MXPA00007471A - Celecoxib compositions - Google Patents

Abstract

Pharmaceutical compositions are provided comprising one or more orally deliverable dose units, each comprising particulate celecoxib in an amount of about 10 mg to about 1000 mg in intimate mixture with one or more pharmaceutically acceptable excipients. The compositions are useful in treatment or prophylaxis of cyclooxygenase-2 mediated conditions and disorders.

Description

COMPOSITIONS OF CELECOXIB FIELD OF THE INVENTION The present invention relates to oral pharmaceutical compositions and orally administrable dosage forms containing celecoxib as an active ingredient, to methods of treatment comprising the administration of such oral pharmaceutical compositions and orally administrable dosage forms to a subject. that you need them, and to the use of such compositions in the manufacture of medicines. BACKGROUND OF THE INVENTION The compound 4- P5- (4-methylphenyl) -3-trifluorophenyl) -lH-pyrazol-1-yl] -benzenesulfonamide (also referred to herein as celecoxib) was previously reported by Talley et al. , US Patent No. 5,666,823, which describes and claims a class of 1,5-diarylpyrazoles and their salts together with processes for the preparation of such compounds. Celecoxib has 1 to the following structure: REF: 120698 The 1,5-diarylpyrazole compounds reported in US Pat. 5,466,823 are described as being useful in the treatment of inflammation and inflammation-related disorders. U.S. Patent No. 5,466,823 contains general references to formulations for administration of these 1,5-diarylpyrazoles, such as tablets and capsules. Talley et al, in US Pat. No. 5,760,068, describe a class of 1,5-diarylpyrazole compounds, including celecoxib, which are described as selective inhibitors of cyclooxygenase-2 and which can be administered for treatment, among others. conditions and disorders, of pathological conditions associated with rheumatoid arthritis and osteoarthritis. Penning et al., In "Synthesis and Biological Evaluation of the 1, 5-Diarylpyrazole Class of Cyclooxygenase-2 Inhibitors: Identification of 4- [5- (4-Methylphenyl) -3- (trifluoromethyl) -lH-pyrazol-1- and l.benzenesulfonamide (SC-58635, Celecoxib) ", J. Med. Chem. 40 (1997): 1347-1365, describe the preparation of a series of 1,5-diarylpyrazole derivatives containing sulfonamide, including celecoxib, and the evaluation of said derivatives as inhibitors of cyclooxygenase-2. Simon et al., "Preliminary Study of the Safety and Efficacy of SC-58635, to Novel Cyclooxygenase 2 Inhibitor," Arthritis & Rheumatism. Vol. 41, No. 9, September 1998, pp. 1591,1602, describe a study of the efficacy and safety of celecoxib in the treatment of osteoarthritis and rheumatoid arthritis. Lipsky et al., "Outcome of Specific COX-2 Inhibition in Rheumatoid Arthritis", J. Rheumatoloay. Vol. 24, Suppl. 49, pp. 9-14 (1977), describe that in patients with rheumatoid arthritis, the specific inhibition of cyclooxygenase-2 by celecoxib is sufficient to suppress the signs and symptoms of the inflammatory activity of the disease. European Patent EP 863 134 Al, published on September 9, 1998, describes compositions comprising a cyclooxygenase-2 inhibitor, specifically 2- (3,5-difluorophenyl) -3- (4-methylsulfonyl) -phenyl) - 2-cyclopenten-l-one, in combination with microcrystalline cellulose, lactose monohydrate, hydroxypropylcellulose, croscarmellose sodium and magnesium stearate.

Effective oral administration of celecoxib to a subject has been complicated by the unique physical and chemical properties of the compound, particularly its low solubility, its cohesiveness, low bulk density and low compressibility. Celecoxib is usually insoluble in aqueous media. Unformed celecoxib does not readily dissolve and disperse for rapid absorption into the gastrointestinal tract, when administered orally in capsule form. In addition, unformulated celecoxib, which has a crystalline morphology that tends to form long cohesive needles, is typically cohesive and fuses into a monolithic mass after compression with punches. Even when mixed with other substances, the celecoxib crystals tend to separate from the other substances and agglomerate together during the mixing of the composition, resulting in a non-uniformly mixed composition that undesirably contains large, agglomerated celecoxib particles. Therefore, it is difficult to prepare a pharmaceutical composition containing celecoxib that possesses the desired blend uniformity. In addition, the properties of celecoxib cause handling problems during the preparation of pharmaceutical compositions comprising celecoxib. The low bulk density of celecoxib makes it difficult to process the small quantities required during the formulation of the pharmaceutical compositions. In addition, the low compressibility of celecoxib hinders its preparation in the form of orally administrable dosage units, in the form of tablets. Accordingly, there is a need for oral pharmaceutical compositions and dosage forms comprising celecoxib, particularly dosage forms orally administrable. In particular, there is a need for celecoxib formulations that have a higher bioavailability when administered orally, than unformed celecoxib, for example, through the improvement of one or more of its pharmacokinetic properties. There is also a need for celecoxib formulations having one or more of the following characteristics, in relation to the unformulated celecoxib or to other compositions: (1) better solubility of the pharmaceutical composition; (2) decreased disintegration time for oral dosage forms; (3) decreased dissolution time for oral dosage forms; (4) decrease in friability of tablets, - (5) increase in tablet hardness, - (6) improve the safety of oral dosage forms; (7) improve the wettability of the composition; (8) better particle size distribution of grain and / or celecoxib; (9) better compressibility of the composition; (10) better flow properties of the composition, - (11) better chemical stability of the final oral dosage form; (12) better physical stability of the final oral dosage form; (13) decrease in the size of the tablets or capsules; (14) better mix uniformity; (15) better dose uniformity; (16) better control of weight variation during encapsulation and / or tabletting; (17) higher granule density for wet granulated compositions; (18) reduce water requirements for wet granulation; (19) reduce the granulation time; and (20) reducing the drying time for wet granular mixtures. Such formulations would represent a significant advance in the treatment of disorders mediated by cyclooxygenase-2. The need for such formulations is now satisfied by the present invention, which is described below. BRIEF DESCRIPTION OF THE INVENTION A pharmaceutical composition comprising one or more orally administrable dosage forms is now provided, each comprising particulate celecoxib in an amount of about 10 to about 1000 mg in intimate admixture with one or more pharmaceutically acceptable excipients. . In one embodiment, a single dose unit (single dose pharmaceutic form), after being administered orally to a fasted subject, provides a serum concentration time of celecoxib characterized by at least one of the following (a) a time to reach 100 ng / ml no greater than about 0.5 hours after administration; (b) a time to reach the maximum concentration (. ^) not greater than about 3 hours after administration; (c) a length of time wherein the concentration remains above 100 ng / ml, not less than about 12 hours; (d) a terminal half-life (TM) of not less than about 10 hours; and (e) a maximum concentration (Cmax) not less than about 200 ng / ml. In another embodiment, the composition has a relative bioavailability of not less than about 50% compared to an orally administered solution containing an equivalent amount of celecoxib. In still another embodiment, the composition has a particle size distribution of celecoxib such that at least 90% of the particles are less than 200 μm, in the longer dimension of the particles. The dosage forms or dosage units comprising the composition may be in the form of discrete solid articles such as tablets, pills, hard or soft gelatin capsules, dragees, pillules or pills; alternatively, the composition can be in the form of a substantially homogeneous fluid mass, such as a particulate or granular solid or a liquid suspension, from which the dose units can be measurably taken. Also provided is a method for the treatment of a disorder or medical condition in a subject, wherein treatment with a cyclooxygenase-2 inhibitor, comprising the oral administration of a composition according to the present invention, is indicated. twice perday. Other features of the present invention will be partly evident and partly pointed out hereinafter. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a flow diagram illustrating a representative method for the preparation of pharmaceutical compositions of the present invention, in the form of capsules. Figure 2 is a flow diagram illustrating an alternative method for the preparation of pharmaceutical compositions according to the present invention, in the form of capsules. DETAILED DESCRIPTION OF THE INVENTION [0002] Novel pharmaceutical compositions comprising one or more orally administrable dosage forms have been discovered, wherein each dosage form comprises particulate celecoxib in an amount of about 10 to about 1000 mg in intimate admixture with celecoxib, which are better pharmaceutical compositions of immediate release. These pharmaceutical compositions are typically immediate release compositions, with the intended benefit of providing rapid relief for a disorder mediated by cyclooxygenase 2 that a subject is suffering from. These pharmaceutical compositions solve the insolubility problems normally associated with celecoxib and provide for the effective dissolution, dispersion and absorption of celecoxib in the gastrointestinal tract. In one embodiment, each orally administrable pharmaceutical form, when administered orally, provides a serum concentration time of celecoxib characterized by at least one of the following: (a) a time to reach a serum concentration of approximately 100 μm / ml, which is not greater than approximately 0.5 hours after administration; (b) a time to reach the maximum serum concentration (T, ^) of celecoxib, which is not greater than about 3 hours after administration, preferably not more than about 2 hours after administration; (c) a length of time in which the serum concentration remains above about 100 -μg / ml, not less than about 12 hours; (d) a terminal half-life (T) which is not less than about 10 hours, - and (e) a maximum serum concentration (C ^.) which is not less than about 100 μg / ml, preferably not less than about 300 μg / ml and more preferably, not less than about 400 μg / ml. In another embodiment, each orally administrable dosage form, after being administered, has a relative bioavailability of not less than about 50%, preferably not less than about 70%, compared to an orally administered solution of celecoxib containing an equivalent amount of celecoxib. In another embodiment, the novel pharmaceutical compositions comprise one or more orally administrable dosage forms comprising celecoxib in an amount of about 10 to about 1000 mg, wherein the particle size distribution of celecoxib, in the largest dimension of said particles, is such that at least 90% of the particles are smaller than approximately 200 microns, preferably smaller than approximately 100 microns, more preferably less than approximately 75 microns, and still • more preferably less than approximately 40 microns and yet more preferably, less than about 25 microns. The particle size reduction of celecoxib as set forth above generally improves the bioavailability thereof. In addition or alternatively, each orally administrable dosage form may contain celecoxib particles having an average particle size of about 1 to about 10 microns, preferably from about 5 to about 7 microns. It has also been discovered that when grinding celecoxib in an impact mill, such as a pin mill, before mixing it with the carrier materials, it is of benefit to solve the problems associated with the cohesive nature of celecoxib during its mixing. with the vehicle materials. Celecoxib milled in an impact mill is less cohesive and does not agglomerate into large celecoxib particles during mixing, as easily as unground celecoxib or ground celecoxib using other types of mills, such as fluid energy mills. Without adhering to any particular theory, it is hypothesized that the impact mill modifies the morphology of the long needle crystal to a more uniform crystal shape - for mixing purposes. It has also been found that the uniformity of the blend is further improved by wet granulating the celecoxib with the carrier materials for preparing the pharmaceutical composition, particularly when the celecoxib raw material used has been impact milled. The impact grinding of the celecoxib raw material up to a particle size as described in the previous paragraph is particularly desirable. In still another embodiment, the new pharmaceutical compositions comprise one or more orally administrable dosage forms comprising celecoxib in an amount of about 10 to about 1000 mg or one or more carrier materials that are selected from the group consisting of diluting agents, disintegrants, binders, humectants and lubricants. Preferably, at least one of the carrier materials is a water-soluble diluent or wetting agent. The water-soluble diluent and wetting agent aid in the dissolution and dispersion of celecoxib when the pharmaceutical composition is ingested. More preferably, the pharmaceutical composition comprises celecoxib and one or more carrier materials which are selected from the group consisting of lactose, sodium lauryl sulfate, polyvinyl pyrrolidone, croscarmellose sodium, microcrystalline cellulose and magnesium stearate. They will be described later in the present application, additional preferred compositions. In another embodiment, the pharmaceutical composition comprises a substantially homogeneous fluid mass from which dose units can be measured measurably. Suitable fluid masses including, but not limited to, particulate or granular solids. Alternatively, the fluid mass may be a liquid suspension containing celecoxib in a solid particulate phase dispersed in an aqueous phase. In preparing such suspension, the use of a wetting agent such as polysorbate 80 or the like, can be beneficial. Precipitating celecoxib in a solvent such as alcohol, preferably ethanol, can also be beneficial in preparing the suspension. The aqueous phase preferably comprises a degustable carrier such as water, syrup and fruit juice, for example apple juice. The compositions of the present invention would be useful for, but not limited to, the treatment of inflammation in a subject and for the treatment of other disorders. mediated by cyclooxygenase 2, such as as an analgesic in the treatment of pain and headaches or as an antipyretic for the treatment of fever. For example, compositions in accordance with the present invention would be useful for the treatment of arthritis, including but not limited to rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis. Such compositions according to the present invention would be useful in the treatment of asthma, bronchitis, menstrual cramps, prepartum labor, tendonitis, bursitis, allergic neuritis, cytomegalovirus infections, apoptosis including HIV-induced apoptosis, lumbago, liver disease including hepatitis, disorders related to the skin such as psoriasis, eczema, acne, damage caused by UV radiation, burns and dermatitis; and for postoperative inflammations including ophthalmic surgery such as cataract surgery and refractive surgery. The compositions of the present invention would also be useful in the treatment of gastrointestinal disorders, such as inflammatory bowel disease, Crohn's disease, gastritis, intestinal irritability syndrome and ulcerative colitis. The compositions according to the present invention would be useful in the treatment of inflammation in diseases such as "migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, scleroderma, rheumatic fever, type I diabetes, neuromuscular joint disease including myasthenia. severe, white matter diseases including multiple sclerosis, -sarcoidosis, nephrotic syndrome, Behcet syndrome, polymyositis, gingivitis, nephritis, hypersensitivity, post-injury inflammations including cerebral edema, myocardial ischemia and the like. treatment of ophthalmic diseases, such as retinitis, conjunctivitis, retinopathies, uveitis, ocular photophobia and acute ocular tissue lesions The compositions would also be useful in the treatment of pulmonary inflammation, such as inflammation associated with viral infections and fibrosis. stica; resorptions and bone such as associated with osteoporosis. The compositions would also be useful in the treatment of certain disorders of the central nervous system, such as cortical dementia including Alzheimer's disease, neurodegeneration and damage to the central nervous system resulting from shock, ischemia or trauma. The term "treatment" includes partial or total inhibition of dementia, including Alzheimer's disease; vascular dementia, dementia due to multiple infarctions, presenile dementia, alcoholic dementia and senile dementia. The compositions of the present invention would be useful as anti-inflammatory agents, for example for the treatment of "arthritis, with the additional benefit of having significantly less dangerous side effects." These compositions would also be useful in the treatment of allergic rhinitis, respiratory distress syndrome. , endotoxin shock syndrome and liver disease The compositions would also be useful in the treatment of pain, but not limited to postoperative, dental, muscular pain and cancer pain The above compositions would be useful for, but not limited to, the treatment and prevention of cardiovascular disorders related to inflammation in a subject The compositions would be useful for the treatment and prevention of vascular diseases, coronary artery disease, aneurysm, vascular rejection, arteriosclerosis, atherosclerosis including atherosclerosis by heart transplantation, myocardial infarction, embolism, heart attack, thrombosis, including venous thrombosis, angina, including unstable angina, inflammation of the coronary plaque, inflammation induced by bacteria including Chlamydia-induced inflammation, virus-induced inflammation and inflammation associated with surgical procedures such as vascular grafts, including coronary artery bypass surgery, revascularization procedures including angioplasty, placement of surgical fasteners, endoarterectomy, or other invasive procedures involving the arteries, veins, and capillaries. The compositions would be useful for, but not limited to, the treatment of disorders related to angiogenesis in a subject. In accordance with the present invention, the compositions can be administered to a subject in need of inhibition of angiogenesis. The compositions would be useful for the treatment of neoplasms, including metastases, ophthalmological disorders such as rejection of grafted corneas, ocular neovascularization, retinal neovascularization including neovascularization following injury or infection, diabetic retinopathy, macular degeneration, retrolental fibroplasia and neovascular glaucoma.; ulcerative diseases such as gastric ulcer; pathological but not malignant disorders such as hemangiomas, including infantile hemangiomas, angiofibroma- of the nasopharynx and avascular bone necrosis, - and disorders of the female reproductive system such as endometriosis. The compositions according to the present invention would be useful for the prevention or treatment of benign and malignant tumors / neoplasms including cancer, such as colorectal cancer, brain cancer, bone cancer, neoplasia derived from epithelial cells (epithelial carcinoma) such as cell carcinoma. Basal, adenocarcinoma, gastrointestinal cancer 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, cancer pulmonary, breast cancer and skin cancer, such as cancer of basal and squamous cellulose cells, prostate cancer, renal cell carcinoma and other known cancers that affect epithelial cells throughout the body. Preferably, the neoplasm is selected from the group consisting of gastrointestinal cancer, Barrett's esophagus, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer, cervical cancer, lung cancer, breast cancer and skin cancer. , such as cancer of cells and squamous cells. The composition can also be used for the treatment of fibrosis that occur by radiation therapy. The compositions can be used to treat subjects suffering from adenomatous polyps, including familial adenomatous polyposis (FAP). Additionally, the compositions can be used to prevent polyps from forming in patients at risk of FAP. The compositions of the present invention also possess anti-inflammatory, antipyretic and analgesic properties, similar to conventional non-steroidal anti-inflammatory drugs. These compositions would also inhibit uterine contractions induced by hormones and would have potential anticancer effects, but with a diminished ability to induce some of the side effects caused by the mechanism of action. In particular, such compositions would have a reduced potential for gastrointestinal toxicity and gastrointestinal irritation, including upper gastrointestinal ulceration and bleeding, a reduced potential for renal side effects such as reduced renal function causing fluid retention and exacerbation of hypertension, an effect Reduced bleeding time, including platelet inhibition and possibly a lower ability to induce asthma attacks in asthmatic subjects sensitive to aspirin. These compositions would also be useful for the relief of pain, fever and inflammation of a variety of disorders, including rheumatic fever, symptoms associated with influenza or other viral infections such as the common cold, pain in the lower back and neck. , dysmenorrhea, headache, dental pain, sprains and strains, myositis, neuralgia, einovitis, arthritis, including rheumatoid arthritis, degenerative diseases of the joints (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns, injuries after surgical and dental procedures . In addition, these compositions would inhibit cellular neoplastic transformations and the growth of metastatic tumors and, therefore, can be used in the treatment of cancer, such as colon cancer. These compositions would also be useful in the treatment and / or prevention of proliferative disorders mediated by cyclooxygenase, such as may occur in diabetic retinopathy and tumor angiogenesis. These compositions could also inhibit the contraction of smooth muscle induced by prostanoids, preventing the synthesis of contractile prostanoids and, in this way, they would be useful in the treatment of dysmenorrhea, premature labor, asthma and disorders related to eosinophils. They would also be useful in the treatment of Alzheimer's disease, to decrease bone loss particularly in postmenopausal women (i.e., treatment of osteoporosis) and for the treatment of glaucoma. By virtue of their high cyclooxygenase-2 (COX-2) activity and / or their specificity for cyclooxygenase-2 over cyclooxygenase-1 (COX-1), these compositions would be useful as an alternative to conventional non-steroidal anti-inflammatory drugs. (NSAID), particularly where such nonsteroidal anti-inflammatory drugs may be contraindicated, as in patients with peptic ulcer, gastritis, regional enteritis, ulcerative colitis, diverticulitis or with a recurrent history of gastrointestinal lesions, - gastrointestinal bleeding, coagulation disorders including anemia such as hypoprothrombinemia, hemophilia or other hemorrhagic problems, - kidney disease; or in patients before surgery or patients taking anticoagulants. A brief description of the potential utility of cyclooxygenase-2 inhibitors is provided in an article by John Vane, Nature, Vol. 367, pp. 215-216, 1994, and in an article in Druq News and Perspectives, Vol. 7, pp. 501-512, 1994. Preferred uses for the pharmaceutical compositions of the present invention are for the treatment of rheumatoid arthritis and osteoarthritis, for the management of pain in general (particularly pain after oral surgery, general postoperative pain, pain after orthopedic surgery and acute injuries due to osteoarthritis), the treatment of Alzheimer's disease and chemical prevention of colon cancer. In addition to being useful for the treatment of humans, these compositions are also useful for veterinary treatments of companion animals, exotic animals and farm animals, including mammals, rodents and the like. The most preferred animals include horses, dogs and cats. The compositions herein can also be used in combination therapies with opioids and other analgesics, including narcotic analgesics, Mu receptor antagonists, kappa receptor antagonists, non-narcotic analgesics (ie non-addictive), monoamine incorporation inhibitors, regulators of adenosine, cannabinoid derivatives, substance P antagonists, neurokinin-1 receptor antagonists and sodium channel blockers, among others. . Combinations with compounds selected from the group consisting of morphine, meperidine, codeine, pentazocine, buprenorphine, butorphanol, dezocin, meptazinol, hyddone, oxycodone, methadone, Tramadol [(+) enenatomer], DuP 747, Dinorphine A, Enadoline would be more preferred. , RP-60180, HN-11608, E-2078, ICI-204448, acetaminophen (paracetamol), propoxyphene, nalbuphine, E-4018, filenadol, mirfentanil, amitriptyline, DuP631, Tramadol [(-) enantiomer], GP-531, acadesine, AKI-1, AKI-2, GP-1683, GP-3269, 4030 92, tramadol racemate, AXC3742, SNX-111, ADL2-1294, CT-3 and CP-99.994. Definitions The term "active ingredient" as used herein means celecoxib. The term "excipient" as used herein, includes any substance used as a vehicle for the administration of the active ingredient to a subject and any substance added to the active ingredient, for example to improve its handling properties or to allow the composition The resultant can be produced in a pharmaceutical form of oral administration having the desired shape and consistency. The excipients may include, by way of illustration and not limitation, diluents, disintegrants, binders, adhesives, humectants, lubricants, glidants, added substances to mask a bad taste, substances added to improve the appearance of a pharmaceutical form and any other substance Conventionally used in the preparation of oral dosage forms. The term "adjuvant" as used herein, means a substance that, when added to a pharmaceutical composition comprising an active ingredient, increases or otherwise enhances the action of the active ingredient. The term "unit dose" as used herein, refers to an amount of a pharmaceutical composition intended for a single administration, for the treatment of a subject suffering from a disorder mediated by cyclooxygenase-2. Each dose unit typically comprises celecoxib plus pharmaceutically acceptable carrier materials. The term "oral administration dosage form" or "oral dosage unit" as used herein, means a dosage unit of a pharmaceutical composition intended to be administered to the gastrointestinal tract of a subject, through the mouth of a patient. said subject and for the purposes of the present invention, the dosage unit may be in the form of a discrete article such as a tablet or a capsule, or a measurable volume of a solution, suspension or the like containing the active ingredient, non-limiting examples of pharmaceutical forms for administering units of Doses are individual tablets, individual gelatin capsules, bulk powders and liquid solutions, emulsions or suspensions.The treatment of the cyclooxygenase-2 mediated disorder may require the periodic administration of dose units, for example: a dose unit two or more times a day, one with each food, one every four hours or any other interval, or only one a day.The term "substantially homogeneous" is used herein to describe a pharmaceutical composition having a combination of components, meaning that the components are completely mixed in such a way that the individual components do not separate into discrete layers on or form concentration gradients within the composition. The term "bioavailability" as used herein, generally means the proportion of a administered dose of the active ingredient that is absorbed into the bloodstream. However, as will be clear from the context, the term "bioavailability" is also more specifically used herein to denote AUC (0_8) for a specific orally administered composition expressed as a percentage of AUC (0.8) for the ingredient active administered intravenously at the same dose. The term "ABC (0.48)" as used herein means the area under the curve that relates serum concentration to time, after administration of 0 to 48 hours, as determined using the rule. linear trapezoidal and is expressed in units of (ng / ml) hour). The term "ABC (0_UCC) as used herein, means the area under the curve that relates the serum concentration to the time after the administration of 0 hours until the time of the last quantifiable concentration (" UCC "), as determined using the linear trapezoidal rule and is expressed in units of (ng / ml) hour The term "ABC (0_8) is calculated as the ABC (0.UCC) + UCC / (- b), where UCC is the last quantifiable serum concentration and b is the slope of the TM calculation and is expressed in units (ng / ml / hour.

The term wCmaxw as used herein means the maximum concentration observed, in units of ng / ml: The term "T ^" as used herein, means time, in units of hours, after the administration to which the ^^ occurs. The term "TH" as used herein, means the terminal half-life, in units of hours, determined by simple linear regression of the natural logarithm (ln) of the concentration versus time, for the data of the points in the phase terminal of the concentration-time curve. T? it is denoted as -ln (2) / - b). The term "Cmax / ABC < 0.UCC" as used herein means the rate of absorption. Celecoxib Dosage of Pharmaceutical Compositions The pharmaceutical compositions of the present invention comprise celecoxib in a daily dose amount of about 10 to about 1000 mg. Preferably, the pharmaceutical compositions comprise celecoxib in an amount of about 50 to about 800 mg, preferably about 75 to about 400 mg, and more preferably about 100 to about 200 mg. Treatment of Conditions and Specific Disorders The pharmaceutical compositions of the present invention are useful when administration of a cyclooxygenase-2 inhibitor is indicated. It has been found that these compositions are particularly effective in the treatment of, for example, rheumatoid arthritis and osteoarthritis, and for the management of pain in general (particularly pain after oral surgery, general postoperative pain, pain after a orthopedic surgery and sudden acute injuries of osteoarthritis), for the treatment of Alzheimer's disease and for the chemical prevention of colon cancer. For the treatment of rheumatoid arthritis, the pharmaceutical compositions provide a daily dose of celecoxib in an amount of from about 50 to about 1000 mg, preferably from about 100 to about 600 mg, more preferably from about 150 to about 500 mg, furthermore preferably from about 175 to about 400 mg and still more preferably about 200 mg. A daily dose of about 0.67 to about 13.3 rog / kg of body weight, preferably between about 1.33 and about 8.00 mg / kg of body weight, more preferably between about 2.00 and about 6.67 mg / kg of body weight, may be appropriate. more preferably between about 2.33 and about 5.33 mg / kg of body weight and still more preferably of about 2.67 mg / kg of body weight. The daily dose can be administered in one to four doses per day, preferably one to two doses per day. Administration of a unit oral dosage form of 100 mg twice daily is preferred for most patients, but some patients could benefit from the administration of a 200 mg oral unit dosage form twice daily. For the treatment of osteoarthritis, the pharmaceutical compositions provide a daily dose of celecoxib in an amount of from about 50 to about 1000 mg, preferably from about 100 to about 600 mg, more preferably from about 150 to about 500 mg, even more preferably from about 175 to about 400 mg and still more preferably about 200 mg. A daily dose of about 0.67 to about 13.3 mg / kg of body weight, preferably between about 1.33 and about 8.00 mg / kg of body weight, more preferably between about 2.00 and about 6.67 mg / kg of body weight, may be appropriate. more preferably between about 2.33 and about 5.33 mg / kg of body weight and still more preferably about 2.67 mg / kg of body weight. The daily dose can be administered in one to four doses per day, preferably one or two doses per day. Administration of a unit oral dosage form of 100 mg twice daily or a unit oral dosage form of 200 mg once a day is preferred. For the treatment of Alzheimer's disease, the pharmaceutical composition provides a daily dose of celecoxib in an amount of from about 50 mg to about 1000 mg, preferably from about 100 to about 800 mg, more preferably from about 150 to about 600 mg, even more preferably from about 175 to about 400 mg and still more preferably about 400 mg. A daily dose of about 0.67 to about 13.3 mg / kg of body weight, preferably between about 1.33 and about 10.67 mg / kg of body weight, more preferably between about 2.00 and about 8.00 mg / kg of body weight, may be appropriate. more preferably between about 2.33- and about 5.33 mg / kg of body weight and still more preferably of about 5.33 mg / kg of body weight. The daily dose can be administered in one to four doses per day, preferably one or two doses per day. For most patients, the administration of a 200 mg oral unit dosage form twice a day is preferred. For the treatment of cancer, the pharmaceutical composition provides a daily dose of celecoxib in an amount of from about 50 to about 1000 mg, preferably from about 100 to about 800 mg, more preferably from about 150 to about 600 mg, even more preferably from about 175 to about 400 mg and still more preferably about 400 mg. A daily dose of from about 0.67 to about 13.3 mg / kg of body weight, preferably from about 1.33 to about 10.67 mg / kg of body weight, more preferably between about 2.00 and about 8.00 mg / kg of body weight, may be appropriate. more preferably between about 2.33 and about 5.33 mg / kg of body weight and still more preferably of about 5.33 mg / kg of body weight. The daily dose can be administered in one to four doses per day, preferably two doses per day. For most patients, administration of a 200 mg oral unit dosage form twice a day is preferred. In general, the pharmaceutical composition is preferably suitable to provide an average celecoxib serum concentration of at least about 100 ng / ml in a subject, for a period of about 24 hours after ingestion of the composition by the subject. It has also been found that the pharmaceutical compositions of the present invention provide a therapeutic effect as inhibitors of cyclooxygenase during a range of about 12 to 24 hours, preferably about 24 hours, after oral administration. Dose Units The dosage unit forms of the pharmaceutical compositions typically contain, for example, a dose of 10, 20, 25, 37.5, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350 or 400 mg of celecoxib. Preferred dosage unit forms contain about 100 mg or about 200 mg of celecoxib. The dosage unit form or dosage form can be selected "to accommodate the desired frequency of administration used to achieve the specified daily dose, the number of dosage unit forms of the pharmaceutical composition that is administered and the dosage regimen for the dosage form. treatment of the condition or disorder, will depend on a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the condition or disorder, the route and frequency of administration, and, therefore, may vary However, it has been found that a regimen of administration once a day or twice a day to achieve the required daily dose of the pharmaceutical compositions of the present invention, exhibits better efficacy in relation to other administration regimens for dosage unit forms described in the examples of the present application. Accordingly, an oral administration once a day or twice a day is preferred to provide a therapeutic or prophylactically effective inhibition of disorders mediated by cyclooxygenase-2.

Preparation of Celecoxib Celecoxib used in the new pharmaceutical compositions of the present invention can be prepared in the manner established in Talley et al., US Patent No. 5,466,823 or in Zhi et al., International Publication 096/37476. FORM OF PHARMACEUTICAL COMPOSITIONS The pharmaceutical compositions of the present invention comprise celecoxib in association with one or more non-toxic pharmaceutically acceptable carriers, excipients and adjuvants (collectively referred to herein as "carrier materials" or "excipients") and are suitable for oral administration. The carrier materials may be acceptable in the sense of being compatible with the other ingredients of the composition and must not be harmful to the container. The pharmaceutical compositions of the present invention can be adapted for administration by any suitable oral route, selecting the appropriate carrier materials and a dose of celecoxib effective for the intended treatment. Accordingly, the carrier material employed may be a solid or a liquid, or both, and the composition is preferably formulated as a dose unit composition, for example, a capsule or tablet, which may contain from about 1 to about 95%, preferably from about • 10 to about 90%, more preferably from about 25 to about 85% and still more preferably from about 30 to about 80% by weight of celecoxib. Such pharmaceutical compositions of the present invention can be prepared by any of the techniques known in pharmacy, which comprise the mixture of the components. For oral administration, the pharmaceutical composition may contain a desired amount of celecoxib and be in the form of, for example, a tablet, a hard or soft gelatin capsule, a dragee, a wafer, a dispersible powder, granules, a suspension, a elixir, a liquid or any other form reasonably adapted for oral administration. Such a pharmaceutical composition is preferably made in the form of a discrete dose unit containing a predetermined amount of celecoxib, such as tablets or capsules. Such oral dosage forms, moreover, may comprise, for example, pH regulating agents. Tablets, pills and the like can additionally be prepared with or without coatings. a Pharmaceutical compositions suitable for buccal (sublingual) administration include, for example, wafers comprising celecoxib in a flavored base, such as sucrose and acacia gum or tragacanth, and lozenges comprising celecoxib in an inert base such as gelatin and glycerin or sucrose and acacia gum. Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. These compositions may also contain, for example, wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents. As indicated above, these pharmaceutical compositions can be prepared by any pharmacy method including the step of bringing the celecoxib into association with the material. or the vehicle materials. In general, the compositions are prepared by uniformly and intimately admixing the active compound with a liquid or a finely divided solid carrier, or both, and then, if necessary, encapsulating or shaping the product. For example, a tablet can be prepared by compressing or molding a powder or granules of the compound, optionally with one or more accessory ingredients. Compressed tablets 4 can be prepared by compressing, "in a suitable machine, the compound in a free-flowing form, such as powder or granules optionally mixed with a binder., lubricant, inert diluent and / or surfactant / dispersant. The molded tablets can be prepared by molding, in a suitable machine, the powder compound moistened with an inert diluent liquid. Vehicle Materials As noted above, the pharmaceutical compositions of the present invention comprise celecoxib in a therapeutically effective amount, in combination with one or more pharmaceutically acceptable carrier materials suitable for oral administration. The oral dosage forms of the pharmaceutical compositions of the present invention, preferably comprise celecoxib in a desired amount mixed with one or more carrier materials that are selected from the group consisting of diluents, disintegrants, binders and adhesives, humectants, lubricants, non-stick and / or other pharmaceutically acceptable materials. Preferably, such compositions are tableted, or encapsulated for convenient administration. Such capsules or tablets may be in the form of capsules or tablets of immediate release. The selection and combination of the carrier materials used in the pharmaceutical compositions of the present invention provide compositions that exhibit improved performance with respect to, among other properties, the efficacy; bioavailability, depuration times, stability, compatibility of celecoxib and vehicle materials, safety, dissolution profile, disintegration profile and / or other pharmacokinetic, chemical and / or physical properties. The carrier materials are preferably water-soluble or water-dispersible and have wetting properties to compensate for the low solubility and hydrophobicity of celecoxib. When the composition is formulated as a tablet, the combination of the selected carrier materials provides tablets which can exhibit, among other properties, better dissolution and disintegration profiles, better hardness, crushing resistance and / or friability. Diluents The pharmaceutical compositions of the present invention may optionally comprise one or more pharmaceutically acceptable diluents as carrier material. Acceptable dilutents may include, either individually or in combination, diluents such as lactose USP; USP anhydrous lactose, USP lactose spray dried, USP starch; directly compressible starch; USP mannitol; sorbitol; dextrose monohydrate; microcrystalline cellulose NF; dibasic calcium phosphate dihydrate NF; sucrose-based diluents; confectionery sugar; monobasic calcium sulfate monohydrate; calcium sulfate dihydrate NF; granular calcium lactate trihydrate NF; NX dextrata (e.g., Emdex), - Celutab; dextrose (e.g., Cerelose), -inositol; hydrolyzed cereal solids such as Maltrons and Mor-Rex, - amylose, Rexcel; cellulose powder (e.g., Elcema), - calcium carbonate, - glycine; bentonite; polyvinyl pyrrolidone and the like. Said diluent, if any, constitutes from about 5 to about 99%, preferably from about 10 to about 85% and more preferably from about 20 to about 80% of the total weight of the composition. The selected diluent or diluents preferably exhibit suitable flow properties and, when tablets are desired, compressibility. Lactose and microcrystalline cellulose, either individually or in combination, are the preferred diluents. Both diluents are chemically compatible with celecoxib. • the use of extragranular microcrystalline cellulose (ie, microcrystalline cellulose to which a wet granulated composition was added after the drying step) can be used to improve the hardness (for tablets) and / or the time of disintegration. Lactose, especially monohydrated lactose, is particularly preferred. Lactose typically provides pharmaceutical compositions having suitable celecoxib release rates, stability, flow before compression and / or drying properties at relatively low cost of diluent. It provides a higher density of the substrate, which helps to densify the granulate (in case wet granulation is used) and, therefore, improves the flow properties of the mixture. Disintegrants The pharmaceutical compositions of the present invention may optionally comprise one or more pharmaceutically acceptable disintegrating agents as a carrier material, particularly for tablet formulations. Suitable disintegrants may include, either individually or in combination, disintegrants such as starches; sodium starch glycolate; clays (such as Veegum HV), - celluloses (such as purified cellulose, methylcellulose and carboxymethylcellulose - sodium and carboxymethylcellulose), - alginates; pregelatinized corn starches (such as National 1551 and National 1550); Crospovidone USP NF; gums (such as agar, guara gum, locust bean gum, Karaya gum, pectin and tragacanth). The disintegrants can be added at any suitable stage during the preparation of the pharmaceutical composition, particularly before granulation or during the lubrication step, before compression. Said disintegrant, if any, constitutes from about 0.2 to about 30%, preferably from about 0.2 about 10% and more preferably from about 0.2 to about 5% of the total weight of the composition. Croscarmellose sodium is a preferred disintegrant for the disintegration of tablets or capsules and, if present, preferably constitutes from about 0.2 to about 10%, preferably from about 0.2 to about 6% and more preferably from about 0.2 to about 5% of the total weight of the composition. Croscarmellose sodium confers superior intragranular disintegration capacities to the pharmaceutical composition of the present invention. Binding Agents and Adhesives The pharmaceutical compositions of the present invention may optionally contain one or more pharmaceutically acceptable binding agents or adhesives as carrier material, particularly for tablet formulations. Such binders and adhesives preferably impart sufficient cohesion to the powders to allow normal processing, such as particle size adjustment, lubrication, compression and packaging, but also allow the tablet to disintegrate and the composition to dissolve afterwards. of its ingestion. Suitable binders and adhesives may include, either individually or in combination, binding agents and adhesives such as acacia gum; tragacanth; sucrose, - gelatin; glucose, - starch; cellulose materials such as, but not limited to, methylcellulose and sodium carboxymethylcellulose (e.g., Tylose), alginic acid and alginic acid salts; aluminum magnesium silicate, - polyethylene glycol; guara gum; acid polysaccharides; Bentonites; polyvinylpyrrolidone, - polymethacrylates; hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (Klucel), ethylcellulose (Ethocel), pregelatinized starch (such as National 1511 and Starch 1500). Said binder and / or adhesive, if present, constitutes from about 0.5 to about 25%, preferably from about 0.75 to about 15% and more preferably from about 1 to about 10% of the total weight of the composition. Polyvinylpyrrolidone is a preferred binding agent used to impart cohesive properties to the mixed powder of the celecoxib formulation. The polyvinyl pyrrolidone, if present, preferably constitutes about 0.5 about 10%, preferably about 0.5 to about 7% and even more preferably about 0.5 about 5% of the total weight of the composition. Polyvinylpyrrolidones with viscosities up to 20 cp can be used, although viscosities of about 6 cp or less, particularly about 3 cp or less, are also preferred. Polyvinylpyrrolidone provides cohesiveness to the mixture and facilitates the agglutination necessary to form granules during wet granulation. In fact, the pharmaceutical compositions of the present invention comprising polyvinylpyrrolidone, particularly in a wet granulated form, exhibit a better bioavailability in relation to other compositions. Moisturizing Agents Celecoxib is very insoluble in aqueous solution. Accordingly, the pharmaceutical compositions of the present invention optionally may comprise one or more pharmaceutically acceptable wetting agents as carrier material. Such wetting agents, preferably, keep celecoxib in solution and improve the relative bioavailability of the pharmaceutical composition. Suitable wetting agents may include, either individually or in combination, wetting agents such as oleic acid; glyceryl monostearate; sorbitan monooleate; sorbitan monolaurate; triethanolamine oleate; polyoxyethylene-sorbitan monooleate; polyoxyethylene-sorbitan monolaurate; sodium oleate and sodium lauryl sulphate. Wetting agents which are anionic surfactants are preferred. Such wetting agents, if any, constitute from about 0.25 to about 15%, preferably from about 0.4 to about 10% and more preferably from about 0.5 to about 5% of the total weight of the composition. Sodium lauryl sulfate is a preferred wetting agent. Sodium lauryl sulfate, if present, constitutes from about 0.25 to about 7%, preferably from about 0.4 to about 6% and still more preferably from about 0.5 to about 5% of the total weight of the composition. Lubricants The pharmaceutical compositions of the present invention may optionally comprise one or more pharmaceutically acceptable lubricants and / or glidants as carrier material. Suitable lubricants and / or glidants may include, either individually or in combination, lubricants and / or glidants such as glyceryl behapate (Compritol 888); stearates (magnesium, calcium, sodium); stearic acid; hydrogenated vegetable oils (e.g., Sterotex), - talc, - waxes; Stearowet; boric acid; sodium benzoate and sodium acetate, - sodium fumarate; sodium chloride, - DL-Leucine, - polyethylene glycols (e.g., Carbowax 4000 and Carbowax 6000), - sodium oleate; sodium benzoate, - sodium acetate; sodium lauryl sulfate and magnesium lauryl sulfate. Said lubricant, if present, constitutes 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% of the total weight of the composition. Magnesium stearate "is a preferred lubricant which is used, for example, to reduce friction between the equipment and the granulated mixture during the compression of tablet formulations.Other carrier materials (such as anti-stick agents, colorants, flavors, sweeteners) and preservatives) are known in the pharmaceutical art and can be used in the preparation of the pharmaceutical compositions of the present invention For example, iron oxide can be added to the composition to provide a yellow color In one embodiment of the present invention The pharmaceutical composition comprises celecoxib in a desired amount and a binding agent The composition preferably further comprises one or more carrier materials which are selected from the group consisting of pharmaceutically acceptable diluents, disintegrants, binders, humectants and lubricants. , the composition comprises one om s carrier materials selected from the group consisting of lactose, sodium lauryl sulfate, polyvinylpyrrolidone, croscarmellose sodium, magnesium stearate and microcrystalline cellulose. Still more preferably, the composition comprises lactose monohydrate and croscarmellose sodium. Even still more preferably, the composition further comprises one or more of the vehicle materials sodium lauryl sulfate, magnesium stearate and microcrystalline cellulose. In another embodiment, the pharmaceutical composition comprises: from "about 95 percent by weight of celecoxib, from about 5 to about 99 percent by weight of a pharmaceutically acceptable diluent, from about 0.5 to about 30 percent by weight of a pharmaceutically acceptable disintegrating agent, and from about 0.5 to about 25 weight percent of a pharmaceutically acceptable binding agent In addition, this pharmaceutical composition may optionally comprise from about 0.25 to about 15% by weight of a pharmaceutically acceptable wetting agent; or from about 0.1 to about 10% by weight of a pharmaceutically acceptable lubricant The term "percent by weight" as used herein means the weight percent of a specific ingredient based on the total weight of all the ingredients of the composition In another modality, the The pharmaceutical composition comprises: from about 1 to about 95 weight percent celecoxib; from about 5 to about 99 weight percent lactose, from about 2 to about 6 weight percent croscarmellose sodium, and from about 0.5 to about 10 weight percent polyvinylpyrrolidone. In addition, this pharmaceutical composition can optionally comprise from about 0.25 to about 7% by weight of sodium lauryl sulfate of from about 0.1 to about 10% by weight of magnesium stearate, and / or from about 1 to about 99% by weight of cellulose microcrystalline In another embodiment, the pharmaceutical composition comprises: from about 80 to about 220 mg of celecoxib; from about 30 to about 225 mg of lactose; from about 0.5 to about 25 mg of croscarmellose sodium, and from about 0.5 to about 25 mg of polyvinylpyrrolidone. In addition, this pharmaceutical composition may optionally comprise from about 0.5 to about 25 mg of sodium lauryl sulfate; from about 0.2 to about 10 mg of magnesium stearate; and / or from about 1 to about 70 mg of microcrystalline cellulose. In yet another embodiment, the pharmaceutical composition is in the form of a dosage unit of tablet or capsule. In yet another embodiment, the pharmaceutical composition comprises celecoxib and a carrier material or carrier materials in the form of an oral dosage unit suitable for oral administration once or twice a day. Still more preferably, this pharmaceutical composition comprises celecoxib in a desired amount and one or more carrier materials that are selected from the group consisting of pharmaceutically acceptable diluents, disintegrants, binders, humectants, lubricants and antiadhesives. More preferably, the composition comprises one or more carrier materials that are selected from the group consisting of lactose, sodium lauryl sulfate, polyvinyl pyrrolidone, croscarmellose sodium, magnesium stearate and microcrystalline cellulose. Still more preferably, the composition comprises lactose monohydrate and croscarmellose sodium. Even more preferably, the composition further comprises one or more of the vehicle materials sodium lauryl sulfate, magnesium stearate and microcrystalline cellulose. It is particularly preferred that the various components of the composition are present in the amounts or fractions of weight that are described later in the present application. In still another embodiment, the pharmaceutical composition comprises celecoxib and a pharmaceutically acceptable carrier material or materials, such that when the composition is administered orally to a human in need thereof, it provides a therapeutic effect as an inhibitor of cyclooxygenase 2. during an interval of about 12 to about 24 hours, preferably at least 24 hours, after oral administration. Still more preferably, the present pharmaceutical composition comprises celecoxib in a desired amount and a binding agent and one or more carrier materials that are selected from the group consisting of pharmaceutically acceptable diluents, disintegrants, binders, humectants, lubricants and antiadhesives. More preferably, the composition comprises one or more carrier materials that are selected from the group consisting of lactose, sodium lauryl sulfate, polyvinyl pyrrolidone, croscarmellose sodium, magnesium stearate and microcrystalline cellulose. Still more preferably, the composition comprises lactose monohydrate and croscarmellose sodium. Even still more preferably, the composition further comprises one or more of the vehicle materials sodium lauryl sulfate, magnesium stearate and microcrystalline cellulose. It is particularly preferred that the various components of the composition are present in the amounts or fractions by weight that are described later in the present application. Tablets and Capsules The pharmaceutical compositions of the present invention are preferably tablets, capsules or the like and more preferably are in the form of tablets or capsules of immediate release. These pharmaceutical compositions comprise celecoxib in an appropriate dosage unit of celecoxib, sufficient to provide the required daily dose, i.e., that such tablets or capsules administered orally in accordance with a predetermined regimen, provide a total daily dose of from about 10 to about 1000 mg, preferably from about 50 to about 800 mg, more preferably from about 75 to about 400 mg and still more preferably from about 100 to about 200 mg of celecoxib. While the amount of celecoxib in such novel compositions is preferably within the ranges previously described, the formulations may also be useful for the administration of an amount of celecoxib that falls outside the desired dose ranges. Celecoxib Particle Size While pharmaceutical compositions are effective for a wide range of particle sizes for the celecoxib raw materials used in the compositions, it has been found that reducing the particle size can improve the bioavailability of celecoxib. Accordingly, the Dg0 of the particle size (90% of the particles in the largest dimension of the particles being smaller than the D90 of particle size) of the celecoxib, preferably is less than about 200 microns, preferably less than about 100 microns, even more preferably less than about 75 microns and still more preferably less than 40 microns. For example, as illustrated in Example 11, the reduction of the D90 particle size of the celecoxib starting material from about 60 to about 30 microns, can materially improve the bioavailability of the pharmaceutical composition. In addition or alternatively, celecoxib can have an average particle size in the range of about 1 to about 10 microns, preferably about 5 to about 7 microns. Flow Properties and Particle Size - in the Granulation While the pharmaceutical compositions of the present invention can be prepared, for example, by direct encapsulation or direct compression, they are preferably wet granulated prior to encapsulation or compression. The wet granulation, among other materials, densifies the compositions obtaining better flow properties, better compression characteristics and a facility to measure or weigh the final compositions. The particle size of the granulation is not critical, the important parameters being the average particle size of the granules, which preferably allow convenient handling and processing and, for tablets, allow the formulation of a directly compressible mixture that forms pharmaceutically tablets. acceptable The densities of compacted and apparent powder of the granulate are usually between about 0.3 and about 1.0 g / ml. Dissolution Profile The compositions of the present invention are preferably immediate release compositions that release at least about 50% celecoxib, in vitro, in a period of about 15 minutes after ingestion. Preferably, they release at least about 60% of celecoxib in vitro, in a period of about 30 minutes after ingestion. Still more preferably, they release at least about 75% of celecoxib in vitro in a period of 45 minutes after ingestion. Disintegration Profile Vehicle materials for immediate release compositions are preferably selected to provide a disintegration time of less than about 30 minutes, preferably about 25 minutes or less, "more preferably of about 20 minutes or less and still more preferably about 15 minutes or less Hardness For tablet formulations, the complete mixture in an amount sufficient to prepare a uniform batch of tablets, is subjected to tabletting in a conventional production scale tablet machine, at a normal compression pressure ( for example, from about 1 to about 50 KN.) Any convenient hardness for the tablet can be used for handling, manufacturing, storage and ingestion For 100 mg tablets, the preferred hardness is at least 4 kp, more preferably at least about 5 kp and still more preferably at least about 6 kp. For 200 mg tablets, the hardness is preferably at least 7 kp, more preferably at least about 9 kp and still more preferably at least 11 kp. However, the mixture is not compressed to such a degree that later difficulties arise in achieving hydration when exposed to gastric fluid.

Friability For tablet formulations, the friability of the tablet is preferably less than about 1.0%, preferably less than 0.8% and still more preferably less than about 0.5%. In another embodiment, the pharmaceutical composition comprises: from about 25 to about 85 weight percent celecoxib; from about 5 to about 70 weight percent lactose, - < from about 0.5 to about 7 weight percent of polyvinyl pyrrolidone; and from about 0.2 to about 5% by weight of croscarmellose sodium. In addition, this pharmaceutical composition may optionally comprise from about 0.4 to about 6 weight percent of sodium lauryl sulfate, from about 0.2 to about 8 weight percent of magnesium stearate; and / or from about 0.1 to about 15 weight percent microcrystalline cellulose. The composition is preferably in the form of a capsule dose unit. In another embodiment, the pharmaceutical composition comprises: from about 27 to about 47 weight percent celecoxib; from about 45 to about 65 weight percent lactose; from about 0.5 to about 5 weight percent of croscarmellose sodium; and from about 0.5 to about 5 weight percent polyvinyl pyrrolidone. In addition, this pharmaceutical composition may optionally comprise from about 0.25 to about 7 weight percent of sodium lauryl sulfate; and / or from about 0.25 to about 5 weight percent of magnesium stearate. Preferably, the composition is in the form of a capsule dose unit. In this embodiment, the pharmaceutical composition preferably comprises: from about 32 to about 42 weight percent celecoxib; from about 50 to about 60 weight percent lactose; from about 0.5 to about 3 weight percent of croscarmellose sodium; and from about 1 to about 5 weight percent of polyvinyl pyrrolidone. In addition, this pharmaceutical composition may optionally comprise from about 0.4 to about 6 weight percent of sodium lauryl sulfate; and / or from about 0.5 to about 3 weight percent of magnesium stearate. In this embodiment, the pharmaceutical composition preferably comprises: from about 35 to about 39 weight percent celecoxib; from about 54 to about 57 weight percent lactose; from about 0.5 to about 2 weight percent of croscarmellose sodium, and from about 1.5 to about 4.5 weight percent of polyvinylpyrrolidone. In addition, this pharmaceutical composition may optionally comprise from about 2 to about 4 weight percent of sodium lauryl sulfate, and / or from about 0.5 to about 2 weight percent of magnesium stearate. In another embodiment, the pharmaceutical composition comprises: from about 65 to about 85 weight percent celecoxib; from about 8 to about 28 weight percent lactose, from about 0.5 to about 5 weight percent of croscarmellose sodium; and from about 0.5 to about 5 weight percent polyvinyl pyrrolidone. In addition, this pharmaceutical composition may optionally comprise from about 0.25 to about 7 weight percent of sodium lauryl sulfate, - and / or from about 0.25 to about 5 weight percent of magnesium stearate. The composition is preferably in the form of a capsule dose unit. In this embodiment, the pharmaceutical composition preferably comprises: from about 69 to about 79 weight percent celecoxib; from about 13.5 to about 23.5 weight percent lactose, - from about 0.5 to about 3 weight percent of croscarmellose sodium, and from about 1 to about 5 weight percent of polyvinylpyrrolidone. In addition, this pharmaceutical composition may optionally comprise from about 0.4 to about 6 weight percent of sodium lauryl sulfate, * and / or from about 0.5 to about 3 weight percent of magnesium stearate. In this embodiment, the pharmaceutical composition more preferably comprises: from about 72 to about 76 weight percent celecoxib; from about 16.5 to about 20.5 weight percent lactose; from about 0.5 to about 2 weight percent of croscarmellose sodium; and from about 1.5 to about 4.5 weight percent of polyvinyl pyrrolidone. In addition, this pharmaceutical composition may optionally comprise from about 2 to about 4 weight percent of sodium lauryl sulfate, and / or from about 0.5 to about 2 weight percent of magnesium stearate. in another embodiment, the pharmaceutical composition comprises: from about 30 to about 50 weight percent celecoxib; from about 30 to about 50 weight percent of lactose, from about 0.5 to about 6 weight percent of croscarmellose sodium, and from about 0.5 to about 5 weight percent of polyvinylpyrrolidone. In addition, this pharmaceutical composition may optionally comprise from about 1 to about 20 weight percent microcrystalline cellulose; from about 0.25 to about 7 weight percent of sodium lauryl sulfate; and / or from about 0.25 to about 5 weight percent of magnesium stearate. The composition is preferably in the form of a tablet dose unit. In this embodiment, the pharmaceutical composition preferably comprises: from about 35 to about 45 weight percent celecoxib; from about 35 to about 45 weight percent lactose; from about 1 to about 5 weight percent of croscarmellose sodium, and from about 1 to about 5 weight percent of polyvinylpyrrolidone. In addition, this pharmaceutical composition may optionally comprise from about 5 to about 15 weight percent microcrystalline cellulose; from about 0.4 to about 6 weight percent of sodium lauryl sulfate, - and / or from about 0.5 to about 3 weight percent of magnesium stearate. In this embodiment, the pharmaceutical composition more preferably comprises: from about 38 to about 42 weight percent celecoxib; from about 38 to about 42 weight percent lactose, from about 1.5 to about 4.5 weight percent croscarmellose sodium, and from about 1.5 to about 4.5 weight percent polyvinylpyrrolidone. In addition, this pharmaceutical composition may optionally comprise from about 8 to about 12 weight percent microcrystalline cellulose, from about 2 to about 4 weight percent sodium lauryl sulfate, and from about 0.5 to about 2 weight percent. 100 weight percent of magnesium stearate. In another embodiment, the pharmaceutical composition comprises: from about 95 to about 105 mg of celecoxib; from about 145 to about 155 mg of lactose monohydrate; from about 0.5 to about 8 mg of croscarmellose sodium, and from about 2 to about 12 mg of polyvinylpyrrolidone. In addition, this pharmaceutical composition may optionally comprise from about 3 to about 13 mg of sodium lauryl sulfate, and / or from about 0.5 to about 8 mg of magnesium stearate. The composition is preferably in the form of a capsule dose unit. In this embodiment, the pharmaceutical composition preferably comprises: from about 98 to about 102 mg of celecoxib; from about 148 to about 152 mg of lactose monohydrate; from about 1.5 to about 4.5 mg of croscarmellose sodium; and from about 4.5 to about 8.5 mg of polyvinylpyrrolidone. In addition, this pharmaceutical composition may optionally comprise from about 6 to about 10 mg of sodium lauryl sulfate, and / or from about 1 to about 5 mg of magnesium stearate. In another embodiment, the pharmaceutical composition comprises: from about 195 to about 205 mg of celecoxib; from about 45 to about 55 mg of lactose monohydrate; from about 0.5 to about 8 mg of croscarmellose sodium; and from about 2 to about 12 mg of polyvinylpyrrolidone. In addition, this composition may optionally comprise from about 3 to about 13 mg of sodium lauryl sulfate, and / or from about 0.5 to about 8 mg of magnesium stearate. The composition is preferably in the form of a capsule dose unit. In this embodiment, the pharmaceutical composition preferably comprises: from about 198 to about 202 mg of celecoxib; from about 48 to about 52 mg of lactose monohydrate; from about 1.5 to about 4.5 mg of croscarmellose sodium, and from about 4.5 to about 8.5 mg of polyvinylpyrrolidone. In addition, this pharmaceutical composition can additionally comprise from about 6 to about 10 mg of sodium lauryl sulfate, and / or from about 1 to about 5 mg of magnesium stearate. In another embodiment, the pharmaceutical composition comprises: from about 95 to about 105 mg of celecoxib; from about 92 to about 112 mg of lactose monohydrate; from about 2 to about 13 mg of croscarmellose sodium, and from about 1 to about 11 mg of polyvinylpyrrolidone. In addition, this pharmaceutical composition may optionally comprise from about 20 to about 30 mg of microcrystalline cellulose; from about 3 to about 13 mg of sodium lauryl sulfate, and / or from about 0.5 to about 7 mg of magnesium stearate. The composition is preferably in the form of a tablet dose unit. In this embodiment, the pharmaceutical composition preferably comprises: from about 98 to about 102 mg of celecoxib; from about 100 to about 104 mg of lactose monohydrate, from about 5 to about 10 mg of croscarmellose sodium; and from about 4 to about 8.5 mg of polyvinylpyrrolidone. In addition, this pharmaceutical composition may optionally comprise from about 23 to about 27 mg of microcrystalline cellulose; from about 5 to about 10 mg of sodium lauryl sulfate, and / or from about 0.5 to about 4 mg of magnesium stearate. In another embodiment, the pharmaceutical composition comprises: from about 195 to about 205 mg of celecoxib; from about 199 to about 209 mg of lactose monohydrate; from about 10 to about 20 mg of croscarmellose sodium, and from about 7.5 to about 17.5 mg of polyvinylpyrrolidone. In addition, this pharmaceutical composition may optionally comprise from about 45 to about 55 mg of microcrystalline cellulose; from about 10 to about 20 mg of sodium lauryl sulfate; and / or from about 0.5 to about 9 mg of magnesium stearate. The composition is preferably in the form of a tablet dose unit. In this embodiment, the pharmaceutical composition preferably comprises: from about 98 to about 102 mg of celecoxib; from about 202 to about 206 mg of lactose monohydrate; from about 13 to about 17 mg of croscarmellose sodium, and from about 10.5 to about 14.5 mg of polyvinylpyrrolidone. In addition, this pharmaceutical composition may optionally comprise from about 48 to about 52 mg of microcrystalline cellulose; from about 13 to about 17 mg of sodium lauryl sulfate, and / or from about 2 to about 6 mg of magnesium stearate. In yet another embodiment, the pharmaceutical composition is able to release at least 50% of the celecoxib contained in the composition in vitro within a period of 15 minutes after ingestion of the composition. In yet another embodiment, the present invention comprises the pharmaceutical compositions described above in dosage unit forms. In still another embodiment, the present invention comprises the pharmaceutical compositions described above in dosage unit forms or pharmaceutical forms suitable for administration once or twice a day. In yet another embodiment, the present invention comprises the pharmaceutical compositions described above in dosage unit forms. In still another embodiment, the present invention comprises the pharmaceutical compositions described above in dosage unit forms or pharmaceutical forms suitable for administration once or twice a day. In yet another embodiment, the present invention comprises the pharmaceutical compositions described above, in immediate release dosage forms, preferably a tablet or a capsule. In still another embodiment, "the pharmaceutical composition comprises celecoxib, wherein the composition is an oral immediate-release dosage form, preferably a tablet or capsule, which releases in vitro at least 50%, preferably at least about 60% and more preferably at least about 75% of the celecoxib contained in the composition, within a period of about 45 minutes after ingestion by a subject.Preferably, the composition further comprises one or more pharmaceutically acceptable carrier materials, which are selected from the group consisting of lactose, polyvinyl pyrrolidone, croscarmellose sodium, sodium lauryl sulfate, magnesium stearate and microcrystalline cellulose It is particularly preferred that the various components of the composition are present in the above-stated amounts or weight fractions. the pharmaceutical composition comprises cel ecoxib and a pharmaceutically acceptable carrier material or materials, wherein the composition when administered orally to a human patient in need thereof, provides a therapeutic effect as an inhibitor of cyclooxygenase-2 over a range of 12 to 24 hours, preference at least approximately 24 hours, after oral administration. Still more preferably, this pharmaceutical composition comprises celecoxib and one or more carrier materials which are selected from the group consisting of lactose, polyvinylpyrrolidone, croscarmellose sodium, sodium lauryl sulfate, magnesium stearate and microcrystalline cellulose. It is particularly preferred that the various components of the composition are present in the amounts or weight fractions set forth above. In still another embodiment, the pharmaceutical composition comprises celecoxib and a pharmaceutically acceptable carrier material or materials in the form of an orally-directed tablet or capsule of immediate release., suitable for oral administration once or twice a day. Still more preferably, this pharmaceutical composition comprises celecoxib and one or more carrier materials which are selected from the group consisting of lactose, polyvinylpyrrolidone, croscarmellose sodium, sodium lauryl sulfate, magnesium stearate and microcrystalline cellulose. It is particularly preferred that the various components of the composition are present in the above-stated amounts or weight fractions. METHOD OF TREATMENT The present inven also relates to a therapeutic method for treating a condition or disorder wherein treatment with a cyclooxygenase-2 inhibitor is indicated, wherein the method comprises the oral administration of one or more of the compositions. of the present inven to a patient in need thereof. The dose regimen for preveg, alleviating or ameliorating the condition or disorder, preferably corresponds to the oral doses once or twice a day previously described, but can be modified in accordance with a variety of factors. These include the type, age, weight, sex, diet and medical condition of the patient and the severity of the disease. Thus, the dosage regimen employed can actually vary widely and, therefore, deviate from the preferred dosage regimen set forth above. Initial treatment of a patient suffering from a condition or disorder where treatment with a cyclooxygenase-2 inhibitor is indicated may begin with the doses indicated above. Treatment usually coues as needed for a period of several weeks to several months or years, u the condition or disorder has been controlled or eliminated. Patients subjected to treatment with the compositions described herein, can be routinely monitored by any of the methods known in the art, to determine the effectiveness of the therapy. The couous analysis of such data allows the modification of the treatment regimen during therapy, so that the optimum effective amounts of the compounds of the present inven are administered at any point of time and so that the duration of the treatment can be determined. In this way, the dosing regimen / program can be modified rationally during the course of therapy, so that the lowest amount of celecoxib is administered that exhibits a satisfactory effectiveness and so that the administration coues only as long as it is necessary for the treatment. successful of the condition or disorder. Formulation Preparation Method The present inven also relates to methods for the preparation of pharmaceutical compositions comprising celecoxib. In particular, the present inven relates to methods for the preparation of pharmaceutical compositions comprising, celecoxib in a dosage unit form, particularly in tablet or capsule dosage forms, such that each dosage unit form includes an amount of celecoxib sufficient to provide a therapeutic effect of approximately 12 to 24 hours. Each unit dosage form preferably contains, for example, from about 100 to about 200 mg of celecoxib. When tablets or capsules are desired, the methods of wet granulation, dry granulation or direct compression or encapsulation may be employed. Wet granulation is a preferred method for preparing the pharmaceutical compositions of the present inven. In the wet granulation process, celecoxib (and, if desired, any of the other carrier materials) is initially milled or micronized to the desired particle size. Although several convenal mills or grinders can be used, impact milling such as in a pin mill of celecoxib, provides a better blend uniformity to the final composition relative to other types of grinding. The cooling of celecoxib, for example using liquid nitrogen, may be necessary during grinding to avoid heating celecoxib to undesirable temperatures. As previously described, the reduction of particle size D90 to less than about 200 microns, preferably less than about 100 microns, more preferably less than about 75 microns and still more preferably less than about 40 microns, may increase materially the bioavailability of celecoxib. Thereafter, ground or micronized celecoxib is mixed, for example in a high shear mixing granulator, a planetary mixer, a twin hopper mixer or a Sigma mixer, with one or more of the carrier materials. Typically, the drug is mixed with the diluent or diluents, disintegrants or disintegrants, binder or binders and, optionally, with the wetting agent or agents at this stage, although it may be possible to add all or a portion of one or more of the materials of vehicle, at a later stage. For example, in tablet formulations where croscarmellose sodium is used as a diluent, it has been found that the addition of a portion of the croscarmellose sodium during this mixing step (intragranular croecarmellose sodium) and the addition of the remaining portion after the step drying which will be described below (extragranular croscarmellose sodium), can improve the disintegration of the tablets produced.

In this situation, approximately 60 to about 75% of the croscarmellose sodium is added intragranularly and from about 25 to about 40% of the croscarmellose sodium is added extragranularly. Similarly, for tablet formulations it has been found that the addition of the microcrystalline cellulose after the drying step, described below (extragranular microcrystalline cellulose), can improve the compressibility of the granulation and the hardness of the prepared tablets. from the granulate. This step of mixing the process, preferably comprises mixing celecoxib, lactose, polyvinylpyrrolidone and croscarmellose sodium. It has been found that a mixing time as short as 3 minutes can provide a dry powder mixture having a sufficiently uniform distribution of celecoxib. For example, dry powder mixtures used in the preparation of capsules of 100 mg dose (total lot size 1080 kg) and capsules of 200 mg dose (total lot size 918 kg), respectively, presented relative measurements of values standard deviation of 3.6% or less and 1.1% or less, respectively. Water is then added to the dry powder mixture and mixed for an additional period of time.

The wetting agent used is preferably first combined with the water and mixed for at least 15 minutes, preferably at least 20 minutes, before adding the water to the dry powder mixture. The water can be added to the mixture in a single portion, gradually over a period of time or in several portions over a period of time. Preferably, the water is added gradually over a period of time. Alternatively, instead of this, the wetting agent can be added to the celecoxib and the carrier materials and then purified water can be added to the resulting mixture. For the illustrative dose 100 mg tablets (1080 kg lot), for example, water addition rates between about 5 and about 25 kg / minute, preferably from about 7 to about 20 kg / minute and still more preferably from about 8 to about 18 kg / minute, provide adequate results. It is preferred to apply an additional period of mixing after concluding the addition of water, to ensure even distribution of the water in the mixture. For this batch, additional mixing times of from about 2 to about 10 minutes, preferably from about 3 to about 9 minutes and more preferably from about 3 to about 7 minutes, provide adequate results. The wet granulated mixture of this batch preferably comprises from about 2 to about 15% by weight of water, more preferably from about 4 to about 12% and still more preferably from about 6 to about 10% by weight. For capsules of 200 mg of illimitable doses (batch of 918 kg), for example, rates of addition of water between about 5 and about 25 kg / minute, preferably from about 7 to about 23 kg / minute and still more preferably from about 8 to about 21 kg / minute, gave adequate results. It is preferred to apply an additional period of mixing after concluding the addition of water, to ensure even distribution of the water in the mixture. For this batch, additional mixing times of from about 2 to about 15 minutes, preferably from about 3 to about 12 minutes and more preferably from about 3 to about 10 minutes, provided adequate results. The wet granulated mixture of this batch preferably comprises from about 2 to about 15% by weight of water, preferably from about 6 to about 14% and still more preferably from about 8 to about 13% Then, the wet granulated mixture is wet milled, for example with a screen mill, to eliminate agglomerations of material that are formed as a by-product of the wet granulation operation. If not removed, these agglomerations would prolong the subsequent fluidized bed drying operation and increase the variation with respect to moisture control. For capsules of 100 mg of illustrative dose (batch of 1080 kg) and capsules of 200 mg of dose (batch of 918 kg), for example, suitable granulations can be obtained using feed rates of up to 50%, preferably of about 2 to about 30% and still more preferably about 5 to about 20%; and sieve sizes of approximately 1 inch. The wet granulation / wet grinding is subsequently dried, for example, in an oven or in a fluidized bed dryer, preferably in a fluidized bed dryer. If desired, the wet granulated mixture can be extruded or spheronized before drying. For the drying process, conditions such as inlet air temperature and drying time are adjusted to achieve the desired moisture content for the dry mix. It may be desirable to combine two or more granulation sections for this drying step and for the subsequent processing steps. For the capsules of 100 mg of illustrative doses (batch of 1080 kg) described above, the inlet temperature of the dryer can be set at 60 ° C, although other inlet temperatures can be used, preferably in the range of about 50 to approximately 70 ° C. The air flow rate can be varied between about 1000 and about 8000 cubic feet per minute, preferably from about 2000 to about 7000 cubic feet. per minute and still more preferably from about 4000 to about 7000 cubic feet per minute, with a throttle opening of from about 10 to about 90%, preferably from about 20 to about 80% and still more preferably from about 30 to about 70% Denser loads of from about 35 to about 100%, preferably from about 50 to about 100% and even more preferably from about 90 to about 100% can be used. The average loss in drying under these conditions will generally be from about 0.1 to about 2.0%. For 250 mg capsules of illustrative doses (batch of 918 kg) described above, the inlet temperature of the dryer can be set at 60 ° C, although other inlet temperatures can be used, preferably in the range of about 50 to approximately 70 ° C. The air flow rate can be varied between about 1000 and about 8000 cubic feet per minute, preferably from about 3000 to about 7000 cubic feet per minute and still more preferably from about 4000 to about 7000 cubic feet per minute, with an opening of the draft regulator from about 10 to about 90%, preferably from about 20 to about 80% and still more preferably from about 30 to about 70%. Denser loads of from about 35 to about 100%, preferably from about 50 to about 100% and even more preferably from about 90 to about 100% can be used. The average loss in drying under these conditions will generally be between about 0.1 and about 2.0%. Then, to the extent necessary, dry granules are reduced in size in their preparation for compression or encapsulation. Conventional particle size reduction equipment, such as oscillators or impact mills (such as fitz mills) can be employed. For 100 mg capsules of illustrative doses (1080 kg batch), for example, suitable granulations can be obtained using feed rates of from about 20 to about 70%, preferably from about 30 to about 60%; mill speeds of from about 20 to about 70%, preferably from about 40 to about 60%; and sieve sizes from about 0.020 to about 0.070 inches, preferably from about 0.028 to about 0.040 inches. For 200 mg capsules of illustrative doses (918 kg batch), for example, suitable granules can be obtained using feed rates of from about 10 to about 70%, preferably from about 20 to about 60%; mill speed from about 20 to about 60%, preferably from about 30 to about 50%; and sieve sizes from about 0.020 to about 0.080 inches, preferably from about 0.028 to about 0.063 inches. However, it was observed that smaller sieve sizes such as 0.028 inches resulted in a lower total yield of the product. However, larger sieve sizes such as 0.063 inches resulted in an increase in the population of granules larger than 850 microns in size. Sieve sizes of approximately 0.040 inches, seem to eliminate an excessive population of granules larger than 850 microns in size, without significantly decreasing the total yield. The variation of the wet granulation and wet milling parameters described above can be used to adjust the granule size distributions. For example, a slight decrease in particle size has been observed as the mixing time increases, for mixtures containing lower amounts of water. It is hypothesized that when the concentration of water is too low to fully activate the binder used, the cohesive forces between the particles are insufficient to survive the shear forces generated by the mixing sheets and wear occurs the granules instead of a growth. Conversely, by increasing the amount of water to fully activate the binder, the cohesive forces between the particles are allowed to survive the shear forces generated by the blades of the mixer and a granule growth occurs instead of a deegaste. , as the mixing time and / or the rate of water addition increases. The variation of the sieve size of the wet mill tended to have a greater impact on the granule size, than the variation in the feed rate and / or the milling speed. Subsequently, the dried granules are placed in a suitable mixer, such as a twin box mixer and the lubricant (such as magnesium stearate) and any other carrier material is added (such as extragranular microcrystalline cellulose and extragranular croscarmellose sodium, in certain tablet formulations). The mixing times depend in part on the process equipment used. For the 100 mg dose capsules and the 200 mg dose capsules (batches of 1080 and 918 kg) described above, the mixing times of at least about 5 minutes at mixer loads ranging from about 15 to about 60 % and rotation speeds of at least about 10 revolutions per minute, consistently provided a mixed material that was extremely uniform with respect to celecoxib concentration. The relative standard deviations measured by dose unit mixture samples were 3.9% or less and 2.2% or less, for the 100 and 200 mg dose capsules, respectively. When the diluents included microcrystalline cellulose, the addition of a portion of the microcrystalline cellulose during this step has been found to materially increase the compressibility of the granule and the hardness of the tablet. In addition, the increase in the amount of magnesium stearate above from about 1% to about 2%, it was observed that the hardness of the tablets decreased and increased the friability and dissolution time. This mixture is then encapsulated (or if tablets are to be prepared, compressed into tablets of the desired weight and hardness, using the appropriate tools). Conventional compression and encapsulation techniques known to those skilled in the art can be employed. Suitable results were obtained for capsules using bed heights ranging from about 20 to about 60 mm, compaction values ranging from about 0 to about 5 mm and speeds from about 60,000 to about 130,000 capsules per hour. It was observed that the weight control of the dose decreased with: (i) a high speed and high compaction, or (ii) a high speed and a higher bed height. Accordingly, these combinations of preference parameters are carefully controlled. It was also discovered that cluster formation can be minimized or eliminated by using the lower compaction values at which the weight control of the capsule can be maintained. When coated tablets are desired, any of the conventional coating techniques known to those skilled in the art may be employed. This combination of unit operations produces granules that are uniform in celecoxib content at the unit dose level, which dissolve easily in vitro, which flow easily enough so that their weight variation is easily controlled during filling of the capsule or the tableting, and that they are sufficiently dense in bulk so that the batch can be processed in the selected equipment and the individual dosies specified in the capsulae or the punches of the tableting machine. Use in the Preparation of Medications The present invention also relates to the use of the compositions of the present invention, in the preparation of medicaments useful in the treatment and / or prophylaxis of conditions and disorders mediated by cyclooxygenase 2. The following Examples illustrate aspects of the present invention, but should not be considered as limitations The experimental procedures used to generate the data shown are described in more detail below The symbols and conventionalisms used in these Examples are consistent with those used in the pharmaceutical literature Contemporary Unless otherwise stated, (i) all percentages mentioned in this Example are percentages by weight, based on the total weight of the composition, (ii) the total weight of the capsule composition is the total weight of filling the capsule and does not include the weight of the actual capsule used and (iii) the tablets The coating materials are coated with a conventional coating material such as Opadry White YS-1-18027A and the weight fraction of the coating is about 3% of the total weight of the coated tablet.

Example 1: Capsule of 100 g of dose A capsule with the following composition was prepared: TABLE 1 The above dose unit composition was placed in a hard gelatin capsule (white opaque, size # 2) comprising titanium dioxide (USP), gelatin (NF) and blue ink (SB-6018). The lactose monohydrate used in each of the examples of the application is commercially available from Formost Farms, Baraboo, Wisconsin. The croscarmellose sodium trademark Ac-Di-Sol used in each of the examples of the application is commercially available from FMC Corporation, Chicago, Illinois. The sodium lauryl sulfate used in each of the examples of the application is commercially available from Henkel Corporation, Cincinnati, Ohio. The commercially-labeled Povidone polyvinylpyrrolidone which was used in each of the examples of the application is commercially available from International Specialty Products. The magnesium stearate used in each of the examples of the application is available commercially from Mallinckrodt Inc., St. Louis, Missouri. The Opadry White «YS-1-18027A used to prepare the coated tablets described in the examples of the present application, is a ready-to-use coating formulation available commercially from Colorcon, West Point, Pennsylvania. Dosage force capsules between 25 and 225 mg can be prepared by increasing or decreasing the amount of lactose, as needed, to obtain a total filling dose of 270 mg. Example 2: Capsule of 200 mg dose A capsule was prepared with the following composition: TABLE 2 INGREDIENT FRACTION IN WEIGHT QUANTITY (g) (%) The above dose unit composition was placed in a hard gelatin capsule (opaque white, # 2) comprising titanium dioxide (USP), gelatin (NF) and blue ink (SB-6018). Example 3: 100 mg dose tablet. Tablets were prepared with the following composition: TABLE 3 The tablets prepared were modified oval shaped tablets of 0.2100 x 0.4650 inches. The commercially available microcrystalline cellulose Avicel used in the preparation of the tablets of Examples 3 and 4 is commercially available from FMC Corporation, Philadelphia, Pennsylvania. Dosage strengths of the tablets may be prepared between 25 and 225 mg, by increasing or decreasing the amount of celecoxib and each of the vehicle materials described above, maintaining the same weight fractions as exemplified above. Example 4: Tablet of 200p mg of dose Tablets were prepared with the following composition: TABLE 4 The tablets prepared were modified capsule-shaped tablets of 0.2750 x 0.4960 inches. Example 5: Disintegration tests Six identical tablets were placed separately in one of six tubes having a bottom with a wire mesh, in a disintegration vessel. A water bath was preheated to 37 ° C ± 2 ° C and maintained at that temperature for the duration of the disintegration test. A 1000 ml container was placed in the water bath. The container was filled with a sufficient amount of water to ensure that the wire mesh of the tubes remained at least 2.5 cm below the surface of the water during the test. The disintegration vessel was inserted into the water at time = 0 minutes and was raised and lowered until the test was completed, while maintaining the wire mesh of the tubes at least 2.5 cm below the surface of the water. The disintegration time for each tablet was the time in which the last tablet portion passed through the wire mesh at the bottom of the tube. The average results for the uncoated tablets of Examples 3 and 4 are presented in Table 5. TABLE 5 Example 6: Dissolution tests The apparatus according to U.S.P. II (with paddles) to determine the dissolution rate of the capsules of examples 1 and 2 and of the uncoated tablets of examples 3 and 4. 1000 ml of a solution of sodium luryl sulfate at l% / 0.04M Na3P04 (pH = 12) was used as dissolution fluid. The solution was maintained at a temperature of 37 ° C ± 5 ° C and was stirred at 50 r.p.m. during the test. 12 identical tablets or capsules were tested. The 12 tablets or capsules were each placed separately in one of twelve standard solution containers, in time = 0 minutes. At times = 15, 30, 45 and 60 minutes, 5 ml aliquots were taken from each container. The samples of each container were filtered and their absorbance was measured (UV spectrophotometer; 2 mm quartz cell path, - 243 nm or maximum UV wavelength, - white: dissolution medium). The percent dissolution was calculated based on the absorbances measured. The average results of the dissolution tests are presented in Table 6. TABLE 6 Example 7: Analysis of particle size Table 7A shows the results of the sieved particle size analysis of the wet granulated pharmaceutical compositions of Examples 1 and 2, respectively, before encapsulation. The column titled "percent retained in the sieve" reports the percentage of the total batch that had a particle size greater than the indicated sieve size. TABLE 7A Table 7B shows the results of a sieve particle size analysis of the wet granulated pharmaceutical compositions of Examples 3 and 4, respectively, before being compressed into tablets. The column entitled "percent of the lot" reports the percentage of the total lot having a particle size between the indicated sieve size and the next smaller indicated sieve size. The column titled "cumulative percent of the lot" reports the percentage of the total lot that has a larger particle size than that indicated in the sieve size. TABLE 7B Example 8: Bulk density analysis Table 8 shows the results of a bulk density analysis of the wet granulated pharmaceutical compositions of examples 1, 2, 3 and 4, before their encapsulation or tablet compression: TABLE 8 Example 9: Tablet analysis program Table 9 shows the results of the tablet analysis program ("PAT analysis") for a sampling of tablets with the composition of the tablets of examples 3 and 4. TABLE 9 Example 10: Frisibility test A number of tablets that collectively weighed 12 g were placed in a spin drum. First the strange dust was removed from the drum and the tablets. The drum was activated and the rotation continued for 10 minutes at a minimum of 25 rotations per minute. The rotation of the drum was stopped and the tablets were removed. The loss of powder in the tablets, as well as any broken tablets were removed and the intact tablets were weighed. The percent loss of samples from Examples 3 and 4 was calculated and reported in Table 10. TABLE 10 Example 11: Bioavailability in a model in dogs Healthy female beagle dogs weighing between nine and thirteen pounds received the following single doses of celecoxib: (1) an intravenous fusion of 0.5 mg / kg body weight of celecoxib, followed for a second intravenous infusion of 5.0 mg / kg body weight of celecoxib; (2) 5 mg / kg body weight of celecoxib in the form of an oral solution; and (3) 5.0 mg / kg body weight of celecoxib alone in an oral capsule. The vehicle for intravenous doses and oral solutions was PEG-400: water (2: 1). Each intravenous infusion was administered in a period of 15 minutes, with separations of 15 to 30 minutes between the two infusions. Multiple blood samples were collected from each animal by venous puncture or catheterization, in heparinized tubes. The average results of the dogs tested are presented in Table 11-1. TABLE 11-1 Example 11-2: Effect of formulation variables on relative bioavailability, wetting performance and disintegration performance The effect of formulation parameters such as the particle size of the drug, increases in surfactant concentration, pH and dispersibility were evaluated in relationship with oral solutions and the drug not formulated in a capsule, in a model in dogs. The effect of micronizing celecoxib (average particle size of 10 to 20 microns) was tested in formulation A. The combined effect of micronization, adding a surfactant (sodium lauryl sulfate) and increasing the microenvironmental pH (Na3Po4-12H20) was tested in formulation B. The effect of bringing the surfactant (Tween 80) into intimate contact with celecoxib (coprecipitation versus simple dry mix) was tested in formulation C. The effect of further reducing the particle size (approximately 1 miera) and dispersing the particles in a suspension was tested in formulation D. A celecoxib solution (formulation E) was included as a reference. In addition, data from experiment 11-1 for celecoxib unground, not formulated in a capsule (formulation F) were also included as reference. The specific compositions of formulations A, B, C, D, E and F are summarized in Table 11-2A. TABLE 11-2A using 5% Tween 80 in aqueous solution as an antisolvent. (2) Prepared in the form of a suspension by grinding in a ball mill the drug in a slurry of polysorbate 80 and polyvinylpyrrolidone, until the particles had a diameter of about 1 miera, which was estimated by microscopy. (3) Solution in propylene glycol 400 / water (2: 1, v / v) The formulations were administered to groups of three male dogs and three females. Dogs of group 1 were given 5 mg per kg of body weight of celecoxib in solution formulation E and in capsule formulations A and B, in a non-randomized crossover design. Group 2 dogs were given 5 mg per kg of body weight of celecóxib in capsule formulation D and in suspension formulation D, in a capsule in a nonrandomized crossover design. Plasma samples were collected over a period of 24 hours and the analysis of celecoxib was carried out using a CLAR method. A dose of 5 mg per kg of body weight of celecoxib was administered to dogs in the capsule formulation F study. The results of the study (tables 11-2B, 11-2C1 and 11-2C2) indicated that the decrease in particle size (A) or increased wetting (C), increased the availability (measured by AUC0.24horas) of celecoxib, compared to previous studies of the drug not formulated in a capsule. The availability of celecoxib was higher for the PEG / H20 solution and the suspension (D). The availability of the suspension was approximately the same as for the solution and indicated that the availability of celecoxib can be improved by controlling the particle size of celecoxib (such as grinding celecoxib), increasing the humectation of celecoxib (such as including lauryl sulfate). of sodium in the granulation fluid) and improving dispersibility (such as including croscarmellose sodium in the granulation). The bioavailability data contained in tables 11-2C1 and 11-2C2 for each formulation represent the bioavailability of that formulation as a percentage of the bioavailability measured experimentally by intravenous administration of celecoxib. TABLE 11-2B Micronized Celecoxib TABLE 11-2C1 TABLE 11-2C2 Several formulations containing sodium lauryl sulfate (0-5%, w / w) and croscarmellose sodium (0-5%) were studied in relation to the relative wettability and the tendency of disintegration. The relative wettability was estimated by measuring the time required for the water to penetrate a column of granular material prepared from each formulation. The decay tendency was determined by measuring the weight of the granulated material retained in a # 20 (850 mm) sieve after immersing the material in water at 37 ° C for 5 minutes. The specific compositions of Formulation A to H evaluated, are summarized in Table 11-2D. TABLE 11-2D dry The results are summarized in Table 11-2E. Penetration tests were performed in triplicate.

The disintegration tests. They were done in duplicate. The results of the penetration study indicated that the wet application of sodium lauryl sulfate (formulation B) was superior to the dry application (formulation A) and that the formulations containing 3 to 5% by weight of sodium lauryl sulphate (formulations B) , G and H) were superior to those that had lower amounts of sodium lauryl sulfate (formulations C to F). The formulations containing 3% sodium lauryl sulfate (formulations B and G) were similar to those containing 5% (formulation H). The results from the disintegration study indicated that complete disintegration could be achieved with croscarmellose sodium concentrations as low as 1% (formulation G) at surfactant concentrations of 3%. Complete disintegration could also be achieved with larger amounts of disintegrant (formulations B, F and H), regardless of the concentration of surfactant. Formulation G exhibited both superior penetration and complete disintegration with the minimum amount of excipients required. TABLE 11-2E dry Example 12 The following formulations were evaluated with respect to the effects of wetting and uniformity of mixture: TABLE 12 In this formulation, polyvinylpyrrolidone was added to the mixture as a dry powder before granulation with water. In this formulation, celecoxib and lactose were granulated with an aqueous solution of polysorbate 80. • Mixtures with 5% celecoxib exhibited better mix homogeneity than mixtures with 60% celecoxib. The relative standard deviations measured for mixtures with 5% celecoxib ranged from 0.4 to 3.5%, while the relative standard deviations measured for mixtures with 60% celecoxib ranged from 4.7 to 6.3%. In addition to being less homogeneous, mixtures with 60% celecoxib contained relatively large granules (greater than 420 microns) that were superpotent (containing 124 to 132% higher concentrations of celecoxib, relative to the other granules). Four similar formulations containing 25% celecoxib were prepared instead of 5 or 60% celecoxib, as above. The bioavailability of these formulations was evaluated in a model in dogs. the wet granulated formulation with polyvinylpyrrolidone exhibited the highest bioavailability (approximately 74%). Example 13 Capsules were prepared and evaluated with the following formulations: TABLE 13A The celecoxib was ground by multiple phases through an oscillating mill equipped with successive sieves of smaller sizes (# 14, # 20, # 40). The particle size of at least 90% of the celecoxib particles added to this mixture was less than about 37 microns. Celecoxib, lactose and polyvinylpyrrolidone were mixed in a planetary mixer and wet granulated with water. Subsequently, the granulate was dried in a tray at 60 ° C, milled through a 40 mesh screen, lubricated with magnesium stearate in a trouser mixer and encapsulated in a dosing type cap. The in vitro dissolution profile of the capsules was determined using method 2 of the USP (United States Pharmacopoeia) and an average solution of a 15 mM phosphate buffer at pH 10. Approximately 50% dissolution was achieved in vitro after approximately 15 minutes, wherein more than 95% of the in vitro solution appeared after approximately 30 minutes. The absorption, distribution, metabolism and elimination profile of this capsule of 100 mg dose was compared with the profile of a suspension of [C14] celecoxib. The study was open label, randomized crossover, and carried out in 10 healthy male subjects. The suspension was prepared by dissolving celecoxib in ethanol containing 5% polysorbate 80 and adding apple juice to that mixture prior to administration. The subjects received the suepeneion with a dose of 300 mg of celecoxib. Subjects receiving celecoxib in the form of a capsule received 3 capsules of 100 mg of doeis for a total dose of 300 mg of celecoxib. The rate of absorption of the capsules was slower than for the suspension, but was equivalent to the suspension when measured by AUC0.48h. The average results are presented in Table 13B. The [c] Celecoxib was metabolized to a large extent, leaving only approximately 2.56% of the radioactive dose in urine or faeces. TABLE 13B Example 14 Capsules were prepared and evaluated with the following formulations: TABLE 14 These formulations were prepared in a manner similar to the formulations of Example 13, except that the impact type spike mill was used instead of an oscillating mill. The particle size was further reduced by the use of the impact mill. For the 100 mg dose capsules, approximately 30% dissolution was achieved in vitro after approximately 15 minutes, the in vitro solution being greater than 85% after approximately 30 minutes. For the 200 mg capsule, approximately 50% dissolution was reached in vitro after approximately 15 minutes, the in vitro solution being greater than 85% after about 30 minutes. Example 15: Preparation of capsules of 100 mg of dose The capsules of 100 and 200 mg doses of Examples 1 and 2, respectively, can be prepared in accordance with acceptable pharmaceutical manufacturing practices, in the manner illustrated in Figure 1 or Figure 2. 100 and 200 mg of doses of Examples 3 and 4, respectively, can be prepared by appropriately modifying this process for the extragranular addition of croscarmellose sodium and microcrystalline cellulose, and tabletting instead of encapsulating the composition. An illustrative process for the bulk formulation of 100 mg dose capsules using the raw materials described below is presented. A typical batch consists of four identical granulation sections, although the number of granulation sections is not critical and depends largely on the handling capacity of the equipment and the required batch size. Grinding: The celecoxib was ground in a mill of spikes or peaks of impact type with counter-rotating discs. At mill speeds ranging from approximately 8960 rpm / 5600 rpm to approximately 11200 rpm / 5600 rpm (rotational rpm / counterrotating rpm), the particle size varied within relatively narrow ranges (at least 90% of the particles). they were 30 microns or less in size), which suggests that the speed of the mill is not. critical for the process of micronization of the bulk drug. Fig. 2 is a flow chart showing a preferred embodiment, wherein the celecoxib raw material is ground by impact before being mixed with the carrier materials. Dry mix: Celecoxib, lactose, Povidone and croscarmellose sodium were transferred to a 1200 L high-speed pelletizer, Niro Fielder PMA-1200 and mixed for about 3 minutes at fast blade speed and pulse. This dry mixing time provided an adequate mixture of celecoxib with the carrier materials before starting the wet granulation step. Wet granulation: Sodium lauryl sulphate (8.1 kg) was dissolved in USP purified water (23.7 kg). This solution was progressively added to the granulator at a rate of approximately 14 kg / minute. The total granulation time was approximately 6.5 minutes. During this granulation, the main blade and the blade of the granulator were placed at fast speed. The wet granulated mixture had about 8.1% by weight of water. Alternatively, sodium lauryl sulfate can be mixed with celecoxib, lactose, povidone and croscarmellose sodium in the dry mixing step and USP purified water can be added to this dry mixture comprising sodium lauryl sulfate. Drying: The wet granulation was deagglutinated using a Quadro Cornil Model 198 S sieve mill equipped with a rotating propeller and a blunt sieve. The wet grinding was used to remove large lumps of materials that were formed as a by-product of the wet granulation operation. If they had not been removed, these lumps would have prolonged the subsequent fluidized bed drying operation and increased the variation with respect to humidity control. - The debonded granulate was transferred to an Aeromatic Fluid Bed Dryer T-8 fluidized bed dryer, the inlet air temperature and the flow velocity were adjusted to approximately 60EC and from approximately 5000 to 6000 ft3 / minute. drying in the fluidized bed dryer to reduce the moisture content to a value between 0.5 and 2.5% The moisture content was monitored using a Computrac Moisture Analyzer Moisture Analyzer Drying continued until the drying loss of the granulate was not It may be desirable to combine two or more granulate sections for this stage of processing and the subsequent stages of processing Dry grinding: Dry granules were passed through an impact mill Fluid Air Mili Model 007 (hammer) conventional) equipped with a 0.028 to 0.063 inch screen, advance knives and 2400 rpm speed. Dry milling was used in combination with the wet granulation step to control the final distribution of granule size. Mixture and lubrication: The ground granules were subsequently placed in a PK Cross-Flow Blender 75 cubic feet / WV mixer mix (or trouser mixer). Magnesium stearate was added and the mixture was mixed. The mixing time produced a mixed material that was uniform with respect to the concentration of celecoxib.The rotational speed of the mixer was 10.6 revolutions per minute.The final mixture was used to combine materials from multiple granulate sections in a single uniform mixture and, eventually, distribute the lubricant in the material before encapsulation to obtain the final dose units Encapsulation: The granulated and mixed powder was encapsulated using an MG2 G100 encapsulator or an MG2 G120 encapsulator. Lae capsules were subsequently polished.The previous sequence of unit operations produced granules that were uniformly in celecoxib content at the unit dose level, which dissolved in vitro, flowed easily enough so that the weight variation could be controlled reliably during the filling of the capsules and that they were sufficiently dense in bulk, so that the batch could be processed in the selected equipment and the individual doses were adjusted to the specified capsules. Example 16: Bioeguivalence study The bioequivalence and dose safety of 200 mg of celecoxib were evaluated in a randomized open-label, single-dose, three-day crossover study in a group of 46 healthy adult humans. Subjects received three single doses of 200 mg of celecoxib administered in the form of a capsule of 200 mg dose (A), two capsules of 100 mg dose (B), two capsules of 100 mg dose (from different lots) (C) The treatments were separated for 7 days. The specific pharmaceutical compositions of the capsules of 100 mg of doses and of the capsules of 200 mg of doses are described in examples 1 and 2, respectively. The subjects, who were fasted for one night, received simple oral doses of the study drug together with approximately 180 ml of water at 0800 hours. The subjects continued fasting and remained in a standing position for four hours after the dose was administered. Blood samples were taken at -0.25 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours after the dose. The analyzes of the separated plasma were performed in PPD • Pharmaco, Richmond, VA. The plasma concentrations of celecoxib were determined using validated high performance liquid chromatography ("CLAR"), with a lower limit of detection of 10.0 ng / ml. Each subject was tested separately after receiving a 200 mg capsule dose and after receiving two doses in 100 mg capsules. A minimum of seven days of rest was allowed between the administration of each 200 mg dose. The average results obtained in the 46 tested subjects are presented in tables 16A and 16B presented below. TABLE 16A TABLE 16B Example 17: Effect of the Food Study A four-day, open-label, randomized, single-dose, cross-over study was used to assess dose proportionality and the effect of foods on the pharmacokinetic profile of celecoxib in healthy adult subjects. Safety was assessed based on adverse events, vital signs and clinical laboratory tests. Twenty-four healthy adult subjects were randomly distributed to receive the following single doses of celecoxib: (A) one 50-rag dose capsule under fasting conditions, (B) one 50-mg dose capsule immediately after a high-calorie breakfast. fats, (C) a capsule of 100 mg of dose under fasting conditions and (D) a capsule of 100 mg of dose immediately after a breakfast with high fat content. The subjects received the study medication on days 1, 8, 15 and 22 in one of four treatment sequences (ADBC, BACD, CBDA, and DCAB). The specific composition of the capsule of 100 mg of dose is described in Example 1. The specific composition of the 50 mg capsule of dosie is described in Table 17A, which is shown below: TABLE 17A The previous dosie unit composition was placed in a hard gelatin capsule (opaque white, size # 2) Blood samples were collected at -0.25 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours after the dose. Plasma analyzes separately were performed at PPD Pharmaco, Richmond, VA. Plasma concentrations of celecoxib were determined using a validated high performance liquid chromatography ("CLAR") procedure with a lower limit of detection of 10.0 ng / ml. There were no clinically significant changes in eignoe vitalee or in physical examinations. All adverse events were mild. The average results obtained in the 24 tested subjects are reported in tables 17B and 17C presented below. TABLE 17B TABLE 17 C Example 18: Suspension versus capsule The pharmacokinetics and bioavailability of a thin oral suspension and two oral capsules containing celecoxib were evaluated in a single-dose randomized, open-label, crossover study. Thirty-six adult subjects were randomly distributed to receive the following doses of celecoxib: (A) one 200 mg dose capsule, (B) two 100 mg dose capsules, and (C) one 200 mg oral fine suspension of dosia. . The duration of the complete treatment was 18 days. On days 1, 8 and 15 the subjects received one of the three treatments according to the randomized program. The treatments were spaced for seven days. The capsule-specific pharmaceutical composition of 200 mg dose is described in example 2. The specific pharmaceutical composition of the capsules of 100 mg dose is described in Table 18A which is presented below. TABLE 18A The pharmaceutical composition used in the capsules of 100 mg of dose, was prepared by passing the raw material celecoxib through a 40-mesh oscillating screen (no grinding was performed), celecoxib, lactose and povidone were granulated wet in a mixer planetary cutting, dried on tray and ground the granulated mixture, adding magnesium stearate to the granulated mixture and mixing it to form the final pharmaceutical composition. The fine oral suspension was prepared by dissolving celecoxib in ethanol containing 5V of polysorbate 80 and adding it to this mixture apple juice before its administration. Blood samples were taken at -0.25 (predose) and for 72 hours after the doeie. Each subject was tested separately after receiving the 200 mg dose capsule, the 100 mg dose capsules and the fine oral suspension. A seven-day rest period was allowed between the administration of each 200 mg dose. The average results obtained in the 36 tested subjects are reported in table 18B, which is presented below. TABLE 18B In general, the absorption rate of celecoxib was higher for the fine oral suepeneion (C. ^ major and T, ^ minor) in comparison with the capsules. The overall degree of absorption for the fine oral suspension, however, was similar to the overall degree of absorption of celecoxib in capsule. Since various changes can be made to the above formulations and methods without departing from the scope of the present invention, it is intended that all material contained in the foregoing description be construed as illustrative and not in a limiting sense. All of the references mentioned are incorporated herein by reference. When elements of the present invention or preferred embodiments thereof are introduced, it is intended that the articles "one or one", "the" and "said or said" mean that one or more of the elements exists. The terms "comprises", "including" and "having" are intended to be inclusive and to mean that there may be additional elements other than the elements listed.

Claims (9)

1. CLAIMS 1. A pharmaceutical composition comprising one or more orally administrable dose units, each comprising particulate celecoxib in an amount of about 10 to about 1000 mg in intimate admixture with one or more pharmaceutically acceptable excipients, wherein one unit Single dose, after oral administration to a fasted subject, provides a serum celecoxib concentration time characterized by at least one of the following (a) a time to reach 100 ng / ml no greater than about 0.5 hours after the administration; (b) a time to reach the maximum concentration (T. ^^.) no greater than about 3 hours after administration; (c) a length of time wherein the concentration remains above 100 ng / ml not less than about 12 hours; (d) a terminal half-life (TM) of not less than about 10 hours; and (e) a maximum concentration (C- ^) not less than about 200 ng / ml.
2. 2. The. The composition of claim 1, wherein the time of celecoxib serum concentration is characterized by not more than about 3 hours, preferably not more than about 2 hours and more preferably not more than 1.7 hours, after administration. The composition of claim 1, wherein the Cmax is not less than about 200 ng / ml, preferably not less than about 400 ng / ml. 4. A pharmaceutical composition comprising one or more orally administrable dose units, each comprising particulate celecoxib in an amount of about 10 to about 1000 mg in intimate admixture with one or more pharmaceutically acceptable excipients and having a relative bioavailability not less than about 50%, preferably not less than about 70%, compared to an orally administered solution containing an equivalent amount of celecoxib. 5. A pharmaceutical composition comprising one or more orally administrable dose units, each comprising particulate celecoxib in an amount of about 10 to about 1000 mg in intimate admixture with one or more pharmaceutically acceptable excipients and having a size distribution of celecoxib particle such that at least 90% of the particles is less than 200 μm, preferably less than 100 μm, more preferably less than 40 μm and most preferably, less than 25 μm, in the largest dimension of particles. 6. A pharmaceutical composition comprising one or more orally administrable dose units, each comprising particulate celecoxib in an amount of about IC to about 1000 mg in intimate admixture with one or more pharmaceutically acceptable excipients and having a particle size Average celecoxib from about 1 to about 10 μm. The composition of any of claims 1 to 6, wherein the amount of celecoxib in each dosage unit is from about 50 to about 800 mg, preferably from about 75 to about 400 mg and more preferably from about 100 to about 200 mg. The composition of any of claims 1 to 7, which is suitable, by oral administration to a subject of a unit dose once or twice a day, to provide a prophylactically or effective therapeutic inhibition of cyclooxygenase-2.
3. 9. The composition of any one of claims 1 to 7 which is suitable, by oral administration to a subject of a dosie unit once or twice a day, for the treatment or prophylaxis of a condition or disorder mediated by cyclooxygenase-2. . The composition of any of claims 1 to 9, wherein the dosage units are in the form of discrete solid articles. The composition of claim 10, wherein said articles are tablets, pills, capsules of hard or soft gelatin, dragees, pillules or pastillae. 12. The composition of claim 10 in the form of capsules or tablets of dosage unit. The composition of claim 12, wherein the excipients are selected from the group consisting of pharmaceutically acceptable diluents, disintegrants, binders, humectants and lubricants. The composition of claim 12, wherein said excipients include one or more pharmaceutically acceptable diluents in a total amount of about 5 to about 99% by weight, preferably about 10 to about 85% by weight of the composition. The composition of claim 14, wherein said diluents are selected from the group consisting of lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose, calcium dibasic phosphate, sucrose-based diluents, confectionery sugar, monobasic sulphate Calcium monohydrate, calcium sulfate dihydrate, calcium lactate trihydrate, dextrates, Celutab, inositol, hydrolysed cereal solids, amylose, Rexcel, powdered cellulose, calcium carbonate, glycine and bentonite. 16. The composition of claim 14, wherein said diluents are selected from the group consisting of lactose and microcrystalline cellulose. The composition of claim 14, wherein said diluents comprise lactose. 18. The composition of claim 12, wherein said excipients include one or more pharmaceutically acceptable disintegrants in a total amount of from about 0.2 to about 30% by weight, preferably from about 0.2 to about 10% by weight of the composition. The composition of claim 18, wherein said disintegrants are selected from the group consisting of starches, sodium starch glycolate, clays, celluloses, alginates, pregelatinized maize starch, crospovidone and gums. The composition of claim 18, wherein said disintegrants comprise croscarmellose sodium. The composition of claim 12, wherein said excipients include one or more pharmaceutically acceptable binding agents, in a total amount of from about 0.5 to about 25% by weight, preferably from about 0.75 to about 15% by weight of the composition . 22. The composition of claim 21, wherein said binding agents are selected from the group consisting of acacia gum, tragacanth, sucrose, gelatin, glucose, starch, celluloses, methylcellulose, sodium carboxymethylcellulose, alginic acid and salts thereof, silicate magnesium and aluminum, polyethylene glycols, guara gum, polysaccharide acids, bentonites, polyvinylpyrrolidone, polymethacrylates, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose and pregelatinized starch. 23. The composition of claim 21, wherein said binding agents comprise polyvinylpyrrolidone. The composition of claim 12, wherein said excipients include one or more pharmaceutically acceptable wetting agents, in a total amount of from about 0.25 to about 15% by weight, preferably from about 0.4 to about 10% by weight of the composition . The composition of claim 24, wherein said wetting agents comprise an anionic surfactant, preferably sodium lauryl sulfate. The composition of claim 12, wherein said excipients include one or more pharmaceutically acceptable lubricants, in a total amount of from about 0.1 to about 10% by weight, preferably from about 0.2 to about 8% by weight of the composition . The composition of claim 26, wherein said lubricants are selected from the group consisting of glyceryl behapate, stearates, stearic acid, hydrogenated vegetable oils, talc, waxes, Stearowet, boric acid, sodium benzoate, sodium acetate, sodium chloride, DL-leucine, polyethylene glycols, sodium oleate, sodium lauryl sulfate and magnesium lauryl sulfate. The composition of claim 26, wherein said lubricants comprise magnesium stearate. The composition of claim 12, comprising (a) one or more pharmaceutically acceptable diluents in a total amount of about 10 to about 85% by weight of the composition; (b) one or more pharmaceutically acceptable disintegrants in a total amount of about 0.2 to about 10% by weight of the composition; and (c) one or more pharmaceutically acceptable binding agents in an amount of about 0.5 to about 10% by weight of the composition. The composition of claim 29, further comprising (d) one or more pharmaceutically acceptable wetting agents in a total amount of about 0.4 to about 10% by weight of the composition. The composition of claim 29 or claim 30, further comprising (e) one or more pharmaceutically acceptable lubricants in a total amount of about 0.2 to about 8% by weight of the composition. 32. The composition of any of claims 29 to 31, wherein said diluents comprise lactose. 33. The composition of any of claims 29 to 32, wherein said disintegrants comprise croscarmellose sodium. 34. The composition of any of claims 29 to 33, wherein said binding agents comprise polyvinylpyrrolidone. 35. The composition of any of claims 30 to 34, wherein said wetting agents comprise sodium lauryl sulfate. 36. The composition of any of claims 31 to 35, wherein said lubricants comprise magnesium stearate. 37. The composition of any of claims 12 to 36, wherein the celecoxib is present in an amount of about 1 to about 95% by weight, preferably about 25 to about 85% by weight of the composition. 38. The composition of claim 12, comprising (a) from about 1 to about 95 weight percent celecoxib; (b) from about 5 to about 99 weight percent lactose; (c) from about 2 to about 10 weight percent of croscarmellose sodium; (d) from about 0.5 to about 10 weight percent polyvinyl pyrrolidone; (e) from 0 to about 7 weight percent of sodium lauryl sulfate; and (f) from 0 to about 5 weight percent of magnesium stearate. 39. The composition of claim 12, comprising (a) from about 25 to about 85 weight percent-celecoxib; (b) from about 5 to about 70 weight percent lactose; (c) from about 0.2 to about 6 weight percent of croscarmellose sodium, - (d) from about 0.5 to about 10 weight percent of polyvinylpyrrolidone; (e) from 0.4 to about 6 weight percent of sodium lauryl sulfate; and (f) from 0.2 to about 8 weight percent of magnesium stearate. 40. The composition of claim 12, comprising (a) from about 27 to about 47 weight percent celecoxib; (b) from about 45 to about 65 weight percent lactose; (c) from about 0.5 to about 5 weight percent croscarmeloea sodium, and (d) from about 0.5 to about 5 weight percent polyvinyl pyrrolidone. 41. The composition of claim 12, comprising (a) from about 32 to about 42 weight percent celecoxib, - (b) from about 50 to about 60 weight percent lactose, - (c) from about 0.5 to about 3 weight percent of croscarmellose sodium; (d) from about 1 to about 5 weight percent of polyvinyl pyrrolidone; and (e) from 0.4 to about 6 weight percent of sodium lauryl sulfate. 42. The composition of claim 12, comprising (a) from about 35 to about 39 weight percent celecoxib; (b) from about 54 to about 57 weight percent lactose, - (c) from about 0.5 to about 2 weight percent croscarmellose sodium, - (d) from about 1.5 'to about 4.5 weight percent of polyvinyl pyrrolidone; (e) from about 2 to about 4 weight percent of sodium lauryl sulfate; and (f) from about 0.5 to about 2 weight percent of magnesium stearate. 43. The composition of claim 12, comprising (a) from about 65 to about 85 weight percent celecoxib; (b) from about 8 to about 28 weight percent lactose; (c) from about 0.5 to about 5 weight percent of croscarmellose sodium, - and (d) from about 0.5 to about 5 weight percent of polyvinylpyrrolidone. 44. The composition of claim 12, comprising (a) from about 69 to about 79 weight percent celecoxib; (b) from about 13.5 to about 23.5 weight percent lactose, - (c) from about 0.5 to about 3 weight percent of croscarmellose sodium; (d) from about 1 to about 5 percent by weight of polyvinylpyrrolidone; and (e) from 0.4 to about 6 weight percent of sodium lauryl sulfate. 45. The composition of claim 12, comprising (a) from about 72 to about 76 weight percent celecoxib; (b) from about 16.5 to about 20.5 weight percent lactose, - (c) from about 0.5 to about 2 < percent by weight of croscarmellose sodium; (d) from about 1.5 to about 4.5 weight percent polyvinylpyrrolidone; (e) from about 2 to about 4 weight percent of sodium lauryl sulfate; and (f) from about 0.5 to about 2 weight percent of magnesium stearate. 46. The composition of claim 12, comprising (a) from about 30 to about 50 weight percent celecoxib; (b) from about 30 to about 50 weight percent lactose, - (c) from about 0.5 to about 10 weight percent croscarmellose sodium, - and (d) from about 0.5 to about 5 weight percent of polyvinyl pyrrolidone. 47. The composition of claim 12, comprising (a) from about 35 to about 45 weight percent celecoxib; (b) from about 35 to about 45 weight percent lactose, - (c) from about 1 to about 5 weight percent of croscarmellose sodium; (d) from about 1 to about 5 weight percent of polyvinyl pyrrolidone; and (e) from about 5 to about 15 weight percent microcrystalline cellulose. 48. The composition of claim 12, comprising (a) from about 38 to about 42 weight percent celecoxib; (b) from about 38 to about 42 weight percent lactose, - (c) from about 1.5 to about 4.5 weight percent croscarmellose sodium, - (d) from about 1.5 to about
4. 4. 5 weight percent of polyvinyl pyrrolidone; (e) from about 8 to about 12 weight percent microcrystalline cellulose; (f) from about 2 to about 4 weight percent of sodium lauryl sulfate; and (g) from about 0.5 to about 2 weight percent of magnesium stearate. 49. The composition of claim 12, comprising, in each dose unit, (a) from about 80 to about 220 mg of celecoxib; (b) from about 30 to about 225 mg of lactose; (c) from about 0.5 to about 25 mg of croscarmellose sodium, - (d) from about 0.5 to about 25 mg of polyvinylpyrrolidone; (e) from 0 to about 70 mg of microcrystalline cellulose; (f) from 0 to about 25 mg of sodium lauryl sulfate, - and (g) from 0 to about 10 mg of magnesium stearate. 50. The composition of claim 12, comprising dosage unit capsules each containing (a) about 100 mg of celecoxib; (b) about 149.75 mg of lactose monohydrate, - (c) about 2.7 mg of croscarmellose sodium; • (d) about 6.75 mg of polyvinylpyrrolidone, - (e) about 8.1 mg of sodium lauryl sulfate, - and (f) about 2.7 mg of magnesium stearate. 51. The composition of claim 12, comprising dosage unit capsules each containing (a) about 200 mg of celecoxib; (b) about 49.75 mg of lactose monohydrate, - (c) about 2.7 mg of croscarmeloea sodium; (d) about 6.75 mg of polyvinylpyrrolidone; (e) about 8.1 mg of sodium lauryl sulfate, - and (f) about 2.7 mg of magnesium stearate. 52. The composition of claim 12, comprising dosage unit tablets each containing (a) about 100 mg of celecoxib; (b) about 101.88 mg of monohydrated lactose, - (c) about 7.5 mg of croscarmellose sodium; (d) about 6.25 mg of polyvinylpyrrolidone, - (e) about 25 mg of microcrystalline cellulose; (f) about 7.5 mg of sodium lauryl sulfate, - and (g) about 1.88 mg of magnesium stearate. 53. The composition of claim 12, comprising tablets with a dosage unit containing (a) about 200 mg of celecoxib; (b) about 203.8 mg of lactoea monohydrate, - (c) about 15 mg of croscarmellose sodium, - (d) about 12.5 mg of polyvinylpyrrolidone; (e) about 50 • mg of microcrystalline cellulose; (f) about 15 mg of sodium lauryl sulfate; and (g) about 3.75 mg of magnesium stearate. 54. The composition of claim 12, comprising capsule or doeie tablet, each containing a dose of 100 or 200 mg of celecoxib. 55. The composition of claim 12, wherein the celecoxib, together with one or more excipients, is directly encapsulated or directly compressed into tablets. 56. The composition of claim 12, wherein celecoxib, together with one or more excipients, is wet granulated prior to encapsulation or tablet compression. 57. The composition of claim 12, wherein celecoxib, together with one or more excipients, is dry granulated prior to encapsulation or tablet compression. 58. The composition of any of claims 1 to 9, which is a substantially homogeneous mass with flowability, from which single dose units can be measurably removed. 59. The composition of claim 58, wherein the flowable mass is a particulate or granular solid. 60. The composition of claim 58, wherein said flowable mass is a suspension having celecoxib in a particulate solid phase dispersed in an aqueous solution. 61. The composition of claim 60, wherein said excipients include a pharmaceutically acceptable wetting agent. 62. The composition of claim 61, wherein said wetting agent is polysorbate 80. 63. The composition of claim 61 or 62, further comprising a solvent from which celecoxib is precipitated to prepare the suspension. 64. The composition of claim 63, wherein said solvent is an alcohol, preferably ethanol. 65. The composition of claim 60, wherein the aqueous phase comprises a degustable carrier selected from the group consisting of water, syrup and fruit juice. 66. The composition of claim 63, wherein the vehicle is. fruit juice, preferably apple juice. 67. The composition of any of claims 1 to 66, which provides, after oral ingestion, a therapeutic effect as an inhibitor of cyclooxygenase-2 during a range of about 12 to about 24 h after ingestion. 68. The composition of claim 67, wherein the therapeutic effect is provided over a range of about 24 h after ingestion. 69. The composition of any of claims 1 to 66, wherein, after oral ingestion, at least about 50% of celecoxib is released, as determined in vitro, within a period of about 15 minutes after the ingestion. 70. The composition of any of claims 1 to 69, further comprising one or more opioid or analgesic drugs. 71. The composition of claim 70, wherein said opioid or analgesic drugs are selected from the group consisting of narcotic analgesics, Mu receptor antagonists, Kappa receptor antagonists, non-narcotic analgesics, inhibitors of monamine incorporation, regulatory agents of adenosine, cannabinoid derivatives, substance P antagonists, neurokinin-1 receptor antagonists, and sodium channel blockers. 72. The composition of claim 70, wherein the opioid or analgesic drugs are selected from the group consisting of morphine, meperidine, codeine, pentacozine, buprenorphine, butorphanol, dexocin, meptazinol, hydrocodone, oxycodone, methadone, tramadol, including racemates and simple enantiomers thereof, DuP 747, dynorphin A, enadoline, RP-60180, HN-11608, E-2078, ICI-204448, acetaminophen, propoxyphene, nalbufen, E-4018, filendol, mirfenantil, amitriptyline, DuP 631, GP-531, acadesin, AKI-1, AKI-2, GP-1683, GP-3269, 4030W92, AXC-3742, SNX-111, ADL2-1294, CT-3 and CP-99994. 73. A method for the treatment of a medical condition or disorder in a subject, wherein treatment with a cyclooxygenase-2 inhibitor is indicated, which comprises administering orally to the subject a composition of any of the claims 1 to 72, once or twice a day. 74. The method of claim 73, wherein the condition or disorder is • rheumatoid arthritis. 75. The method of claim 73, wherein the condition or disorder is osteoarthritis. 76. The method of claim 73, wherein the condition or disorder, or a symptom of the condition or disorder, is pain. 77. A method of using a composition of any of claims 1 to 9 in the manufacture of a medicament, for the treatment or prophylaxis of a condition or disorder mediated by cyclooxygenase-2. 78. The method of claim 77, wherein the condition or disorder is rheumatoid arthritis. 79. The method of claim 77, wherein the condition or disorder is osteoarthritis. 80. The method of claim 77, wherein the condition or disorder, or a symptom of the condition or disorder, is pain. 81. A method for preparing a composition of claim 12, comprising, (a) celecoxib wet granulating together with one or more excipients, to form a wet granulated mixture.; (b) drying the wet granulated mixture, - and (c) encapsulating the dry granulated mixture or compressing the dry granular mixture into tablets. 82. The method of claim 81 wherein, prior to the wet granulation step, celecoxib is milled in such a way that at least 90% of the resulting particles are less than 250 μm, preferably less than 100 μm. μm, more preferably less than 40 μm, and most preferably less than 25 μm, in the largest dimension of said particles. 83. The method of claim 82 wherein the milling is performed with a pin mill to obtain celecoxib particles, from the. which at least 90% is less than 25 μm in the largest dimension of said particles. 84. The method of claim 83, wherein said milling produces celecoxib with an average particle size of from about 1 to about 10 μm, preferably from about 5 to about 7 μm.