and humidity treatment
after the tablet compression step. Such treatment can be performed in a
humidity
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16
chamber, for example, to increase hardness of the tablets. Illustratively,
during this
treatment, tablets are first subjected to low temperature, high humidity air
flow
conditions, for example, about 25°C to about 32°C and about 80%
relative humidity,
for a period of about 45 to about 120 minutes. Tablets are then subjected to
high
temperature, low humidity conditions, for example about 35°C to about
50°C and
30% relative humidity for a period of about 45 to about 120 minutes. Without
being
bound by theory, it is believed that treatment of fast-melt tablets in a low
temperature/high humidity chamber followed by treatment in a high
temperature/low
humidity chamber increases tablet hardness and reduces tablet friability
without
sacrificing desired fast-melt characteristics such as rapid disintegration and
rapid
dissolution.
Utility of compositions of the invention
Molded articles, herein also referred to as compositions, of the present
invention are useful in treatment and prevention of a very wide range of
disorders
mediated by cyclooxygenase-2 (COX-2), including but not restricted to
disorders
characterized by inflammation, pain and/or fever. Such compositions are
especially
useful as anti-inflammatory agents, such as in treatment of arthritis, with
the
additional benefit of having significantly less harmful side effects than
compositions
of conventional nonsteroidal anti-inflammatory drugs (NSAIDs) that lack
selectivity
for COX-2 over COX-1. In particular, such compositions have reduced potential
for
gastrointestinal toxicity and gastrointestinal irntation including upper
gastrointestinal
ulceration and bleeding, reduced potential for renal side effects such as
reduction in
renal function leading to fluid retention and exacerbation of hypertension,
reduced
effect an bleeding times including inhibition of platelet function, and
possibly a
lessened ability to induce asthma attacks in aspirin-sensitive asthmatic
subjects, by
comparison with compositions of conventional NSAIDs. Thus compositions of the
invention comprising a selective COX-2 inhibitory drug are particularly useful
as an
alternative to conventional NSA~s where such NSAIbs are contraindicated, for
example in patients with peptic ulcers, gastritis, regional enteritis,
ulcerative colitis,
diverticulitis or with a recurrent history of gastrointestinal lesions;
gastrointestinal
bleeding, coagulation disorders including anemia such as hypoprothrombinemia,
hemophilia or other bleeding problems; kidney disease; or in patients prior to
surgery
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17
or patients taking anticoagulants.
Such compositions are useful to treat arthritic disorders, including but not
limited to rheumatoid arthritis, spondyloarthropathies, gouty arthritis,
osteoarthritis,
systemic lupus erythematosus and juvenile arthritis.
Such compositions are also useful in treatment of asthma, bronchitis,
menstrual cramps, preterm labor, tendinitis, bursitis, allergic neuritis,
cytomegalovirus
infectivity, apoptosis including HIV-induced apoptosis, lumbago, liver disease
including hepatitis, skin-related conditions such as psoriasis,. eczema, acne,
burns,
dermatitis and ultraviolet radiation damage including sunburn, and post-
operative
inflammation including that following ophthalmic surgery such as cataract
surgery or
refractive surgery.
Such compositions are useful to. treat gastrointestinal conditions such as
inflammatory bowel disease, Crohn's disease, gastritis, irntable bowel
syndrome and
ulcerative colitis.
Such compositions are useful in treating inflammation in such diseases as
migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia,
Hodgkin's
disease, sclerodoma, rheumatic fever, type I diabetes, neuromuscular junction
disease
including myasthenia gravis, white matter disease including multiple
sclerosis,
sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis,
nephritis, hypersensitivity, swelling occurring after injury including brain
edema,
myocardial ischemia, and the like.
Such compositions are useful in treatment of ophthalmic diseases, such as
retinitis, scleritis, episcleritis, conjunctivitis, retinopathies, uveitis,
ocular
photophobia, and of acute injury to eye tissue.
Such compositions are useful in treatment of pulmonary inflammation, such as
that associated with viral infections and cystic fibrosis, and in bone
resorption such as
that associated with osteoporosis.
Such compositions are useful for treatment of certain central nervous system
disorders, such as cortical dementias including Alzheimer's disease,
neurodegeneration, and central nervous system damage resulting from stroke,
ischemia and trauma. The term "treatment" in the present context includes
partial or
total inhibition of demential, including Alzheimer's disease, vascular
dementia,
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18
mufti-infarct dementia, pre-senile dementia, alcoholic dementia and senile
dementia.
Such compositions are useful in treatment of allergic rhinitis, respiratory
distress syndrome, endotoxin shock syndrome and liver disease.
Such compositions are useful in treatment of pain, including but not limited
to
postoperative pain, dental pain, muscular pain, and pain resulting from
cancer. For
example, such compositions are useful for relief of pain, fever and
inflammation in a
variety of conditions including rheumatic fever, influenza and other viral
infections
including common cold, low back and neck pain, dysmenorrhea, headache,
toothache,
sprains and strains, myositis, neuralgia, synovitis, arthritis, including
rheumatoid
arthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing
spondylitis,
bursitis, burns, and trauma following surgical and dental procedures.
Such compositions are useful for, but not limited to, treating and preventing
inflammation-related cardiovascular disorders in a subject. Such compositions
are
useful for treatment and prevention of vascular diseases, coronary artery
disease,
aneurysm, vascular rejection, arteriosclerosis, atherosclerosis including
cardiac
transplant atherosclerosis, myocardial infarction, embolism, stroke,
thrombosis
including venous thrombosis, angina including unstable angina, coronary plaque
inflammation, bacterial-induced inflammation including Chlamydia-induced
inflammation, viral induced inflammation, and inflammation associated with
surgical
procedures such as vascular grafting including coronary artery bypass surgery,
revascularization procedures. including angioplasty, stmt placement,
endarterectomy,
or other invasive procedures involving arteries, veins and capillaries.
Such compositions are useful for, but not limited to, treatment of
angiogenesis-related disorders in a subject, for example to inhibit tumor
angiogenesis.
Such compositions are useful for treatment of neoplasia, including metastasis;
ophthalmological conditions such as corneal graft rejection, ocular
neovascularization,
retinal neovascularization including neovascularization following injury or
infection,
diabetic retinopathy, macular degeneration, retrolental fibroplasia and
glaucoma,
including neovascular glaucoma; ulcerative diseases such as gastric ulcer;
pathological, but non-malignant, conditions such as hemangiomas, including
infantile
hemangiomas, angiofibroma of the nasopharynx and avascular necrosis of bone;
and
disorders of the female reproductive system such as endometriosis.
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19
Such compositions are useful for prevention or treatment of benign and
malignant tumors/neoplasia including cancers, for example colorectal cancer,
brain
cancer, bone cancer, epithelial cell-derived neoplasia (epithelial carcinoma)
such as
basal cell carcinoma, adenocarcinoma, gastrointestinal cancer such as lip
cancer,
mouth cancer, esophageal cancer, small bowel cancer, stomach cancer, colon
cancer,
liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer,
lung
cancer, breast cancer and skin cancer, such as squamous cell and basal cell
cancers,
prostate cancer, renal cell carcinoma, and other known cancers that affect
epithelial
cells throughout the body. Neoplasias for treatment of which compositions of
the
invention are contemplated to be particularly useful are gastrointestinal
cancer,
Barrett's esophagus, liver cancer, bladder cancer, pancreas cancer, ovary
cancer,
prostate cancer, cervical cancer, lung cancer, breast cancer and skin cancer,
such as
squamous cell and basal cell cancers. Compositions of the invention can also
be used
to treat fibrosis that occurs with radiation therapy. Such compositions can be
used to
treat subjects having adenomatous polyps, including those with familial
adenomatous
polyposis (FAP). Additionally, such compositions can be used to prevent polyps
from
forming in patients at risk of FAP.
Such compositions inhibit prostanoid-induced smooth muscle contraction by
preventing synthesis of contractile prostanoids and hence can be of use in
treatment of
dysmenorrhea, premature labor, asthma and eosinophil-related disorders. They
also
can be of use for decreasing bone loss particularly in postmenopausal women
(i.e.,
treatment of osteoporosis), and for treatment of glaucoma.
Preferred uses for compositions of the present invention are for treatment of
rheumatoid arthritis and osteoarthritis, for pain management generally
(particularly
post-oral surgery pain, post-general surgery pain, post-orthopedic surgery
pain, and
acute flares of osteoarthritis), for treatment of Alzheimer's disease, and for
colon
cancer chemoprevention.
Besides being useful for human treatment, compositions of the invention are
also useful for veterinary treatment of companion animals, exotic animals,
farm
animals, and the like, particularly mammals including rodents. More
particularly,
compositions of the invention are useful for veterinary treatment of
cyclooxygenase-2
mediated disorders in horses, dogs and cats.
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The present invention also is directed to a therapeutic method of treating a
condition or disorder where treatment with a cyclooxygenase-2 inhibitory drug
is
indicated, the method comprising oral administration of one or more
compositions of
the present invention to a patient in need thereof. The dosage regimen to
prevent, give
5 relief from, or ameliorate the condition or disorder preferably corresponds
to once-a-
day or twice-a-day treatment, but can be modified in accordance with a variety
of
factors. These include the type, age, weight, sex, diet and medical condition
of the
patient and the nature and severity of the disorder. Thus, the dosage regimen
actually
employed can vary widely and can therefore deviate from the preferred dosage
10 regimens set forth above.
Initial treatment of a patient suffering from a condition or disorder where
treatment with a cyclooxygenase-2 inhibitory drug is indicated can begin with
a dose
regimen as indicated above. Treatment is generally continued as necessary over
a
period of several weeks to several months or years until the condition or
disorder has
15 been controlled or eliminated. Patients undergoing treatment with a
composition of
the invention can be routinely monitored by any of the methods well known in
the art
to determine the effectiveness of therapy. Continuous analysis of data from
such
monitoring permits modification of the treatment regimen during therapy so
that
optimally effective amounts of the drug are administered at any point in time,
and so
20 that the duration of treatment can be determined. In this way, the
treatment regimen
and dosing schedule can be rationally modified over the course of therapy so
that the
lowest amount of the drug exhibiting satisfactory effectiveness is
administered, and so
that administration is continued only for so long as is necessary to
successfully treat
the condition or disorder.
The present compositions can be used in combination therapies with opioids
and other analgesics, including narcotic analgesics, Mu receptor antagonists,
Kappa
receptor antagonists, non-narcotic (i.e. non-addictive) analgesics, monamine
uptake
inhibitors, adenosine regulating agents, cannabinoid derivatives, Substance P
antagonists, neurokinin-1 receptor antagonists and sodium channel Mockers,
among
others. Preferred combination therapies comprise use of a composition of the
invention with one or more compounds selected from aceclofenac, acemetacin,
e-acetamidocaproic acid, acetaminophen, acetaminosalol, acetanilide,
acetylsalicylic
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21
acid (aspirin), S-adenosylrnethionine, alclofenac, alfentanil, allylprodine,
alminoprofen, aloxiprin, alphaprodine, aluminum bis(acetylsalicylate),
amfenac,
aminochlorthenoxazin, 3-amino-4-hydroxybutyric acid, 2-amino-4-picoline,
aminopropylon, aminopyrine, amixetrine, ammonium salicylate, ampiroxicam,
amtolmetin guacil, anileridine, antipyrine, antipyrine salicylate,
antrafenine, apazone,
bendazac, benorylate, benoxaprofen, benzpiperylon, benzydamine,
benzylmorphine,
bermoprofen, bezitramide, oc-bisabolol, bromfenac, p-bromoacetanilide,
5-bromosalicylic acid acetate, bromosaligenin, bucetin, bucloxic acid,
bucolome,
bufexamac, bumadizon, buprenorphine, butacetin, butibufen, butophanol, calcium
acetylsalicylate, carbamazepine, carbiphene, carprofen, carsalam,
chlorobutanol,
chlorthenoxazin, choline salicylate, cinchophen, cinmetacin, ciramadol,
clidanac,
clometacin, clonitazene, clonixin, clopirac, clove, codeine, codeine methyl
bromide,
codeine phosphate, codeine sulfate, cropropamide, crotethamide, desomorphine,
dexoxadrol, dextromoramide, dezocine, diampromide, diclofenac sodium,
difenamizole, difenpiramide, diflunisal, dihydrocodeine, dihydrocodeinone enol
acetate, dihydromorphine, dihydroxyaluminum acetylsalicylate, dimenoxadol,
dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,
diprocetyl,
dipyrone, ditazol, droxicam, emorfazone, enfenamic acid, epirizole,
eptazocine,
etersalate, ethenzamide, ethoheptazine, ethoxazene, ethylmethylthiambutene,
ethylmorphine, etodolac, etofenamate, etonitazene, eugenol, felbinac,
fenbufen,
fenclozic acid, fendosal, fenoprofen, fentanyl, fentiazac, fepradinol,
feprazone,
floctafenine, flufenamic acid, flunoxaprofen, fluoresone, flupirtine,
fluproquazone,
flurbiprofen, fosfosal, gentisic acid, glafenine, glucametacin, glycol
salicylate,
guaiazulene, hydrocodone, hydromorphone, hydroxypethidine, ibufenac,
ibuprofen,
ibuproxam, imidazole salicylate, indomethacin, indoprofen, isofezolac,
isoladol,
isomethadone, isonixin, isoxepac, isoxicam, ketobemidone, ketoprofen,
ketorolac,
p-lactophenetide, lefetamine, levorphanol, lofentanil, lonazolac, lornoxicam,
loxoprofen, lysine acetylsalicylate, magnesium acetylsalicylate, meclofenamic
acid,
mefenamic acid, meperidine, meptazinol, mesalamine, metazocine, methadone
hydrochloride, methotrimeprazine, metiazinic acid, metofoline, metopon,
mofebutazone, mofezolac, morazone, morphine, morphine hydrochloride, morphine
sulfate, morpholine salicylate, myrophine, nabumetone, nalbuphine, 1-naphthyl
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salicylate, naproxen, narceine, nefopam, nicomorphine, nifenazone, niflumic
acid,
nimesulide, 5'-nitro-2'-propoxyacetanilide, norlevorphanol, normethadone,
normorphine, norpipanone, olsalazine, opium, oxaceprol, oxametacine,
oxaprozin,
oxycodone, oxymorphone, oxyphenbutazone, papaveretum, paranyline, parsalmide,
pentazocine, perisoxal, phenacetin, phenadoxone, phenazocine, phenazopyridine
hydrochloride, phenocoll, phenoperidine, phenopyrazone, phenyl
acetylsalicylate,
phenylbutazone, phenyl salicylate, phenyramidol, piketoprofen, piminodine,
pipebuzone, piperylone, piprofen, pirazolac, piritramide, piroxicam,
pranoprofen,
proglumetacin, proheptazine, promedol, propacetamol, propiram, propoxyphene,
propyphenazone, proquazone, protizinic acid, ramifenazone, remifentanil,
rimazolium
metilsulfate, salacetamide, salicin, salicylamide, salicylamide o-acetic acid,
salicylsulfuric acid, salsalte, salverine, simetride, sodium salicylate,
sufentanil,
sulfasalazine, sulindac, superoxide dismutase, suprofen, suxibuzone,
talniflumate,
tenidap, tenoxicam, terofenamate, tetrandrine, thiazolinobutazone, tiaprofenic
acid,
tiaramide, tilidine, tinoridine, tolfenamic acid, tolmetin, tramadol,
tropesin, viminol,
xenbucin, ximoprofen, zaltoprofen and zomepirac (see The Merck Index, 12th
Edition
(1996), Therapeutic Category and Biological,Activity Index, lists therein
headed
"Analgesic", "Anti-inflammatory" and "Antipyretic").
Particularly preferred combination therapies comprise use of a composition of
the invention, for example valdecoxib composition of the invention, with an
opioid
compound, more particularly where the opioid compound is codeine, rneperidine,
morphine or a derivative thereof.
The compound to be administered in combination with valdecoxib can be
formulated separately from the valdecoxib or co-formulated with the valdecoxib
in a
composition of the invention. Where valdecoxib is co-formulated with a second
drug,
for example an opioid drug, the second drug can be formulated in immediate-
release,
rapid-onset, sustained-release or dual-release form.
In an embodiment of the invention, particularly where the cyclooxygenase-2
mediated condition is headache or migraine, the valdecoxib composition is
administered in combination therapy with a vasomodulator, preferably a
xanthine
derivative having vasomodulatory effect, more preferably an alkylxanthine
compound.
Combination therapies wherein an alkylxanthine compound is co-administered
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23
with a valdecoxib composition as provided herein are embraced by the present
embodiment of the invention whether or not the alkylxanthine is a
vasomodulator and
whether or not the therapeutic effectiveness of the combination is to any
degree
attributable to a vasomodulatory effect. The term "alkylxanthine" herein
embraces
xanthine derivatives having one or more Cl_4 alkyl, preferably methyl,
substituents,
and pharmaceutically acceptable salts of such xanthine derivatives.
Dimethylxanthines and trimethylxanthines, including caffeine, theobromine and
theophylline, are especially preferred. Most preferably, the alkylxanthine
compound
is caffeine.
The total and relative dosage amounts of valdecoxib and of the vasomodulator
or alkylxanthine are selected to be therapeutically and/or prophylactically
effective for
relief of pain associated with the headache or migraine. Suitable dosage
amounts will
depend on the severity of pain and the particular vasomodulator or
alkylxanthine
selected. For example, in a combination therapy with valdecoxib and caffeine,
typically the valdecoxib will be administered in a daily dosage amount of
about 1 mg
to about 100 mg, preferably about 5 mg to about 50 mg, and the caffeine in a
daily
dosage amount of about 1 mg to about 500 mg, preferably about 10 mg to about
400
mg, more preferably about 20 mg to about 300 mg.
The vasomodulator or alkylxanthine component of the combination therapy
can be administered in any suitable dosage form by any suitable route,
preferably
orally. The vasomodulator or alkylxanthine can optionally be coformulated with
the
valdecoxib in the molded article of the invention. Thus a molded article of
the
invention optionally comprises both valdecoxib and a vasomodulator or
alkylxanthine
such as caffeine, in total and relative amounts consistent with the dosage
amounts set
out hereinabove.
The phrase "in total and relative amounts effective to relieve pain", with
respect to amounts of valdecoxib and a vasomodulator or alkylxanthine in a
composition of the present embodiment, means that these amounts are such that
(a)
together these components are effective to relieve pain, and (b) each
component is or
would be capable of contribution to a pain-relieving effect if the other
component is or
were not present in so great an amount as to obviate such contribution.
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24
EXAMPLES
The following examples illustrate aspects of the present invention but should
not be construed as limitations.
Example 1
Valdecoxib Fast-Melt Tablets (Batch A, hereinafter also referred to as Fast-
Melt A) were prepared according to the following procedure. Maltose (28.03 g)
and
mannitol (367.6 g} were dissolved in water in a first vessel with heat (70
°C) and
stirnng. Valdecoxib (46.25 g) was dispersed in the maltose/mannitol solution
and
homogenized for ten minutes using a Silverson homogenizer. Sodium lauryl
sulfate
(SLS) was dissolved in water in a second vessel with gentle agitation to form
a
wetting agent solution. The wetting agent solution was added to the first
vessel to
form a sprayable solution. The sprayable solution was spray dried to form a
dry
granulation using a Niro Laboratory Mobile Minor Spray Dryer under the
following
conditions: spray rate: 32 g/min; inlet process gas flow: 2.8 mbar; system
pressure: 1.6
mbar; inlet process gas pressure 20 mbar; atomization pressure 1.6 bar;
percent
atomization flow: 57; inlet temperature: 160 °C; outlet temperature:
about 55 °C;
atomization air heater temperature: 287 °C.
Magnesium stearate (1 g), stearic acid (3 g), acesulfame K (1 g) and
peppermint flavor (1 g) were added to a polyethylene bag and vigorously shaken
to
form a mixture. The mixture was then geometrically diluted with the dry
granulation
prepared above until 200 g of dry granulation had been added. Tablets were
then
prepared by individually compressing 400 mg of the tableting blend to form
tablets
having an intermediate hardness of 1.5 kp. Resulting tablets were placed in a
chamber
maintained at 25 °C and 80% relative humidity for 1 hour, and at 40
°C and 30%
relative humidity for a second hour. Composition (% weight) of Fast-Melt A is
shown
in Table 1.
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Table 1. Composition of Fast-Melt A
Com onentAmount
Valdecoxib10
Maltose 6.06
Mannitol 79.48
SLS 1.45
Magnesium0.5
stearate
Stearic 1.5
acid
Acesulfame0.5
K
Peppermint0.5
Example Z
A study was performed in order to determine pharmacokinetic properties of
the Valdecoxib Fast-Melt A in beagle dogs. Valdecoxib Fast-Melt A was
individually
5 administered to each of 4 dogs. Venous blood was collected pre-dose, and at
0.5, l,
1.5, 2, 2.5, 3, 4, 6, 8, 12 and 24 hours after oral dose administration.
Plasma was
separated from blood by centrifugation at 3000 G and samples were stored at -
20°C
until analysis. Concentrations of valdecoxib in plasma were determined using
an
HPLC assay. Results are shown in Table 2.
10 Table 2 Pharmacokinetic properties of Valdecoxib Fast-Melt A in Dogs
Parameter Fast-Melt
A
Cm~ (n ml) 8800
AUC (h*ng/ml)2710
~~ Tm~ (h) 1.4
Example 3
Valdecoxib Fast-Melt Tablets (Batch B, hereinafter also referred to as Fast-
Melt B) were prepared according to the following procedure. Maltose (0.158 kg)
and
15 mannitol (2.047 kg) were dissolved in water (14.167 kg) with mixing to form
a
solution. Sodium lauryl sulfate (0.037 kg) was added to the solution with
mixing until
dissolved. Valdecoxib (0.258 kg) was dispersed in the solution and homogenized
at
approximately 5000 RPM for 15 minutes using a Silverson homogenizer to form a
slurry. The slurry was then mixed with a conventional marine-type impeller at
20 approximately 300 RPM for approximately 2 hours. The slurry was spray dried
to
form a dry granulation using a Niro Laboratory Mobile Minor Spray Dryer under
the
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26
following conditions: spray rate: 30 g/min; inlet process gas flow: 40 mm H20;
chamber pressure: -100 mm H20; fluid spray atomization pressure 1.0 bar;
percent
atomization flow: 70; inlet air temperature: 175 °C; outlet air
temperature: about 90
°C. The total theoretical yield was 2.500 Kg. The above procedure was
performed in
duplicate to result in spray dried granulation Lot A (1414.3 g) and Lot B
(1971.9 g).
Spray dried granulation Lot A and Lot B were and sieved and the sieved
granulations were dry blended with peppermint flavor (17.5 g) and acesulfame K
(17.5 g) in a V-blender for 15 minutes to form a mixture. Magnesium stearate
(17.5
g), micronized stearic acid (52.5 g)~ and colloidal silicon dioxide (8.8 g)
were added to
the mixture with additional mixing to form a tableting blend. Tablets were
compressed from the tableting blend to a target hardness of 1.5 Kp and a
target tablet
weight of 391.58 mg. After compression, tablets were transferred to an IBC
humidity
treatment chamber (17 liter) maintained at 25 °C, 80% relative humidity
and 75 CFM
air flow for 1 hour, and at 40 °C, 30% relative humidity and 75 CFM air
flow for a
second hour. Composition of Fast-Melt B (mg/tablet) is shown in Table 3.
Table 3. Composition of Fast-Melt B.
Component Amount
(m )
Granulation Lot A 158.22
Granulation Lot B 220.61
Ma esium stearate 1.96
NF
Stearic acid NF (micronized)5.87
Colloidal silicon 1.00
dioxide
Acesulfame K 1.96
Pe ermint 1.96
Total 391.58
Example 4
Irz vitro dissolution profiles of Fast-Melt B of Example 3 and a commercial 40
mg Bextra~ tablet were determined using 1000 ml of 1% sodium lauryl sulfate
solution and USP Type II Apparatus. Data are shown in Table 4. Fast-melt B
exhibited very rapid dissolution with all of the valdecoxib being dissolved by
15
minutes in the assay.
Table 4. Amount (% weight) of valdecoxib dissolved
Time (min) Fast-Melt B Bextra~ Tablet
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15 101 62
30 101 79
45 100 88
GO 101 93
Example 5
Fast-Melt B of Example 3 was individually administered to 25 human
subjects. Oral bioavailability parameters were determined and compared with
those of
a 40 mg commercial Bextra~ tablet. Data are shown in Table 5.
Table 5. Oral bioavailability of Fast-Melt B and a 40 mg
Bextra~ tablet in human subjects
Parameter Fast-Melt Bextra~ tablet
B
Tm~ (hr) 3.22 3.3
Cmax (n 580 468
ml)
AUC 6833 G 126
(ng/ml)/hr
These data indicate that Fast-Melt B exhibits very good bioavailability
properties
upon administration to human subjects.
Example 6
Fast-Melt B of Example 3 was evaluated in a taste study according to the
following procedure. Four to five professional sensory panelists were selected
and
each panelist was given a Fast-Melt tablet to place on his/her tongue. The
panelist
gently rolled the tablet against the roof of his/her mouth without chewing,
and
simultaneously recorded sensory information and time to complete
disintegration.
Sensory information included organoleptic attributes associated with each
tablet such
as flavor quality, bitterness, fullness, texture, mouth feel and aftertaste.
Each of these
attributes were defined along a categorical unit scale of 1 - 5 to express
perceptual
differences from other commercially marketed melt products, by comparison with
comparator valdecoxib fast-melt tablets which comprised one of cherry,
strawberry,
orange, peppermint, or spearmint flavor, and by comparison with fast-melt
tablets
comprising different active ingredients.
After total disintegration of a tablet, the panelist recorded sensory
aftertaste
over a period of 30 minutes. Each tablet was evaluated in triplicate and all
samples
were coded for presentation to panelists. Fast-Melt B exhibited an average
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28
disintegration time of 23.6 seconds. Overall, valdecoxib Fast-Melt B exhibited
acceptable flavor quality (data not shown) and disintegration time.
