Celecoxib compositions and the use thereof

Description of the invention

The present invention relates to pharmaceutical compositions for oral administration containing celecoxib as an active ingredient and the use of such compositions in the manufacture of a medicament for the treatment and / or prevention of a disease and / or disorder mediated by a cyclooxygenase-2 inhibitor.

The compound 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide (also referred to herein as celecoxib) was previously described by Tally, et al. In US Patent No. 5,466 823, which discloses and claims a class of 1,5-diarylpyrazoles and their salts together with methods for the preparation of such compounds. Celecoxib has the following structure:

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1,5-diarylpyrazole compounds disclosed in US Pat. No. 5,466,823 are disclosed therein as being useful in the treatment of inflammation and inflammatory disorders. US Patent No. 5,466,823 contains general references to formulations for the administration of these 1,5-diarylpyrazoles, including orally administered dosage forms such as tablets and capsules. Talley. et al., U.S. Patent No. 5,760,068 teaches a class of 1,5-diarylpyrazole compounds. also celecoxib, which are disclosed as selective inhibitors of cyclooxygenase-2 and can be administered to treat, among other conditions and disorders, 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) -1H-pyrazol-1) -yl] benzenesulfonamide (SC-58635, Celecoxib) ”, J. Med. Chem., 40 (1997): 1347-1365, discloses the preparation of a series of 1,5-diarylpyrazole derivatives containing sulfonamide, also celecoxib, and evaluation of these derivatives as cyclooxygenase-2 inhibitors.

Simon, et al., In "Preliminary Study of the Safety and Efficacy of SC-58635, a Novel Cyclooxygenase 2 Inhibitor", Arthritis &amp; Rheumatism, vol. 41, No. 9, September 1998, pp. 1591-1602, discloses research into the efficacy and safety of celecoxib in the treatment of osteoarthritis and rheumatoid arthritis.

Lipsky, et al., In "Outcome of Specific COX-2-Inhibition in Rheumatoid Arthritis", J. Rheumatology, Vol. 24, Suppl. 49, pp. 9-14 (1997) disclose that in rheumatoid arthritis patients, specific inhibition of cyclooxygenase-2 by celecoxib is sufficient to reduce the signs and symptoms of inflammatory disease activity.

European Patent Application No. 0 863 134 A1, published September 8, 1998, discloses compositions containing a cyclooxygenase-2 inhibitor, namely 2- (3,5-difluorophenyl) -3- (4-methylsulfonyl) phenyl) -2-cyclopenten-1-one in combination with excipient ingredients such as microcrystalline cellulose, lactose monohydrate, hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, and magnesium stearate.

The formulation of celecoxib for effective oral administration to a subject has been hampered by the specific physical and chemical properties of the compound, especially its poor solubility and factors related to its crystal structure, including cohesiveness, low bulk density, and low compressibility. Celecoxib is extremely insoluble in the aquatic environment. Untreated celecoxib is difficult to dissolve and disperse for rapid absorption in the gastrointestinal tract after oral administration, for example in the form of a capsule. In addition, untreated celecoxib, which has a crystalline morphology with a tendency to form long cohesive needles, typically melts into a monolithic mass during compression in a tablet press die. Even when combined with other substances, celecoxib crystals tend to separate from other substances and agglomerate with each other when the composition is mixed, leading to a heterogeneously blended composition containing undesirably large aggregates of celecoxib. Thus, it is difficult to prepare a pharmaceutical composition containing celecoxib which has the desired homogeneity. Further, handling problems arise when formulating pharmaceutical compositions containing celecoxib. For example, the low bulk density of celecoxib makes it difficult to process the small amounts needed in formulating pharmaceutical compositions. Thus, there is a need to solve a number of problems associated with formulating suitable compositions and dosage forms containing celecoxib, especially dosage units for oral administration.

In particular, there is a need for orally administered celecoxib formulations having one or more of the following characteristics as compared to untreated celecoxib or other celecoxib compositions:

(1) increased solubility;

(2) shorter disintegration time;

(3) reduced tablet friability;

(4) increased tablet hardness;

(5) improved wettability;

(6) improved pressure;

(7) improved plasticity of liquid and solid granular compositions;

(8) improved physical stability of the finished composition;

(9) reduced tablet or capsule size;

(10) improved blend uniformity;

(11) improved dose uniformity;

(12) improved control of weight variation during encapsulation and / or tabletting;

(13) increased granule density for post wet granulation composition;

(14) reduced water requirement for wet granulation;

(15) reduced wet granulation time; and (16) reduced drying time for post wet granulation mixtures.

In the publication of A. Piergies et al. in Abstract of paper contributed to the 1997 AAPS Annual Meeting, November 2-6, Boston MA (US), Pharm. Res. 14 (Suppl. 11), 1997, S-617, abstract 3469, a composition containing celocoxib with an AUC of 8763 (ng / ml) h is known. The composition of this publication is referred to as a fine suspension.

As outlined below, treatment with celecoxib is indicated or potentially indicated for a wide variety of conditions and disorders mediated by cyclooxygenase-2. Thus, it would be extremely advantageous to provide a set of formulations having bioavailability characteristics suited to the various indications. It would be extremely advantageous to provide preparations showing the pharmacokinetics appropriate for the rapid onset of action than is possible with untreated celecoxib.

Such preparations should show significantly greater efficacy in the treatment of conditions and disorders mediated by cyclooxygenase-2.

A pharmaceutical composition is provided herein comprising one or more orally administered dosage units each containing granular celecoxib in an amount of about 10 mg to about 1000 mg in intimate admixture with one or more pharmaceutically acceptable excipients.

In one embodiment, a single dose unit orally administered to a fasted subject provides, over time, a serum concentration of celecoxib with at least one of the following parameters:

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

(b) time to reach maximum concentration (Tmax) of no more than about 3 hours. after administration;

(c) the duration at which the concentration is greater than 100 ng / ml not less than about 12 hours;

(d) half-life (Ty₂) not shorter than about 10 hours; and (e) a maximum concentration (Cmax) of no less than about 200 ng / ml.

In another embodiment, the composition has a relative bioavailability of no less than about 50% as compared to an orally administered solution containing an equivalent amount of celecoxib.

In yet another embodiment, the composition has a primary particle size distribution such that D.₉₀ is less than about 200 nm (90% of the sample particles are less than the D value₉₀) for the longest particle size.

The dosage units constituting the composition may be in the form of separate solid articles, such as tablets, pills, hard or soft capsules, lozenges, sachets or lozenges; alternatively

The composition may be in the form of a virtually homogeneous free flowing or fluid mass, such as a granular or granular solid, or a liquid suspension from which single dose units are taken uniformly.

Also provided is a method of treating a medical condition or disorder in a subject for which treatment with a cyclooxygenzay-2 inhibitor is indicated, comprising orally administering a composition of the invention once or twice daily.

Other advantages of the present invention are partly obvious and partly will be emphasized below.

Brief description of the drawings

Figure 1 is a block diagram illustrating a representative method for preparing pharmaceutical compositions of the present invention in capsule form.

Figure 2 is a block diagram illustrating an alternative method for preparing the pharmaceutical compositions of the present invention in capsule form.

Detailed Description of the Invention

The novel pharmaceutical compositions of the present invention comprise one or more orally administered dosage units, each dosage unit containing granular celecoxib in an amount from about 10 mg to about 1000 mg, and are excellent immediate release compositions capable of providing rapid amelioration of a disorder mediated by cyclooxygenase-2, after oral administration to a subject suffering from such a disorder.

It is believed, without being bound by any theory, that the strong clinical benefit obtained with these compositions is due to the improved bioavailability of celecoxib, especially the surprisingly effective absorption of celecoxib from the gastrointestinal tract. Such effective absorption can be verified by one skilled in the art by monitoring the serum concentration of celecoxib in the treated subject for a period of time following administration. It is desirable to achieve, in the shortest possible time, a serum concentration threshold of celecoxib adequate for effective inhibition of cyclooxygenase-2. without further decreasing the concentration too abruptly, so that the beneficial effects of celecoxib can be sustained for as long as possible.

Thus, in one embodiment, a single oral dosage unit, when administered orally, provides a serum concentration of celecoxib over time with at least one of the following parameters:

(a) the time to serum concentration of about 100 ng / ml, which is no more than about 0.5 hours. after administration;

(b) time to maximum serum concentration (Tmax) of celecoxib, which is no longer than about 3 hours. after administration, preferably no more than about 2 hours after administration;

(c) the duration where the serum concentration is greater than 100 ng / ml, which is not less than about 12 hours;

(d) a half-life (T%) that is not less than about 10 hours; and (e) a peak serum concentration (C max) that is not less than about 200 ng / ml, preferably not less than about 300 ng / ml, and more preferably not less than about 400 ng / ml.

It is understood that the amount of celecoxib per dose unit effective to provide serum concentrations meeting criteria (a) to (e) above is dependent upon the body weight of the treated subject. If the subject is, for example, a child or small animal (e.g., dog), a relatively small amount of celecoxib in the indicated range of about 10 mg to about 1000 ng is likely to provide serum concentrations that meet at least one of the criteria (a) for (e). If the subject is an adult human or large animal (e.g., horse), the indicated serum concentrations of celecoxib will likely require dosing units containing higher amounts of celecoxib. For an adult human, the appropriate dose of celecoxib per dose unit in the composition of the present invention to provide the indicated serum concentrations is typically about 75 mg to about 400 mg.

The bioavailability of orally administered celecoxib in absolute terms is difficult to measure because intravenous administration (the standard standard against which bioavailability is determined) is highly problematic for a drug having very low water solubility, such as for celecoxib. Relative bioavailability, however, can be determined by comparing an orally administered celecoxib solution in a suitable solvent. It has been surprisingly found that high relative bioavailability is obtained using the orally administered compositions of the present invention. Thus, in one embodiment of the invention, each orally administered dose unit, when administered orally, has a relative bioavailability of not less than about 50%, preferably not less than about 70%, when compared to an orally administered celecoxib solution containing an equivalent amount of celecoxib. 'at. As shown below, bioavailability

The test was determined from an integrated measurement of the serum concentration of celecoxib over the time period following oral administration.

The invention relates to a pharmaceutical composition comprising one or more separate, solid, orally administered dosage units, each containing granular celecoxib in an amount of 10 mg to 1000 mg in intimate admixture with one or more pharmaceutically acceptable excipients and having a particle size range. celecoxib such that the D90 of the grains is less than 200 μm, preferably less than 100 μm, even more preferably less than 40 μm, and most preferably less than 25 µm longest particle size.

Preferably, the relative bioavailability of the celecoxib is not less than about 50%, preferably not less than about 70%, as compared to an orally administered solution containing the same dose of celecoxib.

Preferably, said dosage units are selected from tablets, pills, hard and soft capsules, lozenges, sachets and lozenges.

Preferably, the unit dose capsules or tablets have excipients selected from the group consisting of pharmaceutically acceptable diluents, disintegrants, binders, wetting agents and lubricants.

Preferably, the above composition comprises:

a) one or more pharmaceutically acceptable diluents in a total amount of from 10% to 85% by weight of the composition,

b) one or more pharmaceutically acceptable disintegrants in a total amount of 0.2% to 10% by weight of the composition.

c) one or more pharmaceutically acceptable binders in a total amount of from 0.75% to 15% by weight of the composition,

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

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

Preferably, the above composition comprises:

a) diluents including lactose,

b) disintegrants including sodium carboxymethylcellulose,

c) binders including polyvinylpyrrolidone;

d) wetting agents, if present, including sodium lauryl sulfate; and

e) lubricants, if present, including magnesium stearate.

Preferably, the above composition is for treating a medical condition or disorder in a subject in which treatment with a cyclooxygenase-2 inhibitor is indicated, wherein the composition is administered to the subject orally, preferably once or twice daily.

Another object of the invention is the use of a composition as defined above for the manufacture of a medicament for the treatment and / or prevention of a condition or disorder mediated by a cyclooxygenase-2 inhibitor.

Preferably the condition or disorder is rheumatoid arthritis, osteoarthritis or pain.

It has been found that grinding celecoxib in an impact mill, such as a pin mill, before mixing the celecoxib with excipients to form the composition of the invention, not only effectively provides improved bioavailability, but also benefits from overcoming the problems associated with the coherent nature of celecoxib crystals. u in the process of such mixing or blending. Celecoxib milled using a pin mill is less cohesive and will not agglomerate into secondary celecoxib particle aggregates on compilation as easily as unground celecoxib or celecoxib milled using other types of mills such as fluidized mills. The reduction in agglomeration allows a high degree of uniformity of the blend, which is of particular importance in the preparation of unit dosage forms such as capsules and tablets. These results are especially surprising since the utility of fluidized mills such as jet mills in the preparation of other pharmaceutical compounds for formulation is known. Without wishing to be bound by any particular theory, it is believed that the impact mill modifies the celecoxib crystal morphology from long needles to a more uniform crystalline shape more suitable for blend preparation, while long needles have a greater tendency to survive in the jet milling process.

It has also been found that the blend homogeneity is further improved by wet granulation of celecoxib, especially if the celecoxib starting material used was impact milled. Especially beneficial

The method is to impact mill a celecoxib starting material with the particle sizes as disclosed above, followed by wet granulation.

The compositions of the present invention are useful in the treatment and prevention of a wide variety of cyclooxygenase-2 mediated disorders. The contemplated compositions herein are useful, without limitation, in treating inflammation in a subject, as an analgesic for example in the treatment of pain and headache, and as an antipyretic in the treatment of fever. The term "treatment" in the present context includes the partial or complete inhibition of dementia, including Alzheimer's disease, vascular dementia, infarct dementia, pre-senile dementia, alcoholic dementia, and senile dementia. The compositions of the invention are especially useful as anti-inflammatory agents, such as for the treatment of arthritis, with the added benefit of exhibiting less deleterious side effects than conventional non-steroidal anti-inflammatory drug (NSAID) compositions.

The contemplated compositions are useful, without limitation, in the treatment and prevention of inflammation-related cardiovascular disorders in a subject. Such compositions are useful in the treatment and prevention of diseases such as vascular disease, coronary artery disease, aneurysm, vascular rejection, hardening of the arteries, hardening of the arteries including hardening of heart transplantation, heart attack, embolism, stroke, thrombosis including venous thrombosis, angina including with angina, coronary plaque inflammation, bacterial-induced inflammation including Chlamydia-induced inflammation, viral-induced inflammation and inflammation associated with surgical operations such as vascular transplantation including coronary artery bypass surgery, revascularization surgery including angioplasty, stent placement, endarterectomy or other invasive procedures involving arteries, veins and capillaries. Such compositions are useful, without limitation, in treating angiogenesis related disorders in a subject. The compositions of the invention can be administered to a subject in need of angiogenesis inhibition. Such compositions are useful in the treatment of tumor formation, including metastasis; ophthalmological conditions such as corneal transplant rejection, ocular neovascularization, retinal neovascularization following trauma or infection, diabetic retinopathy, macular degeneration, extra-lens fibrosis, and neovascular glaucoma; ulcerative diseases such as gastric ulcer; pathological but benign conditions such as hemangioma, including infantile hemangioma, nasopharyngeal angiofibroma, and lack of vascularization induced bone necrosis; and disorders of the female reproductive system such as endometriosis.

The contemplated compositions are useful in preventing or treating benign and malignant neoplasms / neoplasms including cancer such as colorectal cancer, brain cancer, bone cancer, cancer of epithelial origin (epithelial cancer) such as basal cell cancer, adenocarcinoma, gastrointestinal cancer. intestinal cancer such as mouth cancer, oral cancer, esophageal cancer, small intestine cancer and gastric cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer and skin cancer, such as squamous epithelial and basal cell cancer, prostate cancer, kidney cell cancer, and other known cancers that affect epithelial cells throughout the body. Cancers for which the compositions of the invention are considered particularly useful include 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 squamous epithelial carcinoma and basal cell carcinoma. The compositions of the invention can also be used to treat the fibrosis that occurs after radiation therapy. Such compositions can be used to treat subjects having adenomatous polyps, including those with familial adenomatous polyposis (FAP). In addition, such compositions can be used to prevent polyps in patients at risk of FAP.

The compositions of the present invention have anti-inflammatory, antipyretic and analgesic properties similar to or better than conventional non-steroidal anti-inflammatory drug compositions. The contemplated compositions also inhibit hormonally induced uterine contractions and have a potential anti-cancer effect, but with a reduced ability to induce some mechanically induced side effects of conventional NSAIDs. In particular, the compositions of the invention have reduced potential gastrointestinal toxicity and irritation of the stomach, including upper gastrointestinal ulceration and bleeding, reduced potential renal side effects such as reduction of renal function leading to fluid retention and exacerbation of hypertension. reduced effect on the bleeding period including inhibition of platelet function, and possibly less ability to induce asthma attacks in aspirin sensitive asthmatic subjects, compared to conventional NSAID compositions.

PL 200 957 B1

The contemplated compositions are useful for the relief of pain, fever, and inflammation in a variety of disorders, including rheumatic fever, symptoms associated with influenza and other viral infections, common cold, back and neck pain, dysmenorrhea, headache, toothache, joint injuries and strains. , myositis, neuralgia, synovitis, arthritis including rheumatoid arthritis, degenerative bursal disease (osteoarthritis), fundus and ankylosing spondylitis, bursitis, burns and injuries following surgical and dental operations. In addition, contemplated compositions inhibit neoplastic cell transformation and metastatic neoplastic metastasis development, and thus can be used in the treatment of cancer such as colon cancer. The contemplated compositions may also be useful in the treatment and / or prevention of cyclooxygenase-mediated profiling disorders such as can occur in diabetic retinopathy and tumor angiogenesis.

Contemplated compositions inhibit prostanoid-induced smooth muscle contractions by inhibiting the synthesis of contractile prostanoids, and thus can be used in the treatment of dysmenorrhea, premature labor, asthma, and eosinophil related disorders. They can also be used in the treatment of Alzheimer's disease, to reduce bone desorption, especially in postmenopausal women (ie, treat osteoporosis), and to treat glaucoma.

Due to their high cyclooxygenase-2 (COX-2) activity and / or their cyclooxygenase-2 inhibitory specificity compared to cyclooxygenase-1 (COX-1), the compositions of the invention are useful as alternatives to conventional NSAIDs, especially when such NSAIDs are contraindicated in, for example, patients with peptic ulcer, gastritis, local enteritis, colonic ulcer, diverticulitis, or recurrent gastrointestinal lesions; gastrointestinal bleeding, coagulation disorders including anemia such as prothrombin deficiency, haemophilia or other bleeding problems; kidney disease; or in patients before surgery, or in patients taking anticoagulants. A brief overview of the potential use of cyclooxygenase-2 inhibitors is provided in the article by John Vane, Nature, Vol. 367, pp. 215-216, 1994, and in an article in Drug News and Perspectives, Vol. 7, pp 501-512, 1994.

The preferred uses of the pharmaceutical compositions of the present invention are: treatment of rheumatoid arthritis and osteoarthritis, pain control (especially pain after oral surgery, pain after general surgery, pain after orthopedic surgery and in acute relapses of osteoarthritis), treatment of the disease Alzheimer's and colon cancer chemoprevention.

Besides being useful for human treatment, the compositions of the invention are also useful for veterinary treatment of companion animals, exotic animals and farm animals and the like, especially mammals including rodents. More preferably, the compositions of the invention are useful for the veterinary treatment of cyclooxygenase-2 mediated disorders in horses, dogs and cats.

Definitions

The term "active ingredient" herein means celecoxib, unless the context otherwise requires.

The term "excipient" herein includes any substance used as a vehicle for delivering the active ingredient to the subject, and any substance added to the active ingredient, for example to improve its handling properties or to allow the resulting composition to be converted into an orally administered unit dose having the required shape and consistency. The excipients may include, by way of illustration and not limitation purposes, diluents, disintegrating agents, binders, adhesives, wetting agents, lubricants, glidants, masking or counteracting substances, taste correcting agents, dyes, additive agents. enhancement of the dosage form and any substances other than the active ingredient normally used to prepare the oral dosage form.

The term "adjuvant" herein denotes a substance which, when present or added to a pharmaceutical composition containing an active ingredient, enhances or otherwise improves the action of the active ingredient.

The term "unit dose" herein refers to an amount of an active ingredient intended for a single oral administration to a subject to treat or prevent a cyclooxygenase-2 mediated condition or disorder. Treatment of a cyclooxygenase-2 mediated disorder may involve periodic administration of unit doses of celecoxib, for example, one unit dose two or more times daily, one unit dose with each meal, one unit dose every four hours or at different intervals, or only one unit dose daily.

PL 200 957 B1

The term "dose unit" herein means that portion of a pharmaceutical composition that contains a single unit dose of active ingredient. For the purposes of the present invention, the dosage unit may be in the form of a separate article such as a tablet or capsule, or it may be a measurable volume of a solution, suspension or the like containing a unit dose of active ingredient.

The term "orally administered" herein means intended to be administered to the gastrointestinal system of a subject through the mouth of said subject.

The term "substantially homogeneous" when used herein to describe a pharmaceutical composition that contains a combination of ingredients means that the ingredients are completely intermixed such that the individual ingredients neither form separate layers nor form concentration gradients within the composition.

The term "bioavailability" herein refers to a measure of the amount of an active ingredient that is absorbed into the blood stream via the gastrointestinal system. More specifically, "bioavailability" is used herein to measure AUC_(0-/) for a particular orally administered composition, expressed as a percentage of the AUC ₀ for an active ingredient delivered intravenously at the same dosage rate.

The term "relative bioavailability" herein means AUC (_{0 m}) for a specific orally administered composition, expressed as a percentage of the AUC (_{0 m}) for an orally administered solution of the active ingredient at the same dose rate.

The terms "AUC (0-24)", "AUC (0-48)", "AUC (0-72)" hereby mean the area under the serum concentration time curve after administration of 0 to 24 hours, 48 ​​hours, respectively. or 72 hours as determined using the linear trapezoidal rule and are expressed in units (ng / ml) hr.

The term "AUC (0-LQC)" hereby means the area under the serum concentration time curve after administration from 0 to the last point at which the concentration can be quantified ("LQC") as determined using the linear-linear rule. trapezoidal and is expressed in units (ng / ml) h.

The term "AUC (_{0 m}) "Is hereby calculated as AUC (_0-LQC) + LQC / (- b), where LQC is the last quantifiable concentration and b is the tangent of the slope of the T% calculation, and is expressed in units (ng / ml) hr.

The term "Cmax" herein means the maximum observed serum concentration or the maximum serum concentration calculated or estimated from the concentration / time curve, and is expressed in units (ng / ml).

The term "Cmax" herein denotes the time after drug administration where "Cmax" occurs^” is expressed in units of hours.

The term "you₂"Hereby" means terminal serum concentration half-life, defined by the simple linear regression of the natural log (In) concentration versus time for data points in the terminal phase of the concentration-time curve. You₂ is calculated as - ln (2) / (- b) and is expressed in units of hours.

The term "absorption time" herein means Cmax / AUC (0-LQC).

The celecoxib dose provided by the composition of the invention.

The pharmaceutical compositions of the present invention are suitable for the administration of celecoxib in a daily dosage amount of from about 10 mg to about 1000 mg. Each dose unit of a composition of the invention typically comprises an amount of celecoxib from about one-tenth of the amount of the daily dose to the entire amount of the daily dose. The compositions of the invention include celecoxib in an amount from about 10 mg to about 1000 mg, preferably from about 50 mg to about 800 mg, more preferably from about 75 mg to about 400 mg, most preferably from about 100 mg to about 200 mg per dose unit. . When the dosage units are in the form of discrete articles suitable for oral administration, for example capsules or tablets, each such article contains from about 10 mg to about 1000 mg, preferably from about 50 mg to about 800 mg, more preferably from about 75 mg to about 1000 mg. 400 mg, most preferably from about 100 mg to about 200 mg of celecoxib.

Dosage units of the compositions of the invention will typically contain, for example, 10, 20, 25, 37.5, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350 or 400 mg of celecoxib dose. Preferred compositions have dosage units containing 100 mg or about 200 mg of celecoxib. The specific dosage unit may be selected to adjust the desired frequency of administration to be used to achieve the daily dose. The daily dose and frequency of administration, and hence the selection of the appropriate dosage unit, depend on a variety of factors including the age, weight, sex and health condition of the subject, and the nature and severity of the condition or disorder, and can thus vary widely.

However, it has been found that for the compositions disclosed herein, a once or twice daily dosing regimen to deliver the required daily dose of celecoxib exhibits improved efficacy over the other dosing regimens. Accordingly, oral administration once or twice

The daily use of compositions of the invention is beneficial to provide therapeutically or prophylactically effective inhibition of cyclooxygenase-2 mediated disorders.

Treatment of specific conditions and disorders

The pharmaceutical compositions of the present invention are useful where administration of a cyclooxygenase-2 inhibitor is indicated. These compositions have been found to be particularly effective in treating, for example, rheumatoid arthritis and osteoarthritis, and for analgesia in general (especially post-dental surgery pain, post-general surgery pain, post-orthopedic pain, and acute relapses). bone and joint), Alzheimer's disease, and colon cancer chemoprevention.

In the treatment of rheumatoid arthritis, the composition of the invention can be used to provide a daily dose of celecoxib from about 50 mg to about 1000 mg, preferably from about 100 mg to about 600 mg, more preferably from about 150 mg to about 500 mg, and even more. preferably from about 175 to about 400, such as about 200 mg. A daily dose of celecoxib about 0.67 to about 13.3 mg / kg body weight, preferably about 1.33 to about 8.00 mg / kg body weight, more preferably about 2.00 to about 6.67 mg / kg body weight, and even more preferably 2.33 to about 5.33 mg / kg body weight, for example about 2.67 mg / kg body weight, is generally appropriate when administered in a composition according to the invention. The daily dose may be administered in one to four doses per day, preferably one or two doses per day. Administration of the compositions of the invention at a frequency of one 100 mg dose twice daily is beneficial to most patients, but some patients may benefit from administering one 200 mg dose or two 100 mg dose units twice daily.

In the treatment of osteoarthritis, the composition of the invention can be used to provide a daily dose of celecoxib from about 50 mg to about 1000 mg, preferably from about 100 mg to about 600 mg, more preferably from about 150 mg to about 500 mg, and still more more preferably from about 175 to about 400, such as about 200 mg. A daily dose of celecoxib about 0.67 to about 13.3 mg / kg body weight, preferably about 1.33 to about 8.00 mg / kg body weight, more preferably about 2.00 to about 6.67 mg / kg body weight, and even more preferably 2.33 to about 5.33 mg / kg body weight, for example about 2.67 mg / kg body weight, is generally appropriate when administered in a composition according to the invention. The daily dose may be administered in one to four doses per day, preferably one or two doses per day. It is preferred to administer the compositions of the invention at a frequency of one 100 mg dose unit twice a day, or one 200 mg dose unit or two 100 mg dose units once a day.

In the treatment of Alzheimer's disease, the composition of the invention can be used to provide a daily dose of celecoxib of about 50 mg to about 1000 mg, preferably from about 100 mg to about 800 mg, more preferably from about 150 mg to about 600 mg, and still more more preferably from about 175 to about 400, such as about 400 mg. A daily dose of about 0.67 to about 13.3 mg / kg body weight, preferably about 1.33 to about 10.67 mg / kg body weight, more preferably about 2.00 to about 8.00 mg / kg body weight and even more preferably, 2.33 to about 5.33 mg / kg body weight, for example about 5.33 mg / kg body weight, is generally appropriate when administered in a composition according to the invention. The daily dose may be administered in one to four doses per day, preferably one or two doses per day. Most patients benefit from the administration of a composition according to the invention at a frequency of one 200 mg dose unit or two 100 mg dose units twice daily.

In the treatment of cancer, the compositions of the invention can be used to provide a daily dose of celecoxib of about 50 mg to about 1000 mg, preferably from about 100 mg to about 800 mg, more preferably from about 150 mg to about 600 mg, and even more preferably from about 100 mg to about 800 mg. about 175 to about 400, such as about 400 mg. A daily dose of about 0.67 to about 13.3 mg / kg body weight, preferably about 1.33 to about 10.67 mg / kg body weight, more preferably about 2.00 to about 8.00 mg / kg body weight and even more preferably, 2.33 to about 5.33 mg / kg body weight, for example about 5.33 mg / kg body weight, is generally appropriate when administered in a composition according to the invention. The daily dose may be administered in one to four doses per day, preferably two doses per day. Most patients benefit from the administration of a composition according to the invention at a frequency of one 200 mg dose unit or two 100 mg dose units twice daily.

In general, the composition of the invention is preferably administered in a dose sufficient to provide an average serum concentration of celecoxib in the subject's bloodstream of at least about 100 ng / ml within about 24 hours after administration.

The pharmaceutical compositions of the present invention have been found to provide a therapeutic effect as cyclooxygenase-2 inhibitors over a time interval of about 12 to about 24 hours after

By oral administration. The preferred compositions provide this therapeutic effect for 24 hours allowing for oral administration once a day.

While the amount of celecoxib in the novel compositions of the invention is preferably within the range disclosed herein, the compositions may also be useful for administering amounts of celecoxib other than the dosage ranges disclosed.

Receiving celecoxib

Celecoxib used in the novel pharmaceutical compositions of the present invention may be prepared as set forth in Talley, et al., In US Patent No. 5,466,823, or by Zhi, et al., In WO 96/37476.

Forms of compositions according to the invention

The pharmaceutical compositions of the present invention contain celecoxib in association with one or more preferably non-toxic pharmaceutically acceptable carriers, excipients and adjuvants (collectively referred to herein as "carrier materials" or "excipients") suitable for oral administration. The carrier materials must be acceptable in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient of the drug. The compositions of the present invention can be adapted for administration by any suitable oral route by selecting appropriate carrier materials and a dose of celecoxib effective for the treatment intended. Accordingly, any carrier materials used can be solids or liquids or both, and the composition preferably comprises about 1% to about 95%, preferably about 10% to about 90%, more preferably about 25% to about 85%, and even more preferably about 30% to about 80% by weight of celecoxib. Such pharmaceutical compositions of the invention may be prepared by any method well known in the art of pharmacy which includes admixing the ingredients.

The composition according to the invention contains the desired amount of celecoxib per dose unit and may be in the form of, for example, tablets, pills, hard or soft capsules, lozenges, sachets, dispensing powder, granules, suspension, elixir, liquid or any other form. a form reasonably adapted for oral administration. Such a composition is preferably made up as discrete dosage units containing a predetermined amount of celecoxib, such as tablets or capsules. Such oral dosage forms may further contain, for example, buffering agents. Tablets, pills and the like additionally can be prepared with or without coatings.

Compositions of the present invention suitable for buccal or sublingual administration include, for example, lozenges containing celecoxib in a flavored base such as sucrose and acacia or tragacanth, and lozenges containing celecoxib in an inert medium such as gelatin and glycerin or sucrose and acacia gum.

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

As shown above, the compositions of the invention can be prepared by any pharmaceutical process that includes the step of associating the celecoxib and the carrier material or materials. Generally, compositions are prepared by uniformly and intimately admixing celecoxib with a liquid or particulate solid carrier, or both, and then encapsulating or shaping the product as necessary. For example, a tablet may be made by compressing or molding a powder or granules of the compound together with one or more excipients. Compressed tablets can be prepared in suitable machines by compressing a composition with good compression properties such as a powder or granules, containing celecoxib in any admixture with one or more binders, lubricant (s), inert diluent (s), wetting agent (s). and / or dispersing agent (s). Molded tablets may be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid diluent.

Carrier or excipient materials

As shown above, the pharmaceutical compositions of the present invention contain a therapeutically or prophylactically effective amount per dose unit in association with one or more pharmaceutically acceptable carrier materials suitable for oral administration. The compositions of the present invention preferably contain celecoxib in the desired amount mixed with one or more carrier materials selected from the group consisting of pharmaceutically acceptable diluents, disintegrants, binders, tackifiers, wetting agents,

Lubricants and anti-sticking agents. More preferably, such compositions are tableted or encapsulated for convenient administration in the form of capsules or immediate release tablets.

By selecting and combining carrier materials used in the pharmaceutical compositions of the present invention, compositions showing improved performance with respect to, inter alia, efficacy, bioavailability, clearance time, can be provided. stability, compatibility of celecoxib and carrier 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 which compensate for the low water solubility and hydrophobicity of celecoxib. When the composition is formulated as a tablet, the combination of the selected carrier materials produces tablets that can exhibit improved properties, including dissolution and disintegration profiles, hardness, crush strength, and / or friability, among others.

Thinners

The pharmaceutical compositions of the present invention optionally contain one or more pharmaceutically acceptable diluents as carrier material. Suitable diluents include, either individually or in combination, lactose USP; lactose USP anhydrous; spray dried USP lactose; USP starch; ready-to-press starch; USP mannitol; sorbitol; dextrose monohydrate; microcrystalline cellulose NF; NF dibasic calcium phosphate dihydrate; sucrose based diluents; packaged sugar; monobasic calcium sulfate monohydrate; calcium sulfate dihydrate NF; granular calcium lactate trihydrate; dextrans, NF (e.g. Emdex); Celutab; dextrose (e.g. Cerelose); inositol; hydrolyzed cereal solids such as Maltrons and Mor-Rex; amylose; Rexcel; powdered cellulose (e.g. Elcema); calcium carbonate; glycine; bentonite; polyvinylpyrrolidone; and the like. Such diluents, if present, constitute in total about 5% to about 99%, preferably about 10% to about 85%, and more preferably about 20% to about 80%, of the total weight of the composition. The selected diluent or diluents preferably exhibit suitable compression properties and compressibility if tablets are desired.

Preferred diluents are lactose and microcrystalline cellulose either individually or in combination. Both diluents are chemically compatible with celecoxib. The use of externally granulated microcrystalline cellulose (ie, microcrystalline cellulose added to the wet granular composition after the drying step) can be used to improve hardness (for tablets) and / or disintegration time. Lactose, and especially lactose monohydrate, is particularly preferred. Lactose typically provides pharmaceutical compositions having suitable celecoxib release rates, stability, compression properties, and / or drying properties with relatively low diluent costs. This provides a high density substrate which facilitates compaction during granulation (if wet granulation is used) and thus improves the pressing properties of the mix.

Disintegrating agents

The pharmaceutical compositions of the present invention optionally include one or more pharmaceutically acceptable disintegrants as carrier material, particularly for tablet formulations. Suitable disintegrants include, either individually or in combination, starches; sodium starch glycolate; clays (such as Veegum HV); celluloses (such as purified cellulose, methyl cellulose, sodium carboxymethyl cellulose, and carboxymethyl cellulose); alginates; gelled corn starches (such as National 1551 and National 1550); crospovidone USP NF; and gums (such as agar, guar gum, Ceratonia Siliqua gum, Karaya tragacanth, pectin and tragacanth). The disintegrants may be added at any stage during the preparation of the pharmaceutical composition, particularly prior to granulation or during the lubrication step prior to compression. Such disintegrants, if present, add up to a total of about 0.2% to about 30%, preferably about 0.2% to about 10%, and more preferably about 0.2% to about 5%, of the total weight of the composition.

Internally cross-linked sodium carboxymethylcellulose is a preferred disintegrant for tablet or capsule disintegration and, if present, preferably from about 0.2% to about 10%, more preferably from about 0.2% to about 6%, and even more preferably about 0%. 2 to about 5% of the total weight of the composition. The internally cross-linked sodium carboxymethyl cellulose gives the compositions of the present invention an improved internal disintegration capacity of the granules.

Binding agents and adhesives

The pharmaceutical compositions of the present invention optionally contain one or more pharmaceutically acceptable binders or adhesives as carrier material.

Especially for tablet formulations. Such binders and adhesives preferably provide sufficient cohesion to the tabletted powder to allow common processing operations such as sizing, lubrication, compression and packaging, but still allow the tablet to disintegrate and the composition to be absorbed after administration. Suitable binders and adhesives include, either individually or in combination, acacia; tragacanth; sucrose; gelatin; glucose; starch; cellulosic materials such as, but not limited to, methyl cellulose and intrinsically cross-linked carboxymethyl cellulose (e.g. Tylose); alginic acid and alginic acid salts; aluminum magnesium silicate; polyethylene glycol; guar gum; polysaccharide acids; bentonites; polyvinylpyrrolidone; polymethacrylates; hydroxypropyl methylcellulose (HPMC); hydroxypropyl cellulose (Klucel); ethyl cellulose (Ethocel); pregelatinized starch (such as National 1511 and Starch 1500). Such binders and / or adhesives, if present, constitute in total about 0.5% to about 25%, preferably about 0.75% to about 15%, and more preferably about 1% to about 10%, of the total weight of the composition.

Polyvinylpyrrolidone is the preferred binder used to provide cohesive properties to a powdered blend of celecoxib and other excipients for granulating a celecoxib formulation. Polyvinylpyrrolidone, if present, comprises about 0.5% to about 10%, more preferably about 0.5% to about 7%, and even more preferably about 0.5% to about 5%, of the total weight of the composition.

Polyvinylpyrrolidone with a viscosity up to about 20 cPs can be used. although viscosities of about 6 cPs or less are preferred, particularly about 3 cPs or less. Polyvinylpyrrolidone provides cohesiveness to the powder mixture and facilitates the necessary setting to form granules during wet granulation. Additionally, it has been found that compositions of the present invention containing polyvinylpyrrolidone, especially compositions obtained by wet granulation, show increased bioavailability compared to other compositions.

Wetting agents

Celecoxib is largely insoluble in aqueous solution. For this reason, the pharmaceutical compositions of the present invention optionally but preferably contain one or more pharmaceutically acceptable wetting agents as carrier material. Such wetting agents are preferably selected so as to keep the celecoxib in close association with the water; this is believed to be a prerequisite for increasing the relative bioavailability of the pharmaceutical composition. Suitable wetting agents include, either individually or in combination, oleic acid; glycerol monostearate; sorbitan monooleate; sorbitan monolaurate; triethanolamine oleate; polyoxyethylene sorbitan monooleate; polyoxyethylene sorbitan monolaurate; sodium oleate and sodium lauryl sulfate. Wetting agents that are anionic surfactants are preferred. Such wetting agents, if present, constitute in total about 0.25% to about 15%, preferably about 0.4% to about 10%, and more preferably about 0.5% to about 5%, of the total weight of the composition.

Sodium lauryl sulfate is the preferred wetting agent. Sodium Lauryl Sulfate. when present, it is about 0.25% to about 7%, more preferably about 0.4% to about 6%, and even more preferably about 0.5% to about 5%, of the total weight of the composition.

Lubricants

The pharmaceutical compositions of the present invention optionally contain one or more pharmaceutically acceptable lubricants and / or glidants as carrier material. Suitable lubricants and / or glidants include, either individually or in combination, glycerol behenate (Compritol 888); stearates (magnesium, calcium and sodium); stearic acid; hydrogenated vegetable oils (e.g. Sterotex); talc; waxes; Stearowet; Boric acid; sodium benzoate; sodium acetate; sodium fumarate; sodium chloride; DL - leucine; polyethylene glycols (e.g., Carbowax 4000 and Carbowax 6000); sodium oleate; sodium lauryl sulfate and magnesium lauryl sulfate. Such lubricants, if present, total about 0.1% to about 10%, more preferably about 0.2% to about 8%, and even more preferably about 0.25% to about 5%, of the total weight of the composition.

The preferred lubricant used is, for example, magnesium stearate to reduce the friction between the device and the granulation mixture during compression of the tablet formulation.

Other carrier materials (such as anti-adherents, dyes, flavors, sweeteners and preservatives) are known in the pharmaceutical art and can be included in the compositions of the present invention. For example, iron oxide can be added to the composition to provide a yellow color.

Capsules and tablets

In one embodiment of the present invention, the pharmaceutical composition is in unit dose form as a capsule or tablet and comprises the desired amount of celecoxib and a binder. The composition further preferably comprises one or more carrier materials selected from the group consisting of pharmaceutically acceptable diluents, disintegrants, binders, wetting agents and lubricants. More preferably the composition comprises one or two carrier materials selected from the group consisting of lactose, sodium lauryl sulfate, polyvinylpyrrolidone, sodium carboxymethylcellulose, magnesium stearate and microcrystalline cellulose. Even more preferably the composition comprises lactose monohydrate and cross-linked sodium carboxymethyl cellulose. Even more preferably, the composition further comprises one or more carrier materials, sodium lauryl sulfate, magnesium stearate and microcrystalline cellulose.

In another embodiment, the pharmaceutical composition comprises:

(a) about 1 to about 95% by weight of celecoxib;

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

(c) about 0.5 to about 30% by weight of a pharmaceutically acceptable disintegrant; and (d) about 0.5 to about 25% by weight of a pharmaceutically acceptable binder.

In addition, the present pharmaceutical composition optionally comprises:

(e) about 0.25 to about 15% by weight of a pharmaceutically acceptable wetting agent; and / or (f) about 0.1 to about 10% by weight of a pharmaceutically acceptable lubricant.

The term "weight percent" as used herein means the percentage by weight of a particular ingredient based on the total weight of all ingredients of the composition.

Celecoxib grain size in capsules and tablets

It has been found that reducing the particle size of celecoxib may increase the bioavailability of orally administered celecoxib in capsule or tablet form. For this reason, the grain size of the celecoxib D90 is preferably less than about 200 nm, more preferably less than about 100 nm, even more preferably less than about 75 nm, more preferably less than about 40 nm, and most preferably less than about 25 L m. For example, as shown in Example 11, reducing the D90 grain size of the celecoxib starting material from about 60 nm to about 30 nm can significantly improve the bioavailability of the composition. Additionally or alternatively, the celecoxib preferably has an average grain size ranging from about 1 nm to about 10 nm, more preferably from about 5 nm to about 7 nm.

Secondary particles size after granulation and pressing properties

While the pharmaceutical compositions of the present invention may be obtained, for example, by direct encapsulation or direct compression, they are preferably wet granulated prior to encapsulation or compression. Wet granulation, in addition to other effects, thickens the milled compositions, leading to improved flowability properties, improved compression characteristics, and easier measuring or weighing of the encapsulation or tabletting composition. The grain size of the granular secondary particles obtained from granulation (ie the granule size) is not significant in a narrow range; it is important that the average size of the granule is such that it allows convenient handling and processing and, in the case of tablets, it will permit the formation of directly compressible mixtures from which pharmaceutically acceptable tablets are made.

Desired tapped bulk density and granule bulk density is normally about 0.3 g / ml to about 1.0 g / ml.

Capsule and tablet release profile

The encapsulation and tabletting compositions of the present invention are immediate release compositions that release at least 50% of celecoxib as measured in vitro within 45 minutes of ingestion. More preferably, they release at least 60% of the celecoxib within 45 minutes of ingestion. Even more preferably, they release at least 75% of celecoxib within 45 minutes of ingestion. Particularly preferred encapsulation and tabletting compositions of the present invention release at least 50% celecoxib within 15 minutes of ingestion, and / or at least about 60% of celecoxib within 30 minutes of ingestion.

Capsule and tablet disintegration profile

The carrier materials for the encapsulation and tabletting compositions of the present invention are selected to provide a disintegration time of less than about 30 minutes, preferably about 25 minutes or less, more preferably about 20 minutes or less, and even more preferably about 15 minutes or less.

Hardness

In the case of tablet formulations, a sufficient amount of the total mixture to make a uniform batch of tablets is tabletted on a conventional commercial tableting press under normal compression pressure (e.g., applying a pressure of about 1 kN to about 50 kN in a conventional tableting die). Any tablet hardness appropriate in terms of it can be used

Handling, manufacturing, storage and consumption. For 100 mg tablets, the hardness is preferably at least 4 kP, more preferably at least 5 kP and even more preferably at least about 6 kP. For 200 mg tablets, the hardness is preferably at least 7 kP, more preferably at least 9 kP and even more preferably at least about 11 kP. The mixture, however, cannot be compressed to such an extent that it is consequently difficult to achieve hydration after the tablet has been exposed to gastric juice.

Fragility

For tablet formulations, the tablet friability is preferably less than about 1.0%, more preferably less than 0.8%, and even more preferably less than about 0.5% in a standard test.

Way of treatment

The present invention is directed to a method of therapeutically treating a condition or disorder for which treatment with a cyclooxygenase-2 inhibitor is indicated, the method comprising orally administering a pharmaceutical composition of the present invention to a patient in need thereof. The dosage regimen for preventing, ameliorating or ameliorating the condition or disorder preferably corresponds to the once daily or twice daily treatment discussed above, but may be modified according to various factors. These include the type, age, weight, sex, diet, and medical condition of the patient, and the nature and severity of the disorder. Hence, the dosage regimen actually employed can vary widely and thus may differ from the preferred dosage regimen outlined above.

The pretreatment of a patient afflicted with a condition or disorder for which treatment with a cyclooxygenase-2 inhibitor is indicated may be initiated with the doses indicated above. Treatment is generally continued as necessary for several weeks to several months or years until the condition or disorder has been controlled or eliminated. Patients treated with the compositions of the invention may be routinely monitored by any means well known to those skilled in the art to determine the effectiveness of the therapy. Continuous analysis of such data makes it possible to modify the treatment regimen during therapy in such a way that optimally effective amounts of celecoxib are administered at the right time and hence also the duration of the treatment can be determined. In this way, the treatment regimen / dosage regimen can be reasonably modified over the course of the treatment such that the minimum amount of celecoxib showing satisfactory efficacy is administered, and that administration is continued only as long as necessary to effectively treat the condition or disorder.

The present invention is also directed to the use of compositions of the present invention for the preparation of medicaments useful in the treatment and / or prophylaxis of cyclooxygenase-2 mediated conditions and disorders.

Examples

The following examples illustrate aspects of the present invention without limiting its scope. The experimental procedures used to obtain the data shown are detailed below. The symbols and conventions used in these examples are those used in modern pharmaceutical literature. Unless otherwise stated, (i) all percentages shown in these examples are percentages by weight based on the weight of the total composition, (ii) for capsules, the total weight of the composition is the total fill weight of the capsule and does not include the actual weight of the capsule used, and (iii) coated tablets are coated with conventional coating materials such as Opadry White YS-1-18027A, and the weight of the coating is 3% of the total weight of the coated tablet.

Example 1

Capsule - dose 100 mg

The capsule was prepared using the following preparation:

Table 1

<td>Ingredient</td><td>Share (% by weight)</td><td>Amount (mg)</td>

<td> 1</td><td> 2</td><td> 3</td>

<td>Celecoxib</td><td> 37,04</td><td> 100</td>

<td>Lactose Monohydrate (NF, Ph, Eur)</td><td> 55,46</td><td> 149,75</td>

<td>Sodium Lauryl Sulfate (NF, Ph, Eur)</td><td> 3</td><td> 8,1</td>

PL 200 957 B1 cont. table 1

<td> 1</td><td> 2</td><td> 3</td>

<td>Povidone (K29-32 USP)</td><td> 2,5</td><td> 6,75</td>

<td>Cross-linked sodium carboxymethylcellulose (NF, Ph, Eur)</td><td> 1</td><td> 2,7</td>

<td>Magnesium stearate (NF, Ph, Eur)</td><td> 1</td><td> 2,7</td>

<td>Total weight of the capsule filling</td><td> 100</td><td> 270</td>

The above dosage unit composition was packed into a hard gelatin capsule (white, opaque size # 2) containing titanium dioxide (USP), gelatin (NF), and blue dye (SB-6018).

Lactose monohydrate used in each of the examples herein is commercially available from Formost Farms, Baraboo, Wisconsin. The Ac-Di-Sol type of cross-linked sodium carboxymethylcellulose used in each of the examples herein is commercially available from FMC Corporation, Chicago, Illinois. The sodium lauryl sulfate used in each of the examples herein is commercially available from Henkel Corporation, Cicinnati, Ohio. Povidone (polyvinylpyrrolidone) used in each of the examples herein is commercially available from International Specialty Products. The magnesium stearate used in each of the examples herein is commercially available from Mallinckrodt Inc., St. Louis, Missouri. Opadry White YS-1-18027 used to coat the tablets disclosed in the examples of the present application is a finished coating formulation commercially available from Colorcon, West Point, Pennsylvania.

Capsule doses of any desired capacity from 25 mg to 225 mg can be adjusted by adjusting the weight of celecoxib and increasing or decreasing the amount of lactose as needed until a total fill weight of 270 mg is achieved.

Example 2

Capsule - dose of 200 mg

The capsule was prepared using the following preparation:

Table 2

<td>Ingredient</td><td>Share (% by weight)</td><td>Amount (mg)</td>

<td>Celecoxib</td><td> 74,07</td><td> 200</td>

<td>Lactose Monohydrate (NF, Ph, Eur)</td><td> 18,43</td><td> 49,75</td>

<td>Sodium Lauryl Sulfate (NF, Ph, Eur)</td><td> 3</td><td> 8,10</td>

<td>Povidone (K29-32 USP)</td><td> 2,5</td><td> 6,75</td>

<td>Cross-linked sodium carboxymethyl cellulose</td><td> 1</td><td> 2,7</td>

<td>Magnesium stearate (NF, Ph, Eur)</td><td> 1</td><td> 2,7</td>

<td>Total weight of the capsule filling</td><td> 100</td><td> 270</td>

The above dosage unit composition was packed into a hard gelatin capsule (white, opaque size # 2) containing titanium dioxide (USP), gelatin (NF), and blue dye (SB-6018).

Example 3

Tablet - dose 100 mg

The tablets were prepared using the following preparation:

Table 3

<td>Ingredient</td><td>Quantity / Tablet (mg)</td><td>Share (% by weight)</td><td>Quantity / Batch (kg)</td>

<td> 1</td><td> 2</td><td> 3</td><td> 4</td>

<td>Celecoxib</td><td> 100</td><td> 40</td><td> 6,40</td>

<td>Lactose Monohydrate (NF)</td><td> 101,88</td><td> 40,75</td><td> 6,52</td>

PL 200 957 B1 cont. table 3

<td> 1</td><td> 2</td><td> 3</td><td> 4</td>

<td>Sodium Lauryl Sulfate (NF)</td><td> 7,5</td><td> 3</td><td> 0,48</td>

<td>Povidone (K29 / 32, USP)</td><td> 6,25</td><td> 2,5</td><td> 0,40</td>

<td>Cross-linked sodium carboxymethyl cellulose (Type A, NF)</td><td> 7,5</td><td> 3</td><td> 0,48</td>

<td>Microcrystalline cellulose (Avicel PH-102, NF)</td><td> 25</td><td> 10</td><td> 1,60</td>

<td>Magnesium stearate (NF)</td><td> 1,88</td><td> 0,75</td><td> 0,12</td>

<td>Overall</td><td> 250,01</td><td> 100</td><td> 16</td>

<td>Opadry White YS-1-18027A</td><td> 7,50</td><td> -</td><td> -</td>

The prepared tablets were 0.210 inches x 0.465 inches (5.0 mm x 11.2 mm) with a modified oval shape.

Avicel type microcrystalline cellulose used to prepare the tablets of Examples 3 and 4 is commercially available from FMC Corporation, Philadelphia, Pennsylvania.

Tablet doses in the range of 25 to 225 mg can be adjusted by increasing or decreasing the amount of celecoxib and each of the carrier materials disclosed above so as to maintain the same weight percentages as outlined above.

Example 4

Tablet - dose 200 mg

The tablets were prepared using the following composition:

Table 4

<td>Ingredient</td><td>Quantity / Tablet (mg)</td><td>Share (% by weight)</td><td>Quantity / Batch (kg)</td>

<td>Celecoxib</td><td> 200</td><td> 40</td><td> 6,40</td>

<td>Lactose Monohydrate (NF)</td><td> 203,75</td><td> 40,75</td><td> 6,52</td>

<td>Sodium Lauryl Sulfate (NF)</td><td> 15</td><td> 3</td><td> 0,48</td>

<td>Povidone (K29 / 32, USP)</td><td> 12,5</td><td> 2,5</td><td> 0,40</td>

<td>Cross-linked sodium carboxymethylcellulose (Avicel PH-102, NF)</td><td> 15</td><td> 3</td><td> 0,48</td>

<td>Microcrystalline Cellulose (Type A, NF)</td><td> 50</td><td> 10</td><td> 1,60</td>

<td>Magnesium stearate</td><td> 3,75</td><td> 0,75</td><td> 0,12</td>

<td>Overall</td><td> 500</td><td> 100</td><td> 16</td>

<td>Opadry White YS-1-18027A</td><td> 15,0</td><td> -</td><td> -</td>

The prepared tablets had the dimensions of 0.275 inch x 0.496 inch (6.6 mm x 11.9 mm) and the shape of a modified capsule.

Example 5

Disintegration test

Tablets were prepared as in Examples 3 and 4 except that they were left uncoated. Six identical tablets were placed separately in six tubes having a wire mesh bottom in a disintegration basket. The water bath was preheated to 37 ° C ± 2 ° C and held at that temperature throughout the disintegration test. A 1000 ml beaker was placed in a water bath. The beaker was filled with sufficient water to keep the wire mesh of the tubes at least 2.5 cm below the surface of the water during the test. The disintegration basket was placed in the water and repeatedly raised and lowered until the end of the test, all the while keeping 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, measured from the moment the basket was submerged, that the last tablet portion passed through the screen at the bottom of the tube. The average results for the uncoated tablets of Examples 3 and 4 are given in Table 5.

PL 200 957 B1

Table 5

<td>Pill</td><td>Time of disintegration</td>

<td>Example 3: tablet - 100 mg dose (uncoated)</td><td>4 minutes 35 seconds</td>

<td>Example 4: tablet - 200 mg dose (uncoated)</td><td>7 minutes 40 seconds</td>

Example 6

Dissolution test

An apparatus according to USP Method 2 (with stirrer) was used to determine the dissolution rate of the capsules of Examples 1 and 2 and the tablets of Examples 3 and 4, which were left uncoated for the purpose of these tests. A solution of 1% sodium lauryl sulfate / 0.04 Na3PO4 (pH = 12), 1000 ml was used as the dissolution fluid. The solution was kept at 37 ° C 5 ° C and stirred (50 rpm) during the test. Twelve identical tablets or capsules were tested. Each of the 12 tablets or capsules was separately placed in one of the 12 standard dissolving solution vessels, and then at 15, 30, 45 and 60 minutes, 5 ml samples were withdrawn from each vessel. The sample from each vessel was filtered and the absorbance of the sample was measured (UV spectrophotometer; 2 mm optical path, quartz cuvette; 243 nm or most UV wavelength; blank: dissolving medium). The percent dissolution was calculated from the measured absorbances. It should be noted that the solubility at high pH under the conditions of this test does not correspond to the solubility in the gastrointestinal tract.

Table 6

<td rowspan="2">Composition</td><td colspan="4">% dissolution</td>

<td>15 minutes</td><td>Thirty minutes</td><td>45 minutes</td><td>60 minutes</td>

<td>Example 1: 100 mg capsule</td><td> 89</td><td> 99</td><td> 100</td><td> 100</td>

<td>Example 2: 200 mg capsule</td><td> 55</td><td> 82</td><td> 89</td><td> 92</td>

<td>Example 3: 100 mg tablet</td><td> 81</td><td> 93</td><td> 94</td><td> 95</td>

<td>Example 4: 200 mg tablet</td><td> 60</td><td> 96</td><td> 98</td><td> 98</td>

Example 7

Grain size analysis

Table 7A shows the results of a screen grain size analysis of the moist granular pharmaceutical compositions of Examples 1 and 2, respectively, prior to encapsulation. "Percent Remaining Sieve" means the percentage by weight of the total load having a grain size greater than the indicated screen size.

Table 7A

<td rowspan="3">Screen size (pm)</td><td colspan="4">Percent retained on the sieve</td>

<td colspan="2">Example 1: 100 mg capsule</td><td colspan="2">Example 2: 200 mg capsule</td>

<td>lower limit</td><td>upper limit</td><td>lower limit</td><td>upper limit</td>

<td> 850</td><td> 0</td><td> 1,3</td><td> 1,1</td><td> 10,7</td>

<td> 425</td><td> 2,8</td><td> 14,9</td><td> 4,3</td><td> 25,4</td>

<td> 250</td><td> 10,0</td><td> 25,5</td><td> 10,8</td><td> 35,4</td>

<td> 180</td><td> 15,3</td><td> 39,0</td><td> 17,3</td><td> 39,2</td>

<td> 106</td><td> 32,5</td><td> 64,5</td><td> 35,2</td><td> 58,2</td>

<td> 75</td><td> 37,1</td><td> 77,5</td><td> 39,5</td><td> 71,8</td>

<td> 0</td><td> 100</td><td> 100</td><td> 100</td><td> 100</td>

Table 7B shows the results of a sieve analysis of the grain size of the moist granular pharmaceutical compositions of Examples 3 and 4, respectively, prior to compression into tablets. "Percentage of feed" means the weight percentage of the total feed having a grain size between the size indicated

Of the screen followed by the smaller screen size indicated. "Percentage of Batch, Total" indicates the weight percentage of the total batch having a grain size larger than the indicated screen size.

Table 7B

<td rowspan="2">Screen size (nm)</td><td colspan="2">Example 3: 100 mg tablet</td><td colspan="2">Example 4: 200 mg tablet</td>

<td>Percentage of the load</td><td>Percentage of total load</td><td>Percentage of the load</td><td>Percentage of total load</td>

<td>840 (20 mesh screen)</td><td> 1</td><td> 1</td><td> 0,79</td><td> 0,79</td>

<td>420 (40 mesh sieve)</td><td> 24,6</td><td> 25,5</td><td> 24,85</td><td> 25,64</td>

<td>250 (60 mesh screen)</td><td> 18,4</td><td> 44</td><td> 19,13</td><td> 44,77</td>

<td>177 (80 mesh sieve)</td><td> 9,6</td><td> 53,6</td><td> 11,05</td><td> 55,82</td>

<td>149 (100 mesh sieve)</td><td> 6,6</td><td> 60,2</td><td> 6,9</td><td> 62,72</td>

<td>105 (140 mesh sieve)</td><td> 11,6</td><td> 71,8</td><td> 11,44</td><td> 74,16</td>

<td>74 (200 mesh sieve)</td><td> 8,8</td><td> 80,6</td><td> 8,28</td><td> 82,45</td>

<td>Sifting</td><td> 19,4</td><td> 100</td><td> 17,55</td><td> 100</td>

Example 8 Bulk Density Analysis

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

Table 8

<td>Composition</td><td>Bulk density (g / ml)</td><td>Tapped bulk density (g / ml)</td><td>Loss on drying (%)</td>

<td>Example 1: 100 mg capsule</td><td> 0,77</td><td> 1,02</td><td> 0,6</td>

<td>Example 2: 200 mg capsule</td><td> 0,61</td><td> 0,96</td><td> 0,5</td>

<td>Example 3: 100 mg tablet</td><td> 0,73</td><td> 0,87</td><td> 1,37</td>

<td>Example 4: 200 mg tablet</td><td> 0,72</td><td> 0,86</td><td> 1,4</td>

<td>Example 9: Tablet Analysis Program</td><td> -</td><td> -</td><td> -</td>

Table 9 shows the results of the tablet analysis program ("TAP analysis") for the tablet samples having a composition like the tablets of Examples 3 and 4.

Table 9

<td>Pill</td><td>Average weight (mg)</td><td>Average thickness (mm)</td><td>Hardness (kP)</td>

<td>Example 3: 100 mg tablet</td><td> 248</td><td> 3,85</td><td> 8,2</td>

<td>Example 4: 200 mg tablet</td><td> 500</td><td> 5,22</td><td> 14,6</td>

Example 10

Brittleness test

Tablets weighing a total of 12 g were placed in a rotating drum. External dust was first removed from the drum and from the tablets. The drum was started and centrifugation was continued for 10 minutes at a minimum of 25 rpm. The spinning of the drum was stopped and tablets were removed. Loose dust from the tablets was removed as well as any broken tablets and the undamaged tablets were weighed. The percent weight loss was calculated for the tablets of Examples 3 and 4 and is given below in Table 10.

PL 200 957 B1

Table 10

<td>Pill</td><td>Percentage of loss</td>

<td>Example 3: 100 mg tablet</td><td> 0,33</td>

<td>Example 4: 200 mg tablet</td><td> 0,16</td>

Example 11-1

Bioavailability in an animal model (dog)

Healthy female Beagles weighing 9 to 13 pounds (4.1 to 5.9 kg) received the following single doses of celecoxib: (1) an intravenous infusion of 0.5 mg / kg body weight followed by a second intravenous infusion of 5.0 mg / kg body weight of celecoxib; (2) 5 mg / kg body weight of celecoxib oral solution and (3) 5.0 mg / kg body weight of unprepared celecoxib alone, oral capsule formulation. The vehicle for the intravenous doses and the oral solution was a mixture of polyethylene glycol having an average molecular weight of 400 (PEG-400) and water in a 2: 1 v / v ratio. Each intravenous infusion was administered over a 15-minute period with 15 to 30-minute intervals between two infusions.

Multiple blood samples were collected from each animal by venipuncture or indwelling catheter into heparinized tubes. The serum concentration of celecoxib was measured by HPLC and the results were used to calculate the pharmacokinetic parameters shown in Table 11-1 below.

Table 11-1

<td>Parameter pharmacokinetic</td><td>Intravenous infusion</td><td>Oral solution</td><td>Capsule, not prepared</td>

<td>Cmax (ng / ml)</td><td> 6950</td><td> 2190</td><td> 517</td>

<td>^T.max ^(h)</td><td>not applicable</td><td> 0,5</td><td> 3,0</td>

<td>AUCq- ,. (ng / ml) h</td><td> 31200</td><td> 16200</td><td> 4800</td>

<td>Clearance (ml / min kg)</td><td> 3,08</td><td> 5,14</td><td> 17,4</td>

<td>T._% (h)</td><td> 8,84</td><td> 9,15</td><td> 11,8</td>

<td>Bioavailability</td><td>not applicable</td><td> 57,1</td><td> 16,9</td>

Example 11-2

Relative bioavailability of preparations in an animal model (dog)

The effect of formulation parameters on bioavailability such as celecoxib grain size, increased wetting agent concentration, pH and dispersion of celecoxib as a suspension was assessed against the oral solution in an animal model (dog). The micronization effect of celecoxib (mean grain size 10-20 μτη) before preparation was tested in composition A. The combined effect of micronization, the addition of a wetting agent (sodium lauryl sulfate) and an increased microenvironmental pH (Na3PO412H2O) was tested in formulation B. The effect of bringing the wetting agent (Tween 80) into close contact with celecoxib (co-precipitation versus conventional dry mixing) was tested in the formulation C. The effect of further reducing grain size (approximately 1 μm) and dispersing the grains in the suspension was tested in formulation D. A celecoxib solution similar to that used in Example 11-1 (Composition E) is included as standard. In addition, data from Example 11-1 for unground, unprocessed celecoxib in a capsule (Composition F) is also provided as reference. The compositions of formulations A, B, C, D, E and F are summarized in Table 11-2A.

Table 11-2A

<td rowspan="2">Ingredient</td><td colspan="6">Share (% by weight of dry matter)</td>

<td>and</td><td>B</td><td>C.</td><td>D</td><td>E.</td><td>F.</td>

<td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td><td> 6</td><td> 7</td>

<td>Celecoxib (micronized)</td><td> 25</td><td> 25</td><td> -</td><td> -</td><td> -</td><td> -</td>

<td>Celecoxib / Tween80⁽¹⁾</td><td> -</td><td> -</td><td> 25</td><td> -</td><td> -</td><td> -</td>

PL 200 957 B1 cont. Table 11-2A

<td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td><td> 6</td><td> 7</td>

<td>Celecoxib (dispersed)⁽²⁾</td><td> -</td><td> -</td><td> -</td><td> 100</td><td> -</td><td></td>

<td>Celecoxib (solution)⁽³⁾</td><td> -</td><td> -</td><td> -</td><td> -</td><td> 100</td><td> -</td>

<td>Celecoxib (not ground)</td><td> -</td><td> -</td><td> -</td><td> -</td><td> -</td><td> 100</td>

<td>Sodium Lauryl Sulfate</td><td> 2</td><td> 25</td><td> -</td><td> -</td><td> -</td><td> -</td>

<td>Avicel 101</td><td> 73</td><td> 25</td><td> 75</td><td> -</td><td> -</td><td> -</td>

<td>Na3PO4H2O</td><td> -</td><td> 25</td><td> -</td><td> -</td><td> -</td><td> -</td>

<td>Overall</td><td> 100</td><td> 100</td><td> 100</td><td> 100</td><td> 100</td><td> 100</td>

⁽¹⁾ Precipitated from ethanolic solution using 5% aqueous polysorbate 80 as anti-solvent.

⁽²⁾ Prepared as a suspension by ball milling the drug in a suspension of polysorbate 80 and polyvinylpyrrolidone until the grains were approximately 1 µm in diameter as assessed by microscopy.

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

The compositions were administered to a group of three male and three female dogs. 1st group of dogs was administered 5 mg celecoxib per kg body weight in solution E and in encapsulation formulations A and B according to a non-random crossover schedule. 2nd group of dogs were administered 5 mg celecoxib per kg body weight in encapsulation formulation C and suspension D according to a non-random crossover schedule. Plasma samples were collected over 24 hours and analyzed for celecoxib by HPLC.

The results of the study (Tables 11-2B, 11-2C, and 11-2D) showed that with a reduction in grain size (composition A) or co-precipitation of celecoxib with a wetting agent (composition C), bioavailability increased (as measured by AUQ (0-24 )) celecoxib compared to the previous study for unprepared celecoxib presented in Example 11-1. The bioavailability of celecoxib was greater for the PEG-400 / water solution (formulation E) and the suspension (formulation D). The bioavailability of the approximately 1 Lm grain size suspension was similar to that of the solution and provided a clear indication that the availability of celecoxib from wet solid granules could be improved by grain size reduction (e.g. by pin milling the celecoxib prior to preparation). increasing the wettability of celecoxib (e.g. by adding sodium lauryl sulfate to the fluid during granulation) and improving dispersibility (e.g. by adding cross-linked sodium carboxymethyl cellulose during granulation). The bioavailability data in Tables 11-2C and 11-2D for each formulation show the bioavailability of a given formulation as a percentage of the bioavailability experimentally measured for intravenous administration of celecoxib, using the solution (formulation E) as a bridge between the studies of Examples 11-1 and 11- 2.

Table 11-2B

<td rowspan="2">Time (hours)</td><td colspan="6">Serum celecoxib concentration ((pg / ml)</td>

<td>AND</td><td>B</td><td>C.</td><td>D</td><td>E.</td><td>F.</td>

<td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>

<td> 0,5</td><td> 0,0143</td><td> 0,247</td><td> 0,0635</td><td> 0,453</td><td> 0,824</td><td> 0,205</td>

<td> 1,0</td><td> 0,244</td><td> 0,228</td><td> 0,443</td><td> 0,826</td><td> 0,820</td><td> 0,333</td>

<td> 2,0</td><td> 0,318</td><td> 0,138</td><td> 0,717</td><td> 0,865</td><td> 0,604</td><td> 0,262</td>

<td> 3,0</td><td> 0,189</td><td> 0,0860</td><td> 0,492</td><td> 0,741</td><td> 0,517</td><td> 0,517</td>

<td> 4,0</td><td> 0,145</td><td> 0,0707</td><td> 0,384</td><td> 0,576</td><td> 0,413</td><td> 0,234</td>

<td> 6,0</td><td> 0,107</td><td> 0,0664</td><td> 0,233</td><td> 0,354</td><td> 0,286</td><td> -</td>

<td> 7,0</td><td> -</td><td> -</td><td> -</td><td> -</td><td> -</td><td> 0,197</td>

<td> 8,0</td><td> 0,0828</td><td> 0,0624</td><td> 0,160</td><td> 0,234</td><td> 0,187</td><td> -</td>

<td> 12,0</td><td> 0,0939</td><td> 0,0431</td><td> 0,0865</td><td> 0,142</td><td> 0,0802</td><td> -</td>

<td> 24,0</td><td> -</td><td> 0,0404</td><td> 0,0408</td><td> 0,0394</td><td> 0,0159</td><td> -</td>

PL 200 957 B1

Table 11-2C

<td rowspan="2">Parameter pharmacokinetic</td><td colspan="6">Value for female dogs</td>

<td>AND</td><td>B</td><td>C.</td><td>D</td><td>E.</td><td>F.</td>

<td>Cmax (ng / ml)</td><td> 360±60</td><td> 250±70</td><td> 790±190</td><td> 1010±270</td><td> 840±240</td><td> 500</td>

<td>Tmax (h)</td><td> 1,3±0,2</td><td> 0,7±0,2</td><td> 1,5±0,3</td><td> 1,7±0,44</td><td> 0,67±0,18</td><td> 3,0</td>

<td>Bioavailability (%)</td><td> 31,2±2,9</td><td> 24,9±1,4</td><td> 46,3±9,5</td><td> 69,5±9,6</td><td> 62,4±9,4</td><td> 16,9</td>

Table 11-2D

<td rowspan="2">Parameter pharmacokinetic</td><td colspan="6">Value for male dogs</td>

<td>AND</td><td>B</td><td>C.</td><td>D</td><td>E.</td><td>F.</td>

<td>Cmax (ng / ml)</td><td> 520±110</td><td> 450±180</td><td> 640±260</td><td> 830±330</td><td> 1520±200</td><td> 500</td>

<td>Tmax (h)</td><td> 5,3±3,3</td><td> 3,3±1,3</td><td> 1,5±0,5</td><td> 5,7±3,42</td><td> 1,5</td><td> 3,0</td>

<td>Bioavailability (%)</td><td> 49,4±12,0</td><td> 54,2±13,1</td><td> 42,9±13,1</td><td> 87,5±20,6</td><td> 89,4±4,5</td><td> 16,9</td>

Example 11-3

Various formulations containing sodium lauryl sulfate (0-5 wt%) and cross-linked sodium carboxymethylcellulose (0-5 wt%) were screened for relative wettability and disintegration tendency. Relative wettability was estimated by measuring the time required for water to penetrate a column of granular material prepared from each formulation. The disintegration tendency was determined by measuring the weight of the granular material retained on a 20 mesh (850 mm) screen after soaking the material at 37 ° C in water for 5 minutes. The compositions of the evaluated preparations A to H are listed in Table 11-3 A.

Table 11-3A

<td rowspan="2">Composition</td><td colspan="8">Share (% by weight)</td>

<td>AND⁽¹⁾</td><td>B</td><td>C.</td><td>D</td><td>E.</td><td>F.</td><td>G.</td><td>H.</td>

<td>Celecoxib</td><td> 74,7</td><td> 74,7</td><td> 74,7</td><td> 74,7</td><td> 74,7</td><td> 74,7</td><td> 74,7</td><td> 74,7</td>

<td>Lactose</td><td> 15,8</td><td> 15,8</td><td> 21,8</td><td> 19,8</td><td> 17,8</td><td> 15,8</td><td> 17,8</td><td> 11,8</td>

<td>Polyvinylpyrrolidone</td><td> 2,5</td><td> 2,5</td><td> 2,5</td><td> 2,5</td><td> 2,5</td><td> 2,5</td><td> 2,5</td><td> 2,5</td>

<td>Lauryl sulfate soda</td><td> 3,0</td><td> 3,0</td><td> 0,0</td><td> 1,0</td><td> 1,0</td><td> 1,0</td><td> 3,0</td><td> 5,0</td>

<td>Ac-di-sol</td><td> 3,0</td><td> 3,0</td><td> 0,0</td><td> 1,0</td><td> 3,0</td><td> 5,0</td><td> 1,0</td><td> 5,0</td>

<td>Stearate magnesium</td><td> 1,0</td><td> 1,0</td><td> 1,0</td><td> 1,0</td><td> 1,0</td><td> 1,0</td><td> 1,0</td><td> 1,0</td>

⁽¹⁾ Sodium lauryl sulfate was added as a dry powder.

The results are summarized in Table 11-3B. Penetration tests were performed in triplicate. Disintegration tests were performed twice. Penetration test results showed that wet application of sodium lauryl sulphate (formulation B) was better than dry application (formulation A), and that formulations containing 3% to 5% sodium lauryl sulphate (formulations B, G and H) were superior to those with lower amounts. sodium lauryl sulfate (compositions C to F). The formulations containing 3% sodium lauryl sulfate (compositions B and G) were similar to those containing 5% sodium lauryl sulfate (composition H). The results of the disintegration study showed that complete disintegration could be obtained with a cross-linked sodium carboxymethylcellulose concentration as low as 1% (composition G) and a wetting agent concentration of 3%. Complete disintegration can also be achieved with higher amounts of disintegrant (compositions B, F and H) regardless of the concentration of the wetting agent. Composition G shows both better penetration and complete disintegration with the minimum amount of excipient required.

PL 200 957 B1

Table 11-3B

<td>Composition</td><td>% Sodium lauryl sulfate / -% Ac-di-sol</td><td>Penetration time</td><td>Disintegration</td>

<td>AND⁽¹⁾</td><td> 3/3</td><td>&gt; 18 hours</td><td> 0,1 - 0,5%</td>

<td>B</td><td> 3/3</td><td>5 - 60 minutes</td><td>was not found</td>

<td>C.</td><td> 0/0</td><td>&gt; 4 to&gt; 18 hours</td><td> 20 - 26%</td>

<td>D</td><td> 1/1</td><td>&gt; 4 to&gt; 18 hours</td><td> 10 - 13%</td>

<td>E.</td><td> 1/3</td><td>2 to 4 hours</td><td> 4 - 6%</td>

<td>F.</td><td> 1/5</td><td>1 to 4 hours</td><td>was not found</td>

<td>G.</td><td> 3/1</td><td>10 to 40 minutes</td><td>was not found</td>

<td>H.</td><td> 5/5</td><td>10 to 55 minutes</td><td>was not found</td>

Example 12

The following formulations were assessed for wetting effects and mixture homogeneity:

Table 12

<td rowspan="2">Ingredient</td><td colspan="8">Share (% by weight)</td>

<td colspan="2">Lactose, dry mix</td><td colspan="2">Microcrystalline cellulose, dry mix</td><td colspan="2">Polyvinylpyroldone, granules¹</td><td colspan="2">Polysorbate 80, granules²</td>

<td>Celecoxib</td><td> 5</td><td> 60</td><td> 5</td><td> 60</td><td> 5</td><td> 60</td><td> 5</td><td> 60</td>

<td>Lactose</td><td> 94,5</td><td> 39,5</td><td> -</td><td> -</td><td> 92</td><td> 37</td><td> 93,5</td><td> 38,5</td>

<td>Microcrystalline cellulose</td><td> -</td><td> -</td><td> 94,5</td><td> 39,5</td><td> -</td><td> -</td><td> -</td><td> -</td>

<td>Polysorbate 80</td><td> -</td><td> -</td><td> -</td><td> -</td><td> -</td><td> -</td><td> 1,0</td><td> 1,0</td>

<td>Povidone (K29-32)</td><td> -</td><td> -</td><td> -</td><td> -</td><td> 2,5</td><td> 2,5</td><td> -</td><td> -</td>

<td>Stearate magnesium</td><td> 0,5</td><td> 0,5</td><td> 0,5</td><td> 0,5</td><td> 0,5</td><td> 0,5</td><td> 0,5</td><td> 0,5</td>

¹ In this formulation, polyvinylpyrrolidone was added to the blend as a dry powder prior to granulation with water.

² In this formulation, celecoxib and lactose were granulated with an aqueous solution of polysorbate 80.

The 5% celecoxib blends showed better blend homogeneity than the 60% celecoxib blends. Relative standard deviations measured for the 5% celecoxib blends ranged from 0.4% to 3.5%, while the measured relative standard deviations for the 60% celecoxib blends ranged from 4.7% to 6 , 3%. In addition, the less homogeneous blend of 60% celecoxib contained relatively large granules (greater than 420 µm) that were hyperactive (contained 125% to 132% higher celecoxib concentrations than the other granules).

Four similar preparations were prepared containing 25% celecoxib instead of 5% or 60% celecoxib. The bioavailability of these preparations was assessed in an animal model (dog) following a procedure similar to Examples 11-1 and 11-2. The preparation with polyvinylpyrrolidone after wet granulation showed the highest bioavailability (about 74%).

Example 13

Capsules containing the following preparations were prepared and evaluated:

Table 13A

<td rowspan="2">Ingredient</td><td colspan="3">Amount (mg)</td>

<td>5 mg capsule</td><td>20 mg capsule</td><td>100 mg capsule</td>

<td> 1</td><td> 2</td><td> 3</td><td> 4</td>

<td>Celecoxib</td><td> 5</td><td> 20</td><td> 100</td>

<td>Lactose</td><td> 92</td><td> 77</td><td> 61,9</td>

PL 200 957 B1 cont. Table 13A

<td> 1</td><td> 2</td><td> 3</td><td> 4</td>

<td>Povidone (K29-32)</td><td> 2,5</td><td> 2,5</td><td> 4</td>

<td>Magnesium stearate</td><td> 0,5</td><td> 0,5</td><td> 0,8</td>

<td>Overall</td><td> 100</td><td> 100</td><td> 166,7</td>

<td>Capsule shell</td><td> 1</td><td> 1</td><td> 1</td>

<td>Capsule size</td><td> #3</td><td> #3</td><td> #3</td>

Celecoxib was comminuted by repeatedly passing it through an oscillating mill equipped with successively decreasing size of the sieves (# 14, # 20, # 40). The D90 grain size of the celecoxib particles added to this mixture was less than about 37 µm. Celecoxib, lactose and polyvinylpyrrolidone were mixed in a planetary mixer and wet granulated with water. The granulate was then tray dried at 60 ° C, sieved through a 40 mesh screen, lubricated with magnesium stearate in a V-blender and encapsulated in a dispenser encapsulating machine. The in vivo dissolution profile of the capsules was determined using USP method 2 and a 15 mM phosphate buffer at pH 10 as the dissolution medium. About 50% in vitro dissolution was achieved after about 15 minutes and more than 90% in vitro dissolution after about 30 minutes.

The absorption, distribution, metabolism and elimination profile of this 100 mg unit dose-capsule was compared to the suspension profile ¹⁴C-celecoxib. The study was an open label, randomized, crossover study conducted in healthy male subjects. A suspension was prepared by dissolving celecoxib in ethanol containing 5% polysorbate 80 and adding this mixture to apple juice prior to administration. Subjects receiving the suspension ingested a 300 mg dose of celecoxib. Subjects receiving encapsulated celecoxib ingested three 100 mg unit dose capsules for a total dose of 300 mg celecoxib. The rate of absorption from the capsule was slower than from the suspension, but was equivalent to the suspension when measured by AUC0-48. The mean results are shown in Table 13B below. Most of the celecoxib was metabolized and only 2.56% of the radioactive dose was found in urine or faeces.

Table 13B

<td>Pharmacokinetic parameter</td><td>Suspension</td><td>Capsules</td>

<td>AUC (0-48) ((ng / ml) hr)</td><td> 8706,7</td><td> 8763,1</td>

<td>Cmax (ng / ml)</td><td> 1526,5</td><td> 1076,5</td>

<td>Tmax (h)</td><td> 1,42</td><td> 1,94</td>

<td>T% (h)</td><td> 11,53</td><td> 15,57</td>

Example 14

Capsules having the following composition were prepared and evaluated:

Table 14

<td rowspan="2">Ingredient</td><td colspan="2">Amount (mg)</td>

<td>100 mg capsule</td><td>200 mg capsule</td>

<td>Celecoxib</td><td> 100</td><td> 200</td>

<td>Lactose</td><td> 223,4</td><td> 120,1</td>

<td>Povidone (K29-32)</td><td> 8,3</td><td> 8,3</td>

<td>Magnesium stearate</td><td> 1,7</td><td> 5</td>

<td>Overall</td><td> 333,4</td><td> 333,4</td>

<td>Capsule size</td><td> #1</td><td> #1</td>

These formulations were prepared in a similar manner to the formulations of Example 13, except that a pin impact mill was used instead of an oscillating mill. The grain size was further reduced with use

PL 200 957 B1 of a pin mill. For a 100 mg capsule, approximately 305 in vitro dissolution was achieved after approximately 15 minutes and greater than 85% in vitro dissolution after approximately 30 minutes. For a 200 mg capsule, approximately 50% in vitro dissolution was achieved after approximately 15 minutes and greater than 85% in vitro dissolution after approximately 30 minutes.

Example 15

Preparation of capsules with a dose of 100 mg

Capsules providing 100 mg or 200 mg doses of celecoxib and having the composition of Examples 1 and 2, respectively, may be prepared according to acceptable pharmaceutical manufacturing practice as illustrated in Figure 1 or Figure 2. Tablets providing a 100 mg dose. or 200 mg of celecoxib and having the composition set forth in Examples 3 or 4, respectively, can be prepared by appropriately modifying the method of Fig. 1 or Fig. 2, considering the extra-granular addition of cross-linked sodium carboxymethylcellulose and microcrystalline cellulose, and tabletting instead of encapsulating the composition.

In the illustrated method of preparing a large quantity of 100 mg capsules using the starting materials disclosed above, a typical batch is composed of four identical granulation sections, although the number of granulation sections is not narrowly limited and depends mainly on the tooling capacity and the required batch size.

Example 16

Bioequivalence study

The bioequivalence and safety of 200 mg celecoxib doses was evaluated in an open-label, randomized, single-dose, three-way crossover study in 46 healthy adult humans. Subjects received three single 200 mg doses of celecoxib administered as (A) one 200 mg capsule, (B) two 100 mg capsules, or (C) two 100 mg capsules (from different batches). Treatment was carried out at seven-day intervals. Specific pharmaceutical compositions for the 100 mg dose capsule and the 200 mg dose capsule are disclosed in Examples 1 and 2, respectively. Subjects received single oral doses of research medication in a fasted state including about 180 ml of water at 8 o'clock. remained upright for four hours after dosing. Blood samples were collected at -0.25 (pre-dosing), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours post-dose. Separated plasma analyzes were performed with PPD, Pharmaco, Richmond, VA. Plasma celecoxib concentrations were determined by a validated procedure using high performance liquid chromatography ("HPLC") with the lower limit of detection 10.0 ng / ml. Each subject was tested separately. A minimum washout period of seven days was allowed between administration of each single 200 mg dose. The mean results obtained for the 46 subjects studied are given in Tables 16A and 16B below.

Table 16A

<td rowspan="2">Time (hours)</td><td colspan="3">Celecoxib plasma concentration (ng / ml)</td>

<td>One 200 mg capsule</td><td>Two 100 mg capsules (load 1)</td><td>Two 100 mg capsules (load 2)</td>

<td> 1</td><td> 2</td><td> 3</td><td> 4</td>

<td> -0,25</td><td> 0,22</td><td> 0,00</td><td> 0,00</td>

<td> 0,5</td><td> 103,74</td><td> 117,89</td><td> 212,61</td>

<td> 1,0</td><td> 418,24</td><td> 446,39</td><td> 647,00</td>

<td> 1,5</td><td> 575,68</td><td> 606,97</td><td> 826,90</td>

<td> 2,0</td><td> 646,83</td><td> 656,98</td><td> 862,23</td>

<td> 3,0</td><td> 686,19</td><td> 666,55</td><td> 781,13</td>

<td> 4,0</td><td> 621,02</td><td> 595,21</td><td> 660,15</td>

<td> 6,0</td><td> 389,00</td><td> 387,41</td><td> 383,81</td>

<td> 8,0</td><td> 322,24</td><td> 332,51</td><td> 323,59</td>

<td> 12,0</td><td> 214,63</td><td> 208,06</td><td> 209,96</td>

<td> 16,0</td><td> 149,11</td><td> 146,40</td><td> 144,23</td>

PL 200 957 B1 cont. Table 16A

<td> 1</td><td> 2</td><td> 3</td><td> 4</td>

<td> 24,0</td><td> 116,09</td><td> 111,77</td><td> 113,21</td>

<td> 36,0</td><td> 52,76</td><td> 48,27</td><td> 46,98</td>

<td> 48,0</td><td> 27,24</td><td> 26,47</td><td> 22,44</td>

Table 16B

<td rowspan="2">Parameter pharmacokinetic</td><td colspan="3">The value of the pharmacokinetic parameter</td>

<td>One 200 mg capsule</td><td>Two 100 mg capsules (load 1)</td><td>Two 100 mg capsules (load 2)</td>

<td>AUC (0-48) ((ng / ml) hr)</td><td> 8107,07</td><td> 7976,56</td><td> 8535,49</td>

<td>AUC (0-lqc) ((ng / ml) hr)</td><td> 8063,17</td><td> 7953,71</td><td> 8501,94</td>

<td>AUC (0. ") ((ng / ml) hr)</td><td> 8828,64</td><td> 8640,46</td><td> 9229,52</td>

<td>Cmax (ng / ml)</td><td> 801,19</td><td> 815,21</td><td> 959,50</td>

<td>Tmax (h)</td><td> 2,46</td><td> 2,84</td><td> 2,23</td>

<td>You₂ (h)</td><td> 12,22</td><td> 13,52</td><td> 10,67</td>

<td>Cmax / AUC (0-LQC)</td><td> 0,10</td><td> 0,10</td><td> 0,20</td>

Example 17

Food impact study

An open-label, randomized, single-dose, three-way crossover study was used to evaluate dose proportionality and food effect on the pharmacokinetic profile of celecoxib in healthy adult subjects. Safety was assessed based on adverse events, signs of recovery, and clinical laboratory tests. Twenty-four healthy adult subjects randomly received the following single doses of celecoxib: (A) 50 mg capsule fasted, (B) 50 mg capsule immediately after high-fat breakfast, (C) 100 mg capsule fasted, and (D) 100 mg capsule mg immediately after a high-fat breakfast. Subjects received research medication on days 1, 8, 15, and 22 in one or four anxiety sequences (ADBC; BACD; CDDA; and DCAB). A specific 100 mg dose capsule composition is disclosed in Example 1. A specific 50 mg dose capsule composition is disclosed in Table 17A below.

Table 17A

<td>Ingredient</td><td>Amount (mg)</td>

<td>Celecoxib</td><td> 50,00</td>

<td>Lactose Monohydrate</td><td> 199,8</td>

<td>Sodium lauryl sulfate</td><td> 8,1</td>

<td>Povidone (K29-32)</td><td> 6,8</td>

<td>Cross-linked sodium carboxymethyl cellulose</td><td> 2,7</td>

<td>Magnesium stearate</td><td> 2,7</td>

<td>Total weight of the capsule filling</td><td> 270,0</td>

The above dosage unit composition was packed into a hard gelatin capsule (white, opaque, size # 2).

Blood samples were collected at -0.25 (pre-dosing), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours post-dose. Separated plasma analyzes were performed with PPD, Pharmaco, Richmond, VA. Plasma celecoxib concentrations were determined by a validated procedure using high performance liquid chromatography ("HPLC") with the lower limit of detection 10.0 ng / ml. There were no clinically significant changes in signs of recovery or physical examination. All are not ok26

The preferred cases were mild. The mean results obtained for the 24 subjects studied are given in Tables 17B and 17C below.

Table 17B

<td rowspan="2">Time (h)</td><td colspan="4">Celecoxib plasma concentration (ng / ml)</td>

<td>100 mg capsule (fasted)</td><td>100 mg capsule (high fat breakfast)</td><td>50 mg capsule (fasted)</td><td>50 mg capsule (high-fat breakfast)</td>

<td> -0,25</td><td> 0,00</td><td> 0,00</td><td> 0,00</td><td> 0,00</td>

<td> 0,5</td><td> 63,96</td><td> 1,35</td><td> 52,90</td><td> 2,38</td>

<td> 1,0</td><td> 225,65</td><td> 14,00</td><td> 155,07</td><td> 11,98</td>

<td> 1,5</td><td> 344,77</td><td> 49,37</td><td> 202,22</td><td> 29,85</td>

<td> 2,0</td><td> 354,45</td><td> 139,43</td><td> 220,15</td><td> 63,00</td>

<td> 3,0</td><td> 348,03</td><td> 438,99</td><td> 253,85</td><td> 186,94</td>

<td> 4,0</td><td> 333,86</td><td> 600,00</td><td> 244,80</td><td> 298,23</td>

<td> 6,0</td><td> 196,53</td><td> 355,65</td><td> 118,58</td><td> 188,90</td>

<td> 8,0</td><td> 152,35</td><td> 314,54</td><td> 91,79</td><td> 165,85</td>

<td> 12,0</td><td> 121,08</td><td> 179,04</td><td> 61,13</td><td> 88,76</td>

<td> 16,0</td><td> 86,13</td><td> 102,12</td><td> 39,51</td><td> 51,86</td>

<td> 24,0</td><td> 61,77</td><td> 49,31</td><td> 28,22</td><td> 22,81</td>

<td> 36,0</td><td> 38,00</td><td> 17,88</td><td> 10,69</td><td> 8,75</td>

<td> 48,0</td><td> 17,77</td><td> 7,91</td><td> 5,77</td><td> 3,80</td>

Table 17C

<td rowspan="2">Parameter pharmacokinetic</td><td colspan="4">The value of the pharmacokinetic parameter</td>

<td>100 mg capsule (fasted)</td><td>100 mg capsule (high-fat breakfast)</td><td>50 mg capsule (fasted)</td><td>50 mg capsule (high-fat breakfast)</td>

<td>AUC (0-48) ((ng / ml) hr)</td><td> 4463,28</td><td> 5214,86</td><td> 2426,23</td><td> 2601,10</td>

<td>AUC (0-lqc) ((ng / ml) hr)</td><td> 4415,59</td><td> 5105,50</td><td> 2352,68</td><td> 2501,56</td>

<td>AUC (0. ") ((ng / ml) hr)</td><td> 5126,74</td><td> 5419,21</td><td> 2693,80</td><td> 2759,42</td>

<td>Cmax (mg / ml)</td><td> 455,00</td><td> 746,96</td><td> 321,46</td><td> 354,17</td>

<td>Tmax (h)</td><td> 2,60</td><td> 5,00</td><td> 2,92</td><td> 4,46</td>

<td>You₂ (h)</td><td> 16,02</td><td> 6,86</td><td> 11,01</td><td> 6,49</td>

<td>Cmax / AUC (0-LQC)</td><td> 0,11</td><td> 0,15</td><td> 0,16</td><td> 0,16</td>

Example 18

Pharmacokinetics of the suspension relative to the capsule formulation

The pharmacokinetics and bioavailability of the oral fine suspension and the two celecoxib oral capsules were evaluated in an open label, randomized, single dose, crossover study. Thirty-six healthy adult subjects randomly received the following single doses of celecoxib: (A) one 200 mg capsule, (B) two 100 mg capsules, and (C) 100 mg oral fine suspension. The entire treatment lasted 18 days. On days 1, 8, and 15, subjects received one of the three medications on an andomic schedule. Treatments of PL 200 957 B1 were separated by seven-day intervals. A specific pharmaceutical composition for a 200 mg dose capsule is disclosed in Example 2. A specific pharmaceutical composition for a 100 mg dose capsule is disclosed in Table 18A below.

Table 18A

<td>Ingredient</td><td>Amount (mg)</td><td>Weight %</td>

<td>Celecoxib</td><td> 100,00</td><td> 60,0</td>

<td>Lactose Monohydrate</td><td> 61,7</td><td> 37,0</td>

<td>Povidone, K29-32</td><td> 4,20</td><td> 2,51</td>

<td>Magnesium stearate</td><td> 0,80</td><td> 0,48</td>

The pharmaceutical composition used for the 100 mg dose capsules was prepared by passing the starting celecoxib through a 40 mesh vibrating sieve (no additional grinding was performed), wet granulation of celecoxib, lactose and povidone in a planetary shear mixer, drying on trays and grinding the granulated mixture , adding magnesium stearate to the granulation mixture and blending to form the final pharmaceutical composition.

The oral fine suspension was prepared by dissolving celecoxib in ethanol containing 5% polysorbate 80 and adding this mixture to apple juice prior to administration.

Blood samples were drawn at -0.25 (pre-dose) and within 72 hours post-dose. Each subject was tested separately after receiving a 200 mg dose capsule, 100 mg dose capsules and an oral fine suspension. A minimum washout period of seven days was allowed between administration of each 200 mg dose. The mean results obtained for the 36 subjects tested are shown in Table 18B below.

Table 18B

<td rowspan="2">Parameter pharmacokinetic</td><td colspan="3">The value of the pharmacokinetic parameter</td>

<td>Two 100 mg capsules</td><td>One 200 mg capsule</td><td>200 mg oral fine suspension</td>

<td>AUC (0-72) ((ng / ml) hr)</td><td> 7247,5±2427,5</td><td> 7648.1±2412,1</td><td> 7736,2±2488,2</td>

<td>AUC (0- "j ((ng / ml) hr)</td><td> 7562,4±2494,0</td><td> 7830,3±2448,4</td><td> 8001,2±2535,6</td>

<td>Cmax (ng / ml)</td><td> 619,7±249,4</td><td> 704,6±265,7</td><td> 1228,8±452,0</td>

<td>Tmax (h)</td><td> 3,00±0,99</td><td> 2,83±1,06</td><td> 0,79±0,32</td>

<td>T% (h)</td><td> 13,96±5,27</td><td> 11,92±3,60</td><td> 13,33±6,69</td>

<td>Clearance (0-72) (l / h)</td><td> 30,4±9,8</td><td> 28,4±7,8</td><td> 28,1±7,8</td>

In general, the celecoxib absorption rate (higher C max and shorter T max) was faster for the oral fine suspension than for the capsules. However, the overall degree of celecoxib absorption for the Oral Fine suspension, measured as AUC (_0-72) or AUC (_0-"), Was similar for the total celecoxib absorption for the capsules.

Since various modifications can be made to the foregoing formulations and methods without departing from the scope of the invention, all the subject matter contained in the foregoing disclosure should be taken as illustrative, but not intended to limit the scope of the invention.