U.S. patent application number 12/013873 was filed with the patent office on 2008-07-10 for celecoxib compositions.
This patent application is currently assigned to Pfizer, Inc.. Invention is credited to Danchen Gao, Anthony J. Hlinak, Ahmad M. Mazhary, James E. Truelove, Margaret V. Vaughn.
Application Number | 20080167362 12/013873 |
Document ID | / |
Family ID | 22332446 |
Filed Date | 2008-07-10 |
United States Patent
Application |
20080167362 |
Kind Code |
A1 |
Gao; Danchen ; et
al. |
July 10, 2008 |
Celecoxib compositions
Abstract
Pharmaceutical compositions are provided comprising one or more
orally deliverable dose units, each comprising particulate
celecoxib in an amount of about 10 mg to about 1000 mg in intimate
mixture with one or more pharmaceutically acceptable excipients.
The compositions are useful in treatment or prophylaxis of
cyclooxygenase-2 mediated conditions and disorders.
Inventors: |
Gao; Danchen; (Chicago,
IL) ; Hlinak; Anthony J.; (Lindenhurst, IL) ;
Mazhary; Ahmad M.; (Algonquin, IL) ; Truelove; James
E.; (Libertyville, IL) ; Vaughn; Margaret V.;
(Winnetka, IL) |
Correspondence
Address: |
PHARMACIA CORPORATION;GLOBAL PATENT DEPARTMENT
POST OFFICE BOX 1027
ST. LOUIS
MO
63006
US
|
Assignee: |
Pfizer, Inc.
New York
NY
|
Family ID: |
22332446 |
Appl. No.: |
12/013873 |
Filed: |
January 14, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09451641 |
Nov 30, 1999 |
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12013873 |
|
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60110333 |
Nov 30, 1998 |
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Current U.S.
Class: |
514/406 |
Current CPC
Class: |
A61P 19/04 20180101;
A61P 37/08 20180101; A61K 9/4858 20130101; A61P 1/16 20180101; A61P
43/00 20180101; A61P 7/04 20180101; A61P 17/04 20180101; A61P 17/16
20180101; A61P 25/04 20180101; A61P 27/06 20180101; A61K 9/2054
20130101; A61P 19/02 20180101; A61P 11/00 20180101; A61P 17/02
20180101; A61P 27/02 20180101; A61P 3/10 20180101; A61P 21/04
20180101; A61K 9/1694 20130101; A61P 15/00 20180101; A61P 37/00
20180101; A61P 37/06 20180101; A61K 9/2095 20130101; A61K 31/415
20130101; A61P 1/04 20180101; A61P 17/00 20180101; A61P 25/00
20180101; A61P 13/12 20180101; A61P 19/10 20180101; A61P 9/00
20180101; A61P 31/18 20180101; A61K 9/2018 20130101; A61P 9/10
20180101; A61K 9/0053 20130101; A61K 9/4866 20130101; A61P 11/06
20180101; A61P 25/06 20180101; A61P 19/08 20180101; A61K 31/635
20130101; A61P 1/00 20180101; A61P 25/28 20180101; A61K 9/2013
20130101; A61P 17/10 20180101; A61P 27/14 20180101; A61P 35/00
20180101; A61P 17/06 20180101; A61K 9/2027 20130101; A61P 29/00
20180101; A61P 7/06 20180101; A61K 45/06 20130101 |
Class at
Publication: |
514/406 |
International
Class: |
A61K 31/415 20060101
A61K031/415; A61P 25/00 20060101 A61P025/00 |
Claims
1. A pharmaceutical composition comprising one or more orally
deliverable dose units, each comprising particulate celecoxib in an
amount of about 10 mg to about 1000 mg in intimate mixture with one
or more pharmaceutically acceptable excipients, wherein a single
dose unit, upon oral administration to a fasting subject, provides
a time course of blood serum concentration of celecoxib having at
least one of (a) a time to reach 100 ng/ml not greater than about
0.5 h after administration; (b) a time to reach maximum
concentration (T.sub.max) not greater than about 3 h after
administration; (c) a duration of time wherein concentration
remains above 100 ng/ml not less than about 12 h; (d) a terminal
half-life (T.sub.12) not less than about 10 h; and (e) a maximum
concentration (C.sub.max) not less than about 200 ng/ml.
2. The composition of claim 1 wherein the amount of celecoxib in
each dose unit is about 50 mg to about 800 mg.
3. The composition of claim 1 wherein the amount of celecoxib in
each dose unit is about 75 mg to about 400 mg
4. The composition of claim 1 wherein the amount of celecoxib in
each dose unit is about 100 mg to about 200 mg.
5. A composition of claim 1 that is suitable, by oral
administration to a subject of a dose unit once or twice a day, for
providing therapeutically or prophylactically effective inhibition
of cyclooxygenase-2.
6. A composition of claim 1 that is suitable, by oral
administration to a subject of a dose unit once or twice a day, for
treatment or prophylaxis of a cyclooxygenase-2 mediated condition
or disorder.
7. A composition of claim 1 in the form of unit dosage capsules or
tablets.
8. The composition of claim 7 wherein said excipient(s) are
selected from the group consisting of pharmaceutically acceptable
diluents, disintegrants, binding agents, wetting agents and
lubricants.
9. The composition of claim 7 wherein said excipient(s) include one
or more pharmaceutically acceptable diluents in a total amount of
about 5% to about 99% by weight of the composition.
10. The composition of claim 7 wherein said excipients include one
or more pharmaceutically acceptable disintegrants in a total amount
of about 0.2% to about 30% by weight of the composition.
11. The composition of claim 7 wherein said excipients include one
or more pharmaceutically acceptable binding agents in a total
amount of about 0.5% to about 25% by weight of the composition.
12. The composition of claim 7 wherein said excipients include one
or more pharmaceutically acceptable wetting agents in a total
amount of about 0.25% to about 15% by weight of the
composition.
13. The composition of claim 7 wherein said excipients include one
or more pharmaceutically acceptable lubricants in a total amount of
about 0.1% to about 10% by weight of the composition.
14. A composition of claim 7 comprising (a) one or more
pharmaceutically acceptable diluents in a total amount of about 10%
to about 85% by weight of the composition; (b) one or more
pharmaceutically acceptable disintegrants in a total amount of
about 0.2% to about 10% by weight of the composition; and (c) one
or more pharmaceutically acceptable binding agents in an amount of
about 0.5% to about 10% by weight of the composition.
15. A composition of claim 14 further comprising (d) one or more
pharmaceutically acceptable wetting agents in a total amount of
about 0.4% to about 10% by weight of the composition; and/or (e)
one or more pharmaceutically acceptable lubricants in a total
amount of about 0.2% to about 8% by weight of the composition.
16. The composition of claim 7 wherein celecoxib is present in an
amount of about 1% to about 95% by weight of the composition.
17. A composition of claim 7 comprising unit dosage capsules or
tablets each providing a 100 mg or 200 mg dose of celecoxib.
18. A composition of claim 7 prepared by a process wherein the
celecoxib, together with one or more excipients, is directly
encapsulated or directly compressed into tablets.
19. A composition of claim 7 prepared by a process wherein the
celecoxib, together with one or more excipients, is wet granulated
prior to encapsulation or compression into tablets.
20. A composition of claim 7 prepared by a process wherein the
celecoxib, together with one or more excipients, is dry granulated
prior to encapsulation or compression into tablets.
21. A composition of claim 1 providing, upon oral ingestion, a
therapeutic effect as a cyclooxygenase-2 inhibitor over an interval
of about 12 to about 24 h after ingestion.
22. The composition of claim 1 wherein, upon oral ingestion, at
least about 50% of the celecoxib is released, as determined in
vitro, within about 15 minutes after ingestion.
23. A composition of claim 1 further comprising one or more opioid
or analgesic drugs.
24. A method of treating a medical condition or disorder in a
subject where treatment with a cyclooxygenase-2 inhibitor is
indicated, comprising orally administering to the subject a
composition of claim 1 once or twice a day.
25. A method of preparing a composition of claim 7 comprising (a)
wet granulating celecoxib together with one or more excipients to
form a wet granulated mixture; (b) drying the wet granulated
mixture; and (c) encapsulating the dried granulated mixture or
compressing the dried granular mixture into tablets.
Description
[0001] This application claims the benefit of U.S. provisional
application Ser. No. 60/110,333 filed Nov. 30, 1998.
FIELD OF THE INVENTION
[0002] The present invention relates to orally deliverable
pharmaceutical compositions containing celecoxib as an active
ingredient, to processes for preparing such compositions, to
methods of treatment of cyclooxygenase-2 mediated disorders
comprising orally administering such compositions to a subject, and
to the use of such compositions in the manufacture of
medicaments.
BACKGROUND OF THE INVENTION
[0003] The compound
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonam-
ide (also referred to herein as celecoxib) was previously reported
in Talley et al., U.S. Pat. No. 5,466,823 which describes and
claims a class of 1,5-diaryl pyrazoles and their salts together
with processes for the preparation of such compounds. Celecoxib has
the structure:
##STR00001##
[0004] The 1,5-diaryl pyrazole compounds reported in U.S. Pat. No.
5,466,823 are described therein as useful in treating inflammation
and inflammation-related disorders. U.S. Pat. No. 5,466,823
contains general references to formulations for the administration
of these 1,5-diaryl pyrazoles, including orally deliverable dosage
forms such as tablets and capsules. Talley et al., U.S. Pat. No.
5,760,068 reports a class of 1,5-diaryl pyrazole compounds
including celecoxib that are described as selective inhibitors of
cyclooxygenase-2 and that can be administered to treat, among other
conditions and disorders, pathological conditions associated with
rheumatoid arthritis and osteoarthritis.
[0005] Penning et al., "Synthesis and Biological Evaluation of the
1,5-Diarylpyrazole Class of Cyclooxygenase-2 Inhibitors:
Identification of
4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfo-
namide (SC-58635, Celecoxib)", J. Med. Chem. 40 (1997):1347-1365,
discloses the preparation of a series of sulfonamide-containing
1,5-diarylpyrazole derivatives, including celecoxib, and the
evaluation of those derivatives as cyclooxygenase-2 inhibitors.
[0006] Simon et al., "Preliminary Study of the Safety and Efficacy
of SC-58635, a Novel Cyclooxygenase 2 Inhibitor", Arthritis &
Rheumatism, Vol. 41, No. 9, September 1998, pp. 1591-1602,
discloses a study of the efficacy and safety of celecoxib in the
treatment of osteoarthritis and rheumatoid arthritis.
[0007] Lipsky et al., "Outcome of Specific COX-2 Inhibition in
Rheumatoid Arthritis", J. Rheumatology, Vol. 24, Suppl. 49, pp.
9-14 (1997), discloses that in patients with rheumatoid arthritis
the specific inhibition of cyclooxygenase-2 by celecoxib is
sufficient to suppress signs and symptoms of inflammatory disease
activity.
[0008] European Patent Application No. 0 863 134 A1, published Sep.
9, 1998, discloses compositions comprising a cyclooxygenase-2
inhibitor, specifically
2-(3,5-difluorophenyl)-3-(4-methyl-sulfonyl)phenyl)-2-cyclopenten-1-one,
in combination with excipient ingredients including
microcrystalline cellulose, lactose monohydrate, hydroxypropyl
cellulose, croscarmellose sodium and magnesium stearate.
[0009] The formulation of celecoxib for effective oral
administration to a subject has hitherto been complicated by the
unique physical and chemical properties of the compound,
particularly its low solubility and factors associated with its
crystal structure, including cohesiveness, low bulk density and low
compressibility. Celecoxib is unusually insoluble in aqueous media.
Unformulated celecoxib is not readily dissolved and dispersed for
rapid absorption in the gastrointestinal tract when administered
orally, for example in capsule form. In addition, unformulated
celecoxib, which has a crystal morphology that tends to form long
cohesive needles, typically fuses into a monolithic mass upon
compression in a tableting die. Even when blended with other
substances, the celecoxib crystals tend to separate from the other
substances and agglomerate together during mixing of the
composition resulting in a non-uniformly blended composition
containing undesirably large aggregates of celecoxib. Therefore, it
is difficult to prepare a pharmaceutical composition containing
celecoxib that has the desired blend uniformity. Further, handling
problems are encountered during the preparation of pharmaceutical
compositions comprising celecoxib. For example, the low bulk
density of celecoxib makes it difficult to process the small
quantities required during formulation of the pharmaceutical
compositions. Accordingly, a need exists for solutions to numerous
problems associated with preparation of suitable pharmaceutical
compositions and dosage forms comprising celecoxib, particularly
orally deliverable dose units.
[0010] In particular, a need exists for orally deliverable
celecoxib formulations possessing one or more of the following
characteristics relative to unformulated celecoxib or other
celecoxib compositions: [0011] (1) improved solubility; [0012] (2)
shorter disintegration time; [0013] (3) shorter dissolution time;
[0014] (4) decreased tablet friability; [0015] (5) increased tablet
hardness; [0016] (6) improved wettability; [0017] (7) improved
compressibility; [0018] (8) improved flow properties of liquid and
particulate solid compositions; [0019] (9) improved physical
stability of the finished composition; [0020] (10) reduced tablet
or capsule size; [0021] (11) improved blend uniformity; [0022] (12)
improved dose uniformity; [0023] (13) improved control of weight
variation during encapsulation and/or tableting; [0024] (14)
increased granule density for wet granulated compositions; [0025]
(15) reduced water requirement for wet granulation; [0026] (16)
reduced wet granulation time; and [0027] (17) reduced drying time
for wet granulated mixtures.
[0028] As is indicated hereinbelow, celecoxib treatment is
indicated or potentially indicated in a very wide array of
cyclooxygenase-2 mediated conditions and disorders. It would
therefore be of great benefit to provide a range of formulations
having bioavailability characteristics tailored to different
indications. It would be of especial benefit to provide
formulations exhibiting pharmacokinetics consistent with a more
rapid onset effect than is possible with unformulated
celecoxib.
[0029] Such formulations would represent a significant advance in
the treatment of cyclooxygenase-2 mediated conditions and
disorders.
SUMMARY OF THE INVENTION
[0030] There is now provided a pharmaceutical composition
comprising one or more orally deliverable dose units, each
comprising particulate celecoxib in an amount of about 10 mg to
about 1000 mg in intimate mixture with one or more pharmaceutically
acceptable excipients.
[0031] In one embodiment, a single dose unit, upon oral
administration to a fasting subject, provides a time course of
blood serum concentration of celecoxib having at least one of the
following: [0032] (a) a time to reach 100 ng/ml not greater than
about 0.5 h after administration; [0033] (b) a time to reach
maximum concentration (T.sub.max) not greater than about 3 h after
administration; [0034] (c) a duration of time wherein concentration
remains above 100 ng/ml not less than about 12 h; [0035] (d) a
terminal half-life (T.sub.1/2) not less than about 10 h; and [0036]
(e) a maximum concentration (C.sub.max) not less than about 200
ng/ml.
[0037] In another embodiment, the composition has a relative
bioavailability not less than about 50% by comparison with an
orally delivered solution containing an equivalent amount of
celecoxib.
[0038] In still another embodiment, the composition has a
distribution of celecoxib primary particle sizes such that D.sub.90
is less than about 200 .mu.m (90% of a sample of particles is
smaller than the D.sub.90 value) in the longest dimension of the
particles.
[0039] It is to be understood that (a) particular, preferred or
illustrative features or properties, (b) particular, preferred or
illustrative ingredients, and (c) particular, preferred or
illustrative amounts, or ranges of amounts, of such ingredients,
disclosed hereinbelow with respect to any of the above embodiments
of the invention apply to all of these embodiments.
[0040] The dose units comprising the composition can be in the form
of discrete solid articles such as tablets, pills, hard or soft
capsules, lozenges, sachets or pastilles; alternatively the
composition can be in the form of a substantially homogeneous
flowable mass, such as a particulate or granular solid or a liquid
suspension, from which single dose units are measurably
removable.
[0041] Also provided is a method of treating a medical condition or
disorder in a subject where treatment with a cyclooxygenase-2
inhibitor is indicated, comprising orally administering a
composition of the invention once or twice a day.
[0042] Other features of this invention will be in part apparent
and in part pointed out hereinafter.
BRIEF DESCRIPTION OF THE DRAWINGS
[0043] FIG. 1 is a flow diagram illustrating a representative
method for the preparation of pharmaceutical compositions of the
present invention in the form of capsules.
[0044] FIG. 2 is a flow diagram illustrating an alternative method
for the preparation of pharmaceutical compositions of the present
invention in the form of capsules.
DETAILED DESCRIPTION OF THE INVENTION
[0045] Novel pharmaceutical compositions according to the present
invention comprise one or more orally deliverable dose units,
wherein each dose unit comprises particulate celecoxib in an amount
from about 10 mg to about 1000 mg and are superior immediate
release compositions capable of providing rapid relief from a
cyclooxygenase-2 mediated disorder when orally administered to a
subject suffering from such a disorder.
[0046] It is believed, without being bound by theory, that the
strong clinical benefits afforded by these compositions result from
improved bioavailability of celecoxib, in particular from
surprisingly effective absorption of celecoxib in the
gastrointestinal tract. Such effective absorption can be verified
by one of skill in the art by monitoring blood serum concentration
of celecoxib in a treated subject for a period of time following
administration. It is desired to reach, in as short a time as
possible, a threshold of celecoxib concentration in the blood serum
consistent with effective cyclooxygenase-2 inhibition, without
having that concentration subsequently decrease too rapidly so that
the beneficial effects of the celecoxib can be maintained for as
long a time as possible.
[0047] In one embodiment of the invention, therefore, each orally
deliverable dose unit, upon oral administration, provides a time
course of blood serum concentration of celecoxib characterized by
at least one of the following: [0048] (a) a time to reach a blood
serum concentration of about 100 ng/ml that is not greater than
about 0.5 hour after administration; [0049] (b) a time to reach a
maximum blood serum concentration (T.sub.max) of celecoxib that is
not greater than about 3 hours after administration, preferably not
greater than about 2 hours after administration; [0050] (c) a
duration of time wherein the blood serum concentration remains
above about 100 ng/ml that is not less than about 12 hours; [0051]
(d) a terminal half life (T.sub.1/2) that is not less than about 10
hours; and [0052] (e) a maximum blood serum concentration
(C.sub.max) that is not less than about 200 ng/ml, preferably not
less than about 300 ng/ml, and more preferably not less than about
400 ng/ml.
[0053] It will be understood that the amount of celecoxib in a dose
unit effective to provide blood serum concentrations meeting any of
criteria (a) to (e) immediately above is dependent 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 celecoxib
relatively low in the indicated range of about 10 mg to about 1000
mg is likely to provide blood serum concentrations consistent with
at least one of criteria (a) to (e). Where the subject is an adult
human or a large animal (e.g., a horse), the indicated blood serum
concentrations of celecoxib are likely to require dose units
containing a relatively greater amount of celecoxib. For an adult
human, a suitable amount of celecoxib per dose unit in a
composition of the present invention to provide the indicated blood
serum concentrations is typically about 75 mg to about 400 mg.
[0054] Bioavailability of orally delivered celecoxib in an absolute
sense is difficult to measure, because intravenous delivery
(normally the standard against which such bioavailability is
determined) is highly problematical with a drug having very low
solubility in water, as is the case with celecoxib. Relative
bioavailability is, however, determinable by comparison with an
orally administered solution of celecoxib in a suitable solvent. It
has been found that surprisingly high relative bioavailability is
obtainable with orally delivered compositions of the present
invention. Thus in one embodiment of the invention, each orally
deliverable dose unit, upon oral administration, has a relative
bioavailability of not less than about 50%, preferably not less
than about 70%, by comparison with an orally delivered solution of
celecoxib containing an equivalent amount of celecoxib. As
indicated hereinbelow, bioavailability is derived from an
integrated measure of blood serum concentration of celecoxib over a
period of time following oral administration.
[0055] Compositions of the present invention contain celecoxib in
particulate form. Primary celecoxib 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 the clinical effectiveness of celecoxib. Thus in another
embodiment, compositions of the present invention have a
distribution of celecoxib particle sizes such that D.sub.90 of the
particles, in their longest dimension, is less than about 200
.mu.m, preferably less than about 100 .mu.m, more preferably less
than about 75 .mu.m, even more preferably less than about 40 .mu.m,
and most preferably less than about 25 .mu.m. A decrease in
particle size of celecoxib in accordance with this embodiment of
the invention generally improves the bioavailability of the
celecoxib.
[0056] In addition or alternatively, celecoxib particles in a
composition of the invention preferably have a mean particle size
of about 1 .mu.m to about 10 .mu.m, most preferably about 5 .mu.m
to about 7 .mu.m.
[0057] It has been discovered that milling the celecoxib in an
impact mill, such as a pin mill, prior to mixing the celecoxib with
excipients to form a composition of the invention, is not only
effective in pro viding improved bioavailability but is also
beneficial in overcoming problems associated with the cohesive
nature of celecoxib crystals during such mixing or blending.
Celecoxib milled using a pin mill is less cohesive than, and does
not agglomerate into secondary aggregates of celecoxib particles
during blending as readily as, unmilled celecoxib or celecoxib
milled using other types of mills, such as fluid energy mills.
Reduced agglomeration enables a high degree of blend uniformity,
which is of particular importance in formulation of unit dosage
forms such as capsules and tablets. This result is particularly
unexpected given the utility of fluid energy mills such as air jet
mills in preparing other pharmaceutical compounds for formulation.
Without being held to a particular theory, it is hypothesized that
impact milling modifies the crystal morphology of celecoxib from
long needles to a more uniform crystal shape more suitable for
blending purposes, whereas the long needles have a greater tendency
to survive an air jet milling process.
[0058] It has also been discovered that blend uniformity is further
improved by wet granulating celecoxib with the carrier materials to
prepare the pharmaceutical composition, particularly when the
celecoxib starting material used has been impact milled. Impact
milling the celecoxib starting material such that particle sizes
are as described above, followed by wet granulation, is
particularly desirable.
[0059] In yet another embodiment, the novel pharmaceutical
compositions of the invention comprise celecoxib together with one
or more carrier materials or excipients selected from diluents,
disintegrants, binding agents, wetting agents and lubricants.
Preferably at least one of the carrier materials is a water soluble
diluent or wetting agent. Such a water soluble diluent or wetting
agent assists in the dispersion and dissolution of the celecoxib
when the pharmaceutical composition is ingested. Preferably both a
water soluble diluent and a wetting agent are present. A
composition of the invention can be a substantially homogeneous
flowable mass such as a particulate or granular solid or a liquid,
or it can be in the form of discrete articles such as capsules or
tablets each comprising a single dose unit.
[0060] In a composition that is a substantially homogeneous
flowable mass, single dose units are measurably removable using a
suitable volumetric measuring device such as a spoon or cup.
Suitable flowable masses include, but are not limited to, powders
and granules. Alternatively, the flowable mass can be a suspension
having the celecoxib in a solid particulate phase dispersed in a
liquid phase, preferably an aqueous phase. In preparing such a
suspension, use of a wetting agent such as polysorbate 80 or the
like is likely to be beneficial. A suspension can be prepared by
dispersing milled celecoxib in the liquid phase; alternatively the
celecoxib can be precipitated from solution in a solvent such as an
alcohol, preferably ethanol. The aqueous phase preferably comprises
a palatable vehicle such as water, syrup or fruit juice, for
example apple juice.
Utility of Compositions of the Invention
[0061] Compositions of the present invention are useful in
treatment and prevention of a very wide range of disorders mediated
by cyclooxygenase-2. Presently contemplated compositions are useful
for, but not limited to, the treatment of inflammation in a
subject, as an analgesic for example in the treatment of pain and
headaches, and as an antipyretic in the treatment of fever. For
example, 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 the 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, UV damage, burns and
dermatitis, and post-operative inflammation including that
following ophthalmic surgery such as cataract surgery or refractive
surgery. Contemplated compositions are useful to treat
gastrointestinal conditions such as inflammatory bowel disease,
Crohn's disease, gastritis, irritable bowel syndrome and ulcerative
colitis. Contemplated 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. Contemplated compositions
are useful in the treatment of ophthalmic diseases, such as
retinitis, conjunctivitis, retinopathies, uveitis, ocular
photophobia, and of acute injury to the eye tissue. Contemplated
compositions are useful in the treatment of pulmonary inflammation,
such as that associated with viral infections and cystic fibrosis,
and in bone resorption such as that associated with osteoporosis.
Contemplated compositions are useful for the 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 dementias, including Alzheimer's disease,
vascular dementia, multi-infarct dementia, pre-senile dementia,
alcoholic dementia, and senile dementia.
[0062] Compositions of the invention are especially useful as
anti-inflammatory agents, such as for the treatment of arthritis,
with the additional benefit of having significantly less harmful
side effects than compositions of conventional nonsteroidal
anti-inflammatory drugs (NSAIDs).
[0063] Contemplated compositions are useful in the treatment of
allergic rhinitis, respiratory distress syndrome, endotoxin shock
syndrome, and liver disease. Contemplated compositions are useful
in the treatment of pain, including but not limited to
postoperative pain, dental pain, muscular pain, and pain resulting
from cancer.
[0064] Contemplated 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, stent
placement, endarterectomy, or other invasive procedures involving
arteries, veins and capillaries. Such compositions are useful for,
but not limited to, the treatment of angiogenesis-related disorders
in a subject. Compositions of the invention can be administered to
a subject in need of angiogenesis inhibition. Such compositions are
useful for the treatment of neoplasia, including metastasis;
opthalmological conditions such as corneal graft rejection, ocular
neovascularization, retinal neovascularization including
neovascularization following injury or infection, diabetic
retinopathy, macular degeneration, retrolental fibroplasia and
neovascular glaucoma; ulcerative diseases such as gastric ulcer;
pathological, but non-malignant, conditions such as hemangiomas,
including infantile hemaginomas, angiofibroma of the nasopharynx
and avascular necrosis of bone; and disorders of the female
reproductive system such as endometriosis.
[0065] Contemplated compositions are useful for the prevention or
treatment of benign and malignant tumors/neoplasia including
cancer, such as 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, esophogeal cancer, small bowel cancer
and 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 effect epithelial cells throughout the body.
Neoplasias for 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
the fibrosis which 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.
[0066] Compositions of the present invention possess
anti-inflammatory, antipyretic and analgesic properties similar or
superior to those of compositions of conventional nonsteroidal
anti-inflammatory drugs. Contemplated compositions also inhibit
hormone-induced uterine contractions and have potential anti-cancer
effects, but with a diminished ability to induce some of the
mechanism-based side effects of conventional NSAIDs. In particular,
compositions of the invention have reduced potential for
gastrointestinal toxicity and gastrointestinal irritation 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
on 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.
[0067] Contemplated compositions are useful for the relief of pain,
fever and inflammation of a variety of conditions including
rheumatic fever, symptoms associated with influenza or other viral
infections, 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 injuries following surgical and dental
procedures. In addition, contemplated compositions inhibit cellular
neoplastic transformations and metastic tumor growth and hence can
be used in the treatment of cancer, such as cancer of the colon.
Contemplated compositions are also of use in the treatment and/or
prevention of cyclooxygenase-mediated proliferative disorders such
as may occur in diabetic retinopathy and tumor angiogenesis.
[0068] Contemplated compositions inhibit prostanoid-induced smooth
muscle contraction by preventing the synthesis of contractile
prostanoids and hence can be of use in the treatment of
dysmenorrhea, premature labour, asthma and eosinophil-related
disorders. They also can be of use in the treatment of Alzheimer's
disease, for decreasing bone loss particularly in postmenopausal
women (i.e., treatment of osteoporosis), and for treatment of
glaucoma.
[0069] By virtue of their high cyclooxygenase-2 (COX-2) inhibitory
activity and/or their specificity for inhibition of
cyclooxygenase-2 over cyclooxygenase-1 (COX-1), compositions of the
invention are useful as an alternative to conventional NSAIDs,
particularly where such NSAIDs 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 or patients taking anticoagulants. A brief description of
the potential utility of cyclooxygenase-2 inhibitors is given in an
article by John Vane, Nature, Vol. 367, pp. 215-216, 1994, and in
an article in Drug News and Perspectives, Vol. 7, pp. 501-512,
1994.
[0070] Preferred uses for the pharmaceutical compositions of the
present invention are for the 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), the treatment of
Alzheimer's disease, and colon cancer chemoprevention.
[0071] Besides being useful for human treatment, compositions of
the invention are also useful for veterinary treatment of companion
animals, exotic animals and 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.
[0072] 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 blockers, among others. Preferred combination
therapies comprise use of a composition of the invention with
compounds selected from morphine, meperidine, codeine, pentazocine,
buprenorphine, butorphanol, dezocine, meptazinol, hydrocodone,
oxycodone, methadone, DuP-747, Dynorphine A, Enadoline, RP-60180,
HN-11608, E-2078, ICI-204448, acetaminophen (paracetamol),
propoxyphene, nalbuphine, E-4018, filenadol, mirfentanil,
amitriptyline, DuP-631, GP-531, acadesine, AKI-1, AKI-2, GP-1683,
GP-3269, 4030W92, tramadol racemate and isolated (+) and (-)
enantiomers, AXC-3742, SNX-111, ADL2-1294, CT-3, and CP-99994.
DEFINITIONS
[0073] The term "active ingredient" herein means celecoxib unless
the context demands otherwise.
[0074] The term "excipient" herein includes any substance used as a
vehicle for delivery of the active ingredient to a subject, and any
substance added to the active ingredient, for example to improve
its handling properties or to permit the resulting composition to
be formed into an orally deliverable unit dose having the desired
shape and consistency. Excipients can include, by way of
illustration and not by limitation, diluents, disintegrants,
binding agents, adhesives, wetting agents, lubricants, glidants,
substances added to mask or counteract a bad taste or odor,
flavors, dyes, substances added to improve appearance of a dosage
form, and any other substance other than the active ingredient
conventionally used in the preparation of oral dosage forms.
[0075] The term "adjuvant" herein means a substance that, when
present in or added to a pharmaceutical composition comprising an
active ingredient, increases or otherwise improves the action of
the active ingredient.
[0076] The term "unit dose" herein refers to an amount of active
ingredient intended for a single oral administration to a subject
for treatment or prevention of a cyclooxygenase-2 mediated
condition or disorder. Treatment of a cyclooxygenase-2 mediated
disorder may require periodic administration of unit doses of
celecoxib, for example one unit dose two or more times a day, one
unit dose with each meal, one unit dose every four hours or other
interval, or only one unit dose per day.
[0077] The term "dose unit" herein means a portion of a
pharmaceutical composition that contains a single unit dose of the
active ingredient. For purposes of the present invention, a dose
unit can be in the form of a discrete article such as a tablet or
capsule, or can be a measurable volume of a solution, suspension or
the like containing a unit dose of the active ingredient.
[0078] The term "orally deliverable" herein means intended to be
administered to the gastrointestinal tract of a subject via the
mouth of said subject.
[0079] The term "substantially homogeneous", when used herein to
describe a pharmaceutical composition that contains a combination
of components, means that the components are fully mixed so that
the individual components are neither separated into discrete
layers nor form concentration gradients within the composition.
[0080] The term "bioavailability" herein relates to a measure of
the amount of active ingredient that is absorbed via the
gastrointestinal tract into the bloodstream. More specifically,
"bioavailability" is used herein to denote AUC.sub.(0-.infin.) for
a specific orally administered composition expressed as a
percentage of AUC.sub.(0-.infin.) for the active ingredient
delivered intravenously at the same dosage rate.
[0081] The term "relative bioavailability" herein denotes
AUC.sub.(0-.infin.) for a specific orally administered composition
expressed as a percentage of AUC.sub.(0-.infin.) for an orally
administered solution of the active ingredient at the same dosage
rate.
[0082] The terms "AUC.sub.(0-24)", "AUC.sub.(0-48)" and
"AUC.sub.(0-72)" herein mean the area under the curve relating
blood serum concentration to time after administration from 0 to 24
hours, 48 hours or 72 hours respectively, as determined using the
linear trapezoidal rule, and are expressed in units of
(ng/ml)h.
[0083] The term "AUC.sub.(0-LQC)" herein means the area under the
curve relating blood serum concentration to time after
administration from 0 hours to the time of last quantifiable
concentration ("LQC"), as determined using the linear trapezoidal
rule, and is expressed in units of (ng/ml)h.
[0084] The term "AUC.sub.(0-.infin.)" herein is calculated as
AUC.sub.(0-LQC)+LQC/(-b), where LQC is the last quantifiable blood
serum concentration and b is the slope from the calculation of
T.sub.1/2, and is expressed in units of (ng/ml)h.
[0085] The term "C.sub.max" herein means the maximum observed blood
serum concentration or the maximum blood serum concentration
calculated or estimated from a concentration/time curve, and is
expressed in units of ng/ml.
[0086] The term "T.sub.max" herein means the time after
administration at which C.sub.max occurs, and is expressed in units
of hours (h).
[0087] The term "T.sub.1/2" herein means the terminal half-life of
blood serum concentration, determined via simple linear regression
of natural log(ln) concentration vs. time for data points in the
terminal phase of the concentration-time curve. T.sub.1/2 is
computed as -ln(2)/(-b) and is expressed in units of hours (h).
[0088] The term "rate of absorption" herein means
C.sub.max/AUC.sub.(0-LQC).
Celecoxib Dosage Provided by Compositions of the Invention
[0089] The pharmaceutical compositions of the present invention are
suitable for administration of celecoxib in a daily dosage amount
from about 10 mg to about 1000 mg. Each dose unit of a composition
of the invention typically comprises an amount of celecoxib from
about one-tenth of the daily dosage amount to the whole of a daily
dosage amount. Compositions of the invention comprise celecoxib in
an amount of about 10 mg to about 1000 mg, preferably about 50 mg
to about 800 mg, more preferably about 75 mg to about 400 mg, and
most preferably about 100 mg to about 200 mg, per dose unit. Where
the dose units are in the form of discrete articles suitable for
oral administration, for example capsules or tablets, each such
article comprises about 10 mg to about 1000 mg, preferably about 50
mg to about 800 mg, more preferably about 75 mg to about 400 mg,
and most preferably about 100 mg to about 200 mg, of celecoxib.
[0090] Dose units of compositions of the invention typically
contain, for example, a 10, 20, 25, 37.5, 50, 75, 100, 125, 150,
175, 200, 250, 300, 350 or 400 mg dose of celecoxib. Preferred
compositions have dose units containing about 100 mg or about 200
mg of celecoxib. The particular dose unit can be selected to
accommodate the desired frequency of administration used to achieve
a desired daily dosage. The daily dosage and frequency of
administration, and therefore the selection of appropriate dose
unit, depends on a variety of factors, including the age, weight,
sex and medical condition of the subject, and the nature and
severity of the condition or disorder, and thus may vary
widely.
[0091] It has been discovered, however, that a once-a-day or
twice-a-day administration regimen to provide the required daily
dosage of celecoxib exhibits improved efficacy relative to other
administration regimens, for compositions illustrated herein.
Accordingly, once-a-day or twice-a-day oral administration of a
composition of the invention is preferred for providing
therapeutically or prophylactically effective inhibition of
cyclooxygenase-2 mediated disorders.
Treatment of Specific Conditions and Disorders
[0092] The pharmaceutical compositions of the present invention are
useful where administration of a cyclooxygenase-2 inhibitor is
indicated. It has been found that these compositions are
particularly effective in the treatment of, for example, rheumatoid
arthritis and osteoarthritis, and for pain management generally
(particularly post-oral surgery pain, post-general surgery pain,
post-orthopedic surgery pain, and acute flares of osteoarthritis),
the treatment of Alzheimer's disease, and colon cancer
chemoprevention.
[0093] For the treatment of rheumatoid arthritis, compositions of
the invention can be used to provide a daily dosage of celecoxib of
about 50 mg to about 1000 mg, preferably about 100 mg to about 600
mg, more preferably about 150 mg to about 500 mg, and still more
preferably about 175 to about 400, for example about 200 mg. A
daily dose of celecoxib of about 0.67 to about 13.3 mg/kg body
weight, preferably about 1.33 to about 8.00 mg/kg body weight, more
preferably about 2.00 to about 6.67 mg/kg body weight, and still
more preferably about 2.33 to about 5.33 mg/kg body weight, for
example about 2.67 mg/kg body weight, is generally appropriate when
administered in a composition of the invention. The daily dose can
be administered in one to four doses per day, preferably one or two
doses per day. Administration of a composition of the invention at
the rate of one 100 mg dose unit twice a day is preferred for most
patients, but some patients may benefit from administration of one
200 mg dose unit or two 100 mg dose units twice a day.
[0094] For the treatment of osteoarthritis, compositions of the
invention can be used to provide a daily dosage of celecoxib of
about 50 mg to about 1000 mg, preferably about 100 mg to about 600
mg, more preferably about 150 mg to about 500 mg, and still more
preferably about 175 to about 400, for example about 200 mg. A
daily dose of celecoxib of about 0.67 to about 13.3 mg/kg body
weight, preferably about 1.33 to about 8.00 mg/kg body weight, more
preferably about 2.00 to about 6.67 mg/kg body weight, and still
more preferably about 2.33 to about 5.33 mg/kg body weight, for
example about 2.67 mg/kg body weight, is generally appropriate when
administered in a composition of the invention. The daily dose can
be administered in one to four doses per day, preferably one or two
doses per day. Administration of a composition of the invention at
the rate of one 100 mg dose unit twice a day or of one 200 mg dose
unit or two 100 mg dose units once a day is preferred.
[0095] For the treatment of Alzheimer's disease, compositions of
the invention can be used to provide a daily dosage of celecoxib of
about 50 mg to about 1000 mg, preferably about 100 mg to about 800
mg, more preferably about 150 mg to about 600 mg, and still more
preferably about 175 to about 400, for example about 400 mg. A
daily dose of about 0.67 to about 13.3 mg/kg body weight,
preferably about 1.33 to about 10.67 mg/kg body weight, more
preferably about 2.00 to about 8.00 mg/kg body weight, and still
more preferably about 2.33 to about 5.33 mg/kg body weight, for
example about 5.33 mg/kg body weight, is generally appropriate when
administered in a composition of the invention. The daily dose can
be administered in one to four doses per day, preferably one or two
doses per day. Administration of a composition of the invention at
the rate of one 200 mg dose unit or two 100 mg dose units twice a
day is preferred for most patients.
[0096] For the treatment of cancer, compositions of the invention
can be used to provide a daily dosage of celecoxib of about 50 mg
to about 1000 mg, preferably about 100 mg to about 800 mg, more
preferably about 150 mg to about 600 mg, and still more preferably
about 175 to about 400, for example about 400 mg. A daily dose of
about 0.67 to about 13.3 mg/kg body weight, preferably about 1.33
to about 10.67 mg/kg body weight, more preferably about 2.00 to
about 8.00 mg/kg body weight, and still more preferably about 2.33
to about 5.33 mg/kg body weight, for example about 5.33 mg/kg body
weight, is generally appropriate when administered in a composition
of the invention. The daily dose can be administered in one to four
doses per day, preferably two doses per day. Administration of a
composition of the invention at the rate of one 200 mg dose unit or
two 100 mg dose units twice a day is preferred for most
patients.
[0097] In general, a composition of the invention is preferably
administered at a dose suitable to provide an average blood serum
concentration of celecoxib of at least about 100 ng/ml in a subject
over a period of about 24 hours after administration.
[0098] It has been found that the pharmaceutical compositions of
the present invention provide a therapeutic effect as
cyclooxygenase-2 inhibitors over an interval of about 12 to about
24 hours after oral administration. Preferred compositions provide
such therapeutic effect over about 24 hours, enabling once-a-day
oral administration.
[0099] While the amount of celecoxib in the novel compositions of
the invention preferably is in a range disclosed herein, the
compositions also may be useful for the administration of an amount
of celecoxib falling outside the disclosed dosage ranges.
Preparation of Celecoxib
[0100] The celecoxib used in the novel pharmaceutical compositions
of the present invention can be prepared in the manner set forth in
Talley et al., U.S. Pat. No. 5,466,823, or in Zhi et al., WO
96/37476.
Form of Compositions of the Invention
[0101] The pharmaceutical compositions of the present invention
comprise celecoxib in association with one or more preferably
non-toxic, pharmaceutically acceptable carriers, excipients and
adjuvants (collectively referred to herein as "carrier materials"
or "excipients") suitable for oral administration. The carrier
materials must be acceptable in the sense of being compatible with
the other ingredients of the composition and must not be
deleterious to the recipient. Compositions of the present invention
can be adapted for administration by any suitable oral route by
selection of appropriate carrier materials and a dosage of
celecoxib effective for the treatment intended. Accordingly, any
carrier materials employed can be solids or liquids, or both, and
the composition preferably contains about 1% to about 95%,
preferably about 10% to about 90%, more preferably about 25% to
about 85%, and still more preferably about 30% to about 80%, by
weight of celecoxib. Such pharmaceutical compositions of the
invention can be prepared by any of the well known techniques of
pharmacy, comprising admixing the components.
[0102] A composition of the invention contains a desired amount of
celecoxib per dose unit and can be in the form of, for example, a
tablet, a pill, a hard or soft capsule, a lozenge, a cachet, a
dispensable powder, granules, a suspension, an elixir, a liquid, or
any other form reasonably adapted for oral administration. Such a
composition is preferably made in the form of discrete dose units
each containing a predetermined amount of celecoxib, such as
tablets or capsules. These oral dosage forms may further comprise,
for example, buffering agents. Tablets, pills and the like
additionally can be prepared with or without coatings.
[0103] Compositions of the invention suitable for buccal or
sublingual administration include, for example, lozenges comprising
celecoxib in a flavored base, such as sucrose, and acacia or
tragacanth, and pastilles comprising celecoxib in an inert base
such as gelatin and glycerin or sucrose and acacia.
[0104] Liquid dosage forms for oral administration include
pharmaceutically acceptable suspensions, syrups, and elixirs
containing inert diluents commonly used in the art, such as water.
Such compositions may also comprise, for example, wetting agents,
emulsifying and suspending agents, and sweetening, flavoring, and
perfuming agents.
[0105] As indicated above, compositions of the invention can be
prepared by any suitable method of pharmacy which includes the step
of bringing into association the celecoxib and the carrier material
or carrier materials. In general, the compositions are prepared by
uniformly and intimately admixing celecoxib with a liquid or finely
divided solid carrier, or both, and then, if necessary,
encapsulating or shaping the product. For example, a tablet can be
prepared by compressing or molding a powder or granules of the
compound, together with one or more excipients. Compressed tablets
can be prepared by compressing, in a suitable machine, a
free-flowing composition, such as a powder or granules, comprising
celecoxib optionally mixed with one or more binding agent(s),
lubricant(s), inert diluent(s), wetting agent(s) and/or dispersing
agent(s). Molded tablets can be made by molding, in a suitable
machine, the powdered compound moistened with an inert liquid
diluent.
Carrier Materials or Excipients
[0106] As noted above, the pharmaceutical compositions of the
present invention comprise celecoxib in a therapeutically or
prophylactically effective amount per dose unit in combination with
one or more pharmaceutically acceptable carrier materials
appropriate for oral administration. Compositions of the present
invention preferably comprise celecoxib in a desired amount admixed
with one or more carrier materials selected from the group
consisting of pharmaceutically acceptable diluents, disintegrants,
binding agents, adhesives, wetting agents, lubricants, and
anti-adherent agents. More preferably, such compositions are
tableted or encapsulated for convenient administration in the form
of immediate release capsules or tablets.
[0107] Through the selection and combination of carrier materials
used in the pharmaceutical compositions of the present invention,
compositions can be provided exhibiting improved performance with
respect to, among other properties, efficacy, bioavailability,
clearance time, stability, compatibility of celecoxib and carrier
materials, safety, dissolution profile, disintegration profile
and/or other pharmacokinetic, chemical and/or physical properties.
The carrier materials preferably are water soluble or water
dispersible and have wetting properties to offset the low aqueous
solubility and hydrophobicity of celecoxib. Where the composition
is formulated as a tablet, the combination of carrier materials
selected provides tablets that can exhibit improvement, among other
properties, in dissolution and disintegration profiles, hardness,
crushing strength, and/or friability.
Diluents
[0108] The pharmaceutical compositions of the present invention
optionally comprise one or more pharmaceutically acceptable
diluents as a carrier material. Suitable diluents include, either
individually or in combination, lactose USP; lactose USP,
anyhydrous; lactose USP, spray dried; starch USP; directly
compressible starch; mannitol USP; sorbitol; dextrose monohydrate;
microcrystalline cellulose NF; dibasic calcium phosphate dihydrate
NF; sucrose-based diluents; confectioner's sugar; monobasic calcium
sulfate monohydrate; calcium sulfate dihydrate NF; calcium lactate
trihydrate granular NF; dextrates, NF (e.g., Emdex); Celutab;
dextrose (e.g., Cerelose); inositol; hydrolyzed cereal solids such
as the Maltrons and Mor-Rex; amylose; Rexcel; powdered cellulose
(e.g., Elcema); calcium carbonate; glycine; bentonite;
polyvinylpyrrolidone; and the like. Such diluents, if present,
constitute in total about 5% to about 99%, preferably about 10% to
about 85%, and more preferably about 20% to about 80%, of the total
weight of the composition. The diluent or diluents selected
preferably exhibit suitable flow properties and, where tablets are
desired, compressibility.
[0109] Lactose and microcrystalline cellulose, either individually
or in combination, are preferred diluents. Both diluents are
chemically compatible with celecoxib. The use of extragranular
microcrystalline cellulose (that is, microcrystalline cellulose
added to a wet granulated composition after the drying step) can be
used to improve hardness (for tablets) and/or disintegration time.
Lactose, especially lactose monohydrate, is particularly preferred.
Lactose typically provides pharmaceutical compositions having
suitable celecoxib release rates, stability, pre-compression
flowability, and/or drying properties at a relatively low diluent
cost. It provides a high density substrate that aids densification
during granulation (where wet granulation is employed) and
therefore improves blend flow properties.
Disintegrants
[0110] The pharmaceutical compositions of the present invention
optionally comprise one or more pharmaceutically acceptable
disintegrants as a carrier material, particularly for tablet
formulations. Suitable disintegrants include, either individually
or in combination, starches; sodium starch glycolate; clays (such
as Veegum HV); celluloses (such as purified cellulose,
methylcellulose, sodium carboxymethylcellulose and
carboxymethylcellulose); alginates; pregelatinized corn starches
(such as National 1551 and National 1550); crospovidone USP NF; and
gums (such as agar, guar, locust bean, Karaya, pectin, and
tragacanth). Disintegrants may be added at any suitable step during
the preparation of the pharmaceutical composition, particularly
prior to granulation or during the lubrication step prior to
compression. Such disintegrants, if present, constitute in total
about 0.2% to about 30%, preferably about 0.2% to about 10%, and
more preferably about 0.2% to about 5%, of the total weight of the
composition.
[0111] Croscarmellose sodium is a preferred disintegrant for tablet
or capsule disintegration, and, if present, preferably constitutes
about 0.2% to about 10%, more preferably about 0.2% to about 6%,
and still more preferably about 0.2% to about 5%, of the total
weight of the composition. Croscarmellose sodium confers superior
intragranular disintegration capabilities to compositions of the
present invention.
Binding Agents and Adhesives
[0112] The pharmaceutical compositions of the present invention
optionally comprise one or more pharmaceutically-acceptable binding
agents or adhesives as a carrier material, particularly for tablet
formulations. Such binding agents and adhesives preferably impart
sufficient cohesion to the powder being tableted to allow for
normal processing operations such as sizing, lubrication,
compression and packaging, but still allow the tablet to
disintegrate and the composition to be absorbed upon ingestion.
Suitable binding agents and adhesives include, either individually
or in combination, acacia; tragacanth; sucrose; gelatin; glucose;
starch; cellulose materials such as, but not limited to,
methylcellulose and sodium carboxymethylcellulose (e.g., Tylose);
alginic acid and salts of alginic acid; magnesium aluminum
silicate; polyethylene glycol; guar gum; polysaccharide acids;
bentonites; polyvinylpyrrolidone; polymethacrylates;
hydroxypropylmethylcellulose (HPMC); hydroxypropylcellulose
(Klucel); ethylcellulose (Ethocel); pregelatinized starch (such as
National 1511 and Starch 1500). Such binding agents and/or
adhesives, if present, constitute in total about 0.5% to about 25%,
preferably about 0.75% to about 15%, and more preferably about 1%
to about 10%, of the total weight of the composition.
[0113] Polyvinylpyrrolidone is a preferred binding agent used to
impart cohesive properties to a powder blend of celecoxib and other
excipients for granulation of a celecoxib formulation.
Polyvinylpyrrolidone, if present, preferably constitutes about 0.5%
to about 10%, more preferably about 0.5% to about 7%, and still
more preferably about 0.5% to about 5% of the total weight of the
composition. Polyvinylpyrrolidone viscosities up to about 20 cPs
may be used although viscosities of about 6 cPs or lower are
preferred, particularly about 3 cPs or lower. Polyvinylpyrrolidone
provides cohesiveness to the powder blend and facilitates the
necessary binding to form granules during wet granulation. In
addition, compositions of the present invention comprising
polyvinylpyrrolidone, particularly compositions prepared by wet
granulation, have been found to exhibit improved bioavailability
relative to other compositions.
Wetting Agents
[0114] Celecoxib is largely insoluble in aqueous solution.
Accordingly, the pharmaceutical compositions of the present
invention optionally but preferably comprise one or more
pharmaceutically acceptable wetting agents as a carrier material.
Such wetting agents are preferably selected to maintain celecoxib
in close association with water, a condition that is believed to
improve the relative bioavailability of the pharmaceutical
composition. Suitable wetting agents include, either individually
or in combination, oleic acid; glyceryl monostearate; sorbitan
monooleate; sorbitan monolaurate; triethanolamine oleate;
polyoxyethylene sorbitan monooleate; polyoxyethylene sorbitan
monolaurate; sodium oleate; and sodium lauryl sulfate. Wetting
agents that are anionic surfactants are preferred. Such wetting
agents, if present, constitute in total about 0.25% to about 15%,
preferably about 0.4% to about 10%, and more preferably about 0.5%
to about 5%, of the total weight of the composition.
[0115] Sodium lauryl sulfate is a preferred wetting agent. Sodium
lauryl sulfate, if present, constitutes about 0.25% to about 7%,
more preferably about 0.4% to about 6%, and still more preferably
about 0.5 to about 5% of the total weight of the composition.
Lubricants
[0116] The pharmaceutical compositions of the present invention
optionally comprise one or more pharmaceutically acceptable
lubricants and/or glidants as a carrier material. Suitable
lubricants and/or glidants include, either individually or in
combination, glyceryl behapate (Compritol 888); stearates
(magnesium, calcium, and sodium); stearic acid; hydrogenated
vegetable oils (e.g., Sterotex); talc; waxes; Stearowet; boric
acid; sodium benzoate; sodium acetate; sodium fumarate; sodium
chloride; DL-leucine; polyethylene glycols (e.g., Carbowax 4000 and
Carbowax 6000); sodium oleate; sodium lauryl sulfate; and magnesium
lauryl sulfate. Such lubricants, if present, constitute in total
about 0.1% to about 10%, preferably about 0.2% to about 8%, and
more preferably about 0.25% to about 5%, of the total weight of the
composition.
[0117] Magnesium stearate is a preferred lubricant used, for
example, to reduce friction between the equipment and granulated
mixture during compression of tablet formulations.
[0118] Other carrier materials (such as anti-adherent agents,
colorants, flavors, sweeteners and preservatives) are known in the
pharmaceutical art and can be included in compositions of the
present invention. For example, iron oxide can be added to the
composition to provide a yellow color.
Capsules and Tablets
[0119] In one embodiment of the present invention, the
pharmaceutical composition is in the form of unit dose capsules or
tablets and comprises celecoxib in a desired amount and a binding
agent. The composition preferably further comprises one or more
carrier materials selected from the group consisting of
pharmaceutically acceptable diluents, disintegrants, binding
agents, wetting agents, and lubricants. More preferably, the
composition comprises one or more carrier materials selected from
the group consisting of lactose, sodium lauryl sulfate,
polyvinylpyrrolidone, croscarmellose sodium, magnesium stearate,
and microcrystalline cellulose. Still more preferably, the
composition comprises lactose monohydrate and croscarmellose
sodium. Still more preferably, the composition further comprises
one or more of the carrier materials sodium lauryl sulfate,
magnesium stearate, and microcrystalline cellulose.
[0120] In another embodiment, the pharmaceutical composition
comprises: [0121] (a) about 1 to about 95 weight percent of
celecoxib; [0122] (b) about 5 to about 99 weight percent of a
pharmaceutically acceptable diluent; [0123] (c) about 0.5 to about
30 weight percent of a pharmaceutically acceptable disintegrant;
and [0124] (d) about 0.5 to about 25 weight percent of a
pharmaceutically acceptable binding agent.
[0125] In addition, this pharmaceutical composition optionally
comprises: [0126] (e) about 0.25 to about 15 weight percent of a
pharmaceutically acceptable wetting agent; and/or [0127] (f) about
0.1 to about 10 weight percent of a pharmaceutically acceptable
lubricant.
[0128] The term "weight percent" as used herein means the weight
percent of a specified ingredient based upon the total weight of
all ingredients of the composition.
[0129] In another embodiment, the pharmaceutical composition
comprises: [0130] (a) about 1 to about 95 weight percent of
celecoxib; [0131] (b) about 5 to about 99 weight percent of
lactose; [0132] (c) about 2 to about 6 weight percent of
croscarmellose sodium; and [0133] (d) about 0.5 to about 10 weight
percent of polyvinylpyrrolidone.
[0134] In addition, this pharmaceutical composition optionally
comprises: [0135] (e) about 0.25 to about 7 weight percent of
sodium lauryl sulfate; [0136] (f) about 0.1 to about 10 weight
percent of magnesium stearate; and/or [0137] (g) about 1 to about
99 weight percent of microcrystalline cellulose.
[0138] In another embodiment, the pharmaceutical composition
comprises: [0139] (a) about 80 to about 220 mg of celecoxib; [0140]
(b) about 30 to about 225 mg of lactose; [0141] (c) about 0.5 to
about 25 mg of croscarmellose sodium; and [0142] (d) about 0.5 to
about 25 mg of polyvinylpyrrolidone.
[0143] In addition, this pharmaceutical composition optionally
comprises: [0144] (e) about 0.5 to about 25 mg of sodium lauryl
sulfate; [0145] (f) about 0.2 to about 10 mg of magnesium stearate;
and/or [0146] (g) about 1 mg to about 70 mg of microcrystalline
cellulose.
[0147] In another embodiment, the pharmaceutical composition
comprises: [0148] (a) about 25 to about 85 weight percent of
celecoxib; [0149] (b) about 5 to about 70 weight percent of
lactose; [0150] (c) about 0.2 to about 5 weight percent of
croscarmellose sodium; and [0151] (d) about 0.5 to about 7 weight
percent of polyvinylpyrrolidone.
[0152] In addition, this pharmaceutical composition optionally
comprises: [0153] (e) about 0.4 to about 6 weight percent of sodium
lauryl sulfate; [0154] (f) about 0.2 to about 8 weight percent of
magnesium stearate; and/or [0155] (g) about 0.1 to about 15 weight
percent of microcrystalline cellulose.
[0156] The composition of this embodiment preferably is in the form
of a unit dosage capsule.
[0157] In another embodiment, the pharmaceutical composition
comprises: [0158] (a) about 27 to about 47 weight percent of
celecoxib; [0159] (b) about 45 to about 65 weight percent of
lactose; [0160] (c) about 0.5 to about 5 weight percent of
croscarmellose sodium; and [0161] (d) about 0.5 to about 5 weight
percent of polyvinylpyrrolidone.
[0162] In addition, this pharmaceutical composition optionally
comprises: [0163] (e) about 0.25 to about 7 weight percent of
sodium lauryl sulfate; and/or [0164] (f) about 0.25 to about 5
weight percent of magnesium stearate.
[0165] The composition of this embodiment preferably is in the form
of a unit dosage capsule. In this embodiment, the pharmaceutical
composition preferably comprises: [0166] (a) about 32 to about 42
weight percent of celecoxib; [0167] (b) about 50 to about 60 weight
percent of lactose; [0168] (c) about 0.5 to about 3 weight percent
of croscarmellose sodium; and [0169] (d) about 1 to about 5 weight
percent of polyvinylpyrrolidone.
[0170] In addition, this pharmaceutical composition optionally
comprises: [0171] (e) about 0.4 to about 6 weight percent of sodium
lauryl sulfate; and/or [0172] (f) about 0.5 to about 3 weight
percent of magnesium stearate.
[0173] In this embodiment, the pharmaceutical composition more
preferably comprises: [0174] (a) about 35 to about 39 weight
percent of celecoxib; [0175] (b) about 54 to about 57 weight
percent of lactose; [0176] (c) about 0.5 to about 2 weight percent
of croscarmellose sodium; and [0177] (d) about 1.5 to about 4.5
weight percent of polyvinylpyrrolidone.
[0178] In addition, this pharmaceutical composition optionally
comprises: [0179] (e) about 2 to about 4 weight percent of sodium
lauryl sulfate; and/or [0180] (f) about 0.5 to about 2 weight
percent of magnesium stearate.
[0181] In another embodiment, the pharmaceutical composition
comprises: [0182] (a) about 65 to about 85 weight percent of
celecoxib; [0183] (b) about 8 to about 28 weight percent of
lactose; [0184] (c) about 0.5 to about 5 weight percent of
croscarmellose sodium; and [0185] (d) about 0.5 to about 5 weight
percent of polyvinylpyrrolidone.
[0186] In addition, this pharmaceutical composition optionally
comprises: [0187] (e) about 0.25 to about 7 weight percent of
sodium lauryl sulfate; and/or [0188] (f) about 0.25 to about 5
weight percent of magnesium stearate.
[0189] The composition of this embodiment preferably is in the form
of a unit dosage capsule. In this embodiment, the pharmaceutical
composition preferably comprises: [0190] (a) about 69 to about 79
weight percent of celecoxib; [0191] (b) about 13.5 to about 23.5
weight percent of lactose; [0192] (c) about 0.5 to about 3 weight
percent of croscarmellose sodium; and [0193] (d) about 1 to about 5
weight percent of polyvinylpyrrolidone.
[0194] In addition, this pharmaceutical composition optionally
comprises: [0195] (e) about 0.4 to about 6 weight percent of sodium
lauryl sulfate; and/or [0196] (f) about 0.5 to about 3 weight
percent of magnesium stearate.
[0197] In this embodiment, the pharmaceutical composition more
preferably comprises: [0198] (a) about 72 to about 76 weight
percent of celecoxib; [0199] (b) about 16.5 to about 20.5 weight
percent of lactose; [0200] (c) about 0.5 to about 2 weight percent
of croscarmellose sodium; and [0201] (d) about 1.5 to about 4.5
weight percent of polyvinylpyrrolidone.
[0202] In addition, this pharmaceutical composition optionally
comprises: [0203] (e) about 2 to about 4 weight percent of sodium
lauryl sulfate; and/or [0204] (f) about 0.5 to about 2 weight
percent of magnesium stearate.
[0205] In another embodiment, the pharmaceutical composition
comprises: [0206] (a) about 30 to about 50 weight percent of
celecoxib; [0207] (b) about 30 to about 50 weight percent of
lactose; [0208] (c) about 0.5 to about 6 weight percent of
croscarmellose sodium; and [0209] (d) about 0.5 to about 5 weight
percent of polyvinylpyrrolidone.
[0210] In addition, this pharmaceutical composition optionally
comprises: [0211] (e) about 1 to about 20 weight percent of
microcrystalline cellulose; [0212] (f) about 0.25 to about 7 weight
percent of sodium lauryl sulfate; and/or [0213] (g) about 0.25 to
about 5 weight percent of magnesium stearate.
[0214] The composition of this embodiment preferably is in the form
of a unit dosage tablet. In this embodiment, the pharmaceutical
composition preferably comprises: [0215] (a) about 35 to about 45
weight percent of celecoxib; [0216] (b) about 35 to about 45 weight
percent of lactose; [0217] (c) about 1 to about 5 weight percent of
croscarmellose sodium; and [0218] (d) about 1 to about 5 weight
percent of polyvinylpyrrolidone.
[0219] In addition, this pharmaceutical composition optionally
comprises: [0220] (e) about 5 to about 15 weight percent of
microcrystalline cellulose; [0221] (f) about 0.4 to about 6 weight
percent of sodium lauryl sulfate; and/or [0222] (g) about 0.5 to
about 3 weight percent of magnesium stearate.
[0223] In this embodiment, the pharmaceutical composition more
preferably comprises: [0224] (a) about 38 to about 42 weight
percent of celecoxib; [0225] (b) about 38 to about 42 weight
percent of lactose; [0226] (c) about 1.5 to about 4.5 weight
percent of croscarmellose sodium; and [0227] (d) about 1.5 to about
4.5 weight percent of polyvinylpyrrolidone.
[0228] In addition, this pharmaceutical composition optionally
comprises: [0229] (e) about 8 to about 12 weight percent of
microcrystalline cellulose; [0230] (f) about 2 to about 4 weight
percent of sodium lauryl sulfate; and/or [0231] (g) about 0.5 to
about 2 weight percent of magnesium stearate.
[0232] In another embodiment, the pharmaceutical composition
comprises: [0233] (a) about 95 to about 105 mg of celecoxib; [0234]
(b) about 145 to about 155 mg of lactose monohydrate; [0235] (c)
about 0.5 to about 8 mg of croscarmellose sodium; and [0236] (d)
about 2 to about 12 mg of polyvinylpyrrolidone.
[0237] In addition, this pharmaceutical composition optionally
comprises: [0238] (e) about 3 to about 13 mg of sodium lauryl
sulfate; and/or [0239] (f) about 0.5 to about 8 mg of magnesium
stearate.
[0240] The composition of this embodiment preferably is in the form
of a unit dosage capsule. In this embodiment, the pharmaceutical
composition preferably comprises: [0241] (a) about 98 to about 102
mg of celecoxib; [0242] (b) about 148 to about 152 mg of lactose
monohydrate; [0243] (c) about 1.5 to about 4.5 mg of croscarmellose
sodium; and [0244] (d) about 4.5 to about 8.5 mg of
polyvinylpyrrolidone.
[0245] In addition, this pharmaceutical composition optionally
comprises: [0246] (e) about 6 to about 10 mg of sodium lauryl
sulfate; and/or [0247] (f) about 1 to about 5 mg of magnesium
stearate.
[0248] In another embodiment, the pharmaceutical composition
comprises: [0249] (a) about 195 to about 205 mg of celecoxib;
[0250] (b) about 45 to about 55 mg of lactose monohydrate; [0251]
(c) about 0.5 to about 8 mg of croscarmellose sodium; and [0252]
(d) about 2 to about 12 mg of polyvinylpyrrolidone.
[0253] In addition, this pharmaceutical composition optionally
comprises: [0254] (e) about 3 to about 13 mg of sodium lauryl
sulfate; and/or [0255] (f) about 0.5 to about 8 mg of magnesium
stearate.
[0256] The composition of this embodiment preferably is in the form
of a unit dosage capsule. In this embodiment, the pharmaceutical
composition preferably comprises: [0257] (a) about 198 to about 202
mg of celecoxib; [0258] (b) about 48 to about 52 mg of lactose
monohydrate; [0259] (c) about 1.5 to about 4.5 mg of croscarmellose
sodium; and [0260] (d) about 4.5 to about 8.5 mg of
polyvinylpyrrolidone.
[0261] In addition, this pharmaceutical composition optionally
comprises: [0262] (e) about 6 to about 10 mg of sodium lauryl
sulfate; and/or [0263] (f) about 1 to about 5 mg of magnesium
stearate.
[0264] In another embodiment, the pharmaceutical composition
comprises: [0265] (a) about 95 to about 105 mg of celecoxib; [0266]
(b) about 92 to about 112 mg of lactose monohydrate; [0267] (c)
about 2 to about 13 mg of croscarmellose sodium; and [0268] (d)
about 1 to about 11 mg of polyvinylpyrrolidone.
[0269] In addition, this pharmaceutical composition optionally
comprises: [0270] (e) about 20 to about 30 mg of microcrystalline
cellulose; [0271] (f) about 3 to about 13 mg of sodium lauryl
sulfate; and/or [0272] (g) about 0.5 to about 7 mg of magnesium
stearate.
[0273] The composition of this embodiment preferably is in the form
of a unit dosage tablet. In this embodiment, the pharmaceutical
composition preferably comprises: [0274] (a) about 98 to about 102
mg of celecoxib; [0275] (b) about 100 to about 104 mg of lactose
monohydrate; [0276] (c) about 5 to about 10 mg of croscarmellose
sodium; and [0277] (d) about 4 to about 8.5 mg of
polyvinylpyrrolidone.
[0278] In addition, this pharmaceutical composition optionally
comprises: [0279] (e) about 23 to about 27 mg of microcrystalline
cellulose; [0280] (f) about 5 to about 10 mg of sodium lauryl
sulfate; and/or [0281] (g) about 0.5 to about 4 mg of magnesium
stearate.
[0282] In another embodiment, the pharmaceutical composition
comprises: [0283] (a) about 195 to about 205 mg of celecoxib;
[0284] (b) about 199 to about 209 mg of lactose monohydrate; [0285]
(c) about 10 to about 20 mg of croscarmellose sodium; and [0286]
(d) about 7.5 to about 17.5 mg of polyvinylpyrrolidone.
[0287] In addition, this pharmaceutical composition optionally
comprises: [0288] (e) about 45 to about 55 mg of microcrystalline
cellulose; [0289] (f) about 10 to about 20 mg of sodium lauryl
sulfate; and/or [0290] (g) about 0.5 to about 9 mg of magnesium
stearate.
[0291] The composition of this embodiment preferably is in the form
of a unit dosage tablet. In this embodiment, the pharmaceutical
composition preferably comprises: [0292] (a) about 98 to about 102
mg of celecoxib; [0293] (b) about 202 to about 206 mg of lactose
monohydrate; [0294] (c) about 13 to about 17 mg of croscarmellose
sodium; and [0295] (d) about 10.5 to about 14.5 mg of
polyvinylpyrrolidone.
[0296] In addition, this pharmaceutical composition optionally
comprises: [0297] (e) about 48 to about 52 mg of microcrystalline
cellulose; [0298] (f) about 13 to about 17 mg of sodium lauryl
sulfate; and/or [0299] (g) about 2 to about 6 mg of magnesium
stearate.
Celecoxib Particle Size in Capsules and Tablets
[0300] It has been discovered that reduction of celecoxib particle
size can improve celecoxib bioavailability when administered orally
in the form of capsules or tablets. Accordingly, the D.sub.90
particle size of the celecoxib preferably is less than about 200
.mu.m, more preferably less than about 100 .mu.m, still more
preferably less than about 75 .mu.m, still more preferably less
than about 40 .mu.m, and most preferably less than about 25 .mu.m.
For example, as illustrated in Example 11, reducing the D.sub.90
particle size of the starting material celecoxib from about 60
.mu.m to about 30 .mu.m can materially improve the bioavailability
of the composition. In addition or alternatively, the celecoxib
preferably has a mean particle size in the range of about 1 .mu.m
to about 10 .mu.m, more preferably about 5 .mu.m to about 7
.mu.m.
Granulation Secondary Particle Size and Flow Properties
[0301] Although the pharmaceutical compositions of the present
invention can be prepared, for example, by direct encapsulation or
direct compression, they preferably are wet granulated prior to
encapsulation or compression. Wet granulation, among other effects,
densifies milled compositions resulting in improved flow
properties, improved compression characteristics and easier
metering or weight dispensing of the compositions for encapsulation
or tableting. The secondary particle size resulting from
granulation (i.e., granule size) is not narrowly critical, it being
important only that the average granule size preferably is such as
to allow for convenient handling and processing and, for tablets,
to permit the formation of a directly compressible mixture that
forms pharmaceutically acceptable tablets.
[0302] The desired tap and bulk densities of the granules are
normally about 0.3 g/ml to about 1.0 g/ml.
Release Profile of Capsules and Tablets
[0303] Capsule and tablet compositions of the present invention
preferably are immediate release compositions that release at least
about 50% of the celecoxib, as measured in vitro, within about 45
minutes of ingestion. More preferably, they release at least about
60% of the celecoxib within about 45 minutes of ingestion. Still
more preferably, they release at least about 75% of the celecoxib
within about 45 minutes of ingestion.
[0304] Especially preferred capsule and tablet compositions of the
invention release at least about 50% of the celecoxib within about
15 minutes of ingestion, and/or at least about 60% of the celecoxib
within about 30 minutes after ingestion.
Disintegration Profile of Capsules and Tablets
[0305] Carrier materials for immediate release capsule and tablet
compositions of the invention preferably are selected to provide a
disintegration time of less than about 30 minutes, preferably about
25 minutes or less, more preferably about 20 minutes or less, and
still more preferably about 15 minutes or less.
Hardness
[0306] For tablet formulations, 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
normal compression pressure (for example, applying a force of about
1 kN to about 50 kN in a typical tableting die). Any tablet
hardness convenient with respect to handling, manufacture, storage
and ingestion may be employed. For 100 mg tablets, hardness is
preferably at least 4 kP, more preferably at least about 5 kP, and
still more preferably at least about 6 kP. For 200 mg tablets,
hardness is preferably at least 7 kP, more preferably at least
about 9 kP, and still more preferably at least about 11 kP. The
mixture, however, is not to be compressed to such a degree that
there is subsequent difficulty in achieving hydration when exposed
to gastric fluid.
Friability
[0307] For tablet formulations, tablet friability preferably is
less than about 1.0%, more preferably less than 0.8%, and still
more preferably less than about 0.5% in a standard test.
Method of Treatment
[0308] The present invention also is directed to a therapeutic
method of treating a condition or disorder where treatment with a
cyclooxygenase-2 inhibitor is indicated, the method comprising oral
administration of a pharmaceutical composition of the present
invention to a patient in need thereof. The dosage regimen to
prevent, give relief from, or ameliorate the condition or disorder
preferably corresponds to the once-a-day or twice-a-day treatments
discussed above, 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 regimens
set forth above.
[0309] Initial treatment of a patient suffering from a condition or
disorder where treatment with a cyclooxygenase-2 inhibitor is
indicated can begin with the dosages 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 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 such data permits modification of
the treatment regimen during therapy so that optimally effective
amounts of celecoxib are administered at any point in time, and so
that the duration of treatment can be determined as well. In this
way, the treatment regimen/dosing schedule can be rationally
modified over the course of therapy so that the lowest amount of
celecoxib exhibiting satisfactory effectiveness is administered,
and so that administration is continued only so long as is
necessary to successfully treat the condition or disorder.
Methods for Preparation of Celecoxib Compositions
[0310] The present invention also is directed to methods for the
preparation of pharmaceutical compositions comprising celecoxib. In
particular, the invention is directed to methods for preparing
pharmaceutical compositions comprising celecoxib in particulate
form. More particularly, the invention is directed to methods for
preparing celecoxib compositions in the form of discrete unit dose
tablets or capsules, such that each tablet or capsule contains an
amount of celecoxib sufficient to provide a therapeutic effect for
about 12 to 24 hours. Each dose unit preferably contains, for
example, about 100 mg to about 200 mg of celecoxib. According to
the present invention, wet granulation, dry granulation or direct
compression or encapsulation methods can be employed to prepare
tablet or capsule compositions of the invention.
[0311] Wet granulation is a preferred method of preparing
pharmaceutical compositions of the present invention. In the wet
granulation process, celecoxib (if desired, together with one or
more carrier materials) is initially milled or micronized to the
desired particle size. Although various conventional mills or
grinders can be used, impact milling such as pin milling of the
celecoxib provides improved blend uniformity to the final
composition relative to other types of milling. Cooling of the
celecoxib, for example, using liquid nitrogen, may be necessary
during milling to avoid heating the celecoxib to undesirable
temperatures. As previously discussed, reduction of the D.sub.90
particle size during this milling step to less than about 200
.mu.m, preferably less than about 100 .mu.m, more preferably less
than about 75 .mu.m, still more preferably less than about 40
.mu.m, and most preferably less than about 25 .mu.m, can materially
increase the bioavailability of the celecoxib.
[0312] The milled or micronized celecoxib is then blended, for
example in a high shear mixer/granulator, planetary mixer,
twin-shell blender or sigma mixer, with one or more carrier
materials, including carrier materials milled together with the
celecoxib, to form a dry powder mixture. Typically, the drug is
blended with one or more diluent(s), disintegrant(s) and/or binding
agent(s) and, optionally, one or more wetting agent(s) in this
step, but alternatively all or a portion of one or more of the
carrier materials can be added in a later step. For example, in
tablet formulations where croscarmellose sodium is employed as a
disintegrant, it has been discovered that addition of a portion of
the croscarmellose sodium during the blending step (providing
intragranular croscarmellose sodium) and addition of the remaining
portion after the drying step discussed below (providing
extragranular croscarmellose sodium) can improve disintegration of
the tablets produced. In this situation, preferably about 60% to
about 75% of the croscarmellose sodium is added intragranularly and
about 25% to about 40% of the croscarmellose sodium is added
extragranularly. Similarly, for tablet formulations it has been
discovered that addition of microcrystalline cellulose after the
drying step below (extragranular microcrystalline cellulose) can
improve compressibility of the granules and hardness of the tablets
prepared from the granules.
[0313] This blending step of the process preferably comprises
blending of celecoxib, lactose, polyvinylpyrrolidone and
croscarmellose sodium. It has been discovered that blending times
as short as three minutes can provide a dry powder mixture having a
sufficiently uniform distribution of celecoxib. For example, the
dry powder mixtures used in the preparation of 100 mg dose capsules
(1080 kg total batch size) and 200 mg dose capsules (918 kg total
batch size), respectively, had celecoxib concentrations exhibiting
measured relative standard deviation values of 3.6% or less and
1.1% or less, respectively.
[0314] Water, preferably purified water, is then added to the dry
powder mixture and the mixture is blended for an additional period
of time, to form a wet granulated mixture. Preferably a wetting
agent is used, and this is preferably first added to the water and
mixed for at least 15 minutes, preferably at least 20 minutes,
prior to adding the water to the dry powder mixture. The water can
be added to the mixture at once, gradually over a period of time,
or in several portions over a period of time. The water preferably
is added gradually over a period of time. Alternatively, the
wetting agent can be added to the dry powder mixture and water then
can be added to the resulting mixture.
[0315] For the illustrative 100 mg dose capsules (1080 kg batch),
for example, water addition rates of about 5 to about 25 kg/minute,
preferably about 7 to about 20 kg/minute, and still more preferably
about 8 to about 18 kg/minute, provide suitable results. An
additional period of mixing after the water addition is complete is
preferred to ensure the uniform distribution of the water in the
mixture. For this illustrative batch additional mixing times of
about 2 to about 10 minutes, preferably about 3 to about 9 minutes,
and more preferably about 3 to about 7 minutes, provide suitable
results. The wet granulated mixture of this batch preferably
comprises about 2% to about 15%, more preferably about 4% to about
12%, and still more preferably about 6% to about 10%, water by
weight.
[0316] For the illustrative 200 mg dose capsules (918 kg batch),
for example, water addition rates of about 5 to about 25 kg/minute,
preferably about 7 to about 23 kg/minute, and still more preferably
about 8 to about 21 kg/minute, provide suitable results. An
additional period of mixing after the water addition is complete is
preferred to ensure the uniform distribution of the water in the
mixture. For this illustrative batch additional mixing times of
about 2 to about 15 minutes, preferably about 3 to about 12
minutes, and more preferably about 3 to about 10 minutes, provide
suitable results. The wet granulated mixture of this batch
preferably comprises about 2% to about 15%, more preferably about
6% to about 14%, and still more preferably about 8% to about 13%,
water by weight.
[0317] The wet granulated mixture preferably is then wet milled,
for example with a screening mill, to eliminate large
agglomerations of material that form as a by-product of the wet
granulation operation. If not removed, these agglomerations would
prolong the subsequent fluidized bed drying operation and increase
the variation with respect to moisture control. For the
illustrative 100 mg dose capsules (1080 kg batch) and 200 mg dose
capsules (918 kg batch), for example, suitable granulations can be
obtained using feed rates up to about 50%, preferably about 2% to
about 30%, and still more preferably about 5% to about 20%, of
maximum feed rate.
[0318] The wet granulated or wet milled mixture is then dried, for
example, in an oven or a fluidized bed dryer, preferably a
fluidized bed drier, to form dry granules. If desired, the wet
granulated mixture can be extruded or spheronized prior to drying.
For the drying process, conditions such as inlet air temperature
and drying time are adjusted to achieve the desired moisture
content for the dry granules. It may be desirable to combine two or
more granulation sections for this drying step and subsequent
processing steps.
[0319] For the illustrative 100 mg dose capsules (1080 kg batch) or
200 mg dose capsules (918 kg batch) discussed above, dryer inlet
temperature can be fixed at 60.degree. C. although other inlet
temperatures can be used, preferably in the range of about
50.degree. C. to about 70.degree. C. Air flow rate can be varied in
the range of about 1000 to about 8000 cubic feet per minute,
preferably about 2000 to about 7000 cubic feet per minute, and more
preferably about 4000 to about 7000 cubic feet per minute, with a
damper opening of about 10% to about 90%, preferably about 20% to
about 80%, and still more preferably about 30% to about 70%. Dryer
loads of about 35% to about 100%, preferably about 50% to about
100%, and still more preferably about 90% to about 100%, can be
used. Average loss on drying of dry granules prepared under these
conditions is generally about 0.1% to about 2.0% by weight.
[0320] To the extent necessary, the dry granules are then reduced
in size in preparation for compression or encapsulation.
Conventional particle size reduction equipment such as oscillators
or impact mills (such as Fitz mills) can be employed. For the
illustrative 100 mg dose capsules (1080 kg batch), for example,
suitable granule size reduction can be obtained using feed rates of
about 20% to about 70%, preferably about 30% to about 60%; mill
speeds of about 20% to about 70%, preferably about 40% to about
60%; and screen sizes of about 0.020 inch (0.5 mm) to about 0.070
inch (1.7 mm), preferably about 0.028 inch (0.7 mm) to about 0.040
inch (1.0 mm). For the illustrative 200 mg dose capsules (918 kg
batch), for example, suitable granulations can be obtained using
feed rates of about 10% to about 70%, preferably about 20% to about
60%; mill speeds of about 20% to about 60%, preferably about 30% to
about 50%; and screen sizes of about 0.020 inch (0.5 mm) to about
0.080 inch (1.9 mm), preferably about 0.028 inch (0.7 mm) to about
0.063 inch (1.6 mm). Smaller screen sizes such as 0.028 inch (0.7
mm), however, were observed to result in lower throughput of
product. Larger screen sizes such as 0.063 inch (1.6 mm) resulted
in an increased population of granules larger in size than 850
.mu.m. Screen sizes around about 0.040 inch (1.0 mm) appear to
eliminate an excessive population of granules larger in size than
850 .mu.m without significantly decreasing throughput.
[0321] Variation of the wet granulation and wet milling parameters
discussed above can be employed to adjust granule size
distributions. For example, a slight decrease in granule size has
been observed as mixing time increases for mixtures containing
lower water amounts. It is hypothesized that where the water
concentration is too low to fully activate the binding agent
employed, the cohesive forces between the primary particles within
the granules are insufficient to survive the shearing forces
generated by the mixing blades and granule size attrition rather
than growth occurs. Conversely, increasing the amount of water to
fully activate the binding agent allows cohesive forces between the
primary particles to survive the shearing forces generated by the
mixing blades and granule growth rather than attrition occurs with
increased mixing time and/or water addition rate. Variation of the
screen size of the wet mill tends to have a greater impact on the
granule size than variation of the feed rate and/or mill speed.
[0322] The dry granules are then placed in a suitable blender, such
as a twin-shell blender, and optionally a lubricant (such as
magnesium stearate) and any additional carrier materials are added
(such as extragranular microcrystalline cellulose and/or
extragranular croscarmellose sodium in certain tablet formulations)
to form a final blended mixture. Blending times depend in part upon
the process equipment employed. For the 100 mg dose capsules and
200 mg dose capsules (1080 kg and 918 kg batches) discussed above,
blending times of at least about 5 minutes at blender loads ranging
from about 15% to about 60% and blender rotational speeds of at
least about 10 revolutions per minute consistently provided a
blended material that was extremely uniform with respect to
celecoxib concentration. The relative standard deviations measured
for unit dose blend samples were 3.9% or less and 2.2% or less for
the 100 mg and 200 mg dose capsules, respectively. Where the
diluents include microcrystalline cellulose, the addition of a
portion of the microcrystalline cellulose during this step has been
found to materially increase granule compressibility and tablet
hardness. In addition, increasing the amount of magnesium stearate
above about 1% to about 2% was observed to decrease tablet hardness
and increase friability and dissolution time.
[0323] This final blended mixture is then encapsulated (or, if
tablets are to be prepared, compressed into tablets of the desired
weight and hardness using appropriately sized tooling).
Conventional compression and encapsulation techniques known to
those of ordinary skill in the art can be employed. Suitable
results have been obtained for capsules by employing bed heights
ranging from about 20 mm to about 60 mm, compaction settings
ranging from about 0 to about 5 mm, and speeds from about 60,000
capsules per hour to about 130,000 capsules per hour. Weight
control of the dose was observed to decrease with either (i) low
speed and high compaction, or (ii) high speed and high bed heights.
Accordingly, these combinations of parameters preferably are
carefully controlled. It has also been discovered that slug
formation can be minimized or eliminated by using the lowest
compaction setting at which capsule weight control can be
maintained. Where coated tablets are desired, conventional coating
techniques known to those of ordinary skill in the art can be
employed.
[0324] This combination of unit operations produces granules that
are uniform in celecoxib content at the unit dose level, that
readily disintegrate, that flow with sufficient ease so that weight
variation can be reliably controlled during capsule filling or
tableting, and that are dense enough in bulk so that the batch can
be processed in the selected equipment and individual doses fit
into the specified capsules or tablet dies.
Use in the Preparation of Medicaments
[0325] The present invention also is directed to use of
compositions of the present invention in preparation of medicaments
useful in the treatment and/or prophylaxis of cyclooxygenase-2
mediated conditions and disorders.
EXAMPLES
[0326] The following examples illustrate aspects of the present
invention but should not be construed as limitations. The
experimental procedures used to generate the data shown are
discussed in more detail below. The symbols and conventions used in
these examples are consistent with those used in the contemporary
pharmaceutical literature. Unless otherwise stated, (i) all
percentages recited in these examples are by weight based on total
composition weight, (ii) total composition weight for capsules is
the total capsule fill weight and does not include the weight of
the actual capsule employed, and (iii) coated tablets are coated
with a conventional coating material such as Opadry White
YS-1-18027A and the weight fraction of the coating is about 3% of
the total weight of the coated tablet.
Example 1
100 mg Dose Capsule
[0327] A capsule was prepared having the following composition:
TABLE-US-00001 TABLE 1 Weight Ingredient fraction (%) Amount (mg)
Celecoxib 37.04 100 Lactose monohydrate (NF, Ph Eur) 55.46 149.75
Sodium lauryl sulfate (NF, Ph Eur) 3 8.1 Povidone (K29-32 USP) 2.5
6.75 Croscarmellose sodium (NF, Ph Eur) 1 2.7 Magnesium stearate
(NF, Ph Eur) 1 2.7 Total capsule fill weight 100 270
[0328] The above unit dose composition was placed in a hard gelatin
capsule (white opaque, size #2) comprising titanium dioxide (USP),
gelatin (NF), and blue ink (SB-6018).
[0329] The lactose monohydrate used in each of the examples herein
is commercially available from Formost Farms, Baraboo, Wis. The
Ac-Di-Sol brand of croscarmellose sodium used in each of the
examples herein is commercially available from FMC Corporation,
Chicago, Ill. The sodium lauryl sulfate used in each of the
examples herein is commercially available from Henkel Corporation,
Cincinnati, Ohio. The povidone (polyvinylpyrrolidone) used in each
of the examples herein is commercially available from International
Specialty Products. The magnesium stearate used in each of the
examples herein is commercially available from Mallinckrodt Inc.,
St. Louis, Mo. The Opadry White YS-1-18027A used to prepare the
coated tablets disclosed in the examples of this application is a
ready-to-coat coating formulation commercially available from
Colorcon, West Point, Pa.
[0330] Capsule doses of any desired strength from 25 mg to 225 mg
can be accommodated by adjusting the weight of celecoxib and
correspondingly increasing or decreasing the amount of lactose as
necessary to provide a total fill weight of 270 mg.
Example 2
200 mg Dose Capule
[0331] A capsule was prepared having the following composition:
TABLE-US-00002 TABLE 2 Weight Ingredient fraction (%) Amount (mg)
Celecoxib 74.07 200 Lactose monohydrate (NF, Ph Eur) 18.43 49.75
Sodium lauryl sulfate(NF, Ph Eur) 3 8.10 Povidone (K29-32 USP) 2.5
6.75 Croscarmellose sodium 1 2.7 Magnesium stearate (NF, Ph Eur) 1
2.7 Total capsule fill weight 100 270
[0332] The above unit dose composition was placed in a hard gelatin
capsule (white opaque, size #2) comprising titanium dioxide (USP),
gelatin (NF), and blue ink (SB-6018).
Example 3
100 mg Dose Tablet
[0333] Tablets were prepared having the following composition:
TABLE-US-00003 TABLE 3 Amount/ Amount/ tablet Weight batch
Ingredient (mg) fraction (%) (kg) Celecoxib 100 40 6.40 Lactose
monohydrate (NF) 101.88 40.75 6.52 Sodium lauryl sulfate (NF) 7.5 3
0.48 Povidone (K29/32, USP) 6.25 2.5 0.40 Croscarmellose sodium 7.5
3 0.48 (Type A, NF) Microcrystalline cellulose 25 10 1.60 (Avicel
PH-102, NF) Magnesium stearate (NF) 1.88 0.75 0.12 Total 250.01 100
16 Opadry White YS-1-18027A 7.50
[0334] The tablets prepared were 0.210 inch.times.0.465 inch (5.0
mm.times.11.2 mm) modified oval shaped tablets.
[0335] The Avicel brand of microcrystalline cellulose was used in
the preparation of the tablets of Examples 3 and 4 and is
commercially available from FMC Corporation, Philadelphia, Pa.
[0336] Tablet dose strengths between 25 mg to 225 mg can be
accommodated by increasing or decreasing the amounts of celecoxib
and each of the carrier materials described above so as to maintain
the same weight fractions exemplified above.
Example 4
200 mg Dose Tablet
[0337] Tablets were prepared having the following composition:
TABLE-US-00004 TABLE 4 Amount/ Amount/ tablet Weight batch
Ingredient (mg) fraction (%) (kg) Celecoxib 200 40 6.40 Lactose
monohydrate (NF) 203.75 40.75 6.52 Sodium lauryl sulfate (NF) 15 3
0.48 Povidone (K29/32, USP) 12.5 2.5 0.40 Croscarmellose sodium 15
3 0.48 (Avicel PH-102, NF) Microcrystalline cellulose 50 10 1.60
(Type A, NF) Magnesium stearate (NF) 3.75 0.75 0.12 Total 500 100
16 Opadry White YS-1-18027A 15.0
[0338] The tablets prepared were 0.275 inch.times.0.496 inch (6.6
mm.times.11.9 mm) modified capsule shaped tablets.
Example 5
Disintegration Tests
[0339] Tablets were prepared as in Examples 3 and 4 except that
they were left uncoated. Six identical tablets were separately
placed into one of six tubes having a wire mesh screen bottom in a
disintegration basket. A water bath was preheated to 37.degree.
C..+-.2.degree. C. and maintained at that temperature for the
duration of the disintegration test. A 1000 ml beaker was placed in
the water bath. The beaker was filled with a sufficient amount of
water to ensure that the wire mesh screen of the tubes would remain
at least 2.5 cm below the water surface during the test. The
disintegration basket was inserted in the water and repeatedly
raised and lowered until the test was complete while maintaining
the wire mesh screen of the tubes at least 2.5 cm below the water
surface. Disintegration time for each tablet was the time, measured
from time of insertion of the basket, at which the very last
portion of the tablet passed through the screen at the bottom of
the tube. The mean results for the uncoated tablets of Examples 3
and 4 are reported in Table 5.
TABLE-US-00005 TABLE 5 Tablet Disintegration time Example 3: 100 mg
dose tablet (uncoated) 4 minutes 35 seconds Example 4: 200 mg dose
tablet (uncoated) 7 minutes 40 seconds
Example 6
Dissolution Tests
[0340] The apparatus of USP method 2 (with paddles) was used to
determine the dissolution rate of the capsules of Examples 1 and 2
and the tablets of Examples 3 and 4, which for the purpose of these
tests were left uncoated. A 1% sodium lauryl sulfate/0.04M
Na.sub.3PO.sub.4 (pH=12) solution, 1000 ml, was used as the
dissolution fluid. The solution was maintained at a temperature of
37.degree. C..+-.5.degree. C. and stirred at 50 rpm during the
test. Twelve identical tablets or capsules were tested. The 12
tablets or capsules were each separately placed in one of 12
standard dissolution vessels, and at each of 15, 30, 45 and 60
minutes later, a 5 ml aliquot of solution was removed from each
vessel. The sample from each vessel was filtered and the absorbance
of the sample measured (UV spectrophotometer; 2 mm pathlength
quartz cell; 243 nm or wavelength of UV maxima; blank: dissolution
medium). Percent dissolution was calculated based on the measured
absorbances. The mean results of the dissolution tests are reported
in Table 6. Note that solubility at the elevated pH of these test
conditions is not indicative of solubility in the gastrointestinal
tract.
TABLE-US-00006 TABLE 6 % Dissolved 15 30 45 60 Composition minutes
minutes minutes minutes Example 1: 100 mg capsule 89 99 100 100
Example 2: 200 mg capsule 55 82 89 92 Example 3: 100 mg tablet 81
93 94 95 Example 4: 200 mg tablet 60 96 98 98
Example 7
Particle Size Analysis
[0341] Table 7A shows the results of a particle size sieve analysis
of the wet granulated pharmaceutical compositions of Examples 1 and
2, respectively, prior to encapsulation. "Percent retained on
screen" means the percentage by weight of the total batch having a
particle size larger than the indicated sieve size.
TABLE-US-00007 TABLE 7A Percent retained on screen Example 1: 100
mg capsule Example 2: 200 mg capsule Sieve size (.mu.m) Lower limit
Upper limit Lower limit Upper limit 850 0 1.3 1.1 10.7 425 2.8 14.9
4.3 25.4 250 10.0 25.5 10.8 35.4 180 15.3 39.0 17.3 39.2 106 32.5
64.5 35.2 58.2 75 37.1 77.5 39.5 71.8 0 100 100 100 100
[0342] Table 7B shows the results of a particle size sieve analysis
of the wet granulated pharmaceutical compositions of Examples 3 and
4, respectively, prior to compression into the tablets. "Percent of
batch" means the percentage by weight of the total batch having a
particle size between the indicated sieve size and the next smaller
sieve size indicated. "Cumulative percent of batch" reports the
percentage by weight of the total batch having a particle size
larger than the indicated sieve size.
TABLE-US-00008 TABLE 7B Example 3: Example 4: 100 mg tablet 200 mg
tablet Percent Cumulative Percent Cumulative of percent of percent
Sieve size (.mu.m) batch of batch batch of batch 840 1 1 0.79 0.79
(20 mesh screen) 420 24.6 25.6 24.85 25.64 (40 mesh screen) 250
18.4 44 19.13 44.77 (60 mesh screen) 177 9.6 53.6 11.05 55.82 (80
mesh screen) 149 6.6 60.2 6.9 62.72 (100 mesh screen) 105 11.6 71.8
11.44 74.16 (140 mesh screen) 74 8.8 80.6 8.28 82.45 (200 mesh
screen) Fines 19.4 100 17.55 100
Example 8
Bulk Density Analysis
[0343] Table 8 shows the results of a bulk density analysis of the
wet granulated pharmaceutical compositions of Examples 1, 2, 3 and
4 prior to encapsulation or compression into tablets.
TABLE-US-00009 TABLE 8 Bulk density Tapped density Loss on
Composition (g/ml) (g/ml) drying (%) Example 1: 100 mg capsule 0.77
1.02 0.6 Example 2: 200 mg capsule 0.61 0.96 0.5 Example 3: 100 mg
tablet 0.73 0.87 1.37 Example 4: 200 mg tablet 0.72 0.86 1.4
Example 9
Tablet Analysis Program
[0344] Table 9 shows the results of a tablet analysis program ("TAP
analysis") for a sampling of 10 tablets having the composition of
the tablets of each of Examples 3 and 4.
TABLE-US-00010 TABLE 9 Average Average weight thickness Hardness
Tablet (mg) (mm) (kP) Example 3: 100 mg tablet 248 3.85 8.2 Example
4: 200 mg tablet 500 5.22 14.6
Example 10
Friability Test
[0345] Tablets collectively weighing 12 g were placed in a rotating
drum. Extraneous dust was first removed from the drum and the
tablets. The drum was started and rotation continued for ten
minutes at a minimum of 25 rpm. The rotation of the drum was
stopped and the tablets removed. Loose dust on the tablets as well
as any broken tablets were removed and the intact tablets were
weighed. The percent loss of the test samples from the tablets of
Examples 3 and 4 was calculated and is reported below in Table
10.
TABLE-US-00011 TABLE 10 Tablet Percent loss Example 3: 100 mg
tablet 0.33 Example 4: 200 mg tablet 0.16
Example 11-1
Bioavailability in a Dog Model
[0346] Healthy female beagle dogs weighing 9 to 13 pounds (4.1 to
5.9 kg) received the following single doses of celecoxib: (1) an
intravenous infusion of 0.5 mg/kg body weight of celecoxib followed
by a second intravenous infusion of 5.0 mg/kg body weight of
celecoxib; (2) 5 mg/kg body weight celecoxib in the form of an oral
solution; and (3) 5.0 mg/kg body weight of neat unformulated
celecoxib in the form of an oral capsule. The vehicle for the
intravenous and oral solution doses was a mixture of polyethylene
glycol having an average molecular weight of 400 (PEG-400) and
water in a ratio of 2:1 by volume. Each intravenous infusion was
given over a period of 15 minutes with 15 to 30 minutes separating
the two infusions.
[0347] Multiple blood samples were collected from each animal by
venipuncture or indwelling catheter into heparinized tubes.
Celecoxib concentration in blood serum was measured by HPLC and the
resulting data were used to calculate the pharmacokinetic
parameters presented in Table 11-1 below.
TABLE-US-00012 TABLE 11-1 Pharmacokinetic Intravenous Capsule,
parameter infusion Oral solution unformulated C.sub.max (ng/ml)
6950 2190 517 T.sub.max (h) Not applicable 0.5 3.0
AUC.sub.0-.infin. (ng/ml)h 31200 16200 4800 Clearance (ml/min kg)
3.08 5.14 17.4 T.sub.1/2 (h) 8.84 9.15 11.8 Bioavailability (%) Not
applicable 57.1 16.9
Example 11-2
Relative Bioavailability of Formulations in a Dog Model
[0348] The effect of such formulation parameters as celecoxib
particle size, increased concentration of wetting agent, pH, and
dispersion of celecoxib as a suspension were evaluated relative to
an oral solution on bioavailability in a dog model. The effect of
micronizing the celecoxib (mean particle size 10-20 .mu.m) prior to
formulating was tested in composition A. The combined effect of
micronization, added wetting agent (sodium lauryl sulfate), and
increased micro-environmental pH (Na.sub.3PO.sub.4.12H.sub.2O) was
tested in composition B. The effect of bringing wetting agent
(Tween 80) into intimate contact with celecoxib (co-precipitating
vs. simple dry mixing) was tested in composition C. The effect of
further reducing particle size (approximating 1 .mu.m) and
dispersing the particles in a suspension was tested in composition
D. A solution of celecoxib similar to that used in Example 111
(composition E) was included as a reference. In addition, data from
Example 11-1 for unmilled, unformulated celecoxib in a capsule
(composition F) is also included as a reference. The specific
compositions of formulations A, B, C, D, E and F are summarized in
Table 11-2A.
TABLE-US-00013 TABLE 11-2A Weight fraction (% dry basis) Ingredient
A B C D E F celecoxib (micronized) 25 25 celecoxib/tween 80.sup.(1)
25 celecoxib (dispersed).sup.(2) 100 celecoxib (solution).sup.(3)
100 celecoxib (unmilled) 100 sodium lauryl sulfate 2 25 Avicel 101
73 25 75 Na.sub.3PO.sub.4H.sub.2O 25 Total 100 100 100 100 100 100
.sup.(1)Precipitated from ethanol solution using an aqueous
solution of 5% polysorbate 80 as an antisolvent. .sup.(2)Prepared
as a suspension by ball-milling the drug in a slurry of polysorbate
80 and polyvinylpyrollidone until particles were approximately 1
.mu.m in diameter as estimated by microscopy. .sup.(3)Solution in
PEG-400/water (2:1 v/v).
[0349] The compositions were administered to groups of three male
and three female dogs. Group 1 dogs were administered 5 mg per kg
body weight celecoxib in solution E and in capsule formulations A
and B in a nonrandomized crossover design. Group 2 dogs were
administered 5 mg per kg body weight celecoxib in capsule
formulation C and in suspension D in a nonrandomized crossover
design. Plasma samples were collected over a 24-hour period and
analyzed for celecoxib by HPLC.
[0350] The results of the study (Tables 11-2B, 11-2C and 11-2D)
indicated that decreasing the particle size (composition A) or
co-precipitating the celecoxib with a wetting agent (composition C)
increased the bioavailability (as measured by AUC.sub.(0-24)) of
celecoxib compared to the earlier study of unformulated celecoxib
shown in Example 11-1. The bioavailability of celecoxib was greater
from the PEG-400/water solution (composition E) and the suspension
(composition D). The bioavailability from the suspension having
approximately 1 .mu.m particle size was similar to that from the
solution and provided strong indication that celecoxib availability
from wet granulated solid compositions can be improved by reduced
celecoxib particle size (for example by pin milling of celecoxib
prior to formulation), increased wetting of the celecoxib (for
example by including sodium lauryl sulfate in the granulating
fluid) and improved dispersibility (for example by including
croscarmellose sodium in the granulation). The bioavailability data
contained in Tables 11-2C and 11-2D for each formulation represent
the bioavailability of that formulation as a percent of the
bioavailability experimentally measured for intravenous
administration of celecoxib, using the solution (composition E)
data as a bridge between the studies of Examples 11-1 and 11-2.
TABLE-US-00014 TABLE 11-2B Blood serum celecoxib concentration
(.mu.g/ml) Time (h) A B C D E F 0 0 0 0 0 0 0 0.5 0.0143 0.247
0.0635 0.453 0.824 0.205 1.0 0.244 0.228 0.443 0.826 0.820 0.333
2.0 0.318 0.138 0.717 0.865 0.604 0.262 3.0 0.189 0.0860 0.492
0.741 0.517 0.517 4.0 0.145 0.0707 0.384 0.576 0.413 0.234 6.0
0.107 0.0664 0.233 0.354 0.286 -- 7.0 -- -- -- -- -- 0.197 8.0
0.0828 0.0624 0.160 0.234 0.187 -- 12.0 0.0939 0.0431 0.0865 0.142
0.0802 -- 24.0 -- 0.0404 0.0408 0.0394 0.0159 --
TABLE-US-00015 TABLE 11-2C Pharmacokinetic Value for female dogs
parameter A B C D E F C.sub.max (ng/ml) 360 .+-. 60 250 .+-. 70
.sup. 790 .+-. 190.sup. 1010 .+-. 270 840 .+-. 240 500 T.sub.max
(h) .sup. 1.3 .+-. 0.2.sup. .sup. 0.7 .+-. 0.2.sup. .sup. 1.5 .+-.
0.3.sup. 1.7 .+-. 0.44 0.67 .+-. 0.18 3.0 Bioavailability 31.2 .+-.
2.9 24.9 .+-. 1.4 46.3 .+-. 9.5 69.5 .+-. 9.6 .sup. 62.4 .+-.
9.4.sup. 16.9 (%)
TABLE-US-00016 TABLE 11-2D Pharmacokinetic Value for male dogs
parameter A B C D E F C.sub.max (ng/ml) 520 .+-. 110 450 .+-. 180
640 .+-. 260 830 .+-. 330 1520 .+-. 200 500 T.sub.max (h) 5.3 .+-.
3.3 3.3 .+-. 1.3 1.5 .+-. 0.5 .sup. 5.7 .+-. 3.42.sup. 1.5 3.0
Bioavailability 49.4 .+-. 12.0 54.2 .+-. 13.1 42.9 .+-. 13.1 87.5
.+-. 20.6 89.4 .+-. 4.5 16.9 (%)
Example 11-3
[0351] Various formulations containing sodium lauryl sulfate (0-5%
by weight) and croscarmellose sodium (0-5% by weight) were screened
for relative wettability and disintegration tendency. Relative
wettability was estimated by measuring the time required for water
to penetrate a column of granulated material prepared from each
formulation. Disintegration tendency was determined by measuring
the weight of granulated material retained on a 20 mesh (850 mm)
screen after soaking the material in 37.degree. C. water for 5
minutes. The specific compositions of compositions A through H
evaluated are summarized in Table 11-3A.
TABLE-US-00017 TABLE 11-3A Weight fraction (%) Composition
A.sup.(1) B C D E F G H Celecoxib 74.7 74.7 74.7 74.7 74.7 74.7
74.7 74.7 Lactose 15.8 15.8 21.8 19.8 17.8 15.8 17.8 11.8
Polyvinyl- 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 pyrrolidone Sodium 3.0
3.0 0.0 1.0 1.0 1.0 3.0 5.0 lauryl sulfate Ac-di-sol 3.0 3.0 0.0
1.0 3.0 5.0 1.0 5.0 Magnesium 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0
stearate .sup.(1)Sodium lauryl sulfate was added as a dry
powder
[0352] Results are summarized in Table 11-3B. Penetration tests
were done in triplicate. Disintegration tests were done in
duplicate. Results of the penetration study indicated that wet
application of sodium lauryl sulfate (Composition B) was superior
to dry application (Composition A) and that formulations containing
3% to 5% sodium lauryl sulfate (Compositions B, G and H) were
superior to those with lesser amounts of sodium lauryl sulfate
(Compositions C through F). Formulations containing 3% sodium
lauryl sulfate (Compositions B and G) were similar to those
containing 5% sodium lauryl sulfate (Composition H). Results of the
disintegration study indicated that complete disintegration could
be achieved with sodium crosscarmellose concentrations as low as 1%
(Composition G) at a wetting agent concentration of 3%. Complete
disintegration could also be achieved with higher amounts of
disintegrant (Compositions B, F and H) regardless of wetting agent
concentration. Composition G exhibited both superior penetration
and complete disintegration with the minimum amount of excipient
required.
TABLE-US-00018 TABLE 11-3B Compo- % Sodium lauryl sulfate/ sition %
Ac-di-sol Penetration time Disintegration A 3/3 >18 hours
0.1-0.5% B 3/3 5-60 minutes none detected C 0/0 >4 to >18
hours 20-26% D 1/1 >4 to >18 hours 10-13% E 1/3 2 to 4 hours
4-6% F 1/5 1 to 4 hours none detected G 3/1 10 to 40 minutes none
detected H 5/5 10 to 55 minutes none detected
Example 12
[0353] The following formulations were evaluated for wetting
effects and mixture uniformity:
TABLE-US-00019 TABLE 12 Weight fraction (%) Polysor- Lactose
Microcrystal- Polyvinyl- bate 80 Ingre- dry line cellulose
pyrrolidone granu- dient blend dry blend granulation.sup.1
lation.sup.2 Celecoxib 5 60 5 60 5 60 5 60 Lactose 94.5 39.5 -- --
92 37 93.5 38.5 Micro- -- -- 94.5 39.5 -- -- -- -- crystal- line
cellulose Polysor- -- -- -- -- -- -- 1.0 1.0 bate 80 Povidone -- --
-- -- 2.5 2.5 -- -- (K29-32) Magnesium 0.5 0.5 0.5 0.5 0.5 0.5 0.5
0.5 stearate .sup.1In this formulation polyvinylpyrrolidone was
added to the blend as a dry powder prior to granulation with water.
.sup.2In this formulation celecoxib and lactose were granulated
with an aqueous solution of polysorbate 80.
[0354] The 5% celecoxib blends exhibited better blend homogeneity
than the 60% celecoxib blends. The measured relative standard
deviations for the 5% celecoxib blends ranged from 0.4% to 3.5%
while the measured relative standard deviations for the 60%
celecoxib blends ranged from 4.7% to 6.3%. In addition to being
less homogeneous, the 60% celecoxib blends contained relatively
large granules (greater than 420 .mu.m) that were superpotent
(containing 124% to 132% higher concentrations of celecoxib
relative to other granules).
[0355] Four similar formulations were prepared containing 25%
celecoxib loading instead of 5% or 60% celecoxib loading as above.
The bioavailability of these formulations was evaluated in a dog
model, by a procedure similar to that outlined for Examples 11-1
and 11-2. The polyvinylpyrrolidone wet granulation formulation
exhibited the highest bioavailability (about 74%).
Example 13
[0356] Capsules having the following formulations were prepared and
evaluated:
TABLE-US-00020 TABLE 13A Amount (mg) Ingredient 5 mg capsule 20 mg
capsule 100 mg capsule Celecoxib 5 20 100 Lactose 92 77 61.9
Povidone (K29-32) 2.5 2.5 4 Magnesium stearate 0.5 0.5 0.8 Total
100 100 166.7 Capsule shell 1 1 1 Capsule size #3 #3 #3
[0357] The celecoxib was milled by multiple passes through an
oscillating mill fitted with successively smaller screen sizes
(#14, #20, #40). The D.sub.90 particle size of the celecoxib
particles added to this mixture was less than about 37 .mu.m.
Celecoxib, lactose and polyvinylpyrrolidone were mixed in a
planetary mixer bowl and wet-granulated with water. The granulation
was then tray dried at 60.degree. C., milled through a 40 mesh
screen, lubricated with magnesium stearate in a V-blender and
encapsulated on a dosator-type encapsulator. The in vitro
dissolution profile of the capsules was determined using USP method
2 and a 15 mM phosphate buffer at pH 10 as dissolution medium.
About 50% in vitro dissolution was achieved after about 15 minutes
with greater than 95% in vitro dissolution after about 30
minutes.
[0358] The absorption, distribution, metabolism and elimination
profile of this 100 mg unit dose capsule was compared to the
profile of a suspension of .sup.14C-celecoxib. The study was an
open-label, randomized crossover study carried out in ten healthy
male subjects. The suspension was prepared by dissolving celecoxib
in ethanol containing 5% polysorbate 80 and adding that mixture to
apple juice prior to administration. Subjects receiving the
suspension ingested a 300 mg dose of celecoxib. Subjects receiving
capsule-form celecoxib received three 100 mg unit dose capsules for
a total dose of 300 mg of celecoxib. The rate of absorption from
the capsule was slower than from the suspension, but was equivalent
to the suspension when measured by AUC.sub.0-48. Mean results are
reported in Table 13B below. Celecoxib was largely metabolized with
only about 2.56% of the radioactive dose in either urine or
feces.
TABLE-US-00021 TABLE 13B Pharmacokinetic parameter Suspension
Capsules AUC.sub.(0-48) ((ng/ml)h) 8706.7 8763.1 C.sub.max (ng/ml)
1526.5 1076.5 T.sub.max (h) 1.42 1.94 T.sub.1/2 (h) 11.53 15.57
Example 14
[0359] Capsules having the following compositions were prepared and
evaluated:
TABLE-US-00022 TABLE 14 Amount (mg) Ingredient 100 mg capsule 200
mg capsule Celecoxib 100 200 Lactose 223.4 120.1 Povidone (K29-32)
8.3 8.3 Magnesium stearate 1.7 5 Total 333.4 333.4 Capsule size #1
#1
[0360] These formulations were prepared in a manner similar to the
formulations of Example 13 except that an inpact-type pin mill was
used instead of an oscillating mill. Particle size was further
reduced by use of the pin mill. For the 100 mg capsule about 30% in
vitro dissolution was achieved after about 15 minutes with greater
than 85% in vitro dissolution after about 30 minutes. For the 200
mg capsule about 50% in vitro dissolution was achieved after about
15 minutes with greater than 85% in vitro dissolution after about
30 minutes.
Example 15
Preparation of 100 mg Dose Capsules
[0361] Capsules providing a 100 mg or 200 mg dose of celecoxib, and
having the composition shown in Examples 1 or 2 respectively, can
be prepared in accordance with acceptable pharmaceutical
manufacturing practices in the manner illustrated by FIG. 1 or FIG.
2. Tablets provising a 100 mg or 200 mg dose of celecoxib, and
having the composition shown in Examples 3 or 4 respectively, can
be prepared by appropriately modifying the process of FIG. 1 or
FIG. 2 to account for the extragranular addition of croscarmellose
sodium and microcrystalline cellulose, and tableting instead of
encapsulating the composition.
[0362] In an illustrative process for the bulk formulation of 100
mg dose capsules using the starting materials described below, a
typical batch consists of four identical granulation sections,
although the number of granulation sections is not narrowly
critical and depends largely upon equipment handling capacity and
batch size needed.
Milling. The celecoxib was milled in an impact-type pin mill with
counter rotating disks. At mill speeds ranging from about 8960
rpm/5600 rpm to about 11200 rpm/5600 rpm (rotating
rpm/counter-rotating rpm), particle size varied within relatively
narrow ranges (D.sub.90 of 30 .mu.m or less) suggesting that mill
speed is not narrowly critical to the bulk drug micronization
process. FIG. 2 is a flow diagram showing a preferred embodiment
wherein the celecoxib starting material is impact milled,
preferably with a pin mill, prior to blending with the carrier
materials. Dry mixing. The celecoxib, lactose, polyvinylpyrrolidone
and croscarmellose sodium were transferred to a 1200 L Niro Fielder
PMA-1200 high speed granulator and mixed for about 3 minutes at
fast chopper and impeller speeds. This dry mixing time provided
adequate mixing of celecoxib with the carrier materials prior to
the start of the wet granulation step. Wet granulation. Sodium
lauryl sulfate (8.1 kg) was dissolved in purified USP water (23.7
kg). The resulting solution was progressively added to the
granulator at a rate of about 14 kg/minute. Total granulation time
was about 6.5 minutes. During this granulation, the main blade and
chopper blade of the granulator were placed on the fast speed
setting. The wet granulated mixture contained about 8.1% water by
weight. Alternatively, the sodium lauryl sulfate can be mixed with
the celecoxib, lactose, polyvinylpyrrolidone and croscarmellose
sodium in the dry mixing step and purified USP water can be added
to this dry mixture comprising sodium lauryl sulfate. Drying. The
product of the wet granulation operation was delumped using a
Quadro Comil Model 198 S screening mill equipped with rotating
impeller and a coarse screen. Wet milling was used to eliminate
large material lumps that formed as a by-product of the wet
granulation operation. If not removed, these lumps would have
prolonged the subsequent fluidized bed drying operation and
increased the variation with respect to moisture control. The
delumped granules were transferred to an Aeromatic Fluid Bed Dryer
T-8. The inlet air temperature and flow rate were adjusted to about
60.degree. C. and about 5000 to 6000 ft.sup.3/minute (about 140 to
170 m.sup.3/minute). The granules were dried in the fluidized bed
dryer to reduce the moisture content to 0.5% to 2.5%. Moisture
content was monitored using a Computrac Moisture Analyzer. Drying
continued until the loss on drying of the granulation was not more
than 1.0%. It may be desirable to combine two or more granulation
sections for this drying step and subsequent processing steps. Dry
milling. The dry granules were passed through a Fluid Air Mill
Model 007 impact (conventional hammer) mill equipped with a 0.028
inch to 0.063 inch (0.7 mm to 1.5 mm) screen, knives forward, and
operated at 2400 rpm speed. Dry milling was used in combination
with the wet granulation step to control the final size
distribution of the granules. Blending and lubrication. The milled
granules were then placed in a PK Cross-Flow Blender 75 Cubic Foot
diffusion mixer/V-blender. The magnesium stearate was added and the
mixture blended for about 5 minutes. The blending time provided
blended material that was uniform with respect to the concentration
of celecoxib. Blender rotational speed was 10.6 revolutions per
minute. The final blend was used to combine materials from multiple
granulation sections into a single uniform mixture and to evenly
distribute lubricant into the material prior to encapsulation.
Encapsulation. The granulated powder blend was encapsulated using
an MG2 G100 or G120 encapsulator. The capsules were polished.
[0363] The above sequence of unit operations produced granules that
were highly uniform in celecoxib content at the unit dose level,
that readily dissolved in vitro, that flowed with sufficient ease
so that weight variation could be reliably controlled during
capsule filling, and that were dense enough in bulk so that the
batch could be processed in the selected equipment and individual
doses fit into the specified capsules.
Example 16
Bioequivalency Study
[0364] The bioequivalency and safety of 200 mg doses of celecoxib
were evaluated in an open-label, randomized, single dose, three-way
crossover study of a group of 46 healthy adult humans. The subjects
received three single 200 mg doses of celecoxib administered as (A)
one 200 mg dose capsule, (B) two 100 mg dose capsules, or (C) two
100 mg dose capsules (from a different batch run). Treatments were
separated by seven days. The specific pharmaceutical compositions
of the 100 mg dose capsule and the 200 mg dose capsules are
disclosed in Examples 1 and 2, respectively. The subjects, who had
fasted overnight, received single oral doses of the study
medication together with about 180 ml of water at 0800 hours. The
subjects continued to fast and remained in an upright position for
four hours after dose administration. Blood samples were collected
at -0.25 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and
48 hours post dose. Analyses of the separated plasma were performed
at PPD Pharmaco, Richmond, Va. Celecoxib plasma concentrations were
determined using a validated high performance liquid chromatography
("HPLC") procedure with a lower limit of detection of 10.0 ng/ml.
Each subject was separately tested. A minimum seven day wash-out
period was allowed between administration of each single 200 mg
dose. The mean results obtained from the 46 subjects tested are
reported in Tables 16A and 16B below.
TABLE-US-00023 TABLE 16A Plasma celecoxib concentration (ng/ml)
Time One 200 Two 100 mg capsules Two 100 mg capsules (h) mg capsule
(Batch 1) (Batch 2) -0.25 0.22 0.00 0.00 0.5 103.74 117.89 212.61
1.0 418.24 446.39 647.00 1.5 575.68 606.97 826.90 2.0 646.83 656.98
862.23 3.0 686.19 666.55 781.13 4.0 621.02 595.21 660.15 6.0 389.00
387.41 383.81 8.0 322.24 332.51 323.59 12.0 214.63 208.06 209.96
16.0 149.11 146.40 144.23 24.0 116.09 111.77 113.21 36.0 52.76
48.27 46.98 48.0 27.24 26.47 22.44
TABLE-US-00024 TABLE 16B Value of pharmacokinetic parameter Two 100
mg Two 100 mg Pharmacokinetic One 200 mg capsules capsules
parameter capsule (Batch 1) (Batch 2) AUC.sub.(0-48) ((ng/ml)h)
8107.07 7976.56 8535.49 AUC.sub.(0-LQC) ((ng/ml)h) 8063.17 7953.71
8501.94 AUC.sub.(0-.infin.) ((ng/ml)h) 8828.64 8640.46 9229.52
C.sub.max (ng/ml) 801.19 815.21 959.50 T.sub.max (h) 2.46 2.84 2.23
T.sub.1/2 (h) 12.22 13.52 10.67 C.sub.max/AUC.sub.(0-LQC) 0.10 0.10
0.20
Example 17
Effect of Food Study
[0365] An open-label randomized, single dose, four-way crossover
study was employed to evaluate the dose proportionality and the
effect of food on the pharmacokinetic profile of celecoxib in
healthy adult subjects. Safety was assessed based on adverse
events, vital signs and clinical laboratory tests. Twenty four
healthy adult subjects were randomized to receive the following
single doses of celecoxib: (A) a 50 mg dose capsule under fasting
conditions, (B) a 50 mg dose capsule immediately following a high
fat breakfast, (C) a 100 mg dose capsule under fasting conditions,
and (D) a 100 mg dose capsule immediately following a high fat
breakfast. The subjects received the study medication on days 1, 8,
15 and 22 in one of four treatment sequences (ADBC; BACD; CBDA; and
DCAB). The specific composition of the 100 mg dose capsule is
disclosed in Example 1. The specific composition of the 50 mg dose
capsule is disclosed in Table 17A below:
TABLE-US-00025 TABLE 17A Ingredient Amount (mg) Celecoxib 50.00
Lactose monohydrate 199.8 Sodium lauryl sulfate 8.1 Povidone
(K29-32) 6.8 Croscarmellose sodium 2.7 Magnesium stearate 2.7 Total
capsule fill weight 270.0
[0366] The above unit dose composition was placed in a hard gelatin
capsule (white opaque, size #2).
[0367] Blood samples were collected at -0.25 (predose), 0.5, 1,
1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours post dose. Analyses
of the separated plasma were performed at PPD Pharmaco, Richmond,
Va. Celecoxib plasma concentrations were determined using a
validated high performance liquid chromatography ("HPLC") procedure
with a lower limit of detection of 10.0 ng/ml. There were no
clinically significant changes in vital signs or physical
examinations. All adverse events were mild in severity. The mean
results obtained from the 24 subjects tested are reported in Tables
17B and 17C below.
TABLE-US-00026 TABLE 17B Plasma celecoxib concentration (ng/ml) 100
mg 100 mg capsule 50 mg capsule capsule (high fat 50 mg capsule
(high fat Time (h) (fasting) breakfast) (fasting) breakfast) -0.25
0.00 0.00 0.00 0.00 0.5 63.96 1.35 52.90 2.38 1.0 225.65 14.00
155.07 11.98 1.5 344.77 49.37 202.22 29.85 2.0 354.45 139.43 220.15
63.00 3.0 348.03 438.99 253.85 186.94 4.0 333.86 600.00 244.80
298.23 6.0 196.53 355.65 118.58 188.90 8.0 152.35 314.54 91.79
165.85 12.0 121.08 179.04 61.13 88.76 16.0 86.13 102.12 39.51 51.86
24.0 61.77 49.31 28.22 22.81 36.0 38.00 17.88 10.69 8.75 48.0 17.77
7.91 5.77 3.80
TABLE-US-00027 TABLE 17C Value of pharmacokinetic parameter 100 mg
100 mg capsule 50 mg 50 mg capsule Pharmacokinetic capsule (high
fat capsule (high fat parameter (fasting) breakfast) (fasting)
breakfast) AUC.sub.(0-48) 4463.28 5214.86 2426.23 2601.10
((ng/ml)h) AUC.sub.(0-LQC) 4415.59 5105.50 2352.68 2501.56
((ng/ml)h) AUC.sub.(0-.infin.) 5126.74 5419.21 2693.80 2759.42
((ng/ml)h) C.sub.max (ng/ml) 455.00 746.96 321.46 354.17 T.sub.max
(h) 2.60 5.00 2.92 4.46 T.sub.1/2 (h) 16.02 6.86 11.01 6.49
C.sub.max/AUC.sub.(0-LQC) 0.11 0.15 0.16 0.16
Example 18
Pharmacokinetics of Suspension Versus Capsule Formulation
[0368] The pharmacokinetics and bioavailability of an oral fine
suspension and two oral capsules containing celecoxib were
evaluated in an open-label, randomized, single dose, crossover
study. Thirty six healthy adult subjects were randomized to receive
the following single doses of celecoxib: (A) one 200 mg dose
capsule, (B) two 100 mg dose capsules, and (C) a 200 mg oral fine
suspension. The entire treatment duration was 18 days. On days 1, 8
and 15 the subjects received one of the three treatments according
to a randomization schedule. Treatments were separated by seven
days. The specific pharmaceutical composition of the 200 mg dose
capsule is disclosed in Example 2. The specific pharmaceutical
composition of the 100 mg dose capsules is disclosed in Table 18A
below.
TABLE-US-00028 TABLE 18A Ingredient Amount (mg) Weight % Celecoxib
100.0 60.0 Lactose Monohydrate 61.7 37.0 Povidone, K29-32 4.20 2.51
Magnesium Stearate 0.80 0.48
[0369] The pharmaceutical composition used in the 100 mg dose
capsules was prepared by passing the celecoxib starting material
through a 40 mesh oscillating screen (no other milling was
performed), wet granulating the celecoxib, lactose and povidone in
a low shear planetary mixer, tray drying and milling the granulated
mixture, adding magnesium stearate to the granulated mixture and
blending to form the final pharmaceutical composition.
[0370] The oral fine suspension was prepared by dissolving
celecoxib in ethanol containing 5% polysorbate 80 and adding that
mixture to apple juice prior to administration.
[0371] Blood samples were collected at -0.25 (predose) and through
72 hours post dose. Each subject was separately tested after
receiving the 200 dose mg capsule, 100 mg dose capsules and oral
fine suspension. A minimum of a seven day wash-out period was
allowed between administration of each 200 mg dose. The mean
results obtained from the 36 subjects tested are reported in Table
18B below.
TABLE-US-00029 TABLE 18B Pharmaco- Value of pharmacokinetic
parameter kinetic Two 100 mg One 200 mg 200 mg oral fine parameter
capsules capsule suspension AUC.sub.(0-72) 7247.5 .+-. 2427.5
7648.1 .+-. 2412.1 7736.2 .+-. 2488.2 ((ng/ml)h)
AUC.sub.(0-.infin.) 7562.4 .+-. 2494.0 7830.3 .+-. 2448.4 8001.2
.+-. 2535.6 ((ng/ml)h) C.sub.max (ng/ml) 619.7 .+-. 249.4 704.6
.+-. 265.7 1228.8 .+-. 452.0 T.sub.max (h) 3.00 .+-. 0.99 2.83 .+-.
1.06 0.79 .+-. 0.32 T.sub.1/2 (h) 13.96 .+-. 5.27 11.92 .+-. 3.60
13.33 .+-. 6.69 Clearance.sub.(0-72) 30.4 .+-. 9.8 28.4 .+-. 7.8
28.1 .+-. 7.8 (l/h)
[0372] In general, the rate of celecoxib absorption (higher
C.sub.max and shorter T.sub.max) was greater for the oral fine
suspension than for the capsules. The overall extent of celecoxib
absorption for the oral fine suspension, however, as measured by
AUC.sub.(0-72) or AUC.sub.(0-.infin.), was similar to the overall
extent of celecoxib absorption for the capsules.
[0373] As various changes could be made in the above formulations
and methods without departing from the scope of the invention, it
is intended that all matter contained in the above description be
interpreted as illustrative and not in a limiting sense. All
mentioned references are incorporated by reference as if here
written.
* * * * *