HK1069541B

HK1069541B - Celecoxib compositions

Info

Publication number: HK1069541B
Application number: HK05102200.7A
Authority: HK
Inventors: 高丹晨; A．J．赫里纳克; A．M．梅扎雷; J．E．特鲁拉夫; M．B．沃恩
Original assignee: G.D.西尔公司
Priority date: 1998-11-30
Filing date: 2005-03-14
Publication date: 2007-09-14

Description

Celecoxib composition

Technical Field

The present invention relates to orally deliverable pharmaceutical compositions comprising Celecoxib as an active ingredient, methods of making such compositions, methods of treating cyclooxygenase-2 mediated diseases, such methods comprising orally administering such compositions to a subject, and the use of such compositions in the manufacture of medicaments.

Background

Previously, the compound 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] benzenesulfonamide (also referred to herein as Celecoxib) has been reported by Talley et al in U.S. Pat. No. 5,466,823, which describes and claims a class of 1, 5-diaryl pyrazoles and salts thereof and methods for preparing such compounds. Celecoxib (Celecoxib) has the following structure:

1, 5-diaryl pyrazoles are reported in U.S. Pat. No. 5,466,823 to be useful in the treatment of inflammation and inflammation-related disorders. U.S. Pat. No. 5,466,823 contains formulations generally suitable for administering these 1, 5-diaryl pyrazoles, including oral dosage forms such as tablets and capsules. Talley et al, U.S. Pat. No. 5,760,068, report a class of 1, 5-diaryl pyrazole compounds including Celecoxib, which are useful as selective cyclooxygenase-2 inhibitors and for the treatment of, among other conditions, pathological conditions associated with rheumatoid arthritis and osteoarthritis.

Penning et al in "Synthesis and biological evaluation of 1, 5-diaryl pyrazole cyclooxygenase-2 inhibitors: identification of 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] benzenesulfonamide (SC-58635, Celecoxib), "j.med.chem.40 (1997): 1347-1365 discloses the preparation of a series of sulfonamide-containing 1, 5-diaryl pyrazole derivatives, including Celecoxib, and the evaluation of those derivatives for use as cyclooxygenase-2 inhibitors.

Simon et al, "SC-58635, a preliminary study of the safety and efficacy of a novel cyclooxygenase-2 inhibitor",arthritis and rheumatismA study of the efficacy and safety of Celecoxib in the treatment of osteoarthritis and rheumatoid arthritis is described in Vol.41, No. 9, 9 months 1998, p.1591-1602.

Results of Lipsky et al in the study of specific COX-2 inhibitors in rheumatoid arthritis "

Journal of rheumatology, Vol.24, supplement 49, pp.9-14 (1997) disclose that the specific inhibition of cyclooxygenase-2 by Celecoxib is sufficient to inhibit signs and symptoms of inflammatory disease activity in rheumatoid arthritis patients.

A composition comprising a cyclooxygenase-2 inhibitor, particularly 2- (3, 5-difluorophenyl) -3- (4-methyl-sulfonyl) phenyl) -2-cyclopentenyl-1-one, and an excipient component comprising microcrystalline cellulose, lactose monohydrate, hydroxypropyl cellulose, croscarmellose sodium, and magnesium stearate is disclosed in european patent application 0863134 a1, published 9.9.1998.

To date, formulations of Celecoxib for effective oral administration have been complicated by the unique physical and chemical properties of the compound, particularly its low solubility and factors associated with its crystalline structure including cohesiveness, low bulk density, and low compressibility. Celecoxib is unusually insoluble in aqueous media. For example, unformulated Celecoxib is not readily soluble and dispersible when administered orally in the form of a capsule and is therefore not rapidly absorbed in the gastrointestinal tract. In addition, unformulated Celecoxib having a crystalline state that readily forms sticky stringy crystals tends to melt into a mass when compressed on the die of a tablet press. Even when mixed with other materials, the Celecoxib crystals tend to separate from the other materials and agglomerate during mixing of the composition, producing a non-uniformly mixed composition comprising undesirably large aggregates of Celecoxib. Thus, it is difficult to prepare pharmaceutical compositions containing Celecoxib having the desired mixing uniformity. Moreover, handling problems are encountered in preparing pharmaceutical compositions comprising Celecoxib. For example, the low bulk density of Celecoxib makes handling of the small amounts of material required in formulating pharmaceutical compositions difficult. Accordingly, there is a need to address a number of problems associated with preparing suitable pharmaceutical compositions and dosage forms, particularly oral dosage units, comprising Celecoxib.

In particular, oral Celecoxib formulations are required to have one or more of the following properties when compared to unformulated Celecoxib or other Celecoxib compositions:

(1) the solubility is improved;

(2) the disintegration time is shortened;

(3) the dissolution time is shortened;

(4) the friability of the tablet is reduced;

(5) increased hardness of the tablet;

(6) improving the wettability;

(7) the compressibility is improved;

(8) improved flowability of liquid and particulate solid compositions;

(9) improved physical stability of the finished composition;

(10) reduction in the size of the tablet or capsule;

(11) the mixing uniformity is improved;

(12) the dose uniformity is improved;

(13) improved control of weight variation during encapsulation or tableting;

(14) the particle density of wet granulation is increased;

(15) the water required by wet granulation is reduced;

(16) the time for wet granulation is reduced; and

(17) the drying time of the wet granulation mixture is reduced.

As described below, Celecoxib treatment is applicable or potentially applicable to a variety of cyclooxygenase-2 mediated diseases. It would therefore be highly beneficial to provide a formulation with bioavailability characteristics suitable for different indications. It would be particularly effective to provide formulations that exhibit pharmacokinetics with a more rapid onset of action than unformulated Celecoxib.

The formulations represent an important advance in the treatment of cyclooxygenase-2 mediated diseases.

Summary of The Invention

The present invention now provides a pharmaceutical composition comprising one or more orally deliverable dose units, each dose unit comprising particles of celecoxib in an amount from about 10mg to about 1000mg in intimate admixture with one or more pharmaceutically acceptable excipients.

In one embodiment, a single dosage unit when administered orally to a fasted patient produces a celecoxib serum concentration versus time relationship having at least one of the following characteristics:

(a) (ii) a time to reach a concentration of 100ng/ml no more than about 0.5 hours after administration;

(b) maximum concentration (T) reached after administration_max) For no more than about 3 hours;

(c) maintaining the concentration above 100ng/ml for no less than about 12 hours;

(d) half life (T)_1/2) The time for completion is not less than about 10 hours; and

(e) maximum concentration (C)_max) Not less than about 200 ng/ml.

In another embodiment, the composition has a relative bioavailability of not less than about 50% as compared to an orally deliverable solution comprising an equivalent amount of celecoxib.

In yet another embodiment, the composition has a particle maximum dimension D₉₀Less than about 200 μm (90% of the sample particles are smaller than D)₉₀Value) of celecoxib.

Dosage units containing the composition may be in discrete solid forms such as tablets, pills, hard or soft gelatin capsules, lozenges, sachets or pastilles; alternatively, the composition may be in the form of a substantially homogeneous flowable mass such as a granular or granulated solid or liquid suspension from which the single dose units are removed to a measurable extent.

Also provided is a method of treating a disease or condition in a subject in need of treatment with a cyclooxygenase-2 inhibitor comprising orally administering a composition of the present invention once or twice daily.

Other features of the present invention will become apparent and pointed out hereinafter.

Brief Description of Drawings

Fig. 1 is a flow chart illustrating a representative method of preparing a pharmaceutical composition of the present invention in capsule form.

Fig. 2 is a flow chart illustrating another method of preparing a pharmaceutical composition of the present invention in capsule form.

Detailed description of the invention

The novel pharmaceutical compositions of the present invention comprise one or more orally deliverable dose units, wherein each dose unit comprises particles of celecoxib in an amount of about 10mg to about 1000mg, and are good immediate release compositions that provide immediate relief from cyclooxygenase-2 mediated disorders when orally administered to a patient suffering from such disorders.

Without being bound by theory, it is believed that the superior clinical advantages provided by these compositions result from improved bioavailability of celecoxib, particularly as a result of unexpectedly effective absorption of celecoxib in the gastrointestinal tract. Such effective absorption can be demonstrated by one skilled in the art by measuring the serum concentration of celecoxib in the treated subject over a period of time following administration. It is desirable to achieve a concentration of celecoxib in the serum that reaches a threshold for effective cyclooxygenase-2 inhibition in as short a time as possible, without the concentration then decaying too quickly so that the beneficial effects of celecoxib can be maintained for as long a time as possible.

Thus, in one embodiment of the invention, each orally deliverable dose unit when administered orally yields a serum concentration of celecoxib versus time that is at least one of the following:

(a) (ii) a time to reach a serum concentration of about 100ng/ml no more than about 0.5 hours after administration;

(b) maximum serum concentration (T) is reached after administration_max) For a period of no more than about 3 hours, preferably no more than about 2 hours after administration;

(c) maintaining the serum concentration above 100ng/ml for no less than about 12 hours;

(e) maximum serum concentration (C)_max) Not less than about 200ng/ml, preferably not less than about 300ng/ml, and more preferably not less than about 400 ng/ml.

It will be appreciated that the amount of celecoxib in a dosage unit effective to provide a serum concentration meeting any of the conditions (a) - (e) described immediately above will depend upon the body weight of the patient being treated. For example, when the patient is a child or a small animal (e.g., a dog), a lower amount of celecoxib in the range of about 10mg to about 1000mg can result in a serum concentration that meets at least one of the criteria (a) - (e). Where the subject is an adult human or a large animal (e.g., a horse), such serum concentrations of celecoxib would appear to require dosage units containing higher amounts of celecoxib. Suitable amounts of celecoxib per dosage unit in a composition of the invention to provide such serum concentrations are typically from about 75mg to about 400mg for an adult.

The bioavailability of orally delivered celecoxib is difficult to measure in an absolute sense, as intravenous delivery (which is often the relative standard for determining such bioavailability) is highly problematic with drugs that are very poorly water soluble. However, relative bioavailability can be determined by comparison with orally administering a solution of celecoxib dissolved in a suitable solvent. It has been found that unexpectedly higher bioavailability is obtained with the oral delivery compositions of the present invention. Thus, in one embodiment of the invention, each orally deliverable dose unit has a relative bioavailability of no less than about 50%, preferably no less than about 70%, when administered orally as compared to an orally deliverable solution of celecoxib containing an equivalent amount of celecoxib. Bioavailability is obtained by integrating measurements of the serum concentration of celecoxib over time following oral administration, as shown below.

The compositions of the present invention contain celecoxib in particulate form. Primary particles, such as by grinding or milling or by precipitation from solution, may coalesce into secondary agglomerated particles, and unless the context indicates otherwise, the term "particle size" as used herein refers to the largest range of primary particle sizes. Particle size is believed to be an important parameter affecting the clinical efficacy of celecoxib. Thus, in another embodiment, the celecoxib particle size distribution of a composition of the invention is the D of the largest range of particles thereof₉₀Less than about 200 μm, preferably less than about 100 μm, more preferably less than about 75 μm, even more preferably less than about 40 μm, and most preferably less than about 25 μm. According to embodiments of the present invention, a reduction in the particle size of celecoxib generally improves the bioavailability of celecoxib.

In addition, the mean particle size of the celecoxib particles in the compositions of the invention is preferably from about 1 μm to about 10 μm, and most preferably from about 5 μm to about 7 μm.

It has been found that milling celecoxib in an impact mill, such as a pin mill (pin mill), prior to mixing with excipients to form a composition of the invention is not only effective in improving bioavailability but is also advantageous in overcoming problems associated with the binding properties of celecoxib crystals during mixing or blending. Celecoxib that is not milled or milled using other types of mills, such as fluid energy mills, is more cohesive than celecoxib milled using pin mills and the latter are less prone to agglomeration during mixing to form secondary agglomerates of celecoxib particles. Reducing agglomeration can improve the uniformity of mixing, which is particularly important for formulating unit dosage forms such as capsules and tablets. This result is very unexpected compared to the utility of liquid energy mills such as air jet mills shown in the preparation of formulations of other pharmaceutical compounds. Without being bound by a particular theory, it is hypothesized that impact milling changes the long needle-like celecoxib crystal form to a more uniform crystal shape that is more suitable for mixing purposes, whereas the long needle-like crystals are more readily retained during air jet milling.

It has also been found that the uniformity of mixing can be further improved by wet granulating celecoxib with a carrier material to produce a pharmaceutical composition. Particularly when the celecoxib starting material used has been impact milled. Impact milling of the celecoxib starting material to achieve the particle size requirements set forth above, followed by wet granulation is particularly desirable.

In another embodiment, the novel pharmaceutical compositions of the present invention comprise celecoxib and one or more carrier materials or excipients selected from diluents, disintegrants, binders, wetting agents and lubricants. Preferably, at least one carrier material is a water-soluble diluent or wetting agent. Such water soluble diluents or wetting agents aid in the dispersion and dissolution of celecoxib when the pharmaceutical composition is ingested. Preferably, the water soluble diluent and the wetting agent are present simultaneously. The compositions of the present invention may be substantially homogeneous flowable materials such as granules or granular solids or liquids, or may be in dispersed form such as capsules or tablets each containing a single dosage unit.

In a substantially homogeneous flowable composition, a single dosage unit can be measurably removed using a suitable volume measuring device such as a spoon or cup. Suitable flowable substances include, but are not limited to, powders and granules. In addition, the flowable material is a suspension of celecoxib in a solid particulate phase dispersed in a liquid phase, preferably an aqueous phase. In preparing this suspension, it appears advantageous to use a wetting agent such as polysorbate 80. Suspensions may be prepared by dispersing milled celecoxib in the liquid phase; alternatively, celecoxib can be precipitated from solution in a solvent such as an alcohol, preferably ethanol. The aqueous phase preferably contains a palatable carrier such as water, syrup or fruit juice, e.g. apple juice. Applicability of the composition of the present invention

The compositions of the present invention are useful in the treatment and prevention of a wide variety of cyclooxygenase-2 mediated disorders. The compositions are useful, but not limited to, treating inflammation in a patient, as analgesics, e.g., for pain and headache, and as antipyretics for fever. For example, the composition may be used to treat arthritic conditions including, but not limited to, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, and juvenile arthritis. The composition can also be used for treating asthma, bronchitis, dysmenorrhea, premature labor (preterm labor), tendonitis, bursitis, allergic neuritis, cytomegalovirus infection, apoptosis (including HIV-induced apoptosis), lumbago, liver diseases including hepatitis, skin-related diseases such as psoriasis, eczema, acne, ultraviolet injury, burn and dermatitis, and post-operative inflammation including inflammation after ophthalmic surgery such as cataract surgery or refractive surgery. The composition of the present invention can be used for treating gastrointestinal diseases such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis. The composition can be used for treating inflammation, such as migraine, periarteritis nodosa, thyroiditis, aplastic anemia, lymphoblastic granulomatosis, scleroderma, rheumatic fever, type I diabetes, neuromuscular junction diseases including myasthenia gravis, white matter diseases including multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's disease, polymyositis, gingivitis, nephritis, allergy, swelling after injury including cerebral edema, myocardial ischemia, etc. The composition is useful for treating ophthalmic diseases such as retinitis, conjunctivitis, retinopathy, uveitis, ocular photophobia, and acute injury of ocular tissue. The compositions are useful for treating pneumonia, such as pneumonia associated with viral infections and bladder fibrosis, and for treating bone resorption diseases such as bone resorption associated with osteoporosis. The compositions are useful for treating certain central nervous system disorders such as cortical dementias including Alzheimer's disease, neurodegenerative disorders, and central nervous system injury due to stroke, ischemia, and trauma. The term "treatment" as used herein includes partial or total inhibition of dementias, including Alzheimer's disease, vascular dementia, multi-infarct dementia, Alzheimer's disease, alcoholic dementia and senile dementia.

The compositions of the present invention are particularly useful as anti-inflammatory agents, such as in the treatment of arthritis, and have the additional advantage of having significantly less deleterious side effects than conventional non-steroidal anti-inflammatory drug (NSAID) compositions.

The composition can be used for treating allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome and liver diseases. The compositions are useful for treating pain, including but not limited to post-operative pain, dental pain, muscle pain, and pain caused by cancer.

The compositions are useful for, but not limited to, treating and preventing patients with myocardial disorders associated with inflammation. The compositions are useful for the treatment and prevention of vascular disease, coronary artery disease, aneurysm, vascular rejection, arteriosclerosis, atherosclerosis including heart transplant atherosclerosis, myocardial infarction, embolism, stroke, thrombosis including venous thrombosis, angina including unstable angina, coronary plaque inflammation, bacterial induced inflammation including chlamydial induced inflammation, viral induced inflammation, and inflammation associated with surgical procedures such as vascular grafting including coronary artery bypass surgery, revascularization (revascularization) procedures including angioplasty, stent placement, endarterectomy, and other invasive procedures involving arteries, veins, and capillaries. The composition is useful for, but not limited to, treating patients with angiogenesis-related diseases. The compositions of the present invention may be administered to a patient in need of inhibition of angiogenesis. The composition can be used for treating neoplasia, including tumor metastasis; ophthalmic diseases such as corneal graft rejection, ocular neovascularization (neovascularization), retinal neovascularization including that following injury or infection, diabetic retinopathy, macular changes, retrolental fibroplasia, and neovascular glaucoma; ulcerative diseases such as gastric ulcer; pathologic but non-malignant diseases such as hemangiomas including hemangiomas in infants, nasopharyngeal angiofibromas, and avascular necrosis of bone; and diseases of the female reproductive system such as endometriosis.

The compositions are useful for preventing or treating benign and malignant neoplasia including cancers such as colon cancer, brain cancer, bone cancer, epithelial cell derived tumors (epithelial cancers) such as basal cell carcinoma, adenocarcinoma, gastrointestinal cancers such as lip cancer, mouth cancer, esophageal cancer, small bowel cancer and stomach cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer and skin cancers such as squamous cell and basal cell carcinoma, prostate cancer, renal cell carcinoma and other cancers known to affect epithelial cells throughout the body. Tumors in which the compositions of the present invention are particularly effective are gastrointestinal cancer, Barrett's esophageal cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer, cervical cancer, lung cancer, breast cancer, and skin cancers such as squamous cell and basal cell carcinomas. The compositions of the present invention may also be used to treat fibrosis resulting from radiation therapy. The composition can be used for treating patients with adenomatous polyps, including Familial Adenomatous Polyposis (FAP). In addition, the compositions are useful for preventing polyp formation in patients at risk of FAP.

The compositions of the present invention have anti-inflammatory, antipyretic and analgesic properties similar to or superior to conventional non-steroidal anti-inflammatory drug compositions. The compositions also inhibit hormone-induced uterine contractions and have potential anti-cancer effects, but reduce the ability of conventional NSAIDs to induce certain mechanistic side effects. In particular, the compositions of the invention have the ability to reduce gastrointestinal toxicity and gastrointestinal irritation, including upper gastrointestinal ulceration and bleeding, reduce renal side effects such as reduced renal function leading to fluid retention and exacerbation of hypertension, reduce the effects on bleeding time including inhibition of platelet function, and possibly reduce the ability to induce asthma attacks in aspirin-sensitive asthma patients, as compared to conventional NSAID compositions.

The composition is used for relieving pain, fever and inflammation caused by various diseases including rheumatic fever, diseases associated with influenza or other viral infections, common cold, back and neck pain, dysmenorrhea, headache, toothache, contusion and sprain, myositis, neuralgia, synovitis, arthritis including rheumatoid arthritis, degenerative joint disease (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns and injuries caused by surgical and dental procedures. In addition, the composition inhibits the metastasis of tumor cells and the growth of metastases and thus can be used to treat cancers such as colon cancer. The compositions are also useful for the treatment and/or prevention of cyclooxygenase-mediated proliferative disorders such as may occur in diabetic retinopathy and tumor angiogenesis.

The composition inhibits prostanoid-induced smooth muscle contraction by inhibiting synthesis of contractile prostanoid (prostanoid) and thus can be used for treating dysmenorrhea, premature labor, asthma and eosinophil-related diseases. They can also be used in the treatment of alzheimer's disease, for reducing bone loss, particularly in postmenopausal women (i.e. in the treatment of osteoporosis), and for the treatment of glaucoma.

Because the cyclooxygenase-2 (COX-2) inhibitors of the present compositions are highly active and/or their specificity of inhibiting cyclooxygenase-2 exceeds that of inhibiting cyclooxygenase-1 (COX-1), the present compositions are useful as a replacement for conventional NSAIDs, particularly when such NSAIDs are contraindicated, e.g., in patients with peptic ulcers, gastritis, regional enteritis, ulcerative conjunctivitis, diverticulitis, or have a history of recurrence of gastrointestinal damage; gastrointestinal bleeding, blood clotting diseases including anemia, such as hypohemagglutination, hemophilia, or other bleeding problems; renal disease; or a patient prior to surgery or a patient taking anticoagulant. A brief description of the potential utility of cyclooxygenase-2 inhibitors is given in John Vane, Nature, Vol.367.pp.215-216, 1994, and in Drug News and Perspectral, Vol.7, pp.501-512, 1994.

Preferred utility of the pharmaceutical composition of the present invention is for the treatment of rheumatoid arthritis and osteoporosis, for the relief of pain (especially post-oral pain, post-general surgery pain, post-orthopedic pain and acute paroxysmal osteoarthritis), the treatment of alzheimer's disease and the chemoprevention of colon cancer.

In addition to use in human therapy, the compositions of the present invention are also useful in veterinary therapy of companion, exotic, and farm animals and the like, particularly mammals including rodents. In particular, the compositions of the present invention are useful in the veterinary treatment of cyclooxygenase-2 mediated diseases in horses, dogs and cats.

The compositions of the present invention may be used in combination therapy with opioids and other analgesics, including narcotic analgesics, Mu receptor antagonists, Kappa receptor antagonists, non-narcotic (i.e., non-addictive) analgesics, monoamine uptake inhibitors, adenosine modulators, canabinoid derivatives, substance P antagonists, neurokinin-1 receptor antagonists, sodium channel blockers, and the like. A preferred combination therapy comprises the use of a composition of the invention and a compound selected from morphine, meperidine, codeine, pentazocine, buprenorphine, butorphanol, dezocine, meptazinol, hydrocodone, oxycodone, methadone, DuP-747, Dynorphine (Dynorphine) A, enaline, RP-60180, HN-11608, E-2078, ICI-204448, acetaminophen (paracetamol), dexpropoxyphene, nalbuphine, E-4018, felbinat, mirfentanyl, amitriptyline, DuP-631, GP-531, acadesine, AKI-1, AKI-2, GP-1683, GP-3296, 4030W92, tramadol racemate and the isolated (+) and (-) enantiomers, AXC-3742, SNX-111, ADL2-1294, CT-3 and CP-99994.

Definition of

The term "active ingredient" as used herein, unless otherwise indicated, refers to celecoxib.

The term "excipient", as used herein, includes any substance that serves as a vehicle for the release of an active ingredient into a patient's body, and for example, any substance added to an active ingredient to improve its handling or to form the resulting composition into an orally deliverable unit dose having the desired shape and consistency. Excipients may include, but are not limited to, for example, diluents, disintegrants, binders, adhesives, wetting agents, lubricants, glidants, substances that mask or counteract an unpleasant taste or odor, flavoring agents, dyes, substances that improve the appearance of the dosage form, and any other substance than the active ingredient typically used in preparing oral dosage forms.

The term "adjuvant" as used herein refers to a substance that, when present in or added to a pharmaceutical composition containing an active ingredient, increases or improves the action of the active ingredient.

As used herein, the term "unit dose" refers to an amount of active ingredient that is intended for a single oral administration to a subject in order to treat or prevent a cyclooxygenase-2 mediated condition. Treatment of cyclooxygenase-2 mediated diseases may require periodic administration of unit doses of celecoxib, e.g., 1 unit dose per time, 2 to more times per day, 1 unit dose per meal, 1 unit dose per 4 hour or other interval, or only 1 unit dose per day.

The term "dosage unit" as used herein refers to a portion of a pharmaceutical composition containing a single unit dose of an active ingredient. For the purposes of the present invention, a dosage unit may be in the form of a discrete body such as a tablet or capsule, or may be a measurable volume of a solution, suspension or the like containing the active ingredient in a unit dose.

The term "orally deliverable" as used herein refers to a pharmaceutical product that is intended to be administered to the gastrointestinal tract of a patient through the oral cavity of said patient.

As used herein, the term "substantially homogeneous", when used in describing a pharmaceutical composition comprising a combination of components, means that the components are mixed sufficiently that the components are neither separated into discrete layers nor form a concentration gradient within the composition.

The term "bioavailability" as used herein refers to the determination of the amount of active ingredient absorbed into the blood through the gastrointestinal tract. In particular, "bioavailability" as used herein refers to the AUC of a particular orally administered composition_(0-∞)Which is the AUC for the intravenous release of the active ingredient at the same dose rate_(0-∞)Expressed in percent.

In this contextThe term "relative bioavailability" as used herein refers to the AUC of a particular orally administered composition_(0-∞)It is the AUC of the active ingredient solution administered orally at the same dose rate_(0-∞)Expressed in percent.

The term "AUC" as used herein_(0-24)”“AUC_(0-48)"and" AUC_(0-72)"refers to the area under the serum concentration-time curve, measured using linear trapezoidal rule, from 0 to 24 hours, 48 hours, or 72 hours post-administration, and expressed in units of (ng/ml) h, respectively.

The term "AUC" as used herein_(0-LQC)"refers to the area under the serum concentration-time curve from 0 hours post-dose to the lowest quantifiable concentration (" LQC ") as determined by linear trapezoidal rule and expressed in units of (ng/ml) h.

The term "AUC" as used herein_(0-∞)"is the AUC_(0-LQC)+ LQC/(-b) where LQC is the lowest quantifiable serum concentration and b is calculated from T_1/2The resulting slope was calculated and expressed in units of (ng/ml) h.

The term "C" as used herein_max"refers to the maximum serum concentration determined or calculated or estimated from a concentration/time curve and is expressed in units of (ng/ml) h.

The term "T" as used herein_maxBy "is meant the appearance of C after administration_maxTime, and is expressed in units of hours (h).

The term "T" as used herein_1/2"means the terminal half-life of serum concentration as determined by simple linear regression of the end phase data points of the natural log (ln) concentration-time curve using 0ln (2)/(-b) to calculate T_1/2And is expressed in units of hours (h).

The term "absorption rate" as used herein means C_max/AUC_(0-LQC)。

The compositions of the invention provide a dosage of Celecoxib

The pharmaceutical compositions of the invention are suitable for administration of Celecoxib in a daily dose of about 10mg to about 1000 mg. Typically, each dosage unit of a composition of the invention will contain Celecoxib in an amount of about 1/10 daily doses through the entire daily dose. Compositions of the invention contain Celecoxib in an amount of about 10mg to about 1000mg, preferably about 50mg to about 800mg, more preferably about 75mg to about 400mg, and most preferably about 100mg to about 200mg per dosage unit. When the dosage unit is in a form suitable for oral administration as a discrete body, such as a capsule or tablet, each of the discrete body forms contains about 10mg to about 1000mg, preferably about 50mg to about 800mg, more preferably about 75mg to about 400mg, and most preferably about 100mg to about 200mg of Celecoxib.

Typically, for example, a dosage unit of a composition of the invention contains Celecoxib in a dosage of 10, 20, 25, 37.5, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, or 400 mg. Preferred dosage units of the composition contain Celecoxib in a dosage of about 100mg to about 200 mg. The particular dosage unit may be selected to provide the frequency of administration required to obtain the desired daily dosage. The daily dosage and frequency of administration, and thus the selection of an appropriate dosage unit, will depend upon a variety of factors including the age, weight, sex, and medical condition of the patient, as well as the nature and severity of the condition, and may thus vary widely.

However, it has been found that once-a-day or twice-a-day dosing regimens exhibit improved efficacy over other dosing regimens for the compositions exemplified herein in order to provide the desired daily dosage of Celecoxib. Thus, once-a-day or twice-a-day administration of the compositions of the present invention is preferred for providing therapeutically and prophylactically effective inhibition of cyclooxygenase-2 mediated diseases.

Treatment of specific diseases

The pharmaceutical compositions of the present invention are useful for conditions requiring administration of cyclooxygenase-2 inhibitors. These compositions have been found to be particularly effective, for example, in the treatment of rheumatoid arthritis and osteoarthritis and in the relief of pain (particularly post-oral pain, post-general surgery pain, post-orthopedic pain and acute paroxysmal osteoarthritis), the treatment of alzheimer's disease and the chemoprevention of colon cancer.

For the treatment of rheumatoid arthritis, compositions of the invention may be used to provide a daily dosage of Celecoxib of about 50mg to about 1000mg, preferably about 100mg to about 600mg, more preferably about 150mg to about 500mg, and even more preferably about 175mg to about 400mg, for example about 200 mg. When compositions of the invention are administered, a daily dosage of Celecoxib of about 0.67 to about 13.3mg/kg body weight, preferably about 1.33 to about 8.00mg/kg body weight, more preferably about 2.00 to about 6.67mg/kg body weight and even more preferably about 2.33 to about 5.33mg/kg body weight, e.g., about 2.67mg/kg body weight, is generally suitable. The daily dose may be administered in 1-4 divided doses per day, preferably 1 or 2 divided doses per day. For most patients, it is preferred to administer the composition at a rate of one 100mg dosage unit twice daily, but for some patients it may be advantageous to administer the composition at a rate of one 200mg dosage unit or two 100mg dosage units twice daily.

For the treatment of osteoarthritis, the compositions of the invention may be used to provide a daily dosage of Celecoxib of about 50mg to about 1000mg, preferably about 100mg to about 600mg, more preferably about 150mg to about 500mg, and even more preferably about 175mg to about 400mg, for example about 200 mg. When compositions of the invention are administered, a daily dosage of Celecoxib of about 0.67 to about 13.3mg/kg body weight, preferably about 1.33 to about 8.00mg/kg body weight, more preferably about 2.00 to about 6.67mg/kg body weight and even more preferably about 2.33 to about 5.33mg/kg body weight, e.g., about 2.67mg/kg body weight, is generally suitable. The daily dose may be administered in 1-4 divided doses per day, preferably 1 or 2 divided doses per day. Preferably, the compositions of the present invention are administered at a rate of one 100mg dosage unit at a time, twice daily, or one 200mg dosage unit or two 100mg dosage units at a time, once daily.

For the treatment of Alzheimer's disease, compositions of the invention may be used to provide a daily dosage of Celecoxib of about 50mg to about 1000mg, preferably about 100mg to about 800mg, more preferably about 150mg to about 600mg, and even more preferably about 175mg to about 400mg, for example about 400 mg. When compositions of the invention are administered, a daily dosage of Celecoxib of about 0.67 to about 13.3mg/kg body weight, preferably about 1.33 to about 10.67mg/kg body weight, more preferably about 2.00 to about 8.00mg/kg body weight and even more preferably about 2.33 to about 5.33mg/kg body weight, e.g., about 5.33mg/kg body weight, is generally suitable. The daily dose may be administered in 1-4 divided doses per day, preferably 1 or 2 divided doses per day. For most patients, it is preferred to administer the compositions of the present invention at a rate of one 200mg dosage unit or two 100mg dosage units at a time, twice daily.

For the treatment of cancer, compositions of the invention may be used to provide a daily dosage of Celecoxib of about 50mg to about 1000mg, preferably about 100mg to about 800mg, more preferably about 150mg to about 600mg, and even more preferably about 175mg to about 400mg, for example about 400 mg. When compositions of the invention are administered, a daily dosage of Celecoxib of about 0.67 to about 13.3mg/kg body weight, preferably about 1.33 to about 10.67mg/kg body weight, more preferably about 2.00 to about 8.00mg/kg body weight and even more preferably about 2.33 to about 5.33mg/kg body weight, e.g., about 5.33mg/kg body weight, is generally suitable. The daily dose may be administered in 1-4 divided doses per day, preferably 2 divided doses per day. For most patients, it is preferred to administer the compositions of the present invention at a rate of one 200mg dosage unit or two 100mg dosage units at a time, twice daily.

In general, it is preferred that the compositions of the invention be administered at a dosage that provides a mean serum concentration of Celecoxib of at least about 100ng/ml in the patient over a period of about 24 hours after administration.

It has been found that the pharmaceutical compositions of the present invention provide therapeutic effects as cyclooxygenase-2 inhibitors over an interval of about 12 to 24 hours following oral administration. Preferred compositions provide a therapeutic effect for about 24 hours and are therefore capable of once daily oral administration.

While the amount of Celecoxib in the novel compositions of the invention is preferably within the ranges disclosed herein, the compositions can also be used when amounts of Celecoxib outside the disclosed ranges are administered.

Preparation of Celecoxib

Celecoxib used in the novel pharmaceutical compositions of the invention may be prepared according to the procedures described in Talley et al, U.S. Pat. No. 5,466,823, or in Zhi et al, WO 96/37476.

Forms of the compositions of the invention

The pharmaceutical compositions of the present invention comprise Celecoxib in combination 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 material must be acceptable in terms of compatibility with the other components of the composition of the present invention and must be non-hazardous to the user. The compositions of the present invention may be suitably administered by any suitable oral route by selection of suitable carrier materials and dosages of Celecoxib effective for such treatment. Thus, any carrier material used may be solid or liquid 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 even more preferably about 30% to about 80% by weight of Celecoxib. The pharmaceutical compositions of the present invention may be prepared by any of the well-known pharmaceutical techniques, including mixed component techniques.

The compositions of the present invention contain a desired amount of Celecoxib per dosage unit and may be in dosage form as tablets, pills, hard or soft capsules, troches, cachets, powders for dispensing, granules, suspensions, elixirs, liquids, or any other form suitable for oral administration. Preferably, the compositions are prepared in discrete dosage unit forms, such as tablets or capsules, each containing a predetermined amount of Celecoxib. For example, these oral dosage unit forms may further comprise a buffering agent. In addition, tablets, pills, and the like may be prepared with or without a coating agent.

For example, compositions of the invention suitable for buccal or sublingual administration include 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.

Liquid dosage forms for oral administration include pharmaceutically acceptable suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. The compositions also include, for example, wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

As noted above, the compositions of the present invention may be prepared by any suitable pharmaceutical method that includes the step of bringing the Celecoxib into association with a carrier material. In general, the compositions can be prepared by uniformly and intimately admixing Celecoxib with liquid or finely divided solid carriers or both, and then, if necessary, encapsulating or otherwise shaping the product. For example, tablets may be prepared by compressing or molding a powder or granules of the compound with one or more excipients. Compressed tablets may be prepared by compressing in a suitable machine a free-flowing composition, such as a powder or granules, containing Celecoxib, with or without one or more binders, lubricants, inert carriers, wetting agents and/or dispersing agents. Molded tablets may be prepared by casting in a mold, in a suitable machine, the powder-like compound moistened with an inert liquid diluent.

Carrier materials or excipients

As noted above, each dosage unit of the pharmaceutical compositions of the present invention comprises a therapeutically or prophylactically effective amount of Celecoxib and one or more pharmaceutically acceptable carrier materials suitable for oral administration. Compositions of the present invention preferably comprise Celecoxib in the required amount and one or more carrier materials selected from the group consisting of pharmaceutically acceptable diluents, disintegrants, binders, adhesives, wetting agents, lubricants and anti-adherents. More preferably, the composition is compressed or encapsulated in an immediate release capsule or tablet form for conventional administration.

Because of the selection and combination of carrier materials used in the pharmaceutical compositions of the present invention, compositions may be provided that exhibit improved performance in terms of, among other things, efficacy, bioavailability, clearance time, stability, compatibility of the Celecoxib and carrier materials, safety, dissolution profile, disintegration profile, and/or other pharmacokinetic, chemical and/or physical properties. Preferably, the carrier material is water soluble or water dispersible and has wettability to counteract the low water solubility and hydrophobicity of Celecoxib. When the composition is formulated as a tablet, the composition of carrier materials selected provides, among other properties, a tablet having improved dissolution and disintegration profiles, hardness, crushing strength and/or friability.

Diluent

The pharmaceutical compositions of the present invention may contain no or one or more pharmaceutically acceptable diluents as carrier materials. Suitable diluents include lactose USP, alone or in combination; anhydrous lactose US; spray dried lactose USP; starch USP; starch that can be directly tabletted; mannitol USP; sorbitol; glucose monohydrate; microcrystalline cellulose NF; dibasic calcium phosphate dihydrate NF; a sucrose-based diluent; sugar is commercially available; basic (monobasic) calcium sulfate monohydrate; calcium sulfate dihydrate NF; calcium lactate trihydrate particles NF; dextrates NF (e.g., Emdex); celutab; dextrose (e.g., cerelose); inositol; hydrolyzed cereal solids such as Maltrons and Mor-Rex; amylose starch; rexcel; powdered cellulose (e.g., Elcema); calcium carbonate; glycine; bentonite; polyvinylpyrrolidone, and the like. If present, the diluent comprises from about 5% to about 99%, preferably from about 10% to about 85%, and more preferably from about 20% to about 80% by weight of the total composition. Preferably, the diluent is selected to have suitable flow properties and, if a tablet, compressibility.

Lactose and microcrystalline cellulose, alone or in combination, are effective diluents. Both diluents are chemically compatible with Celecoxib. The use of microcrystalline cellulose outside the granules (i.e. microcrystalline cellulose added to the wet granulation composition after the drying step) may be used to improve hardness (for tablets) and/or disintegration time. Lactose, in particular lactose monohydrate, is particularly preferred. Typically, lactose provides a pharmaceutical composition with a suitable Celecoxib release rate, stability, flowability prior to tableting, and/or dryness at relatively low diluent consumption. It provides a high density material which facilitates the granulation (if wet granulation is used) process to increase the density of the composition and thus improve the flowability of the mixture.

Disintegrating agent

Preferably, the pharmaceutical compositions of the present invention comprise one or more pharmaceutically acceptable disintegrants as carrier material, especially for tablets. Suitable disintegrants include starch, alone or in combination; sodium starch glycolate; clays (e.g., Veegum HV); cellulose (e.g., pure cellulose, methyl cellulose, sodium carboxymethyl cellulose, and carboxymethyl cellulose); an alginate; pregelatinized corn starches (e.g., National 1551 and National 1550); crosslinked povidone USPNF and gums (such as agar, guar gum, locust bean gum, karaya gum, pectin, and tragacanth). The disintegrant may be added at any stage of the preparation of the pharmaceutical composition of the invention, in particular prior to granulation or during the lubrication step prior to tableting. If present, the disintegrant comprises from about 0.2% to about 30%, preferably from about 0.2% to about 10%, and more preferably from about 0.2% to about 5% by weight of the total composition.

Croscarmellose sodium is a preferred disintegrant for tablet or capsule disintegration, and if present, preferably comprises from about 0.2% to 10%, more preferably from about 0.2% to 6%, and even more preferably from about 0.2% to 5% by weight of the total composition. Croscarmellose sodium provides greater intragranular disintegration capabilities to the compositions of the present invention.

Adhesive and sticking agent

The pharmaceutical compositions of the present invention may contain no or one or more pharmaceutically acceptable binders or adhesives as carrier materials, especially for tablets. Preferably, the binder and binder provide sufficient viscosity to the tableting powder to allow normal handling such as sizing, lubrication, tableting and packaging and, further when ingested, to enable the tablet to disintegrate and the composition to be absorbed. Suitable binders and adhesives include acacia gum, alone or in combination; tragacanth gum; sucrose; gelatin; glucose; starch; cellulosic materials such as, but not limited to, methylcellulose and sodium carboxymethylcellulose (e.g., Tylose); alginic acid and alginates thereof; magnesium aluminum silicate; polyethylene glycol; guar gum; a gluconic acid; bentonite; polyvinylpyrrolidone; a polyisobutylene ester; hydroxypropylmethylcellulose (HPMC); hydroxypropyl cellulose (Klucel); ethyl cellulose (Ethocel); pregelatinized starches (e.g., National 1551 and Starch 1500). If present, the binder comprises from about 0.5% to about 25%, preferably from about 0.75% to about 15%, and more preferably from about 1% to about 10% by weight of the total composition.

Polyvinylpyrrolidone is a preferred binder for providing viscosity to the Celecoxib and other excipient powder mixtures during granulation of the Celecoxib formulation. If present, the polyvinylpyrrolidone comprises about 0.5% to about 10%, more preferably about 0.5% to about 7%, and even more preferably about 0.5% to about 5% by weight of the total composition. Although it is preferred that the polyvinylpyrrolidone have a viscosity of about 6cPs or less, particularly 3cPs or less, polyvinylpyrrolidones having viscosities up to about 20cPs may also be used. Polyvinylpyrrolidone provides powder mixture cohesiveness and promotes the necessary binding in wet granulation to form granules. In addition, it has been found that the compositions of the present invention comprising polyvinylpyrrolidone, in particular compositions by wet granulation, have improved bioavailability compared to other compositions.

Wetting agent

Celecoxib is extremely insoluble in aqueous solutions. Thus, the pharmaceutical composition of the present invention does not comprise or comprises, but preferably comprises, one or more pharmaceutically acceptable wetting agents as carrier material. Preferably, the wetting agent is selected so as to maintain the Celecoxib in intimate association with water, which is believed to be a condition that improves the relative bioavailability of the pharmaceutical compositions of the invention. Suitable wetting agents include oleic acid, alone or in combination; glycerol monostearate; sorbitan monooleate; sorbitan monolaurate; triethanolamine oleate; polyoxyethylene sorbitan monooleate; polyoxyethylene sorbitan monolaurate; sodium oleate and sodium lauryl sulfate. Anionic surfactant type wetting agents are preferred. If present, the humectant constitutes about 0.25% to about 15%, preferably about 0.4% to about 10%, and more preferably about 0.5% to about 5% by weight of the total composition.

Sodium lauryl sulfate is a preferred wetting agent. If present, the sodium lauryl sulfate comprises about 0.25% to about 7%, more preferably about 0.4% to about 6%, and even more preferably about 0.5% to about 5% by weight of the total composition.

Lubricant agent

The pharmaceutical compositions of the present invention may contain no or one or more pharmaceutically acceptable lubricants and/or glidants as carrier materials. Suitable lubricants and/or glidants include glyceryl behapate (Compritol 888); stearates (magnesium, calcium and sodium stearate); stearic acid; hydrogenated vegetable oils (e.g., Sterotex); talc powder; a wax; stearowe; boric acid; sodium benzoate; sodium acetate; sodium fumarate; sodium chloride; DL-leucine; polyethylene glycols (e.g., polyethylene glycol 4000 and polyethylene glycol 6000); sodium oleate; sodium lauryl sulfate and magnesium lauryl sulfate. If present, the lubricant comprises from about 0.1% to about 10%, preferably from about 0.2% to about 8%, and more preferably from about 0.25% to about 5% by weight of the total composition.

For example, magnesium stearate is a preferred lubricant for reducing friction between equipment and the granulation mixture during tableting.

Other carrier materials (e.g., antiadherents, colorants, flavors, sweeteners, and preservatives) are known in the pharmaceutical art and may be included in the compositions of the present invention. For example, iron oxide may be added to the composition to form a yellow color.

Capsule and tablet

In one embodiment of the invention, the pharmaceutical composition is in the form of a capsule or tablet for absorption as a unit dose and contains the desired amount of Celecoxib and a binder. Preferably, the composition further comprises one or more carrier materials selected from the group consisting of pharmaceutically acceptable diluents, disintegrants, binders, wetting agents and lubricants. More preferably, the composition comprises one or more carrier materials selected from lactose, sodium lauryl sulfate, polyvinylpyrrolidone, croscarmellose sodium, magnesium stearate and microcrystalline cellulose. Even more preferably, the composition comprises lactose monohydrate and croscarmellose sodium. Still preferably, the composition further comprises one or more of the carrier materials sodium lauryl sulfate, magnesium stearate and microcrystalline cellulose.

In another example, a pharmaceutical composition comprises:

(a) about 1-95% by weight Celecoxib;

(b) about 5-99% by weight of a pharmaceutically acceptable diluent;

(c) about 0.5-30% by weight of a pharmaceutically acceptable disintegrant; and

(d) about 0.5 to about 25 weight percent of a pharmaceutically acceptable binder.

In addition, the pharmaceutical composition may comprise no or no:

(e) about 0.25-15% by weight of a pharmaceutically acceptable wetting agent; and/or

(f) About 0.1-10% by weight of a pharmaceutically acceptable lubricant.

The term "% by weight" as used herein refers to the weight percent of a particular component, calculated based on the total weight of all components in the composition.

In another example, a pharmaceutical composition comprises:

(a) about 1-95% by weight Celecoxib;

(b) about 5-99% by weight lactose;

(c) about 2-6% by weight of croscarmellose sodium; and

(d) about 0.5 to about 10 weight percent polyvinylpyrrolidone.

In addition, the pharmaceutical composition may comprise no or no:

(e) about 0.25 to about 7 weight percent sodium lauryl sulfate;

(f) about 0.1-10% by weight magnesium stearate; and/or

(g) About 1-99 wt% microcrystalline cellulose.

In another example, a pharmaceutical composition comprises:

(a) about 80-220mg of Celecoxib;

(b) about 30-225mg lactose;

(c) about 0.5-25mg croscarmellose sodium; and

(d) about 0.5 to 25mg of polyvinylpyrrolidone.

In addition, the pharmaceutical composition may comprise no or no:

(e) about 0.5-25mg sodium lauryl sulfate;

(f) about 0.2-10mg magnesium stearate; and/or

(g) About 1-70mg microcrystalline cellulose.

In another example, a pharmaceutical composition comprises:

(a) about 25-85% by weight Celecoxib;

(b) about 5-70 wt% lactose;

(c) about 0.2-5% by weight of croscarmellose sodium; and

(d) about 0.5 to about 7 weight percent polyvinylpyrrolidone.

In addition, the pharmaceutical composition may comprise no or no:

(e) about 0.4 to about 6 weight percent sodium lauryl sulfate;

(f) about 0.2-8% by weight magnesium stearate; and/or

(g) About 0.1-15 wt% microcrystalline cellulose.

Preferably, the pharmaceutical composition of this embodiment is in the form of a unit dosage capsule.

In another example, a pharmaceutical composition comprises:

(a) about 27-47% by weight Celecoxib;

(b) about 45-65 wt% lactose;

(c) about 0.5-5% by weight of croscarmellose sodium; and

(d) about 0.5 to about 5 weight percent polyvinylpyrrolidone.

In addition, the pharmaceutical composition may comprise no or no:

(e) about 0.25 to about 7 weight percent sodium lauryl sulfate; and/or

(f) About 0.25-5% by weight magnesium stearate.

The pharmaceutical composition of this embodiment is preferably in the form of a unit dosage capsule. In this example, the pharmaceutical composition preferably comprises:

(a) about 32-42% by weight Celecoxib;

(b) about 50-60% by weight lactose;

(c) about 0.5-3% by weight of croscarmellose sodium; and

(d) about 1-5 wt% polyvinylpyrrolidone.

In addition, the pharmaceutical composition may comprise no or no:

(e) about 0.4 to about 6 weight percent sodium lauryl sulfate; and/or

(f) About 0.5-3% by weight magnesium stearate.

The pharmaceutical composition in this example more preferably comprises:

(a) about 35-39% by weight Celecoxib;

(b) about 54-57 wt% lactose;

(c) about 0.5-2% by weight of croscarmellose sodium; and

(d) about 1.5-4.5 wt% polyvinylpyrrolidone.

In addition, the pharmaceutical composition may comprise no or no:

(e) about 2-4% by weight sodium lauryl sulfate; and/or

(f) About 0.5-2% by weight magnesium stearate.

In another example, a pharmaceutical composition comprises:

(a) about 65-85% by weight Celecoxib;

(b) about 8-28 wt% lactose;

(c) about 0.5-5% by weight of croscarmellose sodium; and

(d) about 0.5 to about 5 weight percent polyvinylpyrrolidone.

In addition, the pharmaceutical composition may comprise no or no:

(e) about 0.25 to about 7 weight percent sodium lauryl sulfate; and/or

(f) About 0.25-5% by weight magnesium stearate.

The pharmaceutical composition in this embodiment is preferably in the form of a capsule as a unit dosage form. In this example, the pharmaceutical composition preferably comprises:

(a) about 69 to about 79 weight percent Celecoxib;

(b) about 13.5-23.5 wt% lactose;

(c) about 0.5-3% by weight of croscarmellose sodium; and

(d) about 1-5 wt% polyvinylpyrrolidone.

In addition, the pharmaceutical composition may comprise no or no:

(e) about 0.4 to about 6 weight percent sodium lauryl sulfate; and/or

(f) About 0.5-3% by weight magnesium stearate.

In this example, the pharmaceutical composition more preferably comprises:

(a) about 72-76% by weight Celecoxib;

(b) about 16.5-20.5 wt% lactose;

(c) about 0.5-2% by weight of croscarmellose sodium; and

(d) about 1.5-4.5 wt% polyvinylpyrrolidone.

In addition, the pharmaceutical composition may comprise no or no:

(e) about 2-4% by weight sodium lauryl sulfate; and/or

(f) About 0.5-2% by weight magnesium stearate.

In another example, a pharmaceutical composition comprises:

(a) about 30-50% by weight Celecoxib;

(b) about 30-50 wt% lactose;

(c) about 0.5-6% by weight of croscarmellose sodium; and

(d) about 0.5 to about 5 weight percent polyvinylpyrrolidone.

In addition, the pharmaceutical composition may comprise no or no:

(e) about 1-20 wt% microcrystalline cellulose;

(f) about 0.25 to about 7 weight percent sodium lauryl sulfate; and/or

(g) About 0.25-5% by weight magnesium stearate.

The compositions of this embodiment are preferably presented in tablet form as a unit dosage form. In this example, the pharmaceutical composition preferably comprises:

(a) about 35-45% by weight Celecoxib;

(b) about 35-45% by weight lactose;

(c) about 1-5% by weight of croscarmellose sodium; and

(d) about 1-5 wt% polyvinylpyrrolidone.

In addition, the pharmaceutical composition may comprise no or no:

(e) about 5-15 wt% microcrystalline cellulose;

(f) about 0.4 to about 6 weight percent sodium lauryl sulfate; and/or

(g) About 0.5-3% by weight magnesium stearate.

In this example, the pharmaceutical composition more preferably comprises:

(a) about 38-42% by weight Celecoxib;

(b) about 38-42 wt% lactose;

(c) about 1.5-4.5% by weight of croscarmellose sodium; and

(d) about 1.5-4.5 wt% polyvinylpyrrolidone.

In addition, the pharmaceutical composition may comprise no or no:

(e) about 8-12 wt% microcrystalline cellulose;

(f) about 2-4% by weight sodium lauryl sulfate; and/or

(g) About 0.5-2% by weight magnesium stearate.

In another example, a pharmaceutical composition comprises:

(a) about 95-105mg of Celecoxib;

(b) about 145-155mg lactose monohydrate;

(c) about 0.5-8mg croscarmellose sodium; and

(d) about 2-12mg polyvinylpyrrolidone.

In addition, the pharmaceutical composition may comprise no or no:

(e) about 3-13mg sodium lauryl sulfate; and/or

(f) About 0.5-8mg magnesium stearate.

The compositions of this embodiment are preferably in the form of a unit dosage capsule. In this example, the pharmaceutical composition preferably comprises:

(a) about 98-102mg of Celecoxib;

(b) about 148-152mg lactose monohydrate;

(c) about 1.5-4.5mg croscarmellose sodium; and

(d) about 4.5-8.5mg polyvinylpyrrolidone.

In addition, the pharmaceutical composition may comprise no or no:

(e) about 6-10mg sodium lauryl sulfate; and/or

(f) About 1-5mg magnesium stearate.

In another example, a pharmaceutical composition comprises:

(a) about 195-;

(b) about 45-55mg lactose monohydrate;

(c) about 0.5-8mg croscarmellose sodium; and

(d) about 2-12mg polyvinylpyrrolidone.

In addition, the pharmaceutical composition may comprise no or no:

(e) about 3-13mg sodium lauryl sulfate; and/or

(f) About 0.5-8mg magnesium stearate.

(a) 198-;

(b) about 48-52mg lactose monohydrate;

(c) about 1.5-4.5mg croscarmellose sodium; and

(d) about 4.5-8.5mg polyvinylpyrrolidone.

In addition, the pharmaceutical composition may comprise no or no:

(e) about 6-10mg sodium lauryl sulfate; and/or

(f) About 1-5mg magnesium stearate.

In another example, a pharmaceutical composition comprises:

(a) about 95-105mg of Celecoxib;

(b) about 92-112mg lactose monohydrate;

(c) about 2-13mg croscarmellose sodium; and

(d) about 1-11mg polyvinylpyrrolidone.

In addition, the pharmaceutical composition may comprise no or no:

(e) about 20-30mg microcrystalline cellulose;

(f) about 3-13mg sodium lauryl sulfate; and/or

(g) About 0.5-7mg magnesium stearate.

(a) about 98-102mg of Celecoxib;

(b) about 100-104mg lactose monohydrate;

(c) about 5-10mg croscarmellose sodium; and

(d) about 4-8.5mg polyvinylpyrrolidone.

In addition, the pharmaceutical composition may comprise no or no:

(e) about 23-27mg microcrystalline cellulose;

(f) about 5-10mg sodium lauryl sulfate; and/or

(g) About 0.5-4mg magnesium stearate.

In another example, a pharmaceutical composition comprises:

(a) about 195-;

(b) about 199-209mg lactose monohydrate;

(c) about 10-20mg croscarmellose sodium; and

(d) about 7.5-17.5mg polyvinylpyrrolidone.

In addition, the pharmaceutical composition may comprise no or no:

(e) about 45-55mg microcrystalline cellulose;

(f) about 10-20mg sodium lauryl sulfate; and/or

(g) About 0.5-9mg magnesium stearate.

(a) about 98-102mg of Celecoxib;

(b) about 202-206mg lactose monohydrate;

(c) about 13-17mg croscarmellose sodium; and

(d) about 10.5-14.5mg polyvinylpyrrolidone.

In addition, the pharmaceutical composition may comprise no or no:

(e) about 48-52mg microcrystalline cellulose;

(f) about 13-17mg sodium lauryl sulfate; and/or

(f) About 2-6mg magnesium stearate.

Particle size of Celecoxib in tablets and capsules

It has been found that reducing the size of Celecoxib particles improves the bioavailability of Celecoxib when administered orally in the form of capsules or tablets. Thus, preferably, D of Celecoxib₉₀The particle size is less than about 200 μm, more preferably less than about 100 μm, even more preferably less than about 75 μm, even more preferably less than about 40 μm, and most preferably less than about 25 μm. For example, as described in example 11, starting material D of Celecoxib₉₀The particle size is reduced from about 60 μm to about 30 μmm can greatly improve the bioavailability of the composition. In addition, Celecoxib preferably has an average particle size of about 1 to about 10 μm, more preferably about 5 to about 7 μm.

Secondary particle size and flowability after granulation

For example, although the pharmaceutical compositions of the present invention may be prepared by direct encapsulation or direct compression, they are preferably wet granulated prior to encapsulation or compression. Wet granulation, among other effects, allows for an increase in the density of the milled composition, thus improving flowability, improving compressibility and easier metering or improving the weight distribution of the composition for encapsulation or tableting. The secondary particle size (i.e. the particle size) obtained by granulation is not critical, it being understood that it is important in this regard that the average particle size should preferably be such that handling and processing is convenient and that for tablets a directly compressible mixture for the preparation of pharmaceutically acceptable tablets should be formed.

The required bulk density of the particles is generally about 0.3g/ml to 1.0 g/ml.

Release profiles for capsules and tablets

Capsule and tablet compositions of the present invention are preferably immediate release compositions that release at least about 50% of the Celecoxib within about 45 minutes of ingestion when measured in vitro. More preferably, they release at least about 60% of the Celecoxib within about 45 minutes of ingestion. Further preferably, they release at least about 75% of the Celecoxib within about 45 minutes of ingestion.

It is particularly preferred that capsule and tablet compositions of the present invention release at least about 50% of the Celecoxib within about 15 minutes after ingestion, and/or at least about 60% of the Celecoxib within about 3-minutes after ingestion.

Disintegration of capsules and tablets

Preferably, the carrier materials of the immediate release capsule and tablet compositions of the present invention are selected such that the disintegration time is less than about 30 minutes, preferably less than about 25 minutes, more preferably less than about 20 minutes or less, and still more preferably less than about 15 minutes or less.

Hardness of

For tablets, the entire mixture, sufficient to prepare a uniform batch of tablets, is compressed in a conventional production scale tablet press at normal pressures (e.g., using pressures of about 1KN to 50KN in a typical tablet press die). Any tablet hardness that is convenient to process, manufacture, store and ingest may be used. For a 100mg tablet, the hardness is preferably at least 4KP, more preferably at least about 5KP, and even more preferably at least about 6 KP. For a 200mg tablet, the hardness is preferably at least 7KP, more preferably at least about 9KP, and even more preferably at least about 11 KP. However, the mixture does not have to be pressed to such an extent that subsequent hydration is difficult to accomplish when exposed to gastric fluid.

Fragility of

For tablets, the friability of the tablet is preferably less than about 1.0%, more preferably, in a standard test.

Preferably less than 0.8% and even more preferably less than about 0.5%.

Method of treatment

The invention also relates to a method of treating a disease for which a cyclooxygenase-2 inhibitor is indicated, the method comprising orally administering to a subject in need thereof a pharmaceutical composition of the invention. The dosage regimen for inhibiting, alleviating or ameliorating a disease preferably conforms to the once-daily or twice-daily treatment regimen described above, but the regimen may vary depending on various factors. These factors include the species, age, weight, sex, diet and disease status of the patient and the nature and severity of the disease. Thus, the dosage regimen actually employed can vary within wide limits and can therefore differ from the preferred dosage regimen described above.

Initial treatment of a patient suffering from a condition amenable to treatment with a cyclooxygenase inhibitor-2 can be initiated with the dosages described above. If necessary, treatment may continue for weeks to months or years until the disease is controlled or eliminated. Patients treated with the compositions of the present invention can be routinely monitored by any method known to those skilled in the art to determine the efficacy of the treatment. Continuous analysis of data measured during the course of treatment is used to adjust the treatment regimen so that the optimum effective amount of Celecoxib can be administered at any point in time, so that the minimum amount of Celecoxib that exhibits satisfactory efficacy can be administered, and so that the administration is continued for the period of time necessary to successfully treat the disease.

Process for preparing Celecoxib compositions

The invention also relates to methods of preparing pharmaceutical compositions comprising Celecoxib. In particular, the invention relates to methods for preparing pharmaceutical compositions comprising Celecoxib in particulate form. In particular, the present invention relates to a process for preparing Celecoxib compositions in the form of discrete unit dose tablets or capsules, wherein each tablet or capsule contains an amount of Celecoxib sufficient to produce a therapeutic effect for about 12 to 24 hours. For example, each dosage unit preferably contains about 100mg to about 200mg of Celecoxib. According to the present invention, the tablet or capsule composition of the present invention can be prepared using wet granulation, dry granulation or direct compression or encapsulation methods.

Wet granulation is a preferred method of preparing the pharmaceutical compositions of the present invention. In a wet granulation process, Celecoxib (along with one or more carrier materials, if desired) is first milled or micronized to the desired particle size. Although various conventional mills or grinding beds can be used, impact milling, such as needle milling of Celecoxib, can provide improved mixing uniformity of the final composition as compared to other types of milling. Cooling of the Celecoxib, for example, using liquid nitrogen, may be necessary to avoid heating the Celecoxib to undesirable temperatures during milling. In this grinding step, D is added₉₀Reduction of particle size to less than about 200 μm, preferably less than about 100 μm, more preferably less than about 75 μm, even more preferably less than about 40 μm, and most preferably less than about 25 μm, can greatly increase the bioavailability of Celecoxib。

The milled or micronized Celecoxib is then mixed with one or more carrier materials, including carrier materials milled with the Celecoxib, for example, in a high shear mixer/granulator, planetary mixer, double wall blender, or Sigma mixer, to form a dry powder mixture. Typically, the drug is mixed with one or more diluents, disintegrants and/or binders and, in this step, optionally with one or more wetting agents, but in a final step, all or part of the one or more carrier materials may be added. For example, in a tablet having sodium carboxymethylcellulose as a disintegrant, it has been found that adding a portion of the sodium carboxymethylcellulose during the mixing step (intragranular sodium carboxymethylcellulose) and adding the remaining portion of the sodium carboxymethylcellulose after the drying step (extragranular sodium carboxymethylcellulose) as described below can improve the disintegration of the prepared tablet. In this case, it is preferred to add about 60% to 75% sodium carboxymethylcellulose intragranularly and about 25% to 40% sodium carboxymethylcellulose extragranularly. Similarly, for tablets, it has been found that the addition of microcrystalline cellulose (extragranular microcrystalline cellulose) after the following drying step improves the compressibility of the granules and the hardness of tablets made from the granules.

The mixing step of the method preferably comprises mixing Celecoxib, lactose, polyvinylpyrrolidone and croscarmellose sodium. It has been found that mixing times as short as 3 minutes provide a dry powder mixture containing a substantially uniform distribution of Celecoxib. For example, the concentrations of Celecoxib in the dry powder mixtures used to prepare 100mg dose capsules (1080kg total batch) and 200mg dose capsules (918kg total batch), respectively, exhibited measured relative standard deviations of 3.6% or less and 1.1% or less, respectively.

Water, preferably purified water, is then added to the dry powder mixture and the mixture is mixed for an additional period of time to form a wet granulated mixture. Preferably a wetting agent is used and preferably the wetting agent is first added to the water and mixed for at least 15 minutes, preferably at least 20 minutes, before the water is added to the dry powder mixture. The water may be added to the mixture gradually over a period of time or in several portions over a period of time. The water is preferably added gradually over a period of time. Alternatively, the wetting agent may be added to the dry powder mixture and then water added to the remaining mixture.

For example, for the illustrated 100mg dose capsule (1080kg batch), a water addition rate of about 5-25 kg/minute, preferably about 7-20 kg/minute, and more preferably about 8-18 kg/minute produces suitable results. Preferably, water is added followed by further mixing to ensure uniform distribution of the water in the mixture. Remixing times of about 2 to 10 minutes, preferably about 3 to 9 minutes, and more preferably about 3 to 7 minutes produce suitable results for the illustrated batch. The batch of wet granulated mixture preferably comprises about 2% to 15%, more preferably about 4% to 12%, and even more preferably about 6% to 10% by weight of water.

For example, for the illustrated 200mg dose capsule (918kg batch), a water addition rate of about 5-25 kg/minute, preferably about 7-23 kg/minute, and more preferably about 8-21 kg/minute, produces suitable results. Preferably, water is added followed by further mixing to ensure uniform distribution of the water in the mixture. Remixing times of about 2 to 15 minutes, preferably about 3 to 12 minutes, and more preferably about 3 to 10 minutes produce suitable results for the illustrated batch. The batch of wet granulated mixture preferably comprises about 2% -15%, more preferably about 6% -14%, and even more preferably about 8% -13% by weight of water.

The wet granulated mixture is then preferably wet milled, for example by screen milling, to eliminate bulk material as a by-product of the wet granulation. If not removed, these chunks may prolong the subsequent fluidized bed drying operation and increase variability in humidity control. For example, for the illustrated 100mg dose capsules (1080kg total batch) and 200mg dose capsules (918kg total batch), suitable granules can be obtained by using a feed rate of no more than about 50%, preferably about 2% to about 30%, and even more preferably about 5% to about 20% of the maximum feed rate.

The wet granulated or wet milled mixture is then dried, for example in an oven or fluid bed dryer, preferably a fluid bed dryer, to form dry granules. The wet granulated mixture may be extruded or spheronized, if desired, prior to drying. For the drying process, conditions such as inlet air temperature and drying time are adjusted to obtain the desired moisture content of the dried pellets. It may be required for the drying step and the subsequent processing steps to combine two or more granulation sections.

For example, for the 100mg dose capsules (1080kg batch) and 200mg dose capsules (918kg batch) exemplified above, the dryer inlet temperature may be fixed at about 60 ℃, preferably at about 50 ℃ to 70 ℃, although other inlet temperatures may be used. The air flow rate may vary from about 1000-8000 cubic feet per minute, preferably from about 2000-7000 cubic feet per minute, and more preferably from about 4000-7000 cubic feet per minute, with the dampers open from about 10% to 90%, preferably from about 20% to 80%, and even more preferably from about 30% to 70%. The dryer capacity is about 35% to 100%, preferably about 50% to 100%, and even more preferably about 90% to 100%. The average loss on drying of the dry granules prepared under these conditions is typically about 0.1% to 2.0% by weight.

To the extent necessary, the dry granules to be compressed or encapsulated are reduced in size. Conventional particle size reduction equipment such as a shaker or impact mill (e.g., Fitz mill) may be used. For example, for the illustrated 100mg dose capsule (1080kg batch), a suitably reduced particle size can be achieved by using a feed rate of about 20% to about 70%, preferably about 30% to about 60%; a grinding speed of about 20% to about 70%, preferably about 40% to about 60%; and screen sizes of about 0.020 inch (0.5mm) to about 0.070 inch (1.7mm), preferably about 0.028 inch (0.7mm) to about 0.040 inch (1.0 mm). For example, for the illustrated 200mg dose capsule (918kg batch), suitable granules can be obtained by using a feed rate of about 10% to 70%, preferably about 20% to 60%; a grinding speed of about 20% to about 60%, preferably about 30% to about 50%; and screen sizes of about 0.020 inch (0.5mm) to about 0.080 inch (1.9mm), preferably about 0.028 inch (0.7mm) to about 0.063 inch (1.6 mm). However, it has been found that smaller screen sizes, such as 0.028 inch (0.7mm), result in lower product yields. Larger screen sizes, such as 0.063 inch (1.6mm), result in an increase in the total number of particles having a particle size greater than 850 μm. A screen size of about 0.040 inch (1.0mm) eliminates excessive particle counts larger than 850 μm without significantly reducing throughput.

Varying the parameters of wet granulation and wet milling discussed above can be used to adjust the particle size distribution. For example, it has been found that for mixtures with lower water content, the particle size decreases slightly as the mixing time increases. It is hypothesized that if the water content is too low to activate the binder used sufficiently, the cohesion between the primary particles within the particles is not sufficient to overcome the shear forces generated by the mixing blades and the attrition of the particle size is greater than growth. Conversely, increasing the amount of water and increasing the activation time and/or water addition rate, activates the binder sufficiently that the cohesive forces between the primary particles overcome (survive) the shear forces generated by the mixing blade and the growth of the particles is greater than the attrition. Varying the wet-milled screen size has a greater effect on particle size than varying the feed rate and/or milling rate.

The dry granules are then placed in a suitable blender, such as a twin-wall blender, without the addition or addition of lubricants (e.g., magnesium stearate) and other carrier materials (e.g., extragranular microcrystalline cellulose and/or extragranular sodium carboxymethylcellulose in certain tablets) to form a final blended mixture. The stirring time depends in part on the processing equipment used. For example, for the 100mg dose capsules and 200mg dose capsules discussed above (1080kg and 918kg batches), a stirring time of at least about 5 minutes at a stirrer load of about 15% to about 60% and a stirrer speed of at least about 10 revolutions per minute consistently provides a stirred material having a substantially uniform concentration of Celecoxib. The relative standard deviations of the 100mg and 200mg dose capsules obtained by measuring the unit dose mixed samples were 3.9% or less and 2.2% or less, respectively. Where the diluent comprises microcrystalline cellulose, it has been found that the addition of a portion of microcrystalline cellulose during this step substantially increases the compressibility of the granules and the hardness of the tablet. In addition, it was observed that increasing the amount of the above-mentioned about 1% magnesium stearate to about 2% reduced the hardness of the tablets and increased friability and dissolution time.

The final blended mixture is then filled into capsules (or, if tablets are being prepared, compressed into tablets of the desired weight and hardness using a tablet press of the appropriate type). Conventional tableting and encapsulating techniques known to those of ordinary skill in the art may be employed. For capsules, suitable results were obtained by employing a bed height in the range of about 20mm to 60mm, a compressibility scale in the range of about 0 to 5mm, and a speed of about 60000 capsules per hour to 130000 capsules per hour. Low speed and high compressibility or high speed and high bed height were observed to reduce dose weight control. Therefore, careful control of these combined parameters is preferred. It has also been found that sludge formation can be minimized or eliminated by using the lowest compressibility scale 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 may be employed.

The granules produced in combination with the individual operations are uniform in Celecoxib content at the unit dose level, readily disintegratable, sufficiently flowable to allow reliable control of weight differences during capsule filling or tableting, and sufficiently dense in bulk to be prepared in batches in selected equipment and filled with individual doses into specific capsules or tableting dies.

Use in the manufacture of a medicament

The invention also relates to the use of the compositions of the invention in the manufacture of a medicament for the treatment and/or prevention of cyclooxygenase-mediated diseases and conditions.

Examples

The following examples are intended to illustrate the invention without limiting it. The experimental methods 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 pharmaceutical literature at the same time. If not otherwise specified, (i) all percentages recited in these examples are weight percentages based on total composition weight, (ii) the total composition weight of the capsules is the total capsule fill weight and does not include the weight of the capsule shell itself used, and (iii) the coated tablets are coated with conventional materials such as Opadry white YS-1-18027A and the amount of coating material is about 3% of the total weight of the coated tablet.

Example 1: 100mg dosage capsule

Capsules were prepared having the following composition:

TABLE 1

Components	Parts by weight (%)	Amount (mg)
Components	Parts by weight (%)	Amount (mg)	Celecoxib	37.04	100
Lactose monohydrate (NF, Ph Eur)	55.46	149.75	Celecoxib	37.04	100
Lactose monohydrate (NF, Ph Eur)	55.46	149.75	Sodium dodecyl sulfate (NF, Ph Eur)	3	8.1
Polyvinylpyrrolidone (K29-32USP)	2.5	6.75	Sodium dodecyl sulfate (NF, Ph Eur)	3	8.1
Polyvinylpyrrolidone (K29-32USP)	2.5	6.75	Cross-linked sodium carboxymethylcellulose (NF, Ph Eur)	1	2.7
Magnesium stearate (NF, Ph Eur)	1	2.7	Cross-linked sodium carboxymethylcellulose (NF, Ph Eur)	1	2.7
Magnesium stearate (NF, Ph Eur)	1	2.7	Total capsule fill	100	270

The above unit dose composition was placed in a hard gelatin capsule (white opaque, size 2) containing titanium dioxide (USP), gelatin (NF) and blue ink (SB-6018).

Lactose monohydrate used in the examples herein is commercially available from Formost Farms Baraboo, Wisconsin. The Ac-Di-Sol brand croscarmellose sodium used in the various examples herein is commercially available from FMC corporation, Chicago, Illinois. Sodium lauryl sulfate used in the examples herein is commercially available from Henkel corporation, Cincinnati, Ohio. Povidone (polyvinylpyrrolidone) used in the examples herein is commercially available from international specialty Products. Magnesium stearate for use in the examples herein is commercially available from Mallinckrodt inc. The Opadry White YS-1-18027A used in the preparation of the coated tablets disclosed in the examples of this application is a commercially available coating formulation ready for coating from Colorcon, West Point, Pennsylvania.

Any desired capsule dose of 25mg to 225mg can be provided by adjusting the weight of Celecoxib and correspondingly increasing or decreasing the amount of lactose as needed to provide a total fill of 270 mg.

Example 2: 200mg dosage capsule

Capsules were prepared having the following composition:

TABLE 2

Components	Parts by weight (%)	Amount (mg)
Components	Parts by weight (%)	Amount (mg)	Celecoxib	74.07	200
Lactose monohydrate (NF, Ph Eur)	18.43	49.75	Celecoxib	74.07	200
Lactose monohydrate (NF, Ph Eur)	18.43	49.75	Sodium dodecyl sulfate (NF, Ph Eur)	3	8.10
Polyvinylpyrrolidone (K29-32USP)	2.5	6.75	Sodium dodecyl sulfate (NF, Ph Eur)	3	8.10
Polyvinylpyrrolidone (K29-32USP)	2.5	6.75	Croscarmellose sodium	1	2.7
Magnesium stearate (NF, Ph Eur)	1	2.7	Croscarmellose sodium	1	2.7
Magnesium stearate (NF, Ph Eur)	1	2.7	Total capsule fill	100	270

The above unit cross-linked composition was placed in a hard gelatin capsule (white opaque, No. 2) containing titanium dioxide (USP), gelatin (NF) and blue ink (SB-6018).

Example 3: 100mg dosage tablet

Tablets having the following composition were prepared:

TABLE 3

Components	Amount/tablet (mg)	Parts by weight (%)	Batch/lot (kg)
Components	Amount/tablet (mg)	Parts by weight (%)	Batch/lot (kg)	Celecoxib	100	40	6.40
Lactose monohydrate (NF)	101.88	40.75	6.52	Celecoxib	100	40	6.40
Lactose monohydrate (NF)	101.88	40.75	6.52	Sodium dodecyl sulfate (NF)	7.5	3	0.48
Povidone (K29/32, USP)	6.25	2.5	0.40	Sodium dodecyl sulfate (NF)	7.5	3	0.48
Povidone (K29/32, USP)	6.25	2.5	0.40	Croscarmellose sodium (type A, NF)	7.5	3	0.48
Microcrystalline cellulose (Avicel PH-102, NF)	25	10	1.60	Croscarmellose sodium (type A, NF)	7.5	3	0.48
Microcrystalline cellulose (Avicel PH-102, NF)	25	10	1.60	Magnesium stearate (NF)	1.88	0.75	0.12
Total amount of	250.01	100	16	Magnesium stearate (NF)	1.88	0.75	0.12
Total amount of	250.01	100	16	Opadry White YS-1-18027A	7.50

The tablets prepared were modified oval tablets of 0.210 inch by 0.465 inch (5.0mm by 11.2 mm).

Tablets of examples 3 and 4 were prepared using Avicel brand microcrystalline cellulose and the microcrystalline cellulose was commercially available from FMC corporation, philiadelphia, Pennsylvania.

Tablet doses of 25mg to 225mg can be provided by increasing or decreasing the amount of Celecoxib and each of the carrier materials described above so as to maintain the same parts by weight as exemplified above.

Example 4: tablet with 200mg dose

Tablets having the following composition were prepared:

TABLE 4

Components	Amount/tablet (mg)	Parts by weight (%)	Batch/lot (kg)
Components	Amount/tablet (mg)	Parts by weight (%)	Batch/lot (kg)	Celecoxib	200	40	6.40
Lactose monohydrate (NF)	203.75	40.75	6.52	Celecoxib	200	40	6.40
Lactose monohydrate (NF)	203.75	40.75	6.52	Sodium dodecyl sulfate (NF)	15	3	0.48
Povidone (K29/32, USP)	12.5	2.5	0.40	Sodium dodecyl sulfate (NF)	15	3	0.48
Povidone (K29/32, USP)	12.5	2.5	0.40	Croscarmellose sodium (Avicel PH-102, NF)	15	3	0.48
Microcrystalline cellulose (A type, NF)	50	10	1.60	Croscarmellose sodium (Avicel PH-102, NF)	15	3	0.48
Microcrystalline cellulose (A type, NF)	50	10	1.60	Magnesium stearate (NF)	3.75	0.75	0.12
Total amount of	500	100	16	Magnesium stearate (NF)	3.75	0.75	0.12
Total amount of	500	100	16	Opadry White YS-1-18027A	15.0

The tablets prepared were modified caplets of 0.275 inch by 0.496 inch (6.6mm by 11.9 mm).

Example 5: disintegration test

Tablets were prepared as in examples 3 and 4 except that no coating was applied. 6 identical tablets were placed in 6 tubes each having a wire mesh bottom in a disintegration basket. The water bath was preheated to 37 ℃. + -. 2 ℃ and this temperature was maintained during the disintegration test. Place 1000ml beaker in water bath. The beaker was filled with sufficient water to ensure that the wire screen of the test tube remained at least 2.5cm below the water surface during the test. The disintegrating basket was immersed in water and repeatedly moved up and down until the test was completed while the test tube wire mesh was kept at least 2.5cm below the water surface. The disintegration time for each tablet is the time from the start of placement in the disintegration basket to the last part of the tablet passing through the screen at the bottom of the tube. The average results for the uncoated tablets of examples 3 and 4 are shown in table 5.

TABLE 5

Tablet formulation	Disintegration time
Tablet formulation	Disintegration time	Example 3: 100mg dose tablets (uncoated)	4 minutes 35 seconds
Example 4: tablet (uncoated) at a dose of 200mg	7 minutes 45 seconds	Example 3: 100mg dose tablets (uncoated)	4 minutes 35 seconds

Example 6: dissolution test

The dissolution rates of the capsules of examples 1 and 2 and the tablets of examples 3 and 4 (the tablets used for these test purposes were uncoated) were determined using the apparatus of USP method 2 (with paddle). 1000ml of 1% sodium lauryl sulfate/0.04M Na₃PO₄(pH 12) solution was used as the eluent. The solution was maintained at a temperature of 37 ℃. + -. 5 ℃ and stirred at 50rpm during the test. 12 identical tablets or capsules were tested. 12 tablets or capsules were placed in 12 standard dissolution vessels, respectively, and at 15, 30, 45 and 60 minutes thereafter, 5ml aliquots of the solution were removed from each vessel. The samples taken from each vessel were filtered and the absorbance of the samples was determined (UV spectrophotometer, 2mm path length quartz cell; 243nm or UV maximum wavelength; blank: dissolution medium). The percent dissolution was calculated based on the measured absorbance. The average results of the dissolution tests are shown in table 6, noting that the solubility under elevated pH test conditions is not indicative of the solubility in the gastrointestinal tract.

TABLE 6

Composition comprising a metal oxide and a metal oxide	Percentage of dissolution
	Percentage of dissolution				15 minutes	30 minutes	45 minutes	60 minutes
	Example 1: 100mg capsule	89	99	100	15 minutes	30 minutes	45 minutes	60 minutes	100
Example 2: 200mg capsule	Example 1: 100mg capsule	89	99	100	55	82	89	92	100
Example 2: 200mg capsule	Example 3: 100mg tablet	81	93	94	55	82	89	92	95
Example 4: 200mg tablet	Example 3: 100mg tablet	81	93	94	60	96	98	98	95

Example 7: particle size analysis

Table 7A shows the results of size screening of the wet granulated pharmaceutical compositions of examples 1 and 2, respectively, prior to encapsulation. "percent particles remaining on the sieve" refers to the percentage of particles having a particle size greater than the specified sieve size by weight of the total batch.

TABLE 7A

Sieve number (mum)	Percentage of particles remaining on the screen
	Percentage of particles remaining on the screen				Example 1: 100mg capsule		Example 2: 200mg capsule
	Lower limit of	Upper limit of	Lower limit of	Upper limit of	Example 1: 100mg capsule		Example 2: 200mg capsule
	Lower limit of	Upper limit of	Lower limit of	Upper limit of	850	0	1.3	1.1	10.7
425	2.8	14.9	4.3	25.4	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	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	106	32.5	64.5	35.2	58.2
75	37.1	77.5	39.5	71.8	0	100	100	100	100

Table 7B shows the results of particle size screenout of the wet granulated example 3 and 4 pharmaceutical compositions, respectively, prior to compression into tablets. "batch percentage" refers to the weight percentage of the total batch of particles having a particle size between the specified sieve size and the next specified smaller sieve size. "cumulative percentage of batch" shows the percentage of particles having a particle size greater than the specified sieve size by weight of the total batch.

TABLE 7B

Sieve number (mum)	Example 3: 100mg tablet		Example 4: 200mg tablet
	Example 3: 100mg tablet		Example 4: 200mg tablet		Percentage of batch	Cumulative batch percentage	Percentage of batch	Cumulative batch percentage
	840(20 mesh sieve)	1	1	0.79	Percentage of batch	Cumulative batch percentage	Percentage of batch	Cumulative batch percentage	0.79
420(40 mesh screen)	840(20 mesh sieve)	1	1	0.79	24.6	25.6	24.85	25.64	0.79
420(40 mesh screen)	250(60 mesh sieve)	18.4	44	19.13	24.6	25.6	24.85	25.64	44.77
177(80 mesh sieve)	250(60 mesh sieve)	18.4	44	19.13	9.6	53.6	11.05	55.82	44.77
177(80 mesh sieve)	149(100 mesh sieve)	6.6	60.2	6.9	9.6	53.6	11.05	55.82	62.72
105(140 mesh sieve)	149(100 mesh sieve)	6.6	60.2	6.9	11.6	71.8	11.44	74.16	62.72
105(140 mesh sieve)	74(200 mesh sieve)	8.8	80.6	8.28	11.6	71.8	11.44	74.16	82.45
Fine powder particles	74(200 mesh sieve)	8.8	80.6	8.28	19.4	100	17.55	100	82.45

Example 8: bulk density analysis

Table 8 shows the results of bulk density analysis of the wet granulated pharmaceutical compositions of examples 1, 2, 3 and 4 prior to encapsulation or compression into tablets.

TABLE 8

Composition comprising a metal oxide and a metal oxide	Bulk density (g/ml)	Tap Density (tapped density/ml)	Loss on drying (%)
Composition comprising a metal oxide and a metal oxide	Bulk density (g/ml)	Tap Density (tapped density/ml)	Loss on drying (%)	Example 1: 100mg capsule	0.77	1.02	0.6
Example 2: 200mg capsule	0.61	0.96	0.5	Example 1: 100mg capsule	0.77	1.02	0.6
Example 2: 200mg capsule	0.61	0.96	0.5	Example 3: 100mg tablet	0.73	0.87	1.37
Example 4: 200mg tablet	0.72	0.86	1.4	Example 3: 100mg tablet	0.73	0.87	1.37

Example 9: tablet analysis protocol

Table 9 shows the results of the tablet analysis protocol ("TAP analysis") for 10 samples, 10 tablets being the tablet compositions of examples 3 or 4.

TABLE 9

Tablet formulation	Average weight (mg)	Average thickness (mg)	Hardness (kP)
Tablet formulation	Average weight (mg)	Average thickness (mg)	Hardness (kP)	Example 3: 100mg tablet	248	3.85	8.2
Example 4: 200mg tablet	500	5.22	14.6	Example 3: 100mg tablet	248	3.85	8.2

Example 10: brittleness test

12 grams of tablets were weighed and placed in a rotating drum. Foreign dust is first removed from the drum and tablets. The drum starts to rotate and continues to rotate at a minimum speed of 25rpm for 10 minutes. The rotation of the drum is stopped and the tablets are removed. Loose dust on the tablets, as well as any broken tablets, were removed and the complete tablets were weighed. The percent lost of the tablet test samples of examples 3 and 4 was calculated and shown in table 10 below.

Watch 10

Tablet formulation	Percent loss
Tablet formulation	Percent loss	Example 3: 100mg tablet	0.33
Example 4: 200mg tablet	0.16	Example 3: 100mg tablet	0.33

Example 11-1: bioavailability in dog model

Healthy female beagle dogs with long ears and short legs weighing 9 to 13 pounds (4.1-5.9kg) received the following single dose of Celecoxib: (1) intravenous infusion of 0.5mg/kg body weight Celecoxib followed by a second intravenous infusion of 5.0mg/kg body weight Celecoxib; (2) celecoxib in an oral solution at 5mg/kg body weight; and (3) Celecoxib in the form of a pure, unformulated oral capsule at 5mg/kg body weight. The carrier for intravenous and oral solution dosages is a 2: 1 volume ratio of polyethylene glycol of average molecular weight 400 (PEG-400) and water. The time for each intravenous infusion was 15 minutes and the interval between infusions was 15 to 30 minutes.

Blood samples were collected multiple times from each animal by venipuncture or cannulation and placed in heparinized sample tubes. The concentration of Celecoxib in serum was determined by HPLC and the resulting data were used to calculate the pharmacokinetic parameters shown in table 11-1 below.

TABLE 11-1

Pharmacokinetic parameters	Intravenous infusion	Oral solution	Capsules, unformulated
Pharmacokinetic parameters	Intravenous infusion	Oral solution	Capsules, unformulated	C_max(ng/ml)	6950	2190	517
T_max(h)	Not applicable to	0.5	3.0	C_max(ng/ml)	6950	2190	517
T_max(h)	Not applicable to	0.5	3.0	AUC_0-∞(ng/ml)h	31200	16200	4800
Clearance (ml/min. kg)	3.08	5.14	17.4	AUC_0-∞(ng/ml)h	31200	16200	4800
Clearance (ml/min. kg)	3.08	5.14	17.4	T_1/2(h)	8.84	9.15	11.8
Bioavailability (%)	Not applicable to	57.1	16.9	T_1/2(h)	8.84	9.15	11.8

Example 11-2: relative bioavailability of formulations in dog model

The effect of formulation parameters Celecoxib particle size, increased humectant concentration, pH and Celecoxib dispersion as a suspension on the relative bioavailability of oral solutions was evaluated in a dog model. The effect of micronizing Celecoxib (average particle size 10-20 μm) prior to formulation in composition a was tested. Composition B test micronization, addition of wetting agent (sodium lauryl sulfate) and increase of microenvironment pH (Na)₃PO₄.12H₂O) in the reaction mixture. Composition C tested the effect of intimately contacting the humectant (tween 80) with Celecoxib (co-precipitation versus simple dry blending). Composition D was tested for the effect of further reducing the particle size (about 1 μm) and dispersing the particles in suspension. A solution of Celecoxib similar to that used in example 11-1 (composition E) was included as a reference. In addition, data for the unground unformulated capsule form of Celecoxib (composition F) from example 11-1 is also included as a reference. The specific components of formulations A, B, C, D, E and F are summarized in Table 11-2A.

TABLE 11-2A

Components	Parts by weight (% dry matter)
	Parts by weight (% dry matter)						A	B	C	D	E	F
	Celecoxib (micronized)	25	25				A	B	C	D	E	F
Celecoxib/tween 80⁽¹⁾	Celecoxib (micronized)	25	25						25
Celecoxib/tween 80⁽¹⁾	Celecoxib (dispersed)⁽²⁾				100				25
Celecoxib (solution)⁽³⁾	Celecoxib (dispersed)⁽²⁾				100						100
Celecoxib (solution)⁽³⁾	Celecoxib (unground)										100		100
Sodium dodecyl sulfate	Celecoxib (unground)						2	25					100
Sodium dodecyl sulfate	Avicel 101	73	25	75			2	25
Na₃PO₄.12H₂O	Avicel 101	73	25	75				25
Na₃PO₄.12H₂O	Total amount of	100	100	100	100	100		25					100

(1) An aqueous solution of 5% polysorbate 80 was used as an anti-solvent to precipitate from the ethanol solution.

(2) Suspensions were made by ball milling the drug in polysorbate 80 and polyvinylpyrrolidone slurries until the particle size was approximately 1 μm as estimated microscopically.

(3) Solution in PEG-400/water (2: 1 v/v).

The composition was administered to a test group consisting of 3 male and 3 female dogs. Group 1 solution E and capsule formulations A and B were administered with 5mg/kg body weight Celecoxib on a non-random crossover schedule. Group 2 capsules formulation C and suspension D were administered with 5mg/kg body weight Celecoxib on a non-random crossover schedule. Plasma samples were collected over a 24 hour period and analyzed for Celecoxib by HPLC.

The results of the study (tables 11-2B, 11-2C, and 11-2D) show that reducing the particle size (composition A) or co-precipitating Celecoxib with a wetting agent (composition C) increases the bioavailability of Celecoxib (by AUC) as compared to unformulated Celecoxib as shown in example 11-1 of the above study_(0-24)Measured). The bioavailability of Celecoxib was higher for PEG-400/water solutions (composition E) and suspensions (composition D). The bioavailability of suspensions having particle sizes of about 1 μm is similar to that of solutions and is sufficient to demonstrate that the availability of Celecoxib in a wet granulated solid composition can be improved by reducing the particle size of the Celecoxib (e.g., by plug milling the Celecoxib prior to formulation), increasing the wettability of the Celecoxib (e.g., by including sodium lauryl sulfate in the granulation liquid), and improving dispersibility (e.g., by including cross-linked sodium carboxymethylcellulose in the granules). The bioavailability data for each formulation contained in tables 11-2C and 11-2D represent the bioavailability of the formulations calculated as a percentage of the bioavailability measured experimentally after intravenous administration of Celecoxib using the solution (composition E) data as a bridge between examples 11-1 and 11-2.

Tables 11-2B

Time of day(h)	Serum Celecoxib concentration (μ g/ml)
	Serum Celecoxib concentration (μ g/ml)						A	B	C	D	E	F
	0	0	0	0	0	0	A	B	C	D	E	F	0
0.5	0	0	0	0	0	0	0.0143	0.247	0.0635	0.453	0.824	0.205	0
0.5	1.0	0.244	0.228	0.443	0.826	0.820	0.0143	0.247	0.0635	0.453	0.824	0.205	0.333
2.0	1.0	0.244	0.228	0.443	0.826	0.820	0.318	0.138	0.717	0.865	0.604	0.262	0.333
2.0	3.0	0.189	0.0860	0.492	0.741	0.517	0.318	0.138	0.717	0.865	0.604	0.262	0.517
4.0	3.0	0.189	0.0860	0.492	0.741	0.517	0.145	0.0707	0.384	0.576	0.413	0.234	0.517
4.0	6.0	0.107	0.0664	0.233	0.354	0.286	0.145	0.0707	0.384	0.576	0.413	0.234	--
7.0	6.0	0.107	0.0664	0.233	0.354	0.286	--	--	--	--	--	0.197	--
7.0	8.0	0.0828	0.0624	0.160	0.234	0.187	--	--	--	--	--	0.197	--
12.0	8.0	0.0828	0.0624	0.160	0.234	0.187	0.0939	0.0431	0.0865	0.142	0.0802	--	--
12.0	24.0	--	0.0404	0.0408	0.0394	0.0159	0.0939	0.0431	0.0865	0.142	0.0802	--	--

Tables 11-2C

Pharmacokinetic parameters	Value of female dog
	Value of female dog						A	B	C	D	E	F
	C_max(ng/ml)	360±60	250±70	790±270	1010±270	840±240	A	B	C	D	E	F	500
T_max(h)	C_max(ng/ml)	360±60	250±70	790±270	1010±270	840±240	1.3±0.2	0.7±0.2	1.5±0.3	1.7±0.44	0.67±0.18	3.0	500
T_max(h)	Bioavailability (%)	31.2±2.9	24.9±1.4	46.3±9.5	69.5±9.6	62.4±9.4	1.3±0.2	0.7±0.2	1.5±0.3	1.7±0.44	0.67±0.18	3.0	16.9

TABLE 11-2D

Pharmacokinetic parameters	Value of Male dog
	Value of Male dog						A	B	C	D	E	F
	C_max(ng/ml)	520±110	450±180	640±260	830±330	1520±200	A	B	C	D	E	F	500
T_max(h)	C_max(ng/ml)	520±110	450±180	640±260	830±330	1520±200	5.3±3.3	3.3±1.3	1.5±0.5	5.7±3.42	1.5	3.0	500
T_max(h)	Bioavailability (%)	49.4±12.0	54.2±13.1	42.9±13.1	87.5±20.6	89.4±4.5	5.3±3.3	3.3±1.3	1.5±0.5	5.7±3.42	1.5	3.0	16.9

Examples 11 to 3

The relative wettability and tendency to disintegrate were examined for various formulations containing sodium lauryl sulfate (0-5% by weight) and croscarmellose sodium (0-5% by weight). Relative wetability was evaluated by measuring the time required for water to penetrate into a column of particulate material prepared from each formulation. The tendency to disintegrate was determined by measuring the weight of the granular material retained on a 20 mesh (850mm) screen after the material was soaked in water at 37 ℃ for 5 minutes. The specific components of compositions a to H evaluated are summarized in tables 11-3A.

Tables 11-3A

Components	Parts by weight (%)
	Parts by weight (%)								A(1)	B	C	D	E	F	G	H
	Celecoxib	74.4	74.4	74.4	74.4	74.4	74.4	74.4	A(1)	B	C	D	E	F	G	H	74.4
Lactose	Celecoxib	74.4	74.4	74.4	74.4	74.4	74.4	74.4	15.8	15.8	21.8	19.8	17.8	15.8	17.8	11.8	74.4
Lactose	Polyvinylpyrrolidone	2.5	2.5	2.5	2.5	2.5	2.5	2.5	15.8	15.8	21.8	19.8	17.8	15.8	17.8	11.8	2.5
Sodium dodecyl sulfate	Polyvinylpyrrolidone	2.5	2.5	2.5	2.5	2.5	2.5	2.5	3.0	3.0	0.0	1.0	1.0	1.0	3.0	5.0	2.5
Sodium dodecyl sulfate	Aci-di-sol	3.0	3.0	0.0	1.0	3.0	5.0	1.0	3.0	3.0	0.0	1.0	1.0	1.0	3.0	5.0	5.0
Magnesium stearate	Aci-di-sol	3.0	3.0	0.0	1.0	3.0	5.0	1.0	1.0	1.0	1.0	1.0	1.0	1.0	1.0	1.0	5.0

(1) Sodium lauryl sulfate is added as a dry powder

The results obtained are summarized in tables 11-3B. The permeation test was repeated 3 times. The disintegration test was repeated twice. The results of the permeation study showed that: wet application sodium lauryl sulfate (composition B) was superior to dry application (composition A) and formulations containing 3% to 5% sodium lauryl sulfate (compositions B, G and H) were superior to formulations containing lesser amounts of sodium lauryl sulfate (compositions C-F). Formulations containing 3% sodium lauryl sulfate (compositions B and G) were similar to the formulation containing 5% sodium lauryl sulfate (composition H). The results of the disintegration study showed that: at a humectant concentration of 3%, complete disintegration was achieved with croscarmellose sodium (composition G) at concentrations as low as 1%. Complete disintegration can also be achieved with larger amounts of disintegrant (compositions B, F and H) when the concentration of wetting agent is neglected. Composition G required only a minimal amount of excipients to exhibit good permeability and complete disintegration.

Tables 11-3B

Composition comprising a metal oxide and a metal oxide	% sodium dodecyl sulfate/% Ac-di-sol	Time of penetration	Disintegration
Composition comprising a metal oxide and a metal oxide	% sodium dodecyl sulfate/% Ac-di-sol	Time of penetration	Disintegration	A⁽¹⁾	3/3	Greater than 18 hours	0.1-0.5％
B	3/3	5-60 minutes	Not detected	A⁽¹⁾	3/3	Greater than 18 hours	0.1-0.5％
B	3/3	5-60 minutes	Not detected	C	0/0	4- > 18 hours	20-26％
D	1/1	4- > 18 hours	10-13％	C	0/0	4- > 18 hours	20-26％
D	1/1	4- > 18 hours	10-13％	E	1/3	2-4 hours	4-6％
F	1/5	1-4 hours	Not detected	E	1/3	2-4 hours	4-6％
F	1/5	1-4 hours	Not detected	G	3/1	10-40 minutes	Not detected
H	5/5	10-55 minutes	To detect	G	3/1	10-40 minutes	Not detected

Example 12

The following formulations were used to assess wetting and homogeneity of the mixture:

TABLE 12

Components	Weight fraction (%)
Components	Weight fraction (%)									Lactose dry mix		Microcrystalline cellulose dry mixture		Polyvinylpyrrolidone particles¹		Polysorbate 80 granule²
Celecoxib	5	60	5	60	5	60	5	60		Lactose dry mix		Microcrystalline cellulose dry mixture		Polyvinylpyrrolidone particles¹		Polysorbate 80 granule²
Celecoxib	5	60	5	60	5	60	5	60	Lactose	94.5	39.5	…	…	92	37	93.5	38.5
Microcrystalline cellulose	…	…	94.5	39.5	…	…	…	…	Lactose	94.5	39.5	…	…	92	37	93.5	38.5
Microcrystalline cellulose	…	…	94.5	39.5	…	…	…	…	Polysorbate 80	…	…	…	…	…	…	1.0	1.0
Povidone (K29-32)	…	…	…	…	2.5	2.5	…	…	Polysorbate 80	…	…	…	…	…	…	1.0	1.0
Povidone (K29-32)	…	…	…	…	2.5	2.5	…	…	Magnesium stearate	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5

¹In this formulation, the polyvinylpyrrolidone is added to the mixture in the form of a dry powder before granulation with water.

²In this formulation, Celecoxib and lactose are granulated together with an aqueous solution of polysorbate 80.

The 5% Celecoxib mixture was shown to have better mixing uniformity than the 60% Celecoxib mixture. The relative standard deviation of the 5% Celecoxib mixture measured ranged from 0.4% to 3.5%, while the relative standard deviation of the 60% Celecoxib mixture measured ranged from 4.7% to 6.3%. In addition to the low homogeneity, the 60% Celecoxib mixture contains relatively large particles (greater than 420 μm) that are ultra-strong (containing high concentrations of Celecoxib ranging from 124% to 132% compared to other particles).

Instead of the 5% or 60% Celecoxib loading formulations described above, 4 formulations were prepared containing 25% Celecoxib loading. The bioavailability of these formulations was evaluated in a dog model by methods similar to those set forth in examples 11-1 and 11-2. The polyvinylpyrrolidone wet granulation formulation was shown to have the highest bioavailability (about 74%).

Example 13

Capsules having the following formulation were prepared and evaluated.

TABLE 13A

Components	Amount (mg)
	Amount (mg)			5mg capsule	20mg capsule	100mg capsule
	Celecoxib	5	20	5mg capsule	20mg capsule	100mg capsule	100
Lactose	Celecoxib	5	20	92	77	61.9	100
Lactose	Povidone (K29-32)	2.5	2.5	92	77	61.9	4
Magnesium stearate	Povidone (K29-32)	2.5	2.5	0.5	0.5	0.8	4
Magnesium stearate	Total amount of	100	100	0.5	0.5	0.8	166.7
Capsule shell	Total amount of	100	100	1	1	1	166.7
Capsule shell	Size of capsule	#3	#3	1	1	1	#3

Celecoxib is milled by passing it through a plurality of reciprocating mills successively fitted with smaller screen sizes (#14, #20, # 40). The Celecoxib particles added to the mixture have a D90 particle size less than about 37 μm. Celecoxib, lactose and polyvinylpyrrolidone are mixed in a planetary mixer drum and wet granulated with water. The granules were then pan dried at 60 ℃, milled through a 40 mesh screen, lubricated with magnesium stearate in a V-blender and filled into capsules on a dosator-type capsule filling machine. The in vitro dissolution of the capsules was determined using USP method 2 and 15mM phosphate buffer pH10 as dissolution medium. About 50% in vitro after about 15 minutes and more than 95% after 30 minutes.

Absorption, distribution, metabolism and elimination of 100mg unit dose capsules¹⁴The behavior of the C-Celecoxib suspensions was compared. The study is a public standardMnemonic and randomized crossover, and were performed on 10 healthy male subjects. Suspensions were prepared by dissolving Celecoxib in ethanol containing 5% polygalinol ester 80 and adding the mixture to apple juice prior to administration. Subjects receiving the suspension ingested a 300mg dose of Celecoxib. Subjects receiving Celecoxib in capsule form received 3 times a 100mg unit dose of Celecoxib for a total dose of 300 mg. The capsules absorbed slower than the suspension, but the AUC measured_0-48As with the suspension. The average results are shown in table 13B below. Celecoxib is metabolized abundantly, and the radioactive dose in urine or feces is only about 2.56%.

TABLE 13B

Pharmacokinetic parameters	Suspension liquid	Capsule
Pharmacokinetic parameters	Suspension liquid	Capsule	AUC_(0-48)((ng/ml)h)	8706.7	8763.1
C_max(ng/ml)	1526.5	1076.5	AUC_(0-48)((ng/ml)h)	8706.7	8763.1
C_max(ng/ml)	1526.5	1076.5	T_max(h)	1.42	1.94
T_1/2(h)	11.53	15.57	T_max(h)	1.42	1.94

Example 14

Capsules having the following composition were prepared and evaluated:

TABLE 14

Components	Amount (mg)
	Amount (mg)		100mg capsule	200mg capsule
	Celecoxib	100	100mg capsule	200mg capsule	200
Lactose	Celecoxib	100	223.4	120.1	200
Lactose	Povidone (K29-32)	8.3	223.4	120.1	8.3
Magnesium stearate	Povidone (K29-32)	8.3	1.7	5	8.3
Magnesium stearate	Total amount of	333.4	1.7	5	333.4
Size of capsule	Total amount of	333.4	#1	#1	333.4

These formulations were prepared in a similar manner to the formulation of example 13, except that impact pin milling was used instead of oscillatory milling. The particle size is further reduced by performing pin milling. For 100mg capsules, about 30% was dissolved in vitro after about 15 minutes and more than 85% was dissolved in vitro after about 30 minutes. For a 200mg capsule, about 50% is dissolved in vitro after about 15 minutes and more than 85% is dissolved in vitro after about 30 minutes.

Example 15: preparing capsules of 100mg dose

Capsules providing 100mg or 200mg doses of Celecoxib and having the compositions shown in examples 1 or 2, respectively, were prepared according to the acceptable pharmaceutical manufacturing process described in figure 1 or figure 2. Tablets providing a 100mg or 200mg dose of Celecoxib and having the composition shown in example 3 or 4, respectively, were prepared by modifying the process of figure 1 or figure 2 appropriately to add croscarmellose sodium and microcrystalline cellulose extragranularly and compressing the composition instead of filling capsules.

The process for formulating a large quantity of 100mg dose capsules is illustrated using the raw materials described below, typically a batch consisting of 4 identical granulation sections, although the number of granulation sections is not critical and depends primarily on the operating capacity of the equipment and the size of the batch required.

Grinding: celecoxib is milled in an impact pin mill having opposed rotating discs. At milling speeds in the range of about 8960rpm/5600rpm to 11200rpm/5600rpm (rotational rpm/counter rpm), the particle size varied over a smaller range (30 μm or less for D90), suggesting that milling speed was not critical for bulk drug micronization processes. Figure 2 is a flow diagram showing a preferred embodiment in which Celecoxib starting material is impact milled, preferably in a pin mill, prior to mixing with the carrier material.

Dry mixing: celecoxib, lactose, polyvinylpyrrolidone and croscarmellose sodium were transferred to a 1200L Niro Fielder PMA-1200 high speed granulator and mixed for about 3 minutes at high shear and impeller speed. Such dry mixing time is sufficient to allow the Celecoxib to be mixed with the carrier material prior to the wet granulation step.

And (3) wet granulation: sodium lauryl sulfate (8.1kg) was dissolved in pure USP water (23.7 kg). The resulting solution was gradually fed into the granulator at a rate of about 14 kg/min. The total granulation time was about 6.5 minutes. During this granulation, the main blades and the shear blades of the granulator are set in a fast position. The wet granulated mixture contained about 8.1% water by weight. Alternatively, sodium lauryl sulfate can be mixed with Celecoxib, lactose, polyvinylpyrrolidone, and croscarmellose sodium in a dry mixing step and neat USP water added to this dry mixture containing sodium lauryl sulfate.

And (3) drying: the Quadro Comil Model 198S screen mill, fitted with a rotating impeller and a coarse screen, was used to remove large pieces of the wet granulated product. Wet milling is used to eliminate large lumps of material as a by-product of wet granulation. If not removed, these chunks may prolong the subsequent fluidized bed drying operation and increase the difference in humidity control. The bulk-removed granules were transferred to Aeromatic fluid bed dryer T-8. The inlet air temperature and flow rate were adjusted to about 60 ℃ and about 5000-³A/min (about 140-³In terms of minutes). The granules are dried in a fluid bed dryer to a moisture content reduced to 0.5% to 2.5%. Moisture content was monitored with a Computrac moisture analyzer. Drying is continued until the loss on drying of the granules is not more than 1.0%. For this drying step and the subsequent processing steps, it may be necessary to combine two or more particle fractions.

And (3) dry grinding: the dry granules were passed through a Fluid Air Mill Model 007 impact (conventional hammer) grinder fitted with a 0.028-0.063 inch (0.7-1.5 mm) screen, with a knife forward and running at 2400 rpm. A combination of dry milling and wet granulation steps are used to control the final size distribution of the granules.

Mixing and lubricating: the milled particles were then placed in a PK Cross-Flow Blender 75CubicFoot diffusion mixer/V-mixer. Magnesium stearate was added and the mixture was mixed for about 5 minutes. The mixing time is conditioned on the uniformity of the concentration of Celecoxib in the mixed material. The mixer speed was 10.6 revolutions per minute. The final blend is used to combine the materials in the various granulation steps together to form a homogeneous blend and to evenly distribute the lubricant prior to filling the capsules.

And (3) filling capsules: the granulated powder mixture was loaded using a MG2G100 or G120 capsule filling machine. The capsules were polished.

The sequence of operations described above produces particles that are highly uniform in Celecoxib content at the unit dose level, readily soluble in vitro, readily flowable such that weight variation can be reliably controlled during capsule filling, and bulk density sufficiently high to enable batch processing in the selected equipment and filling of individual doses into designated capsules.

Example 16: bioequivalence study

Bioequivalence and safety of Celecoxib at a 200mg dose were evaluated in open label, randomized, single dose, triplicate crossover studies, with 46 healthy adults per test group. Subjects were administered 3 single 200mg single doses of Celecoxib, the 200mg doses being (a) one 200mg dose capsule, (B) two 100mg dose capsules, or (C) two 100mg capsules (from different batches), respectively. The treatment interval was 7 days. The prescribed 100mg dose capsules and 200mg dose capsules are disclosed in examples 1 and 2, respectively. Subjects fasted overnight were given a single oral dose of the drug under study and approximately 180ml of water at 0800 hours. Subjects continued to fast and remained in an upright position for 4 hours after dosing. Blood samples were taken at-0.25 (pre-dose) and 0.5, 1, 1.5, 2, 3, 4, 6,8, 12, 16, 24, 36 and 48 hours post-dose. Analysis of the separated plasma was performed on PPD Pharmaco, Richmond, VA. Plasma concentrations of Celecoxib were determined by validated high performance liquid chromatography ("HPLC") methods with a lower detection limit of 10.0 ng/ml. Each subject was tested individually. The washout period between each single 200mg dose was a minimum of 7 days. The average results obtained from 46 subjects are reported in tables 16A and 16B below.

TABLE 16A

Time (h)	Plasma Celecoxib concentration (ng/ml)
	Plasma Celecoxib concentration (ng/ml)			A tablet of 200mg capsule	Two 100mg capsules (first batch)	Two 100mg capsules (second batch)
	-0.25	0.22	0.00	A tablet of 200mg capsule	Two 100mg capsules (first batch)	Two 100mg capsules (second batch)	0.00
0.5	-0.25	0.22	0.00	103.74	117.89	212.61	0.00
0.5	1.0	418.24	446.39	103.74	117.89	212.61	647.00
1.5	1.0	418.24	446.39	575.68	606.97	826.90	647.00
1.5	2.0	646.83	656.98	575.68	606.97	826.90	862.23
3.0	2.0	646.83	656.98	686.19	666.55	781.13	862.23
3.0	4.0	621.02	595.21	686.19	666.55	781.13	660.15
6.0	4.0	621.02	595.21	389.00	387.41	383.81	660.15
6.0	8.0	322.24	332.51	389.00	387.41	383.81	323.59
12.0	8.0	322.24	332.51	214.63	208.06	209.96	323.59
12.0	16.0	149.11	146.40	214.63	208.06	209.96	144.23
24.0	16.0	149.11	146.40	116.09	111.77	113.21	144.23
24.0	36.0	52.76	48.27	116.09	111.77	113.21	46.98
48.0	36.0	52.76	48.27	27.24	26.47	22.44	46.98

TABLE 16B

Pharmacokinetic parameters	Values of pharmacokinetic parameters
	Values of pharmacokinetic parameters			A tablet of 200mg capsule	Two pieces of 100mgCapsule (first batch)	Two 100mg capsules (second batch)
	AUC_(0-48)((ng/ml)h)	8107.07	7976.56	A tablet of 200mg capsule	Two pieces of 100mgCapsule (first batch)	Two 100mg capsules (second batch)	8535.49
AUC_{(0- LQC)}((ng/ml)h)	AUC_(0-48)((ng/ml)h)	8107.07	7976.56	8063.17	7953.71	8501.94	8535.49
AUC_{(0- LQC)}((ng/ml)h)	AUC_(0-∞)((ng/ml)h)	8828.64	8640.46	8063.17	7953.71	8501.94	9229.52
C_max(ng/ml)	AUC_(0-∞)((ng/ml)h)	8828.64	8640.46	801.19	815.21	959.50	9229.52
C_max(ng/ml)	T_max(h)	2.46	2.84	801.19	815.21	959.50	2.23
T_1/2(h)	T_max(h)	2.46	2.84	12.22	13.52	10.67	2.23
T_1/2(h)	C_max/AUC_(0-LQC)	0.10	0.10	12.22	13.52	10.67	0.20

Example 17: study of food Effect

The effect of dose ratios and food on Celecoxib pharmacokinetic parameters was assessed in healthy adults using open label, randomized, single dose, four-fold crossover studies. Safety was assessed based on adverse events, life and clinical laboratory tests. 24 healthy adult subjects were randomly administered the following single doses of Celecoxib: (A) administering a 50mg dose of capsules under fasting conditions, (B) administering 50mg dose of capsules immediately after a high fat breakfast, (C) administering 100mg dose of capsules under fasting conditions, and (D) administering 100mg dose of capsules immediately after a high fat breakfast. Study drugs were administered to subjects on days 1, 8, 15, and 22 of each treatment in the four treatment sequences (ADBC; BACD; CBDA and DCAB). A specified 100mg dose capsule composition is disclosed in example 1. The specified 50mg capsule composition is disclosed in table 17A below:

TABLE 17A

Components	Amount (mg)
Components	Amount (mg)	Celecoxib	50.00
Lactose monohydrate	199.8	Celecoxib	50.00
Lactose monohydrate	199.8	Sodium dodecyl sulfate	8.1
Povidone (K29-32)	6.8	Sodium dodecyl sulfate	8.1
Povidone (K29-32)	6.8	Croscarmellose sodium	2.7
Magnesium stearate	2.7	Croscarmellose sodium	2.7
Magnesium stearate	2.7	Total capsule fill	270.0

The above unit dosage composition was filled into hard gelatin capsules (white opaque, size # 2).

Blood samples were taken at-0.25 (pre-dose) and 0.5, 1, 1.5, 2, 3, 4, 6,8, 12, 16, 24, 36 and 48 hours post-dose. Analysis of the separated plasma was performed on PPD Pharmaco, Richmond, VA. Plasma concentrations of Celecoxib were determined by validated high performance liquid chromatography ("HPLC") methods with a lower detection limit of 10.0 ng/ml. There were no significant clinical changes in vital signs or physical measurements. All adverse events were less severe. The average results obtained from 24 subjects are reported in tables 17B and 17C below.

TABLE 17B

Time (h)	Plasma Celecoxib concentrations(ng.ml)
	Plasma Celecoxib concentrations(ng.ml)				100mg capsule (fasting)	100mg capsule (high fat breakfast)	50mg capsule (fasting)	50mg capsule (high fat breakfast)
	-0.25	0.00	0.00	0.00	100mg capsule (fasting)	100mg capsule (high fat breakfast)	50mg capsule (fasting)	50mg capsule (high fat breakfast)	0.00
0.5	-0.25	0.00	0.00	0.00	63.96	1.35	52.9	2.38	0.00
0.5	1.0	225.65	14.00	155.07	63.96	1.35	52.9	2.38	11.98
1.5	1.0	225.65	14.00	155.07	344.77	49.37	202.22	29.85	11.98
1.5	2.0	354.45	139.43	220.15	344.77	49.37	202.22	29.85	63.00
3.0	2.0	354.45	139.43	220.15	348.03	438.99	253.85	186.94	63.00
3.0	4.0	333.86	600.00	244.80	348.03	438.99	253.85	186.94	298.23
6.0	4.0	333.86	600.00	244.80	196.53	355.65	118.58	188.90	298.23
6.0	8.0	152.35	314.54	91.79	196.53	355.65	118.58	188.90	165.85
12.0	8.0	152.35	314.54	91.79	121.08	179.04	61.13	88.76	165.85
12.0	16.0	86.13	102.12	39.51	121.08	179.04	61.13	88.76	51.86
24.0	16.0	86.13	102.12	39.51	61.77	49.31	28.22	22.81	51.86
24.0	36.0	38.00	17.88	10.69	61.77	49.31	28.22	22.81	8.75
48.0	36.0	38.00	17.88	10.69	17.77	7.91	5.77	3.80	8.75

TABLE 17C

Pharmacokinetic parameters	Values of pharmacokinetic parameters
Pharmacokinetic parameters	Values of pharmacokinetic parameters					100mg capsule (fasting)	100mg capsule (high fat breakfast)	50mg capsule (fasting)	50mg capsule (high fat breakfast)
AUC_{(0- 48)}((ng/ml)h)	4463.28	5214.86	2426.23	2601.10		100mg capsule (fasting)	100mg capsule (high fat breakfast)	50mg capsule (fasting)	50mg capsule (high fat breakfast)
AUC_{(0- 48)}((ng/ml)h)	4463.28	5214.86	2426.23	2601.10	AUC_{(0- LQC)}((ng/ml)h)	4415.59	5105.50	2352.68	2501.56
AUC_(0-∞)((ng/ml)h)	5126.74	5419.21	2693.80	2759.42	AUC_{(0- LQC)}((ng/ml)h)	4415.59	5105.50	2352.68	2501.56
AUC_(0-∞)((ng/ml)h)	5126.74	5419.21	2693.80	2759.42	C_max(ng/ml)	455.00	746.96	321.46	354.17
T_max(h)	2.60	5.00	2.92	4.46	C_max(ng/ml)	455.00	746.96	321.46	354.17
T_max(h)	2.60	5.00	2.92	4.46	T_1/2(h)	16.02	6.86	11.01	6.49
C_max/AUC_(0-LQC)	0.11	0.15	0.16	0.16	T_1/2(h)	16.02	6.86	11.01	6.49

Example 18: pharmacokinetics of suspension-capsules

The pharmacokinetics and bioavailability of oral fine suspensions and two oral capsules containing Celecoxib were evaluated in open label, randomized, single dose, crossover studies. 36 healthy adult subjects received the following single doses of Celecoxib at random: (A) one 200mg dose of capsules, (B) two 100mg dose capsules and (C)200mg oral fine suspension. The whole treatment period is 18 days. On days 1, 8 and 15, subjects received one of the three treatments according to a randomized schedule. The treatment is divided into 7 days. Specific pharmaceutical compositions of 200mg dose capsules are disclosed in example 2. Specific pharmaceutical compositions of the 100mg dose capsule are disclosed in table 18A below.

TABLE 18A

Components	Amount (mg)	By weight%
Components	Amount (mg)	By weight%	Celecoxib	100.0	60.0
Lactose monohydrate	61.7	37.0	Celecoxib	100.0	60.0
Lactose monohydrate	61.7	37.0	Povidone, K29-32	4.20	2.51
Magnesium stearate	0.80	0.48	Povidone, K29-32	4.20	2.51

Pharmaceutical compositions for use as 100mg dose capsules are prepared by passing Celecoxib material through a 40 mesh shaker screen (without additional milling), wet granulating Celecoxib, lactose and povidone in a low shear moving mixer, drying in a pan and milling the granulated mixture, adding magnesium stearate to the granulated mixture and mixing to form the final pharmaceutical composition.

An oral fine suspension is prepared by dissolving Celecoxib in ethanol containing 5% polysorbate 80 and adding the mixture to apple juice prior to administration.

Blood samples were collected from 0.25 hours before the first dose to 72 hours after the dose. Each subject was tested after receiving a 200mg dose of capsules, a 100mg dose of capsules and an oral fine suspension, respectively. A wash-out period of at least 7 days was allowed between each 200mg dose. The average results obtained from the 36 subject trial are shown in table 18B below.

TABLE 18B

Pharmacokinetic parameters	Values of pharmacokinetic parameters
	Values of pharmacokinetic parameters			Two 100mg capsules	A200 mg capsule	200mg oral fine suspension
	AUC_(0-72)((ng/ml)h)	7247.5±2427.5	7648.1±2412.1	Two 100mg capsules	A200 mg capsule	200mg oral fine suspension	7736.2±2488.2
AUC_(0-∞)((ng/ml)h)	AUC_(0-72)((ng/ml)h)	7247.5±2427.5	7648.1±2412.1	7562.4±2494.0	7830.3±2448.4	8001.2±2535.6	7736.2±2488.2
AUC_(0-∞)((ng/ml)h)	C_max(ng/ml)	619.7±249.4	704.6±265.7	7562.4±2494.0	7830.3±2448.4	8001.2±2535.6	1228.8±452.0
T_max(h)	C_max(ng/ml)	619.7±249.4	704.6±265.7	3.00±0.99	2.83±1.06	0.79±0.32	1228.8±452.0
T_max(h)	T_1/2(h)	13.96±5.27	11.92±3.60	3.00±0.99	2.83±1.06	0.79±0.32	13.33±6.69
Clearance rate_(0-72)(l/h)	T_1/2(h)	13.96±5.27	11.92±3.60	30.4±9.8	28.4±7.8	28.1±7.8	13.33±6.69

Overall, Celecoxib uptake (higher C) of fine oral suspensions_maxAnd shorter T_max) Is higher than the capsule. However, by measuring AUC_(0-72)Or AUC_(0-∞)Showing that the total absorption of Celecoxib from the oral fine suspension is similar to that of the capsule Celecoxib.

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.

Claims

1. A pharmaceutical composition comprising one or more orally deliverable dose units, each dose unit comprising a compacted mixture of particles of celecoxib having a dose range from 10mg to 1000mg and one or more pharmaceutically acceptable excipients, wherein D of the celecoxib is₉₀A particle size of less than about 200 μm, wherein the one or more orally-deliverable dose units is in the form of a substantially homogeneous flowable substance.

2. The pharmaceutical composition of claim 1, wherein the one or more orally-deliverable dose units are removed from the flowable material to a measurable extent.

3. The pharmaceutical composition of claim 2, wherein the flowable substance is selected from the group consisting of microparticles, particulate solids, suspensions, and solutions.

4. The pharmaceutical composition of claim 3, wherein the flowable material is a suspension, and wherein the suspension comprises celecoxib dispersed in an aqueous phase in the form of a solid particulate phase.

5. The pharmaceutical composition of claim 4, wherein the aqueous phase is selected from the group consisting of water, syrup, and fruit juice.

6. The pharmaceutical composition of claim 1, wherein the one or more pharmaceutically acceptable excipients further comprises at least one of:

(a) one or more pharmaceutically acceptable diluents in a total amount of 5-99% by weight of the composition;

(b) one or more pharmaceutically acceptable disintegrants in a total amount of 0.2-30 wt% of the composition;

(c) one or more pharmaceutically acceptable binders in a total amount of 0.5 to 25% by weight of the composition;

(d) one or more pharmaceutically acceptable wetting agents in a total amount of 0.25 to 15% by weight of the composition; and

(e) one or more pharmaceutically acceptable lubricants in a total amount of 0.1 to 10% by weight of the composition.

7. The pharmaceutical composition of claim 1, wherein the one or more pharmaceutically acceptable excipients further comprises at least one of:

(a) one or more pharmaceutically acceptable diluents in a total amount of 10-85% by weight of the composition;

(b) one or more pharmaceutically acceptable disintegrants in a total amount of 0.2-10 wt% of the composition;

(c) one or more pharmaceutically acceptable binders in a total amount of 0.75 to 15 wt% of the composition;

(d) one or more pharmaceutically acceptable wetting agents in a total amount of 0.4 to 10% by weight of the composition; and

(e) one or more pharmaceutically acceptable lubricants in a total amount of 0.2 to 8% by weight of the composition.

8. The pharmaceutical composition of claim 6, wherein the one or more excipients is at least one selected from the group consisting of 5-99 wt% lactose, 0.2-10 wt% croscarmellose sodium, 0.5-10 wt% polyvinylpyrrolidone, 0.25-7 wt% sodium lauryl sulfate, and 0.1-10 wt% magnesium stearate.

9. A pharmaceutical composition comprising one or more orally deliverable dose units, wherein each dose unit comprises a compacted mixture of particles of celecoxib in an amount from 10mg to 1000mg and croscarmellose sodium in a total amount of 0.2 to 30% by weight of the composition.

10. The pharmaceutical composition of claim 9, wherein the composition is in the form of a tablet or capsule.

11. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients further comprises at least one of:

(b) one or more pharmaceutically acceptable binders in a total amount of 0.5 to 25% by weight of the composition;

(c) one or more pharmaceutically acceptable wetting agents in a total amount of 0.25 to 15% by weight of the composition; and

(d) one or more pharmaceutically acceptable lubricants in a total amount of 0.1 to 10% by weight of the composition.

12. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients further comprises at least one of:

(b) one or more pharmaceutically acceptable binders in a total amount of 0.75 to 15 wt% of the composition;

(c) one or more pharmaceutically acceptable wetting agents in a total amount of 0.4 to 10% by weight of the composition; and

(d) one or more pharmaceutically acceptable lubricants in a total amount of 0.2 to 8% by weight of the composition.

13. The pharmaceutical composition of claim 11, wherein the one or more excipients is at least one selected from the group consisting of 5-99 wt% lactose, 0.5-10 wt% polyvinylpyrrolidone, 0.25-7 wt% sodium lauryl sulfate, and 0.1-10 wt% magnesium stearate.

14. The pharmaceutical composition according to claim 9, wherein the croscarmellose sodium is present in an amount of 1-5 wt%, and wherein the composition further comprises 0.25-7 wt%, preferably 3-5 wt% sodium lauryl sulfate.

15. A pharmaceutical composition comprising one or more orally-deliverable dose units, each dose unit comprising a compacted mixture of particles of celecoxib in an amount of from 10mg to 1000mg and from 5-99 wt% microcrystalline cellulose, wherein the pharmaceutical composition is in the form of a capsule.

16. A pharmaceutical composition comprising one or more orally deliverable dose units, each dose unit comprising a compacted mixture of particles of celecoxib in an amount from 10mg to 1000mg and 0.5 to 10 weight percent polyvinylpyrrolidone.

17. A pharmaceutical composition comprising, in unit dose capsule form:

(a) 65-85 wt% of celecoxib;

(b) 8-28 wt% lactose;

(c) 0.5-5 wt% of croscarmellose sodium; and

(d) 0.5-5 wt% of polyvinylpyrrolidone;

(e) optionally 0.25-7 wt% sodium lauryl sulfate;

(f) optionally 0.25-5 wt% magnesium stearate.

18. A process for preparing the composition of claim 9 comprising:

(a) grinding celecoxib in an impact grinder;

(b) wet granulating the ground celecoxib and croscarmellose sodium together to form a wet granulated mixture;

(c) drying the mixture obtained by wet granulation; and

(d) filling the dried granulate mixture into capsules or compressing the dried granulate mixture into tablets.

19. The method of claim 18, wherein said grinding is performed using a pin mill.

20. The process of claim 18, wherein 60-75% of the total amount of croscarmellose sodium is added in said wet granulation step (b) and 25-40% of the total amount of croscarmellose sodium is added after said drying step (c) and prior to the step of filling capsules or compressing into tablets (d).