HK1059561A - Cycloxooxygenase-2 inhibitor compositions havign rapid onset of therapeutic effect - Google Patents

Description

Cyclooxygenase-2 inhibitor composition capable of rapidly starting therapeutic action

Technical Field

The present invention relates to oral pharmaceutical compositions containing a selective cyclooxygenase-2 inhibitory drug as an active ingredient, methods of preparing said compositions, methods of treating cyclooxygenase-2 mediated diseases by orally administering said compositions to a subject, and the use of said compositions in the manufacture of a medicament.

Background

Many compounds have been reported to have selective cyclooxygenase-2 (COX-2) inhibition that is of value in therapy and/or prophylaxis, and they are disclosed as being useful in the treatment or prophylaxis of specific COX-2 mediated diseases or of most such diseases. Among such compounds, there are a number of substituted pyrazolyl benzenesulfonamides as disclosed in U.S. Pat. No. 5760068 to Talley et al, including, for example, the compound 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl]Benzenesulfonamides, also referred to herein as celecoxib (I), and the compound 4- [5- (3-fluoro-4-methoxyphenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl]Benzenesulfonamides, also referred to herein as deracoxib (ii).

Other compounds reported to have selective COX-2 inhibitory effects for therapeutic and/or prophylactic use are the substituted isoxazolyl benzenesulfonamides disclosed in U.S. Pat. No. 5633272 to Talley et al, including the compound 4- [ 5-methyl-3-phenylisoxazol-4-yl]Benzenesulfonamides, also referred to herein as valdecoxib (iii).

Other compounds reported to have selective COX-2 inhibition for therapeutic and/or prophylactic use are also substituted (methylsulfonyl) phenyl furanones (furanones) disclosed in U.S. Pat. No. 5474995 to Ducharme et al, including the compound 3-phenyl-4- [4- (methylsulfonyl) phenyl-]-5H-furan-2-one, also referred to herein as rofecoxib (iv).

U.S. patent 5981576 to Belley et al discloses another series of (methylsulfonyl) phenyl furanones described as useful as selective COX-2 inhibitory drugs, including 3- (1-cyclopropylmethoxy) -5, 5-dimethyl-4- [4- (methylsulfonyl) phenyl ] -5H-furan-2-one and 3- (1-cyclopropylethoxy) -5, 5-dimethyl-4- [4- (methylsulfonyl) phenyl ] -5H-furan-2-one.

Dube et al, U.S. Pat. No. 5861419, discloses substituted pyridines stated to be useful as selective COX-2 inhibitory drugs, including, for example, the compound 5-chloro-3- (4-methylsulfonyl) phenyl-2- (2-methyl-5-pyridyl) pyridine (V).

European patent application 0863134 discloses the compound 2- (3, 5-difluorophenyl) -3- [4- (methylsulfonyl) phenyl ] -2-cyclopenten-1-one which is stated to be useful as a selective COX-2 inhibitory drug.

U.S. Pat. No. 6034256 discloses a series of benzopyrans described as useful as selective COX-2 inhibitory drugs, packageComprises a compound (S) -6, 8-dichloro-2- (trifluoromethyl) -2H-1-benzopyran-3-formic acid (VI).

Many selective COX-2 inhibitory drugs, including celecoxib, deracoxib, valdecoxib, and rofecoxib, are hydrophobic and have little solubility in water. This presents practical difficulties in formulating such drugs for oral administration, particularly when it is desired or necessary for such drugs to begin their therapeutic action rapidly.

For example, to date, the formulation of celecoxib for effective oral administration to a subject has been complicated by its unique physical and chemical properties, particularly its low solubility and factors associated with its crystal structure, including cohesiveness, low bulk density, and low compressibility. celecoxib is generally insoluble in aqueous media. Unformulated celecoxib is not readily dissolved or dispersed and, therefore, is not rapidly absorbed in the gastrointestinal tract when administered orally, for example, in capsule form. In addition, unformulated celecoxib, which has a crystal morphology that tends to form long, sticky needles, typically melts into a monolithic mass when compressed in a tableting die. Even when mixed with other materials, the ce1ecoxib crystals tend to separate from the other materials and agglomerate together during mixing of the composition, resulting in the formation of an ununiformly mixed composition containing undesirably large agglomerates of celecoxib. Thus, it is difficult to prepare a pharmaceutical composition containing celecoxib having the desired mixing uniformity. In addition, handling problems resulting from, for example, low bulk density of celecoxib are also encountered during the preparation of celecoxib compositions. Accordingly, there is a need to address many of the problems associated with preparing compositions and dosage forms, particularly oral unit dosage forms, containing celecoxib.

Furthermore, there is a particular need for such formulations: i.e., oral formulations of selective COX-2 inhibitory drugs, including celecoxib, that have low aqueous solubility, such formulations are able to begin therapeutic action more rapidly than the corresponding unformulated drugs or known formulations of such drugs. The extent of rapid onset of therapeutic action and pharmacokinetic parameters such as high drug maximum bloodClear concentration (C)_max) And a short time to reach maximum serum concentration (T) after oral administration_max) In connection with this, there is a particular need for such formulations: i.e., oral formulations of selective COX-2 inhibitory drugs, including celecoxib, having low aqueous solubility, which provide a C greater than that of the corresponding unformulated drug or known formulations of such drugs_maxAnd/or shorter T_max。

As described below, a number of COX-2 mediated conditions and diseases can be treated or potentially treated with selective COX-2 inhibitory drugs, including celecoxib. In particular for the treatment of acute conditions where pain or other symptoms need or must be relieved as early as possible, it would be beneficial to provide a formulation whose pharmacokinetics are consistent with a rapid onset of therapeutic action.

Such formulations would represent a significant advance in the treatment of COX-2 mediated conditions and diseases.

Selective COX-2 inhibitory drugs, including celecoxib, which have low aqueous solubility are most conveniently formulated in solid particulate form. The individual or primary drug particles may be dispersed in a liquid medium, such as in a suspending agent, or they may be agglomerated to form secondary particles or granules that may be encapsulated to provide a capsule dosage form, or they may be compressed or molded to provide a tablet dosage form.

It is known that there are many ways to prepare a powder having a desired range of primary particle sizes, or having a desired average particle size, or having a desired particle size defined by a parameter such as D₉₀Method for characterizing a particle size distribution of a pharmaceutical preparation, wherein D₉₀Defined herein as a linear measurement of the diameter: wherein 90% by weight of the particles in the formulation are smaller than this diameter in the longest particle dimension. Other granularity parameters used herein are defined in a similar manner; for example, D₁₀、D₂₅And D₅₀The parameters refer to such linear measurements of diameter: wherein 10%, 25% and 50% by weight of the particles, respectively, are smaller than the diameter.

For consistency with prior art publications, the terms "microparticles" and "nanoparticles" are defined herein as in Courteille et al, U.S. patent 5384124, referring to particles having a diameter of about 1 μm to about 2000 μm and a diameter of less than about 1 μm (1000nm), respectively. According to us patent 5384124, micro-and nanoparticle formulations "are used primarily to delay dissolution of the active ingredient". However, U.S. patent 5145684 to Liversidge et al discloses nanoparticle compositions that are stated to provide "unexpectedly high bioavailability" to drugs, particularly drugs that have low solubility in liquid media such as water. The international publication WO93/25190 provides pharmacokinetic data from rat experiments, which show that significantly faster absorption rates are obtained with dispersions of nanoparticles (average particle size 240-300nm) of orally administered naproxen compared to dispersions of microparticles (particle size 20-30 μm) of orally administered naproxen.

A number of methods are known for preparing nanoparticle compositions of therapeutic agents. These methods typically use mechanical means such as milling to reduce the particle size to the nanometer (below 1 μm) range, or to precipitate nano-sized particles from solution.

Brief description of the invention

According to the present invention, a poorly water soluble selective COX-2 inhibitory drug exhibiting a serum maximum concentration (C) that results in a greater drug is caused to begin therapeutic action more rapidly following oral administration of a composition containing the drug_max) And/or shorter time to reach maximum serum concentration (T) after administration_max) The pharmacokinetic profile of (a). Larger C's can be obtained by reducing the size of the solid particles comprising the drug so that the majority (by weight) of the particles are less than about 1 μm in diameter at the longest particle dimension_maxAnd/or shorter T_max. Without being bound by theory, it is believed that the larger C_maxAnd/or shorter T_maxDue to the faster dissolution of the drug when the particle size is reduced below about 1 μm.

Accordingly, the present invention provides pharmaceutical compositions comprising one or more oral dosage units, each dosage unit comprising a therapeutically effective amount of a low aqueous solubilityA sex selective COX-2 inhibitory drug, wherein the drug is present in D₉₀Of solid particles having a particle size of from about 0.01 to about 200 μm, and having a sufficient weight fraction of particles less than 1 μm to provide a substantially increased C as compared to an otherwise similar composition having substantially all particles greater than 1 μm_maxAnd/or substantially shortened T_max。

The invention also provides a pharmaceutical composition comprising one or more oral dosage units, each dosage unit comprising a therapeutically effective amount of a selective COX-2 inhibitory drug of low water solubility, wherein the drug is present in D₉₀Solid particles having a particle size of about 0.01 to about 200 μm, and about 25% to 100% by weight of the particles are smaller than 1 μm.

Dosage units containing the compositions can be in the form of discrete solid products, such as tablets, pills, hard or soft capsules, lozenges, sachets, or pastilles; alternatively the composition may be in the form of a substantially homogeneous flowable mass, such as a particulate or finely divided solid or liquid suspension, from which single dose units may be removed by measurement.

The present invention also provides a method of treating a condition or disease in an individual for which a COX-2 inhibitor is indicated, which method comprises orally administering one or more dosage units of a composition of the present invention 1 to about 6 times per day, preferably 1 or 2 times per day. The method is particularly useful for conditions or diseases in which acute pain is associated.

Other features of the present invention will be in part apparent and in part pointed out hereinafter.

Brief Description of Drawings

FIG. 1 shows particle size data for celecoxib dispersions D1-D4 prepared as described in example 1 as determined by Fraunhofer diffraction.

FIG. 2 shows optical micrographs of samples of dispersions D1-D4 measured in unpolarized light (left) and polarized light (right).

FIG. 3 shows in vitro dissolution time-course curves for dispersions D1-D4.

FIG. 4 is a diagram of an apparatus for performing the in vitro dissolution assay of example 3.

Detailed Description

Selective COX-2 inhibitory drugs suitable for use in the present invention are drugs that inhibit COX-2 to a therapeutically useful degree, while inhibiting cyclooxygenase-1 (COX-1) to a significantly lesser degree than conventional non-steroidal anti-inflammatory drugs (NSAIDs).

The invention is particularly applicable to selective COX-2 inhibitory drugs of low water solubility, especially selective COX-2 inhibitory drugs having a solubility in distilled water at 25 ℃ of less than about 10g/l, preferably less than about 1 g/l.

The term "oral administration" as used herein includes any form of administration of a therapeutic agent or composition thereof to a subject, wherein the therapeutic agent or composition is placed in the mouth of the subject, whether or not the agent or composition is ingested. Thus "oral administration" includes buccal and sublingual as well as esophageal administration. Absorption of the therapeutic agent may occur in any part of the gastrointestinal tract, including the mouth, esophagus, stomach, duodenum, ileum, and colon.

The term "oral" as used herein means suitable for oral administration.

The term "dosage unit" as used herein refers to a portion of a pharmaceutical composition containing an amount of a therapeutic agent (in the present invention, a selective COX-2 inhibitory drug) suitable for a single oral administration to provide a therapeutic effect. One dosage unit or a plurality (up to about 4) of small dosage units are typically administered as a single oral administration to provide an amount of the therapeutic agent sufficient to produce the desired therapeutic effect.

The term "present in the solid particles" as applied herein to a selective COX-2 inhibitory drug includes compositions wherein the solid particles consist essentially of the drug, and compositions wherein the solid particles comprise the drug in intimate admixture with one or more other components. These additional components may include one or more therapeutic agents other than selective COX-2 inhibitory drugs and/or one or more pharmaceutically acceptable excipients.

The term "excipient" herein refers to a substance that is not a therapeutic agent by itself, but is used as a carrier or excipient for delivery of the therapeutic agent to a subject, or is added to a pharmaceutical composition to improve its handling, storage, disintegration, dispersion, dissolution, release or sensory properties, or to permit or facilitate formation of a unit dose of the composition into a discrete product suitable for oral administration, such as a capsule or tablet. Excipients may include, for example, but are not limited to, diluents, disintegrants, binders, adhesives, wetting agents, lubricants, glidants, substances that mask or counteract an undesirable taste or odor, flavoring agents, dyes, flavorants, and substances that improve the appearance of the composition.

The term "substantially homogeneous" with respect to a pharmaceutical composition comprising several components means that the components are sufficiently mixed such that the components do not exist as discrete layers and do not form concentration gradients within the composition.

The compositions of the present invention comprise one or more oral dosage units. Each dosage unit contains a therapeutically effective amount, preferably from about 10mg to about 1000mg, of a selective COX-2 inhibitory drug, such as celecoxib.

It will be appreciated that the therapeutically effective amount of the selective COX-2 inhibitory drug for a subject will depend, inter alia, on the body weight of the subject being treated. When the drug is celecoxib and the subject is a child or a small animal (e.g., dog), a lower amount of celecoxib, preferably in the range of about 10mg to about 1000mg, may provide a serum concentration consistent with therapeutic efficacy. When the subject is an adult human or a large animal (e.g., a horse), obtaining such serum concentrations of celecoxib may require dosage units containing relatively large amounts of celecoxib. For adults, a therapeutically effective amount of celecoxib per dosage unit in the compositions of the invention will generally be from about 50mg to about 400 mg. A particularly preferred amount of celecoxib for each dosage unit is about 100mg to about 200mg, e.g., about 100mg to about 200 mg.

For other selective COX-2 inhibitory drugs, the amount of the drug per dosage unit may be within a range of known dosages to achieve the therapeutic effect of the drug. The amount of drug per dosage unit is preferably within a dosage range that provides a therapeutic effect equivalent to the dosage range described above for celecoxib.

Dosage units of celecoxib compositions of the invention will generally contain a dosage of about 10mg to about 400mg celecoxib, e.g., a dosage of 10, 20, 37.5, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350 or 400mg celecoxib. Preferred dosage units contain from about 25mg to about 400mg celecoxib. More preferred dosage units contain from about 50mg to about 200mg celecoxib. The particular dosage unit can be selected to accommodate the frequency of administration required to achieve a particular daily dosage. The amount and regimen of administration of a unit dosage form of a composition of the invention for the treatment of a disorder or disease will depend upon a variety of factors including the age, weight, sex, and physical condition of the subject, the severity of the disorder or disease, the route and frequency of administration, and the particular selective COX-2 inhibitory drug selected, and thus can vary widely. One or more dosage units may be administered up to 6 times per day. However, for most cases, once-daily or twice-daily dosing regimens provide the desired therapeutic effect.

The compositions of the present invention preferably contain from about 1% to about 95%, preferably from about 10% to about 90%, more preferably from about 25% to about 85%, and still more preferably from about 30% to about 80%, by weight of the selective COX-2 inhibitory drug, alone or in intimate admixture with one or more excipients. At least a portion of the drug is in the form of nanoparticles, i.e., solid particles having a diameter less than 1 μm in the longest particle dimension.

The pharmacokinetic effects resulting from reducing the particle size from the microparticle range (greater than 1 μm in diameter) to the nanoparticle range are generally unpredictable for any particular drug or class of drug. According to the present invention, the nanoparticle composition exhibits a higher C for selective COX-2 inhibitory drugs of low water solubility than the microparticle composition_maxAnd/or shorter T_max. Thus, in one embodiment of the invention, the weight percentage of nanoparticles is sufficient to provide a C that is substantially increased as compared to a reference composition in which substantially all of the particles are greater than 1 μm_maxAnd/or substantially shortened T_max. The composition of this embodiment has a sufficient weight percentage of nanoparticles to provide a substantially reduced T as compared to a reference composition_maxMore preferably, with sufficient weight percent of nanoparticles to provide a substantially increased C_maxAnd substantially shortened T_max。

A100 mg dosage unit of celecoxib preferably exhibits a T of less than about 90 minutes, more preferably less than about 60 minutes, and most preferably less than about 45 minutes when administered orally to fasted adults_maxAnd a C of at least about 100ng/ml, more preferably at least about 200ng/ml_max. The celecoxib compositions of the invention typically provide a serum concentration of at least about 50ng/ml celecoxib within 30 minutes of oral administration; preferred compositions achieve such concentrations in as little as 15 minutes. It is believed that this rapid increase in serum concentration allows the composition of the invention to rapidly begin therapeutic action.

For selective COX-2 inhibitory drugs other than celecoxib, preferred compositions provide a minimum drug serum concentration that is therapeutically equivalent to the minimum celecoxib concentration described above.

In another embodiment of the invention, a selective COX-2 inhibitory drug, such as celecoxib, is present in D₉₀Solid particles having a particle size of about 0.01 to about 200 μm, wherein about 25% to 100% by weight of the particles are nanoparticles. When the weight percentage of nanoparticles is low, e.g., about 25% to about 50%, D₉₀The particle size is preferably from about 0.01 to about 100 μm, more preferably from about 0.01 to about 75 μm, still more preferably from about 0.01 to about 40 μm, and even more preferably from about 0.01 to about 25 μm. The particle size may vary continuously between the nanoparticle and microparticle range, or the composition may have a bi-or multi-modal particle size distribution in which one set of particles has a D below 1 μm₉₀Particle size, another group of particles having a D substantially greater than 1 μm₉₀Particle size. It is generally preferred that at least about 50%At least about 75% by weight, particularly preferably at least about 75% by weight, of the particles are nanoparticles. In one embodiment, substantially all of the particles are less than 1 μm, i.e., the weight percent of nanoparticles is 100% or close to 100%.

Primary particles made by, for example, milling or grinding or by precipitation from solution may be aggregated to form secondary aggregated particles. The term "particle size" as used herein, unless the context indicates otherwise, refers to the size in the longest dimension of the original particle.

In preferred embodiments, the weight average particle size of the compositions of the present invention is from about 100nm to about 1000nm, more preferably from about 100nm to about 900nm, for example from about 200nm to about 400nm, or from about 500nm to about 900 nm. The drug may be in a crystalline or amorphous form in the nanoparticle. Processing methods for preparing nanoparticles using milling or grinding typically provide the drug in a crystalline form, while methods for preparing nanoparticles by precipitation from solution typically, but not always, provide the drug in a partially or fully amorphous form.

The compositions of the present invention comprise the selective COX-2 inhibitory drug of low water solubility, e.g., celecoxib, described above, partially or completely in nanoparticle form, and optionally one or more excipients selected from diluents, disintegrants, binders, wetting agents, and lubricants. In one embodiment, the drug-containing nanoparticle has an surface-modifying agent adsorbed on its surface. In another embodiment, the nanoparticles of the drug are contained in a matrix formed from a polymer. Preferably, at least one excipient is a water-soluble diluent or wetting agent. Such water-soluble diluents or wetting agents facilitate dispersion and dissolution of the drug when the composition of the invention is ingested. Preferably, both a water-soluble diluent and a wetting agent are present.

The compositions of the present invention may be substantially homogeneous flowable materials such as particulate or finely divided solids or liquids, or may be in the form of discrete products such as capsules or tablets each containing a single dosage unit.

In compositions that are substantially homogeneous flowable substances, the individual dosage units are removed by measurement using a suitable volumetric device such as a spoon or cup. Suitable flowable substances include, but are not limited to, powders and granules. Alternatively, the flowable substance may be a suspension of the drug in a solid particulate phase dispersed in a liquid phase, preferably an aqueous phase. At least a portion of the particulate phase is nanoparticles. In preparing such suspensions, it may be beneficial to use wetting agents such as polysorbate and the like. Suspensions may be prepared by dispersing the nanoparticle or partially nanoparticle drug in a liquid phase; or the drug may be precipitated from a solution in a solvent, such as an alcohol, preferably ethanol. The aqueous phase preferably comprises a palatable carrier such as water, syrup or fruit juice such as apple juice.

The selective COX-2 inhibitory drug may be any such drug known in the art, including, but not limited to, the compounds disclosed in the following patents and publications, each of which is individually incorporated herein by reference.

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The compositions of the invention are particularly useful for compounds of formula (VI):wherein R is³Is methyl or amino, R⁴Is hydrogen or C_1-4Alkyl or alkoxy, X is N or CR⁵Wherein R is⁵Is hydrogen or halogen and Y and Z are independently carbon or nitrogen atoms defining adjacent atoms of a 5-6 membered ring, which 5-6 membered ring is unsubstituted or substituted in one or more positions by oxo, halogen, methyl or halomethyl. Preferred said 5-6 membered rings are cyclopentenone, furanone, methylpyrazole, isoxazole and pyridine rings substituted in no more than one position.

For example, the compositions of the present invention are suitable for celecoxib, deracoxib, valdecoxib, rofecoxib, 5-chloro-3- (4-methylsulfonyl) phenyl-2- (2-methyl-5-pyridyl) pyridine, 2- (3, 5-difluorophenyl) -3- [4- (methylsulfonyl) phenyl ] -2-cyclopenten-1-one, and (S) -6, 8-dichloro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid, more preferably celecoxib and valdecoxib, and most preferably celecoxib.

The invention is exemplified herein with particular reference to celecoxib, it being understood that any other selective COX-2 inhibitory compound of low water solubility may be substituted in whole or in part for celecoxib in the compositions described herein, if desired.

The compositions of the present invention are useful in the treatment and prevention of a variety of COX-2 mediated disorders, including but not limited to those characterized by inflammation, pain, and/or fever. The compositions of the present invention are particularly useful as anti-inflammatory agents, for example, for the treatment of arthritis, and have the added advantage that their deleterious side effects are significantly lower than those of conventional non-steroidal anti-inflammatory drugs (NSAIDs), which lack selectivity for COX-2 and COX-1 over COX-2. In particular, the compositions of the invention have reduced gastrointestinal toxicity and gastrointestinal irritation, including ulceration and bleeding in the upper gastrointestinal tract, reduced renal side effects, such as reduced renal function leading to fluid retention and exacerbation of hypertension, reduced effects on bleeding time, including inhibition of platelet function, and possibly reduced ability to cause asthma attacks in aspirin allergic asthmatic individuals, as compared to conventional NSAIDs compositions. The compositions of the invention are therefore particularly suitable for replacing conventional NSAIDs in patients for which NSAIDs are contraindicated, for example in the following patients: patients with peptic ulcer, gastritis, regional enteritis, ulcerative colitis, diverticulitis, or patients with a history of recurring gastrointestinal tract injury; gastrointestinal bleeding patients, patients with blood clotting disorders including anemia such as hypoprothrombin, hemophilia or other bleeding disorders; patients with renal disease; or a preoperative patient or a patient taking anticoagulants.

The compositions of the present invention may be used to treat a variety of arthritic conditions including, but not limited to, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis.

The compositions of the invention are useful in the treatment of asthma, bronchitis, menstrual cramps, premature labor, tendonitis, bursitis, allergic neuritis, cytomegalovirus infection, apoptosis including HIV-induced apoptosis, lumbago, liver diseases including hepatitis, skin-related disorders such as psoriasis, eczema, acne, burns, dermatitis, and ultraviolet radiation injury including sunburn, and post-operative inflammation including inflammation following ophthalmic surgery such as cataract surgery or refractive surgery.

The compositions of the invention are useful in the treatment of gastrointestinal disorders such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis.

The compositions of the present invention are useful for treating inflammation in the following diseases: migraine, adventitial nodularis, thyroiditis, aplastic anemia, Hodgkin's disease, scleropathy, rheumatic fever, type I diabetes, neuromuscular junction diseases including myasthenia gravis, white matter diseases including multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's disease, polymyositis, gingivitis, nephritis, allergy, swelling after injury including cerebral edema, myocardial ischemia, and the like.

The compositions of the present invention are useful for treating ocular diseases such as retinitis, conjunctivitis, retinopathy, uveitis, ocular photophobia, and acute injury to ocular tissues.

The compositions of the invention are useful in the treatment of pneumonia, such as pneumonia and cystic fibrosis associated with viral infections, bone resorption such as osteoarthritis.

The compositions of the present invention are useful in the treatment of certain disorders of the central nervous system, such as cortical dementias including Alzheimer's disease, neurodegeneration, and damage to the central nervous system caused by stroke, ischemia, and trauma. In this context, the term "treatment" includes the partial or complete inhibition of dementias, including Alzheimer's disease, vascular dementia, multi-infarct dementia, Alzheimer's disease, alcoholic dementia and senile dementia.

The compositions of the present invention are useful for the treatment of allergic rhinitis, respiratory distress syndrome, endotoxic shock syndrome and liver disease.

The compositions of the present invention are useful for treating pain, including but not limited to post-operative pain, dental pain, muscle pain, and pain due to cancer. For example, the compositions of the present invention may be used to relieve pain, fever and inflammation in a variety of conditions including rheumatic fever, influenza and other viral infections including colds, back and neck pain, dysmenorrhea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis including rheumatoid arthritis, degenerative joint disease (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns, and trauma following surgical and dental procedures.

The compositions of the invention are useful in the treatment and prevention of cardiovascular disease associated with inflammation, including vascular disease, coronary artery disease, aneurysm, vascular rejection, atherosclerosis including cardiac transplant atherosclerosis, myocardial infarction, embolism, stroke, thrombosis including venous thrombosis, angina including unstable angina, coronary plaque inflammation, bacteria-induced inflammation including chlamydial-induced inflammation, virus-induced inflammation, and inflammation resulting from surgery, such as vascular transplantation including coronary artery bypass surgery, revascularization including angioplasty, stent placement, endarterectomy, or other invasive procedures involving arteries, veins and capillaries.

The compositions of the invention are useful for treating angiogenesis-related diseases in an individual, for example inhibiting tumor angiogenesis. The compositions of the present invention are useful for treating neoplasia, including tumor metastasis; eye disorders such as corneal graft rejection, ocular neovascularization, retinal neovascularization including that following surgery or infection, diabetic retinopathy, macular degeneration, retrolental fibroplasia, and neovascular glaucoma; ulcerative diseases such as gastric ulcer; pathological but non-malignant conditions such as hemangiomas, including infantile hemangiomas, nasopharyngeal angiofibromas, and avascular necrosis of bone; and diseases of the female reproductive system such as endometriosis.

The compositions of the invention are useful in the prevention and treatment of benign and malignant tumors and neoplasias, including cancers such as colorectal cancer, brain cancer, bone cancer, neoplasias derived from epithelial cells (epithelial cancers) such as basal cell carcinoma, adenocarcinoma, gastrointestinal tract cancers such as lip cancer, oral cancer, esophageal cancer, small intestine cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancers such as squamous cell and basal cell carcinoma, prostate cancer, renal cell carcinoma, and other known cancers that affect the whole body by epithelial cells. Neoplasias for which the compositions of the present invention are particularly useful are gastrointestinal cancer, Barrette's esophagus, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer, cervical cancer, lung cancer, breast cancer, and skin cancer. The compositions of the present invention may also be used to treat fibrosis that occurs when radiation therapy is used. The compositions of the invention are useful for treating individuals having adenomatous polyps, including individuals having Familial Adenomatous Polyps (FAP). In addition, the compositions of the present invention may be used to prevent polyp formation in patients at risk for FAP.

The composition of the present invention can inhibit prostanoid-induced smooth muscle contraction by inhibiting synthesis of contractile prostanoids, and thus can be used for treating dysmenorrhea, premature labor, asthma and eosinophil-related diseases. The compositions of the present invention are also useful for reducing bone loss, particularly in postmenopausal women (i.e., treating osteoporosis), and for treating glaucoma.

Preferred uses of the compositions of the invention are in the treatment of rheumatoid arthritis and osteoarthritis, general pain management (particularly post-oral surgery pain, general post-surgical pain, post-orthopedic surgery pain, and acute flawed osteoarthritis), treatment of alzheimer's disease, and chemoprevention of colon cancer.

For the treatment of rheumatoid arthritis or osteoarthritis, the compositions of the present invention may be used to provide a daily dosage of celecoxib of from about 50mg to about 1000mg, preferably from about 100mg to about 600mg, more preferably from about 150mg to about 500mg, still more preferably from about 175mg to about 400mg, for example about 200 mg. When administering the compositions of the present invention, a daily dosage of celecoxib of about 0.7 to about 13mg/kg body weight, preferably about 1.3 to about 8mg/kg body weight, more preferably about 2 to about 6.7mg/kg body weight, still more preferably about 2.3 to about 5.3mg/kg body weight, e.g., about 2.7mg/kg body weight, is generally suitable. The daily dose may be administered in 1 to about 4, preferably 1 or 2, divided doses per day.

For the treatment of Alzheimer's disease or cancer, the compositions of the present invention may be used to provide a daily dosage of celecoxib of about 50mg to about 1000mg, preferably about 100mg to about 800mg, more preferably about 150mg to about 600mg, still more preferably about 175mg to about 400mg, for example about 400 mg. When administering the compositions of the present invention, a daily dosage of celecoxib of about 0.7 to about 13mg/kg body weight, preferably about 1.3 to about 10.7mg/kg body weight, more preferably about 2 to about 8mg/kg body weight, still more preferably about 2.3 to about 5.3mg/kg body weight, e.g., about 5.3mg/kg body weight, is generally suitable. The daily dose may be administered in 1 to about 4, preferably 1 or 2, doses per day.

To control pain, the compositions of the present invention may be used to provide a daily dosage of celecoxib of from about 50mg to about 1000mg, preferably from about 100mg to about 600mg, more preferably from about 150mg to about 500mg, still more preferably from about 175mg to about 400mg, for example about 200 mg. When administering the compositions of the present invention, a daily dosage of celecoxib of about 0.7 to about 13mg/kg body weight, preferably about 1.3 to about 8mg/kg body weight, more preferably about 2 to about 6.7mg/kg body weight, still more preferably about 2.3 to about 5.3mg/kg body weight, e.g., about 2.7mg/kg body weight, is generally suitable. The daily dose may be administered in 1 to about 4 doses per day. It is preferred to administer the drug at a rate of 4 times a day, one 50mg dosage unit at a time, 2 times a day, one 100mg dosage unit at a time, or two 50mg dosage units, one 200mg dosage unit at a time, or two 100mg dosage units, or four 50mg dosage units.

For selective COX-2 inhibitory drugs other than celecoxib, the appropriate dosage can be selected by reference to the patent literature cited above.

In addition to being useful for treating humans, the compositions of the present invention may also be useful for veterinary treatment of pets, exotic animals, agricultural animals and the like, particularly mammals. The compositions of the present invention are more particularly useful for treating COX-2 mediated diseases in horses, dogs and cats.

The invention also relates to a method of treatment of a condition or disease for which a COX-2 inhibiting drug is indicated, which method comprises orally administering to a subject in need thereof a composition of the invention. The dosage regimen for preventing, alleviating or ameliorating the condition or disease is preferably consistent with once-a-day or twice-a-day treatment, but may be adjusted depending on a number of factors. These factors include the type, age, weight, sex, diet, and physical condition of the subject, as well as the nature and severity of the disease. Thus, the actual dosage regimen employed may vary widely and thus may deviate from the preferred dosage regimen described above.

Initial treatment may be initiated according to the dosing regimen described above. Treatment is generally continued as needed over a period of weeks to months or years until the condition or disease has been controlled or eliminated. For patients treated with the compositions of the present invention, they may be routinely monitored by any method well known in the art to determine efficacy. The data obtained from monitoring continues to be analyzed to adjust the treatment regimen during the treatment so that the optimal effective dose can be administered at any point in time and the duration of the treatment can be determined. By this method, the treatment regimen and dosing schedule can be rationally adjusted during the course of treatment so that the minimum amount of the composition that exhibits satisfactory therapeutic efficacy can be administered and the dosing required only to successfully treat the condition or disease can be continued.

The compositions of the present invention may be used in combination therapy with opioids and other analgesics, including narcotic analgesics, Mu receptor antagonists, Kappa receptor antagonists, non-narcotic (i.e., non-addictive) analgesics, monoamine uptake inhibitors, adenosine modulators, cannabinoid derivatives, substance P antagonists, neurokinin-1 receptor antagonists, sodium channel blockers, and the like. Preferred combination therapies include the use of a composition of the present invention and one or more compounds selected from the group consisting of: aceclofenac, acemetacin, e-acetamidohexanoic acid, acetaminophen, p-acetaminophenyl salicylate, acetanilide, acetylsalicylic acid (aspirin), S-adenosylmethionine, acloniolic acid, alfentanil, allylphenylpiperidine, alminoprofen, aloxiprin, alphapropylenedine, aluminum bisacetylsalicylate, aminophenol, aminochlororthexazin, 3-amino-4-hydroxybutyric acid, 2-amino-4-methylpyridine, amidopropylon, aminopyridine, amiciclovir, ammonium salicylate, ampiroxicam, amtolmetin, anilide, antipyrine, antrodil, azahydrazone, benindac, benorilate, benoxaprofen, benpirone, benzydamine, morphine, Belprofen, fenpropidine, alpha-bisabolol, bromfenamic acid, p-bromoacetanilide, 5-acetyl salicylic acid, bromacifluorfen, and the like, Bromosalicylic acid, butacetin, chlorocyclohexanepolyoxypropionic acid, butylcyclohexarbital, butylbenzoic acid, butapropaquizamide, buprenorphine, butylacetanilide, butenafine, cyclobutyloxymutan, calcium aspirin, carbamazepine, carbifene, carprofen, phenoxazinedione, chlorobutanol, chloroacetophenone, choline salicylate, cinchophene, indomethacin, aminophenol cyclohexanol, clidanac, chlophenellinic acid, niclofenamide, clonazelate, chlorpropyrrolic acid, clove, codeine, bromomeclocodeine, codeine phosphate, codeine sulfate, barbituric amide, barbituric acetamide, dihydrodeoxymorphine, dextrodiphenylpiperidine dioxane, molindomethacin, dizocine, diamidonamide, diclofenac sodium, bisphenylamidopyrazole, bisphenylacetimidamide, diflunisal, dihydrocodeine, hydrocodone, dihydromorphine acetate, aluminum disalicylate, acetylsalicylic acid, Ethyl phenylacetamide, methadol, methylbutyl, meptylamine, moroxydiphenyl, diphenoxylate, dipyrone, mebendazole, zuxicam, emofazone, phenethylanisic acid, pyrizole, etazocine, imatinib, ethacrysal, ethyl hydrogen nitrogen , ethoxydiazazobenzene, ethiofencarb, ethylmorphine, etodolac, etofenamate, ethoxazole, eugenol, felbinac, fenbufen, chlorothiazole acetic acid, bensalac acid, phenoxyphenylpropionic acid, fentanyl, diphenoxylate, fexol, phenylbutazone, fluquinamine phenyl, clofenamic acid, fenoprofen, p-ethylsulfone, flupirtine, fluquinacridone, flurbiprofen, salix phosphate, gentisic acid, glatiramer, meglumine, hydroxyethyl salicylate, guaiazulene, dichlorocodeinone, dimedone, hydroxypyrone, isorphanol acetate, isoxadifenon, mefenoxate, mefenoxaprop-p-l acetate, Ibuprofen, bucloxin, imidazole salicylate, indomethacin, triphenicol, isoladol, isometholone, hydroxytoluene, oxy  acetic acid, isoproxetamide, phenacetone, ketoprofen, ketorolac, p-lactophenetide, lefetamine, levorphanol, remifentanil, clofenamic acid, lornoxicam, roxoprofen, lysyl acetylsalicylic acid, magnesium acetylsalicylate, meclofenamic acid, mefenamic acid, meperidine, azone  phenol, mesalamine, metazacin, methadone hydrochloride, levomepromazine, methylthiophenazine acetic acid, methoxazine, hydromorphone, tolylflunisolone, mofebelac, phenoxazine, morphine hydrochloride, morphine sulfate, salicylic acid, morphine myristate, nabumetone, bucindomethacin, L-naphthylsalicylate, naproxen, pinine, pinoxanil, oxyphenicoline, nicotinamide, nicotiniolide, nicotine, morphine hydrochloride, morphine sulfate, morphine hydrochloride, morphine myristate, nabumetone, naloxone, naloxon, 5 '-Nitro-2' -propoxylacetanilide, levo-3-hydroxymorphinane, normethadone, normorphine, diphehexanone, azosalicylic acid, opium, acetohydroxyproline, indoximic acid, oxaprazosin, oxycodone, oxymorphone, oxyphenbutazone, opirox, guanylfluorene, propiolamide, pentazocine, piperazole, phenacetin, pimolone, phenazocine, phenazopyridine hydrochloride, phenodol, benperidine, phenylpyrazolone, phenyl acetylsalicylate, phenylbutazone, phenyl salicylate, phenylpyrazole, piroctone, dolol, nordolidine, piperazinone, pipobrazone, pipopyrone, piprofen, ropyrole, cyanophenylbisperamide, piroxicam, pranoprofen, tyrosinate, propylheptazine, meperidine, propacetapimetamol, propidine, propiram, propiverine, isopropamide, iprodione, propinquinone, propinquene, propinquenzapine, phenothiazine, propinquenzapine, propinqim, propinquinarine, propinquinarin, ramifenazene, remifentanil, pyriminobac-methyl sulfate, acetylsalicylamide, salicin, salicylamide, salicylamidoacetic acid, salicylic acid, salsalate, aminoethoxyanilide, sodium salicylate, sufentanil, sulfasalazine, sulindac, superoxide dismutase, thenoylibuprofen, butanedione, flurophthalate, tenidap, tenoxicam, cumidine, tetrandrine, thiazolidinobenzone, thiopropionic acid, tiaramide, ethyl aminocyclohexyl, ampicillin, o-meclofenamic acid, tolmetin, tramadol, tropyl alcohol, benzidine, diphenylbutyric acid, acticyclopropyrric acid, zaprofen, and sodium benzoylate (see The Merck Index, 12 Edition, Therapeutic cam and Biological Index, analysis. s. pharmaceutical, theragr, 3-alc), norgesic acid, trin, and sodium benzoate, anti-inflimatory (innosteroid)).

A particularly preferred combination therapy comprises the use of a composition of the invention and an opioid, more particularly wherein the opioid is codeine, meperidine, morphine or a derivative thereof.

The celecoxib compositions of the invention can also be administered in combination with another selective COX-2 inhibitory drug, such as valdecoxib, rofecoxib, and the like.

The compound administered in combination with celecoxib can be formulated separately from celecoxib or together with celecoxib in a composition of the invention. When celecoxib is formulated with another drug, such as an opioid, the other drug can be formulated as an immediate release, rapid onset, sustained release, or dual release dosage form.

Nanoparticles comprising or consisting essentially of a selective COX-2 inhibitory drug of low water solubility may be prepared according to any method known in the art to be suitable for preparing other poorly water soluble drugs in nanoparticle form. Suitable methods are, for example and without limitation, those disclosed for other such drugs in the following patents and publications, which are incorporated herein by reference.

U.S. Pat. No.4,826,689to violatono & Fischer.

The aforementioned U.S. Pat. No.5,145,684.

U.S. patent No.5,298,262 to Na & Rajagopalan.

U.S. patent No.5,302,401 to Liversidge et al.

U.S. patent No.5,336,507 to Na & Rajagopalan.

U.S. patent No.5,340,564 to Illig & Sarpotdar.

U.S. patent No.5,346,702 to Na & Rajagopalan.

U.S. patent No.5,352,459 to Holliste et al.

U.S. patent No.5,354,560 to lovreich.

The above-mentioned U.S. patent No.5,384,124.

U.S. patent No.5,429,824 to June.

U.S. patent No.5,503,723 to Ruddy et al.

U.S. Pat. No.5,510,118 to Bosch et al.

U.S. Pat. No.5,518,187 to Bruno et al.

U.S. patent No.5,518,738 to Eickhoff et al.

U.S. patent No.5,534,270 to De Castro.

U.S. patent No.5,536,508 to Canal et al.

U.S. patent No.5,552,160 to Liversidge et al.

U.S. patent No.5,560,931 to Eickhoff et al.

U.S. patent No.5,560,932 to Bagchi et al.

U.S. Pat. No.5,565,188 to Wong et al.

U.S. patent No.5,569,448 to Wong et al.

U.S. patent No.5,571,536 to Eickhoff et al.

U.S. patent No.5,573,783 to Desieno & Stetsko.

U.S. patent No.5,580,579 to Ruddy et al.

U.S. patent No.5,585,108 to Ruddy et al.

U.S. patent No.5,587,143 to Wong.

U.S. patent No.5,591,456 to Franson et al.

U.S. patent No.5,622,938 to Wong.

U.S. patent No.5,662,883 to Bagchi et al.

U.S. patent No.5,665,331 to Bagchi et al.

U.S. patent No.5,718,919 to Ruddy et al.

U.S. patent No.5,747,001 to Wiedmann et al.

The above international patent publication No. WO93/25190.

International patent publication No. WO96/24336.

International patent publication No. WO97/14407.

International patent publication No. WO98/35666.

International patent publication No. WO99/65469.

International patent publication No. WO00/18374.

International patent publication No. WO00/27369.

International patent publication No. WO00/30615.

The method described therein can be easily modified by the skilled person to prepare selective COX-2 inhibitory drugs of low water solubility in the form of nanoparticles.

In one embodiment of the invention, nanoparticles of a selective COX-2 inhibitory drug are prepared by a milling process, preferably a wet milling process in the presence of a surface modifier that inhibits agglomeration and/or crystal growth of the nanoparticles (once prepared). In another embodiment of the invention, nanoparticles of a selective COX-2 inhibitory drug are prepared by precipitation, preferably from a solution of the drug in a non-aqueous solvent in an aqueous medium. The non-aqueous solvent may be, for example, a supercritical gas that liquefies under pressure. Examples of these and other methods of preparing nanoparticles of selective COX-2 inhibitory drugs are described in more detail below.

In a particular embodiment of the invention, the nanoparticles are prepared by a process comprising the steps of: as disclosed substantially in the above-mentioned U.S. patent 5145684, (a) dispersing a selective COX-2 inhibitory drug and a surface modifier in a liquid dispersion medium; and (b) wet milling the resulting drug dispersion in the presence of a milling medium to obtain drug nanoparticles in crystalline form, wherein the particles have adsorbed on their surface a surface modifier in an amount sufficient to result in a weight average particle size of less than about 400 nm. The surface modifier inhibits the agglomeration of nanoparticles and may be any polymer, low molecular weight oligomer, natural product, surfactant, or the like. In this and related embodiments, the nanoparticles are comprised of nanocrystalline drug/surface modifier complexes.

In a related embodiment of the invention, the nanocrystalline drug/surface modifier complex prepared as described above comprises a purified surface modifier, such as a purified polymeric surfactant, to prevent agglomeration of the particles during a subsequent sterilization step, substantially as disclosed in U.S. patent 5352459, supra.

In another related embodiment of the invention, the nanocrystalline drug/surface modifier composite prepared as described above comprises the surfactant para-isononylphenoxy poly (glycidol) as a surface modifier, substantially as disclosed in the aforementioned U.S. patent 5340564.

In another related embodiment of the invention, nanocrystalline drug/surface conditioner complexes prepared as described above have an anionic or cationic cloud point modifier to increase the cloud point of the surface conditioner, substantially as described in the above-mentioned U.S. patent 5298262 (cationic or anionic surfactant as cloud point modifier), 5336507 (charged phospholipid as cloud point modifier), or 5346702 (nonionic cloud point modifier).

In another related embodiment of the invention, the nanocrystalline drug/surface modifier complex prepared as described above further comprises a cryoprotectant, such as a hydrocarbon or sugar alcohol, in an amount sufficient to allow lyophilization of the nanoparticles, substantially as described in U.S. patent 5302401 above. The preferred cryoprotectant of this embodiment is sucrose. A method of making nanoparticles having a surface modifier adsorbed on a surface thereof and a cryoprotectant complexed therewith includes contacting the nanoparticles with the cryoprotectant for a time and under conditions sufficient to allow lyophilization of the nanoparticles.

In another related embodiment of the invention, nanoparticulate drug particles having a surface modifier adsorbed on their surface in an amount sufficient to maintain a weight average particle size of less than about 400nm are prepared by a process comprising the steps of: as disclosed substantially in the above-mentioned U.S. patent 5552160, (a) dispersing a drug in a liquid dispersion medium in which the drug is insoluble; and (b) milling the media in the presence of rigid milling media (e.g., in a dispersion mill), wherein the pH of the media is maintained in the range of from about 2 to about 6.

In another related embodiment of the invention, the nanoparticles are made by a process comprising the steps of: as disclosed substantially in the above-mentioned U.S. patent 5534270, (a) providing a selective COX-2 inhibitory drug; (b) deactivating the rigid grinding media for a period of time, e.g., in an oven at a temperature of about 200 ℃ to about 300 ℃ for about 6 to about 20 hours; mixing the drug with the milling media and autoclaving at about 100 ℃ to about 150 ℃ for about 10 to about 60 minutes; and (c) adding a surface modifier (e.g., selected from the group consisting of polymers, low molecular weight oligomers, natural products, and surfactants) to the resulting autoclaved drug, followed by wet milling to provide and maintain a weight average particle size of less than about 400 nm.

In another related embodiment of the invention, the nanoparticles are made by a method comprising the operations of: contacting a selective COX-2 inhibitory drug with a surface modifier under conditions (e.g., by adding the drug to a liquid medium containing the surface modifier and wet milling in a dispersion mill) and for a time sufficient to provide and maintain a weight average particle size of less than about 400nm, substantially as disclosed in the above-mentioned U.S. patent 5429824. In this embodiment, the surface conditioner is an alkylaryl polyether alcohol type nonionic liquid polymer, such as tyloxapol. Other surface modifiers may optionally also be present.

In another related embodiment of the invention, the nanoparticles are made by a method comprising the steps of: as disclosed substantially in the above-mentioned U.S. patent 5510118, (a) forming a premix of a selective COX-2 inhibitory drug and a surface modifier (e.g., selected from polymers, low molecular weight oligomers, surfactants, etc.) in a liquid dispersion medium (e.g., water, saline solution, ethanol, etc.); (b) transferring the premix into a microfluidizer having an interaction chamber capable of generating shear, impact, cavitation, and friction forces; (c) applying these forces to the premix by flowing the premix through the interaction chamber at a temperature not exceeding about 40 ℃ and a fluid pressure of about 20000 to about 200000kPa to reduce the particle size of the drug and obtain a homogeneous slurry thereof; (d) collecting the slurry from the interaction chamber into a receiving tank; (e) reintroducing the slurry into the interaction chamber to further reduce particle size; and (f) repeating the collecting and reintroducing steps until the weight average particle size of the drug substance is less than about 400 nm.

In another related embodiment of the invention, the nanoparticles are made by a method comprising the steps of: a selective COX-2 inhibitory drug is milled (e.g., in a dispersion mill) in the presence of (a) a surface modifier (e.g., gelatin, casein, lecithin, polyvinylpyrrolidone, tyloxapol, poloxamer, other block copolymers, etc.), and optionally in the presence of an oil, substantially as disclosed in U.S. patent 5560931. In this embodiment, the drug particles have the uncrosslinked modifier adsorbed on their surface and are suspended in an aqueous phase emulsified in a continuous oil phase. The weight average particle size is less than about 1000 nm. As disclosed in the aforementioned us patent 5571536, the oil phase may be oleic acid.

In another related embodiment of the invention, the nanoparticles are made by a method comprising the steps of: as disclosed in essentially the above-mentioned U.S. patents 5565188 (block copolymers containing one or more polyoxyethylene blocks and one or more poly (higher alkylene) blocks, with at least some of the blocks being linked together by oxymethylene linkages) and 5587143 (block copolymers of ethylene oxide and butylene oxide as surface modifiers) by placing (a) a selective COX-2 inhibiting drug, a liquid medium, a grinding medium, and a surface modifier in a grinding vessel; and (b) wet milling to reduce the weight average particle size of the drug substance to less than about 1000 nm.

In another related embodiment of the invention, the invention provides a composition comprising a nanoparticle selective COX-2 inhibitory drug particle having adsorbed on its surface a block copolymer linked to at least one anionic group as a surface modifier. The composition is prepared by a method comprising the following steps: preparing a drug in particulate form, preferably in particulate form having a particle size of less than about 100 μm, substantially as disclosed in the aforementioned U.S. patent 5569448; (b) adding the drug to a substantially insoluble liquid medium thereof to form a premix; and (c) machining the pre-mixture to reduce the average particle size in the pre-mixture to less than about 1000 nm. Preferably, a surface modifier is present in the premix.

In another related aspect of the invention, the nanoparticles are prepared by a method comprising the steps of: (a) adding a selective COX-2 inhibitory drug and a surface modifying agent (e.g., a sterile stabilizer such as gelatin, casein, lecithin, acacia, cholesterol, tragacanth, sorbitan esters, polyethylene glycol, polyoxyethylene alkyl esters, polyoxyethylene stearates, and the like) to a liquid in which the drug is insoluble to form a premix, and (b) mechanically (e.g., in a dispersion mill) reducing the average particle size to about 400nm (substantially as disclosed in U.S. patent 5573783, supra).

In another related aspect of the invention, the nanoparticles are prepared by a method comprising the steps of: (a) selective COX-2 inhibitory drugs and surfactants (e.g., poloxamers having a molecular weight of about 1000 to about 15000 daltons, polyvinyl alcohol, polyvinyl pyrrolidone, hydroxypropylmethylcellulose, and polyoxyethylene sorbitan monooleate) are dispersed in a poorly drug-soluble liquid dispersion medium, and the mean particle size of the drug is then reduced to less than about 400nm by mechanical means (e.g., a dispersion mill) (substantially as disclosed in U.S. patent 5585108, supra).

In another related aspect of the invention, the nanoparticles are prepared by a method comprising the steps of: (a) the selective COX-2 inhibitory drug and hydroxypropylcellulose as a surface modifier are added to a liquid medium in which the drug is substantially insoluble to form a premix and the mean particle size of the drug is reduced to less than about 1000nm, preferably less than about 400nm, using mechanical means (e.g., in a dispersion mill) (substantially as disclosed in the aforementioned U.S. patent 5591456).

In another related embodiment of the invention, the nanoparticles are prepared by the method described herein using a surface modifier selected such that the resulting composition has a Hydrophilic Lipophilic Balance (HLB) of from about 4 to about 9, substantially as disclosed in the above international patent publication No. wo00/30615.

In a particular embodiment of the invention, the nanoparticles are prepared by a process comprising the steps of: (a) mixing the selective COX-2 inhibitory drug with a support material, preferably a cross-linked water-swellable polymer; (b) milling the resulting mixture in a milling chamber saturated with solvent (e.g., water, ethanol, isopropanol, chloroform, methanol, etc.) vapor; (c) drying the milled mixture under vacuum; and (d) sieving the dried milled mixture to remove any aggregates formed (a process substantially as disclosed in the above-mentioned U.S. patent 5354560).

In another particular embodiment of the invention, the nanoparticles are prepared by a process comprising the steps of: (a) forming a paste comprising: (i) nanoparticles of a selective COX-2 inhibitory drug, (ii) at least one thickener or binder (e.g., selected from polypeptides, high molecular polymers, colloids, etc.) and/or extender, (iii) one or more stabilizers to avoid sagging or bulging of the nanoparticle surface, and (iv) an appropriate amount of water to adjust the viscosity; and (b) lyophilizing the paste (substantially as disclosed in the aforementioned U.S. patent 5384124).

In another particular embodiment of the invention, the nanoparticles are prepared by a process comprising the steps of: (a) preparing a selective COX-2 inhibitory drug in the form of granules, the granules preferably having a particle size of less than about 100 μm; (b) adding the prepared drug to a liquid medium (preferably containing a surface modifying agent such as a hygroscopic sugar) in which the drug is substantially insoluble to form a premix; and (c) mechanically reducing the particle size of the premix to less than about 1000nm (substantially as disclosed in the aforementioned U.S. patent 5518738). The premix preferably also contains polyvinylpyrrolidone and/or a wetting agent, such as sodium lauryl sulfate. The composition prepared by the method preferably has a film comprising polyvinylpyrrolidone, hygroscopic sugar and sodium lauryl sulfate attached to the surface of the nanoparticles.

In another particular embodiment of the invention, the nanoparticles are prepared by a process comprising the steps of: (a) co-solubilizing one or more polymeric components, including, for example, biodegradable polymers (e.g., polylactic acid, polyglycolic acid or copolymers thereof, polyhydroxybutyric acid, polycaprolactone, polyorthoesters, etc.), gel-forming polysaccharides and/or bioadhesive polymers and/or amphiphilic polymers (e.g., polyethylene glycol, polyvinylpyrrolidone or polyvinyl alcohol), optionally in the presence of one or more solvents, with a substance that modifies interfacial properties, to form a polymer premix; (b) dissolving or suspending a selective COX-2 inhibitory drug in the polymer mixture; and (c) forming particles consisting of the polymer, the substance modifying interfacial properties and the drug by emulsification, extrusion, spray drying or spray congealing techniques (substantially as disclosed in the aforementioned us patent 5536508). The nanoparticles prepared using this method preferably have a weight average particle size of about 0.1 μm to 150 μm.

In another particular embodiment of the invention, the nanoparticles are prepared by a process comprising the steps of: (a) preparing a solution of a selective COX-2 inhibitory drug in a water-miscible organic solvent; (b) injecting an aqueous precipitating liquid (such as water, an inorganic salt solution or a surfactant solution) into the solution to produce a suspension of the precipitated amorphous solid drug in the form of non-aggregated particles; and (c) separating the particles from the precipitated liquid and washing with an aqueous washing liquid (substantially as disclosed in the aforementioned us patent 4826689).

In another particular embodiment of the invention, the nanoparticles are prepared by a process comprising the steps of: (a) dissolving selective COX-2 inhibitory drugs in an aqueous alkaline solution (such as NaOH, KOH, CsOH, etc.) under stirring to form a solution; (b) adding surface modifier (such as various polymers, surfactants, low molecular weight oligomers, etc.) to form clear solution; and (c) stirring with a suitable acid solution (e.g., HCl, HNO)₃，HClO₄，H₂SO₄Formic acid, propionic acid, acetic acid, butyric acid, etc.) to neutralize the clear solution (essentially as disclosed in the above-mentioned us patent 5560932 and 5580579).

In another related aspect of the invention, the nanoparticles are prepared by a method comprising the steps of: (a) dissolving a selective COX-2 inhibitory drug in an alkaline liquid medium (e.g., NaOH, KON, CsOH, trialkylamine, pyridine, etc.) containing a non-toxic solvent in which the drug is poorly soluble to form a solution; (b) adding an aqueous solution of one or more surface modifying agents (e.g. anionic or nonionic surfactants, polymers or oligomers), (c) neutralizing the resulting alkaline solution, and treating with an acid (HCl, HNO)₃、HClO₄、H₂SO₄Formic acid, propionic acid, acetic acid, butyric acid, etc.) to form a dispersion, wherein the energy spectrum is correlated by light quantaThe Z-average particle size as measured by the method is preferably less than about 100nm (substantially as disclosed in the aforementioned U.S. Pat. No. 5662883).

In another related aspect of the invention, the nanoparticles are prepared by a method comprising the steps of: (a) dissolving a selective COX-2 inhibitory drug and a crystal growth modifier (i.e., a compound having substantially the same structure as the drug) in an aqueous alkaline solution (e.g., NaOH, KOH, CsOH, trialkylamine, pyridine, etc.) to form a solution; (b) adding an aqueous solution of one or more surface modifying agents (e.g., a mixture of anionic surfactants, nonionic surfactants, polymers or oligomers); subjecting the resulting alkaline solution to an acid (e.g., HCl, HNO)₃，HClO₄，H₂SO₄Formic acid, propionic acid, acetic acid, butyric acid, etc.) to form a dispersion, preferably wherein the Z-average particle size of the drug particles is less than about 400nm as determined by photon correlation spectroscopy (substantially as disclosed in the above-mentioned us patent 5665331).

In another particular embodiment of the invention, nanoparticles having a weight average particle size of less than about 400nm are prepared from a dispersion comprising a selective COX-2 inhibitory drug having a first particle size distribution and a surface modifier, such as tyloxapol polysulfate, prepared by a process comprising the steps of: (a) placing the dispersion between a first electrode and a second electrode; and (b) discarding a portion of the dispersion between the first electrode and the second electrode, the portion of the dispersion having a second particle size distribution less than the first particle size distribution (substantially as disclosed in U.S. patent 5503723).

In another particular embodiment of the invention, nanoparticles having a weight average particle size of no greater than about 300nm are prepared by a process comprising the steps of: (a) dissolving a selective COX-2 inhibitory drug in a solvent to form a solution; and (b) spraying the solution into a liquefied gas or supercritical liquid in the presence of a surface modifier dispersed or dissolved in the aqueous phase (substantially as disclosed in international patent publication No. wo 97/14407).

In another related embodiment of the invention, nanoparticles having a weight average particle size of no greater than about 300nm are prepared by a process comprising the steps of: (a) dissolving a selective COX-2 inhibitory drug in a liquefied gas or supercritical fluid to form a solution; (b) preparing an aqueous phase containing a surface modifier; and (c) spraying the solution into an aqueous phase (substantially as disclosed in international patent publication No. wo 97/14407).

In another related embodiment of the invention, the nanoparticles are prepared by a method comprising the steps of: (a) dissolving a selective COX-2 inhibitory drug and a surface modifier in a liquefied gas or supercritical fluid to form a solution; and (b) adding the solution to an aqueous medium (substantially as disclosed in international patent publication No. wo 99/13755).

The excipients included in the compositions of the present invention may be solid or liquid or both. The compositions of the invention containing excipients may be prepared according to any pharmaceutical technique, including mixing the selective COX-2 inhibitory drug, at least partially in the form of pre-prepared nanoparticles as described above, with an excipient, optionally with one or more excipients.

Compositions suitable for buccal or sublingual administration include, for example, lozenges comprising a selective COX-2 inhibitory drug in a flavoured base, such as sucrose and acacia or tragacanth; and lozenges comprising the drug in an inert base such as gelatin and glycerin or sucrose and acacia.

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

Solid unit dosage forms for oral administration contain the selective COX-2 inhibitory drug in the form of nanoparticles and the most commonly used excipients in tablet or capsule formulations. The following non-limiting examples of excipients may be used in the preparation of the pharmaceutical compositions of the present invention.

The compositions of the present invention may optionally contain one or more pharmaceutically acceptable diluents as excipients.Suitable diluents include one or a combination of the following: lactose, including anhydrous lactose and lactose monohydrate; starches, including directly compressible starches and hydrolyzed starches (e.g., Celutab)^TMAnd Emdex^TM) (ii) a Mannitol; sorbitol; xylitol; glucose (e.g. Cerelose)^TM2000) And glucose monohydrate; calcium dihydrogen phosphate dihydrate; sucrose-based diluents, sugar for confectionery, calcium hydrogen sulfate monohydrate, calcium sulfate dihydrate; calcium lactate trihydrate particles; dextrates; inositol, hydrolyzed cereal solids; amylose starch; cellulose, including microcrystalline cellulose, alpha-and amorphous cellulose of food grade origin (e.g., Rexcel)^TM) And powdered cellulose; calcium carbonate; glycerol; bentonite; polyvinylpyrrolidone, and the like. If present, such diluents may be present in a total amount of about 5 to about 99%, preferably about 10 to about 85%, more preferably about 20 to about 80% by weight of the total composition. The diluent is preferably selected to have suitable flow properties and (if tablets are desired) compressibility.

Preferred diluents are lactose and microcrystalline cellulose or mixtures thereof. Both diluents are chemically compatible with celecoxib. Additional granular microcrystalline cellulose (i.e., microcrystalline cellulose added to the wet granular composition after the drying step) may be used to improve hardness (tablet) and/or disintegration time. Lactose, especially lactose monohydrate, is particularly preferred. Lactose generally provides compositions with suitable celecoxib release rates, stability, precompression flowability and/or drying characteristics at relatively low diluent cost. It provides a high density matrix which helps to compact during granulation (when wet granulation is used) and thus improves the flow characteristics of the mixture.

The compositions of the present invention may optionally contain one or more pharmaceutically acceptable disintegrants as excipients, especially for tablets. Suitable disintegrants include one or a combination of the following: starches, including sodium starch glycolate (e.g., Explotab from Pen West)^TM) And pregelatinized corn starch (e.g., National starch)^TM1551，National^TM1550 and Colocorn^TM1500) (ii) a Clay (e.g. Veegum)^TMHV); cellulose, e.g. purificationCellulose, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, croscarmellose sodium (e.g. Ac-Di-Sol from FMC)^TM) (ii) a An alginate; crospovidone; and gums, such as agar, guar gum, locust bean gum, karaya gum, pectin, and tragacanth.

The disintegrant may be added at any suitable step during the preparation of the composition, especially during the lubrication step prior to granulation or prior to compression. If present, such disintegrants are present in a total amount of about 0.2 to about 30%, preferably about 0.2 to about 10%, more preferably about 0.2 to about 5% by weight of the total composition.

For tablet or capsule disintegration, croscarmellose sodium is a preferred disintegrant, if present, preferably comprising from about 0.2 to about 10%, more preferably from about 0.2 to about 7%, most preferably from about 0.2 to about 5% by weight of the total composition. Croscarmellose sodium imparts superior particle disintegration properties to the particulate compositions of the present invention.

The compositions of the present invention may optionally contain one or more pharmaceutically acceptable binders or adhesives as excipients, especially for tablets. Such binders and adhesives preferably impart sufficient tackiness to the tableting powder to allow it to undergo conventional processing operations such as sieving, lubrication, compression and packaging while the tablet is still disintegrable and the components are digested and absorbed. Suitable binders and adhesives include one or a combination of the following: acacia gum; gum tragacanth; sucrose; gelatin; glucose; starches, such as, but not limited to, pregelatinized starches (e.g., National)^TM1511 and National^TM1500) (ii) a Celluloses, such as, but not limited to, methylcellulose and carboxymethylcellulose (e.g., Tylose)^TM) (ii) a Alginic acid and alginates; magnesium aluminum silicate; PEG; guar gum; a gluconic acid; bentonite; povidone such as povidone K-15, K-30 and K-29/32; polymethacrylates; HPMC; hydroxypropyl cellulose (e.g. Klucel)^TM) (ii) a And ethyl cellulose (e.g., Ethocel)^TM). If such binders and/or adhesives are present, the total amount thereof is from about 0.5 to about 25%, preferably from about 0.75 to about 15%, more preferably from about 0.75 to about 15%, by weight of the total compositionPreferably from about 1 to about 10%.

The compositions of the present invention may optionally contain one or more pharmaceutically acceptable wetting agents as excipients. Such wetting agents are preferably selected from substances that maintain the selective COX-2 inhibitory drug in intimate association with water, provided that they are believed to improve the bioavailability of the composition.

In the compositions of the present invention, examples of non-limiting surfactants that can be used as wetting agents include quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, dioctyl sodium sulfosuccinate, polyoxyethylene alkylphenyl ethers such as nonoxynol 9, nonoxynol 10 and octoxynol 9; poloxamers (polyoxyethylene and polyoxypropylene block copolymers); polyoxyethylene fatty acid glycerides and oils, e.g. polyoxyethylene (8) caprylic/capric mono-and diglycerides (e.g. Labrasol by Gattefoss é)^TM) Polyoxyethylene (35) castor oil, polyoxyethylene (40) hydrogenated castor oil; polyoxyethylene alkyl ethers such as polyoxyethylene (20) cetyl stearyl ether; polyoxyethylene fatty acid esters, for example polyoxyethylene (40) stearate, polyoxyethylene sorbitan esters, such as polysorbate 20 and polysorbate (e.g. Tween of ICI)^TM80) (ii) a Propylene glycol fatty acid esters, e.g. propylene glycol laurate (e.g. Lauroglycol from Gattefoss^TM) (ii) a Sodium lauryl sulfate; fatty acids and salts thereof, such as oleic acid, sodium oleate, and triethanolamine oleate; glycerol fatty acid esters such as glycerol monostearate; sorbitan esters such as sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate and sorbitan monostearate; tyloxapol and mixtures thereof. The wetting agents, if present, collectively comprise from about 0.25% to about 15%, preferably from about 0.4% to about 10%, more preferably from about 0.5% to about 5%, by weight of the total composition.

Anionic surfactant wetting agents are preferred. Sodium lauryl sulfate is a particularly preferred wetting agent. Sodium lauryl sulfate, if present, comprises from about 0.25 to about 7%, more preferably from about 0.4 to about 4%, and more preferably from about 0.5 to about 2% by weight of the total composition.

The compositions of the present invention may optionally contain one or more pharmaceutically acceptable lubricants (including anti-adhesion agents and/or glidants) as excipients. Suitable lubricants include one or a combination of the following: bhapate glycerides (e.g. Compritol)^TM888) (ii) a Stearic acid and its salts, including magnesium, calcium and sodium salts of stearic acid; hydrogenated vegetable oils (e.g. Sterotex)^TM) (ii) a Colloidal silicon dioxide; talc; a wax; boric acid; sodium benzoate; sodium acetate; fumaric acid; sodium chloride; DL-leucine; PEG (e.g. Carbowax)^TM4000 and Carbowax^TM6000) (ii) a Sodium oleate; sodium lauryl sulfate; and magnesium lauryl sulfate. Such lubricants, if present, are present in a total amount of about 0.1 to about 10%, preferably about 0.2 to about 8%, more preferably about 0.25 to about 5% by weight of the total composition.

Magnesium stearate is a preferred lubricant used, for example, to reduce friction between equipment and the granulation mixture during tableting.

Suitable antisticking agents include talc, corn starch, DL-leucine, sodium lauryl sulfate and metal salts of stearic acid. Talc is a preferred anti-tack or slip agent to, for example, reduce sticking of the formulation to the surface of the device while also reducing the repose of the mixture. If present, talc will comprise from about 0.1 to about 10%, preferably from 0.25 to about 5%, more preferably from 0.5 to about 2% by weight of the total composition.

Other excipients, such as coloring agents, flavoring agents and sweetening agents, are known in the pharmaceutical art and may be used in the compositions of the present invention. Tablets may be coated, for example with an enteric coating or uncoated. The compositions of the present invention may also contain, for example, buffering agents.

One or more effervescent agents may also optionally be used as disintegrants and/or to enhance the special sensory properties of the compositions of the invention. When a dosage form that promotes disintegration of the dosage form is included in the compositions of the present invention, the total amount of the one or more effervescent agents preferably comprises from about 30 to about 75%, preferably from about 45 to about 70%, for example about 60% by weight of the composition.

In one embodiment of the invention, the composition is in the form of a unit dose capsule or tablet and contains a desired amount of a selective COX-2 inhibitor, such as celecoxib, partially or completely in nanoparticulate form and one or more excipients selected from pharmaceutically acceptable diluents, disintegrants, binders, wetting agents and lubricants. More preferably, the composition contains one or more excipients selected from the group consisting of: lactose (most preferably lactose monohydrate), sodium lauryl sulfate, polyvinylpyrrolidone, croscarmellose sodium, magnesium stearate, and microcrystalline cellulose. More preferably, the composition comprises lactose monohydrate and croscarmellose sodium. Such compositions particularly preferably also contain one or more carrier materials: sodium lauryl sulfate, magnesium stearate, and microcrystalline cellulose.

The excipients used in the capsule and tablet compositions of the present invention are preferably selected from materials that provide the following properties: in a standard disintegration assay, the disintegration time is less than about 30 minutes, preferably less than about 25 minutes or less, more preferably less than about 20 minutes or less, and most preferably less than about 15 minutes or less.

To illustrate tablets, a mixture of all ingredients in an amount sufficient to produce a homogeneous batch of tablets is compressed at atmospheric pressure in a conventional production scale tablet press (e.g., using a force of about 1kN to about 50kN on a typical tablet punch). Any tablet hardness that is convenient to process, manufacture, store and digest can be achieved. For a 100mg tablet, the hardness is preferably at least 4kP, more preferably at least about 5kP, more preferably at least about 6 kP. For a 200mg tablet, the hardness is preferably at least 7kP, more preferably at least about 9kP, and most preferably at least about 11 kP. However, the mixture should not be compressed to such an extent that it is difficult to achieve hydration upon subsequent contact with gastric fluid.

The friability of the tablet is preferably less than about 1.0%, more preferably less than 0.8%, and most preferably less than about 0.5% in a standard test.

Wet granulation, dry granulation or direct compression or encapsulation methods may be used to prepare the tablet or capsule compositions of the present invention.

Although the unit dose capsule and tablet compositions of the present invention may be prepared, for example, by direct encapsulation or direct compression, wet granulation prior to encapsulation or compression is preferred. Wet granulation, among other effects, can provide intimate association of the milled composition, resulting in improved flowability, improved tableting characteristics and ease of metering or weight dispersion of the composition in encapsulation or tableting. There is no critical limitation on the second particle size (i.e., the size of the granules) obtained by granulation, and it is only important that the average particle size should preferably be convenient to handle and process and, for tablets, that the mixture be directly compressible into pharmaceutically acceptable tablets.

In a representative wet granulation process, any drug moiety in non-nanoparticulate form (with one or more carrier materials, if desired) is first milled or micronized to the desired particle size range of greater than 1 μm. While various conventional mills or pulverizers may be used, impact milling, such as pin milling, of the medicament may provide greater homogeneity of the final mixture relative to other types of mills. During milling, to avoid heating the drug to an undesirable temperature, it may be desirable to cool the milled mixture, for example, using liquid nitrogen. During the grinding step D₉₀The particle size is preferably reduced to less than about 25 μm.

If a milled or micronized drug is present, it is mixed with the desired amount of nanoparticulate drug as indicated above, resulting in a drug substance that is partially or completely in nanoparticulate form. Simultaneously or subsequently, the drug substance is mixed with one or more excipients, including excipients milled with celecoxib or excipients contained in the nanoparticles, for example in a high shear mixer/granulator, planetary mixer, double shell mixer or sigma mixer, to give a dry powder mixture. Typically, the drug substance is mixed with one or more diluents, disintegrants and/or binders, and optionally one or more wetting agents in this step; or all or part of one or more excipients may be added in a subsequent step. For example, in tablets using croscarmellose sodium as a disintegrant, it has been found that the addition of a portion of croscarmellose sodium during the mixing step (to provide intragranular croscarmellose sodium) and the remainder thereof after the drying step discussed below (e.g., extra granular croscarmellose sodium) can improve the disintegration properties of the tablets produced. In this case, it is preferred to add from about 60 to about 75% croscarmellose sodium within the granule and from about 25 to about 40% croscarmellose sodium outside the granule. It has also been found that for tablets, the addition of microcrystalline cellulose (ultra-granular microcrystalline cellulose) after the following drying step improves the compressibility of the granules and increases the hardness of tablets made from these granules.

The mixing step of the process preferably comprises mixing the drug substance, lactose, polyvinylpyrrolidone and croscarmellose sodium. It was found that mixing times as short as 3 minutes gave a dry powder mixture with a homogeneous distribution of drug sufficient to obtain commercially available tablets.

Water, preferably pure water, is then added to the dry powder mixture and the mixture is stirred for an additional period of time to form a wet particulate mixture. Preferably, a wetting agent is used, which is preferably added and stirred for at least 15 minutes, preferably at least 20 minutes, before the water is added to the dry powder mixture, and then the water is added to the mixture immediately, or stepwise over a period of time, or in several portions over a period of time. Preferably, the water is added gradually over a period of time or, alternatively, the wetting agent may be added to the dry powder mixture and then the water added to the resulting mixture. It is preferred to add the water followed by sufficient mixing for a period of time to ensure uniform distribution of the water in the mixture.

The wet granulation mixture is then preferably wet milled, for example with a milling screen, to remove larger agglomerates of material that are incidentally formed by the wet granulation operation. If not removed, these lumps will prolong the subsequent drying process, increasing the difference in moisture control.

The wet granulated or wet milled mixture is dried to obtain dry granules, for example in an oven or a fluid bed dryer, preferably the latter. If desired, the wet particulate mixture may be extruded and spheronized prior to drying. For the drying process, drying conditions, such as inlet air temperature and drying time, are adjusted to obtain dry granules of the desired moisture content. For this drying step and subsequent processing steps, it may be necessary to mix two or more granulation sections.

The dry granules may be reduced in size, if desired, in preparation for tableting and encapsulation. Conventional particle size reduction devices such as a shaker or impact mill (e.g., a Fitz mill) may be used.

For mixtures with lower water content, a slight decrease in particle size was observed with prolonged mixing time. It is speculated that when the water concentration is too low to fully activate the binder used, the adhesion between the primary particles within the particles will not be able to withstand the shear forces generated by the mixing blades and the particle size of the particles will be reduced without increasing. Conversely, increasing the water content to fully activate the binder will allow the bonding forces between the primary particles to withstand the shear forces generated by the mixing blades, and as the mixing time and/or rate of water addition increases, the particles will grow without decreasing. Changing the mesh size of wet grinding has a greater effect on particle size than changing the feed rate and/or grinding rate.

The dry granules are then placed in a suitable mixer, such as a double-shell mixer, and optionally a lubricant (e.g., magnesium stearate) and other additional carrier materials (e.g., super-granular microcrystalline cellulose and/or super-granular croscarmellose sodium in certain tablet formulations) are added to form a final mixture. When the diluent comprises microcrystalline cellulose, it has been found that the addition of a portion of microcrystalline cellulose during this step can greatly increase the compressibility of the granules and the hardness of the tablet. However, increasing the amount of magnesium stearate above about 1% to about 2% decreases tablet hardness and increases friability and dissolution time.

The final blended mixture is then encapsulated (or, if tablets are to be made, compressed into tablets of the desired weight and hardness using a tool of appropriate size). Conventional tableting and encapsulation techniques known in the art may be employed. Suitable results are obtained by using a bed height range of about 20mm to about 60mm, a compaction setting range of about 0 to about 5mm, and a speed of about 60000 capsules/hour to about 130000 capsules/hour. The use of a minimum compaction setting that can maintain control over the weight of the capsule minimizes or eliminates the formation of small lumps. Where a coated tablet is desired, conventional coating techniques known in the art may be employed.

This combination of operations produces a single dose of uniform drug content, easily disintegrable granules that are sufficiently flowable to reliably control weight variation during capsule filling or tableting, and sufficiently dense to be prepared in batches at the selected equipment and individual doses fitted with the particular capsule or tablet die.

The invention also relates to the use of the compositions of the invention in the manufacture of a medicament useful in the treatment and/or prevention of COX-2 mediated diseases and conditions, particularly where rapid onset of therapeutic action is required or desired for such diseases and conditions.

Description of the particularly preferred embodiments

Patents and other references relating to nanoparticulate pharmaceutical compositions teach that smaller drug particle sizes generally favor the onset of therapeutic action or other pharmacodynamic advantages following oral administration. For example, at least the following patents propose reducing the particle size to about 400nm or less.

U.S. Pat. No.5,145,684, cited above.

U.S. patent No.5,298,262, cited above.

U.S. patent No.5,302,401, cited above.

U.S. patent No.5,336,507, cited above.

U.S. patent No.5,340,564, cited above.

U.S. patent No.5,346,702, cited above.

U.S. patent No.5,352,459, cited above.

U.S. Pat. No.5,429,824, cited above.

U.S. patent No.5,503,723, cited above.

U.S. Pat. No.5,510,118, cited above.

U.S. Pat. No.5,534,270, cited above.

U.S. patent No.5,552,160, cited above.

U.S. patent No.5,573,783, cited above.

U.S. patent No.5,585,108, cited above.

U.S. patent No.5,591,456, cited above.

U.S. patent No.5,662,883, cited above.

U.S. patent No.5,665,331, cited above.

However, the smaller the drug particle size, the longer grinding or pulverizing time, more energy and labor are generally required to produce the particles, and thus the more costly and less efficient the process. Therefore, producing a quantity of drug particles that are smaller than nanometer size is generally significantly more expensive and labor intensive than drug particles that are larger than nanometer size.

Surprisingly, we have now found that selective COX-2 inhibitor pharmaceutical compositions having a weight average particle size of about 450nm to about 1000nm (referred to herein as "submicron" formulations and particle sizes) exhibit a time of onset and bioavailability that is substantially equivalent to a reference composition having a weight average particle size of about 200nm to about 400nm, as measured in vitro and in vivo. Submicron formulations require shorter milling times and less energy than formulations containing nanoparticles in the weight average particle size range 200 and 400 nm.

It is also envisaged that sub-micron as opposed to smaller particle sizes may achieve some advantages other than saving money. For example, where ultrafine particles tend to agglomerate or otherwise fail to disperse in gastrointestinal fluids, slightly larger submicron particles may exhibit enhanced dispersibility.

Thus, in a particularly preferred embodiment of the present invention, there is provided a pharmaceutical composition comprising one or more orally deliverable dose units, each dose unit comprising a selective COX-2 inhibitor drug of low water solubility in a therapeutically effective amount, wherein the drug is administered at a D of about 450nm to about 1000nm₂₅Solid particles of a size present, and more preferably from about 500nm to about 900nm, with D₂₅The compositions of the present invention provide at least substantially similar C compared to otherwise similar compositions having a particle size of less than 400nm_maxAnd/or at most substantially similar T_maxAnd/or with D₂₅The compositions of the present invention provide substantially greater C than otherwise similar compositions having a particle size greater than 1000nm_maxAnd/or substantially shorter T_max。

Also provided is a pharmaceutical composition comprising one or more orally deliverable dose units, each dose unit comprising a selective COX-2 inhibitor drug of low water solubility in a therapeutically effective amount, wherein the drug is present as solid particles and wherein about 25% to 100% by weight of the particles have a particle size in the range of about 450nm to about 1000nm, more preferably in the range of about 500nm to about 900 nm.

Also provided is a pharmaceutical composition comprising one or more orally deliverable dose units, each dose unit comprising a selective COX-2 inhibitor drug of low water solubility in a therapeutically effective amount, wherein the drug is present as solid particles having a weight average particle size of about 450nm to about 1000nm, and more preferably having a solid particle size of about 500nm to about 900nm, the composition of the invention providing at least substantially similar C compared to an otherwise similar composition having a weight average particle size of less than 400nm_maxAnd/or at most substantially similar T_maxAnd/or the compositions of the present invention provide substantially greater C than an otherwise similar composition having a weight average particle size of greater than 1000nm_maxAnd/or substantially shorter T_max. For ease of description, "weight average particle size" may be considered to be D₅₀Synonym for particle size.

Submicron particles of a selective COX-2 inhibitor drug can be prepared by modifying the method described above in the preparation of nanoparticles or by the method described by way of example in example 1 below.

Examples

Example 1

Dispersions D1-D4 containing 5% by weight celecoxib were prepared by the method described below. The dispersions differ only in the size range of celecoxib.

1. Celecoxib is micronized in an air jet mill to form a drug powder.

2. The drug powder was added to an aqueous solution containing 2.5% low viscosity hydroxypropyl cellulose (HPC-SL) and 0.12% sodium lauryl sulfate to form a suspension.

3. The suspension was wet milled to form an intermediate dispersion as follows. A sample size of 6.0ml of suspension (containing 20% celecoxib), a magnetic stir bar, 8ml of lead-free glass beads and 50. mu.l of Antifoam (Sigma Antifoam A concentrate) were added to a 20ml scintillation vial. To provide an intermediate dispersion with a target particle size range of 6-7 μm (i.e. the particle size range reached in the micronization step, used to provide the control composition), the scintillation vial was shaken for 2 minutes. To provide an intermediate dispersion with a smaller target particle size range, the scintillation vial was suspended on a high intensity rotating magnet to provide a magnetic stir bar to rotationally stir the glass beads for milling. The target particle size range was varied by controlling magnet rotation speed, milling time and/or glass bead size as per table 1. Aliquots were taken at intervals to check the progress of particle size reduction.

4. The intermediate dispersions obtained each time were transferred to larger bottles and diluted with fresh carrier to form the final dispersion. The normal celecoxib concentration in the final dispersion is 5% by weight. TABLE 1 milling conditions for producing celecoxib dispersions D1-D4

Dispersion product	Target size Range (μm)	Glass bead size (mm)	Grinding time (min)	Grinding speed (rpm)
					D1	6-7	3.3-3.6	--	--
D2	1-3	3.3-3.6	26	900
					D3	0.5-0.9	1.25-1.55	25	900
D4	0.2-0.4	0.5	52	1250

Example 2

The particle size of celecoxib in dispersions D1-D4 prepared in example 1 was determined by laser (Fraunhofer) diffraction and by optical microscopy.

Fraunhofer scattering of static dispersion samples was determined using a Sympatec spectrometer. The sample was diluted with water to a static cell that maintained a reduction in laser intensity of approximately 20% concentration. The choice of specimen lens is determined by the total number of large substances present in the suspension, and therefore the choice is different for each sample. However, the minimum focal length appropriate for the eye is suitable for various situations. Mie scatter correction was not performed. The results shown in FIG. 1 indicate that D₅₀The particle size is consistent with the target particle size range. It is believed that D is shown in FIG. 1 for a dispersion of celecoxib of 0.2 to 0.4 μm₅₀And other particle size parameters are evaluated too high because the particle size range is the detection limit of the technique.

To determine particle size by vision, optical microscopy was used. Observations were made with an Olympus BH-2 microscope attached to a video camera. The image is then digitized (Snappy 4.0; Play Inc., Rancho Cordova, Calif.) and processed as appropriate (Paint Shop Pro6.02; JASC, Eden Prairie, MN). FIG. 2 shows micrographs of samples of celecoxib dispersion D1-D4 in unpolarized (left) and polarized (right) light. The bar graph represents 10 μm. Significant brownian motion was observed in dispersions D3 and D4, consistent with the presence of very small nanoparticles. Note instead that dispersion D2 had only slight brownian motion and dispersion D1 did not have it at all.

Example 3

The dissolution characteristics of the celecoxib crystals in dispersions D1-D4 of example 1 were evaluated in an in vitro dissolution assay as described below. FIG. 4 is a diagrammatic representation of the apparatus used in this experiment. The dissolution vessel was a 600ml jacketed beaker. The jacket was connected to a temperature controlled water circulator which served to maintain the temperature of the digestion solution at 37 ℃. The digestion solution was stirred using a standard USP II digestion paddle. The paddle was driven by a computer controlled constant speed motor and was adjusted to run at 75rpm throughout the assay.

The dispersion sample was injected into the dissolution vessel just below the surface of the dissolution fluid. Introducing a sample in the process minimizes the possibility of particles collecting on the surface of the liquid. At the same time, the get data program begins to run. During the measurement, sample points were taken at 30 seconds and every 30 seconds thereafter. The dissolution process lasted 60 minutes for each sample studied. The concentration of dissolved drug in the vessel is monitored in situ by a fiber optic probe for measuring the optical absorbance of the dissolved drug in the dissolution fluid. The probe remains submerged in the liquid throughout the assay. Determining the concentration of the dissolved drug in the liquid from the measured absorbance values according to the Beer-Lambert equationWhere A is the absorbance measured at 254nm, l is the path length in cm, ε is the absorption coefficient at 254nm in ml/(μ g-cm), and c is the drug concentration in μ g/ml. The path length of the optical fiber probe was fixed at 1 cm. A typical calibration procedure with a standard celecoxib solution was used to determine the absorption coefficient at 254 nm.

An additional personal computer was equipped to record absorbance values every 30 seconds. Such a set of test data consists in situ of absorbance values at 30 second intervals throughout the test. The absorbance values were then converted to drug concentrations by the Beer-Lambert equation described above.

Before analyzing the dispersion according to the invention, 500ml of dissolution liquid (deionized water) were added to the dissolution vessel and equilibrated at 37 ℃. The elution paddle and fiber optic probe were placed in a container and also equilibrated at 37 ℃. Celecoxib dispersions D1-D4 prepared in example 1 were sonicated for approximately 5 minutes prior to testing. Each dispersion was shaken by hand and then a 40. mu.l sample of the dispersion was immediately pipetted into the above-mentioned dissolution solution.

FIG. 3 shows the dissolution rates of dispersions D1-D4. For ease of comparison, all dissolution traces were normalized to the same value at 60 minutes. This normalization step is necessary to compensate for slight differences in the samples when comparing very similar dissolution profiles. The dissolution plot shows the normalized percentage of celecoxib dissolved as a function of time.

Overall, the dissolution of reference dispersion D1 was much slower than that of the inventive dispersions D2, D3 and D4, all of which dissolved at a substantially similar rate. The results suggest that there is no significant functional advantage in the dissolution rate obtained by milling celecoxib particles to a weight average particle size below 400nm as compared to celecoxib particles having a weight average particle size in the range of 450nm to 1000 nm. All nanoparticle dispersions showed significant advantages in dissolution rate compared to micronized celecoxib dispersions.Example 4

The pharmacokinetic properties of celecoxib dispersions D1-D4 prepared in example 1 were evaluated in an in vivo study in dogs.

One of the four celecoxib dispersions D1-D4 was administered to beagle dogs in 8 males at a dose of 10 mg/kg. Venous blood was collected before dosing and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3,5, 8 and 24 hours post-dosing. Plasma was separated from blood by centrifugation and then plasma drug concentration was determined by high performance liquid chromatography. The pharmacokinetic data obtained are shown in table 2.

Table 2: pharmacokinetic parameters of celecoxib dispersions D1-D4

	Dispersion product
					D1	D2	D3	D4
	Tmax(h)	1.2	0.84	0.72					0.72
Cmax(ng/m1)					1400	4850	6120	6310
	AUC(h*ng/ml)	14600	32700	37500					43500

T of dispersions D3 (target particle size range 0.5-0.9 μm) and D4 (target particle size range 0.2-0.4 μm)_max、C_maxAnd AUC (total bioavailability) values are very similar. Dispersion D2 (target particle size range 1-3 μm) showed a slightly extended T compared with dispersions D4 and D3_maxAnd C of reduced degree_maxAnd AUC values. T of Dispersion D1_maxIs much longer, and C_maxAnd AUC was also much lower than that of dispersions D2, D3, and D4.

These results show that it is possible to determine,when a rapid onset of therapeutic effect is desired, D is used which is ground to a target particle size in the range of 0.5-0.9 μm and measured by Fraunhofer scattering (FIG. 1)₅₀Good bioavailability is obtained with celecoxib having a particle size of about 0.9 μm. It takes more time and energy to grind celecoxib particles to a target particle size range of 0.2-0.4 μm without significant benefit.

Claims (18)

1. A pharmaceutical composition comprising one or more oral dosage units, each dosage unit comprising a therapeutically effective amount of a selective cyclooxygenase-2 inhibitory drug of low water solubility, wherein said drug is present in D₉₀Of solid particles having a particle size of from about 0.01 μm to about 200 μm, and a sufficient weight fraction of the particles being less than 1 μm to provide a substantially increased C as compared to an otherwise similar composition having substantially all of the particles being greater than 1 μm_maxAnd/or substantially shortened T_max。

2. ComprisesA pharmaceutical composition of one or more oral dosage units, each dosage unit comprising a therapeutically effective amount of a selective cyclooxygenase-2 inhibitory drug of low water solubility, wherein said drug is present in D₉₀Solid particles having a particle size of from about 0.01 μm to about 200 μm, and wherein from about 25% to 100% by weight of the particles are less than 1 μm.

3. The composition of claim 1 or 2, wherein substantially all of the particles are less than 1 μm.

4. The composition of any one of claims 1-3, wherein the dosage unit is in the form of a discrete solid product.

5. The composition of claim 4, wherein the solid product is a tablet or capsule.

6. The composition of any one of claims 1-3, wherein the composition is in the form of a substantially homogeneous flowable substance that can be removed by measurement as a single dose unit.

7. The composition of claim 6, wherein the substantially homogeneous flowable substance is a liquid suspension.

8. The composition of any of claims 1-7, wherein the solid particles have a D of about 450nm to about 1000nm₂₅Particle size.

9. The composition of any one of claims 1 to 7, wherein from about 25% to 100% by weight of the solid particles have a particle size of from about 450nm to about 1000 nm.

10. The composition of any one of claims 1 to 7, wherein the solid particles have a weight average particle size of about 450nm to about 1000 nm.

11. The composition of any one of claims 1-10, wherein the selective cyclooxygenase-2 inhibitory drug is a compound of the formulaWherein R is³Is methyl or amino, R⁴Is hydrogen or C_1-4Alkyl or alkoxy, X is N or CW⁵Wherein R is⁵Is hydrogen or halogen and Y and Z are independently carbon or nitrogen atoms defining adjacent atoms of a 5-6 membered ring, which 5-6 membered ring is unsubstituted or substituted in one or more positions by oxo, halogen, methyl or halomethyl.

12. The composition of claim 11, wherein the 5-6 membered ring is selected from the group consisting of cyclopentenone, furanone, methylpyrazole, isoxazole, and pyridine rings substituted in no more than one position.

13. The composition of any one of claims 1-10, wherein the selective cyclooxygenase-2 inhibitory drug is selected from the group consisting of celecoxib, deracoxib, valdecoxib, rofecoxib, 5-chloro-3- (4-methylsulfonyl) phenyl-2- (2-methyl-5-pyridyl) pyridine, 2- (3, 5-difluorophenyl) -3- [4- (methylsulfonyl) phenyl ] -2-cyclopenten-1-one, and (S) -6, 8-dichloro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid.

14. The composition of claim 13 wherein the selective cyclooxygenase-2 inhibitory drug is celecoxib.

15. The composition of claim 14, wherein from about 10mg to about 1000mg celecoxib is included in each dosage unit.

16. A method of treating a disorder or disease for which a cyclooxygenase-2 inhibitor is indicated in an individual, the method comprising orally administering one or more dosage units of the composition of any one of claims 1-15 from 1 to about 6 times per day.

17. The method of claim 16, wherein the condition or disease is accompanied by acute pain.

18. A method of using solid particles of a selective cyclooxygenase-2 inhibitory drug of low water solubility in the manufacture of a medicament for the treatment or prevention of a COX-2 mediated disorder or disease, wherein said solid particles have a D of about 0.01 μm to about 200 μm₉₀Particle size and from about 25% to 100% by weight of the solid particles are less than 1 μm.