CN1433308A - Cyclooxygenase-2 inhibitor compositions having rapid on set therapeutic effect - Google Patents

Abstract

Pharmaceutical compositions are provided comprising one or more orally deliverable dose units, each comprising a selective cyclooxygenase-2 inhibitory drug of low ater solubility in atherapeutically effective amount, wherein the drug is present in the form of solid particles, about 25% to 100% by weight of which are smaller than 1 mu m. The composition are useful in treatment or prophylaxis of cyclooxygenase-2 mediated conditions and disorders and have particular advantages where rapid onset of therapeutic effect is desired.

Description

Energy is the COX-2 inhibitors compositions of begin treatment effect rapidly

Invention field

The present invention relates to contain selective COX-2 and suppress the combination of oral medication of medicine as active component, prepare described method for compositions, by giving the method and the application of described compositions in the preparation medicine of the disease that the Orally administered described compositions of treatment target treats the COX-2 mediation.

Background of invention

It is reported that a lot of chemical compounds have the selectivity of use value COX-2 (COX-2) inhibitory action is arranged aspect treating and/or preventing, and can be used for treating or preventing disease or most of such disease of specific C OX-2 mediation according to disclosing them.In the middle of such chemical compound, pyrazolyl benzene sulfone amides a large amount of as the disclosed replacement in people's such as Talley United States Patent (USP) 5760068 is arranged, comprise for example chemical compound 4-[5-(4-aminomethyl phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzsulfamide, this chemical compound is also referred to as celecoxib (I) in this article, with chemical compound 4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl] benzsulfamide, this chemical compound is also referred to as deracoxib (II) in this article.

It is reported that inhibiting other chemical compound of the selective COX-2-2 with the usefulness for the treatment of and/or preventing has disclosed replacement De isoxazolyl benzene sulfonamide in people's such as Talley United States Patent (USP) 5633272, comprise chemical compound 4-[5-methyl-3-phenyl-isoxazole azoles-4-yl] benzsulfamide, this chemical compound is also referred to as valdecoxib (III) in this article.

It is reported that inhibiting other chemical compound of the selective COX-2-2 with the usefulness for the treatment of and/or preventing also has (methyl sulphonyl) benzofurane ketone (furanones) of disclosed replacement in people's such as Ducharme United States Patent (USP) 5474995; comprise chemical compound 3-phenyl-4-[4-(methyl sulphonyl) phenyl]-5H-furan-2-ketone, this chemical compound is also referred to as rofecoxib (IV) in this article.

People's such as Belley United States Patent (USP) 5981576 discloses (methyl sulphonyl) benzofurane ketone that other a series of certificate is stated useful as selective Arcoxia thing; comprise 3-(1-cyclo propyl methoxy)-5; 5-dimethyl-4-[4-(methyl sulphonyl) phenyl]-5H-furan-2-ketone and 3-(1-cyclopropyl ethyoxyl)-5,5-dimethyl-4-[4-(methyl sulphonyl) phenyl]-5H-furan-2-ketone.

People's such as Dube United States Patent (USP) 5861419 discloses according to the pyridines of stating the replacement of useful as selective Arcoxia thing, comprises for example chemical compound 5-chloro-3-(4-methyl sulphonyl) phenyl-2-(2-methyl-5-pyridine radicals) pyridine (V).

European patent application 0863134 discloses according to chemical compound 2-(3, the 5-difluorophenyl)-3-[4-(methyl sulphonyl) phenyl of stating useful as selective Arcoxia thing]-2-cyclopentenes-1-ketone.

United States Patent (USP) 6034256 discloses according to a series of benzo pyrans of stating useful as selective Arcoxia thing, comprises chemical compound (S)-6,8-two chloro-2-(trifluoromethyl)-2H-1-.alpha.-5:6-benzopyran-3-formic acid (VI).

A lot of selective COX-2s-2 inhibition the medicine that comprises celecoxib, deracoxib, valdecoxib and rofecoxib is hydrophobic, and the dissolubility in water is very little.This makes and be faced with practical difficulty when this class medicine of preparation oral administration, particularly when need or must the rapid begin treatment of this class medicine to do the time spent all the more so.

For example, up to now, for Orally administered to treatment target effectively, the preparation of celecoxib is because its unique physics and chemical property, particularly its low solubility and the factor relevant with its crystal structure comprise caking property, low bulk density and low compressibility and become very complicated.The common water insoluble medium of celecoxib.When oral administration during for example with the capsule form administration, Pei Zhi celecoxib is difficult for dissolving and disperses, thereby can not absorb rapidly in gastrointestinal tract.In addition, when tabletting in the film-making mould, the not preparation celecoxib that its crystal habit is tending towards forming long viscosity spicule generally can be fused into the monoblock material.Even when mixing with other material, the ce1ecoxib crystal also often separates with other material and coalesces together between the mixing period of compositions, causes forming the mixed uniformly compositions of failing that contains disadvantageous big celecoxib caking.Therefore, be difficult to prepare the pharmaceutical composition that contains celecoxib with required mixing uniformity.In addition, during preparation celecoxib compositions, also can run into by the operational issue due to the low bulk density of for example celecoxib.Therefore, need solution to contain the compositions of celecoxib and a lot of problems that dosage form, particularly oral unit dosage form are brought by preparation.

In addition, especially need such preparation: comprise that promptly the low aqueous solubility selective COX-2-2 of celecoxib suppresses the oral formulations of medicine, such preparation can be than the known formulations begin treatment effect quickly of corresponding not compounding pharmaceutical or these medicines.The medicine maximum serum-concentration (C that the degree of begin treatment effect and pharmacokinetic parameters are for example high rapidly _Max) and short oral administration after reach maximum serum-concentration required time (T _Max) relevant, especially need such preparation: comprise that promptly the low aqueous solubility selective COX-2-2 of celecoxib suppresses the oral formulations of medicine, such preparation can provide the bigger C of known formulations than corresponding not compounding pharmaceutical or these medicines _MaxAnd/or shorter T _Max

As described below, suppress medicine with the selective COX-2-2 that comprises celecoxib and can treat disease and the disease that maybe might treat a lot of COX-2 mediations.Special in the treatment that wherein needs or must remove as early as possible the acute disease of pain or other symptom, it is very useful that its pharmacokinetics and the rapid corresponding to preparation of begin treatment effect are provided.

Such preparation will represented in the disease of treatment COX-2 mediation and the marked improvement aspect the disease.

The low aqueous solubility selective COX-2-2 that comprises celecoxib suppresses medicine, and to be mixed with solid particulate form be most convenient.Independent or original drug particles can be dispersed in and for example be dispersed in the liquid medium in the suspending agent, perhaps it can be assembled secondary granule or the particulate that can seal so that capsule formulation to be provided to form, perhaps can be with its compression or molded so that Tabules to be provided.

Known have a lot of preparations to have the original particle size of required scope or have required particle mean size or have by parameter D for example ₉₀The method of the pharmaceutical preparation of the particle size distribution of description feature, wherein D ₉₀Be defined as the linear measured value of such diameter in this article: wherein in the preparation granule of 90% weight on long grain size less than this diameter.Other grain size parameter of Shi Yonging is to define in a similar manner in this article; For example, D ₁₀, D ₂₅And D ₅₀Parameter is meant the linear measured value of such diameter: the granule that 10%, 25% and 50% weight is wherein arranged respectively is less than this diameter.

For consistent with the prior art publication, the definition of term " microparticle " and " nano-particle " is identical with people's such as Courteille United States Patent (USP) 5384124 in this article, is meant that respectively diameter is the about 2000 μ m of about 1 μ m-and the diameter granule less than about 1 μ m (1000nm).According to United States Patent (USP) 5384124, microparticle and nanoparticle formulations " mainly being the dissolving that is used to postpone active component ".Yet people's such as Liversidge United States Patent (USP) 5145684 discloses according to stating can give medicine, particularly for example have the Nanoparticulate compositions that low solubility drugs provides " unforeseeable high bioavailability " in the water at liquid medium.International publication WO93/25190 provides terrible pharmacokinetic data from the rat test, these data show, compare with microparticle (granularity the is 20-30 μ m) dispersion of Orally administered naproxen, the nano-particle of Orally administered naproxen (particle mean size is 240-300nm) disperses physical ability to obtain obvious faster absorption speed.

Known have a lot of methods that prepare the therapeutic agent Nanoparticulate compositions.These methods generally are to use mechanical means for example to mill granularity is reduced to nanometer (being lower than 1 μ m) scope, perhaps are settled out nano-scale particle from solution.

The invention summary

According to the present invention, after the Orally administered compositions that contains medicine, make weak water solublity selective COX-2-2 suppress medicine begin treatment effect quickly, this medicine shows and causes the maximum serum-concentration (C of bigger medicine _Max) and/or shorter administration after reach maximum serum-concentration required time (T _Max) pharmacokinetic characteristic.The size of the solid particle by will comprising this medicine reduces, so that the diameter of most of (weight) granule on long grain size can obtain bigger C less than about 1 μ m _MaxAnd/or shorter T _MaxBe not entangled in theory, it is believed that described bigger C _MaxAnd/or shorter T _MaxBe because due to medicine can dissolve quickly when granularity is brought down below about 1 μ m.

Therefore, the invention provides the pharmaceutical composition that comprises one or more oral dosage units, each dosage unit comprises the low aqueous solubility selective COX-2-2 for the treatment of effective dose and suppresses medicine, and wherein said medicine is present in D ₉₀Granularity is in the solid particle of the about 200 μ m of about 0.01-, and the granule that enough wt parts are arranged is less than 1 μ m, has the C that essence increases to provide all to compare greater than other analogous compositions of 1 μ m with all granules basically _MaxAnd/or the T of essence shortening _Max

The present invention also provides the pharmaceutical composition that comprises one or more oral dosage units, and each dosage unit comprises the low aqueous solubility selective COX-2-2 for the treatment of effective dose and suppresses medicine, and wherein said medicine is present in D ₉₀Granularity is in the solid particle of the about 200 μ m of about 0.01-, and the granule of the 25%-100% weight of having an appointment is less than 1 μ m.

The dosage unit that comprises described compositions can be the form of discontinuous solid product, for example tablet, pill, hard or soft capsule, lozenge, sachet or pastille; Perhaps described compositions can be basically the evenly form of flowable mass, and for example granule or fine-grained solids or liquid suspension therefrom can take out single dosage unit by measuring.

The present invention also provides in the treatment individuality as the disease of cox 2 inhibitor indication or the method for disease, and this method comprises the present composition of Orally administered one or more dosage units, about 6 times of administration every day 1-, preferred administration every day 1 time or 2 times.This method is specially adapted to wherein follow the disease or the disease of acute pain.

Further feature of the present invention is partly high-visible, and part is pointed out hereinafter.

The accompanying drawing summary

Accompanying drawing 1 expression be the granularity data of measuring by the Fraunhofer diffraction as the celecoxib dispersion D1-D4 that makes as described in the embodiment 1.

What accompanying drawing 2 was represented is the light micrograph of the dispersion D1-D4 sample of mensuration under non-polarized light (left side) and polarized light (right side).

Dissolution in vitro time-conditional curve of the dispersion D1-D4 of accompanying drawing 3 expressions.

Accompanying drawing 4 is the figure that are used to carry out the device that embodiment 3 dissolution in vitro measure.

Detailed Description Of The Invention

Being applicable to selective COX-2 of the present invention-2 inhibition medicine is COX-2 can be suppressed to treating useful degree, and the degree that simultaneously cyclooxygenase-1 (COX-1) is suppressed significantly be lower than the medicine of conventional nonsteroidal anti-inflammatory drug (NSAIDs).

The present invention is specially adapted to low aqueous solubility selective COX-2-2 and suppresses medicine, especially is lower than about 10g/l, preferably is lower than the selective COX-2-2 inhibition medicine of about 1g/l 25 ℃ of solubility in distilled water.

Term " Orally administered " comprises the arbitrary form that therapeutic agent or its composition is administered to treatment target in this article, wherein is the mouth that therapeutic agent or composition is placed treatment target, no matter whether swallows down this therapeutic agent or composition. Therefore " Orally administered " comprises cheek and hypogloeeis and oesophagus administration. The absorption of therapeutic agent can be carried out at the intestines and stomach arbitrary portion that comprises mouth, oesophagus, Stomach duodenum, ileum and colon.

Term " oral " refers to be suitable for oral administration in this article.

Term " dosage " unit in this article " refer to be suitable for single oral administration so that a part of pharmaceutical composition of a certain amount of therapeutic agent of containing of therapeutic action (being that selective COX-2-2 suppresses medicine in the present invention) to be provided. Generally be as the single oral administration administration, so that the therapeutic agent of the amount that is enough to produce required curative effect to be provided with a dosage unit or a plurality of (being up to about 4) small dosage units.

Be applied in this article term that selective COX-2-2 suppresses medicine and " be present in the solid particle " and comprise solid particle wherein basically by the composition of ingredients, and wherein solid particle comprises composition with the well-mixed medicine of one or more other components. These other components can comprise that one or more suppress therapeutic agent and/or one or more pharmaceutically acceptable excipient of medicine except selective COX-2-2.

Term " excipient " is meant such material in this article, it himself not therapeutic agent, but as therapeutic agent delivery being given the carrier or the excipient of treatment target, or be added in the pharmaceutical composition to improve its operability, storage, disintegrate, dispersion, dissolving, release or sense quality or to allow or promotes discontinuous product that the compositions formation of unit dose is suitable for oral administration for example capsule or tablet.Excipient can comprise, such as but not limited to diluent, disintegrating agent, binding agent, sticker, wetting agent, lubricant, fluidizer, the material of covering up or offsetting disagreeable taste or abnormal smells from the patient, correctives, dyestuff, spice with improve the material of compositions outward appearance.

Term " even basically " about the pharmaceutical composition that contains several components is meant that these components are fully mixed, and makes each component not exist as discontinuity layer, and do not form Concentraton gradient in compositions.

The present composition comprises one or more oral dosage units.Each dosage unit comprises the treatment effective dose, preferably the about 1000mg selective COX-2-2 of about 10mg-suppresses for example celecoxib of medicine.

Should be appreciated that for treatment target the treatment effective dose of selective COX-2-2 inhibition medicine depends on the body weight of treatment target especially.When medicine is celecoxib and treatment target when being child or toy (for example Canis familiaris L.), preferable range may provide and the corresponding to serum-concentration of curative effect for the low amount celecoxib of the about 1000mg of about 10mg-.When treatment target was adult or large animal (for example horse), the serum-concentration that obtains such celecoxib may need to contain the dosage unit of relatively large celecoxib.For the adult, the celecoxib of each dosage unit treatment effective dose is generally the about 400mg of about 50mg-in the present composition.For each dosage unit, the special preferred amounts of celecoxib is the about 200mg of about 100mg-, the about 200mg of for example about 100mg-.

Suppress medicine for other selective COX-2-2, the amount of every this medicine of dosage unit can be for to reach in the known dose scope of this curative effect of medication.This medication amount of each dosage unit is preferably the dosage range that the curative effect that is equal to above-mentioned dosage range celecoxib can be provided.

The dosage unit of celecoxib compositions of the present invention generally contains the about 400mg celecoxib of the 10mg-that has an appointment, and for example 10,20,37.5,50,75,100,125,150,175,200,250,300,350 or the celecoxib of 400mg dosage.Preferred dosage unit contains the about 400mg celecoxib of the 25mg-that has an appointment.More preferred dose unit contains the about 200mg celecoxib of the 50mg-that has an appointment.Can select given dose unit to be adapted to and realize the required administration frequency of particular day dosage.In order to treat disease or disease, the dosage of present composition unit dosage forms and dosage regimen will depend on multiple factor, the age, body weight, sex and the health that comprise treatment target, the order of severity of disease or disease, route of administration and frequency, and selected specific selective COX-2-2 inhibition medicine, therefore can in wide range, change.Can use every day and be up to 6 next or a plurality of dosage units.Yet, for most applications, once a day or every day twice dosage regimen required curative effect can be provided.

The present composition contains preferably that the 1%-that has an appointment is about 95%, preferably about 10%-is about 90%, more preferably from about 25%-is about 85%, also more preferably from about the selective COX-2-2 of about 80% weight of 30%-suppresses medicine, these medicine individualisms or with the abundant mixture of one or more excipient in.Medicine has at least a part to be form of nanoparticles, promptly is the solid particulate form that on long grain size diameter is lower than 1 μ m.

For the medicine of any specific medicine or classification, it is normally unpredictable that granularity is reduced to the pharmacokinetics effect that nanoparticle range produces from microparticle scope (diameter is greater than 1 μ m).According to the present invention, for the selective COX-2-2 inhibition medicine of low aqueous solubility, Nanoparticulate compositions shows the C higher than microparticle compositions _MaxAnd/or shorter T _MaxTherefore, in an embodiment of the present invention, the percentage by weight of nano-particle is enough to provide all compare greater than the reference composition of 1 μ m with all granules basically and has the C that essence increases _MaxAnd/or the T of essence shortening _MaxCompare with reference composition, the compositions of this embodiment has the nano-particle of enough percentage by weights to provide the T that essence shortens _Max, the nano-particle that more preferably has enough percentage by weights has the C that essence increases to provide _MaxT with the essence shortening _Max

Be administered to fasting when adult when oral, celecoxib 100mg dosage unit preferably show be lower than about 90 minutes, more preferably less than about 60 minutes, most preferably be lower than about 45 minutes T _MaxWith at least about 100ng/ml, more preferably at least about the C of 200ng/ml _MaxCelecoxib compositions of the present invention provides the celecoxib serum-concentration at least about 50ng/ml usually in 30 minutes behind oral administration; Preferred compositions reaches such concentration being as short as in 15 minutes.It is believed that this serum-concentration increases the present composition begin treatment effect rapidly that makes fast.

Suppress medicine for the selective COX-2 except celecoxib-2, preferred compositions can be provided at the minimum drug serum concentration that is equal to above-mentioned minimum celecoxib concentration in the treatment.

In another embodiment of the present invention, selective COX-2-2 inhibition medicine for example celecoxib is present in D ₉₀Granularity is about in the solid particle of the about 200 μ m of about 0.01-, and the granule of wherein about 25%-100% weight is a nano-particle.When the weight percent of nano-particle is lower, for example be about 50% o'clock of about 25%-, D ₉₀Granularity is preferably the about 100 μ m of about 0.01-, the more preferably about 75 μ m of about 0.01-, also about 40 μ m of more preferably about 0.01-even the about 25 μ m of more preferably about 0.01-.Granularity can continue to change between nano-particle and microparticle scope, and perhaps compositions can have bimodal or multi-modal particle size distribution, and wherein one group of granule has the D that is lower than 1 μ m ₉₀Granularity, another group granule has basically the D greater than 1 μ m ₉₀Granularity.Usually be nano-particle preferably at least about 50% weight, especially preferred granule at least about 75% weight.In one embodiment, all granules are all less than 1 μ m basically, and promptly the percentage by weight of nano-particle is 100% or near 100%.

By for example milling or grinding or can assemble to form the secondary aggregated particle by the primary granule that makes of precipitation from solution.Unless otherwise indicated herein, otherwise in this article the term " granularity " that uses is meant the size on the longest dimension of primary granule.

In preferred embodiments, the average particle size of the present composition is the about 1000nm of about 100nm-, the about 900nm of more preferably about 100nm-, the about 400nm of for example about 200nm-or the about 900nm of about 500nm-.This medicine can be crystal or amorphous form in nano-particle.Use is milled or the processing method of the preparation nano-particle that grinds provides the medicine of crystal form usually, and the method for preparing nano-particle by precipitation from solution usually but always do not provide the medicine that partially or completely is amorphous form.

The present composition comprises the above-mentioned low aqueous solubility selective COX-2-2 that partially or completely is form of nanoparticles and suppresses for example celecoxib of medicine, and optional exist one or more be selected from the excipient of diluent, disintegrating agent, binding agent, wetting agent and lubricant.In one embodiment, the nano-particle that comprises medicine has and is adsorbed on its lip-deep regulator that shows.In another embodiment, the nano-particle of medicine is included in the substrate by polymer formation.Preferably having at least a excipient is water-soluble diluent or wetting agent.When taking in the present composition, such water-soluble diluent or wetting agent can promote the dispersion and the dissolving of medicine.Preferably both there had been water-soluble diluent, had wetting agent again.

The present composition can be for example granule or fine-grained solids or a liquid of uniform basically flowable mass, perhaps can be the form that discontinuous product form for example contains the capsule or the tablet of single dosage unit respectively.

Be basically evenly in the compositions of flowable mass, uses suitable stereometry device for example spoon or cup by measuring the single dosage unit of taking-up.Suitable flowable mass includes but not limited to powder and granule.Perhaps, flowable mass can be the suspension that has medicine at the solid particle that is scattered in liquid phase, preferred aqueous phase in mutually.Having a part of granule at least is nano-particle mutually.When the such suspension of preparation, use wetting agent for example Spheron MD 30/70 etc. may be useful.Suspension can make by nano-particle or part nano-particle medicine are dispersed in the liquid phase; Perhaps can from the solution for example pure preferred alcohol of solvent, be settled out medicine.Water preferably comprises for example water, syrup or fruit juice Sucus Mali pumilae for example of agreeable to the taste carrier.

It can be any such medicine known in the art that selective COX-2-2 suppresses medicine, includes but not limited to disclosed chemical compound in following patent and publication, and every piece of patent and publication all are introduced separately into the present invention with for referencial use.

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European patent application No.0 799 823.

European patent application No.0 846 689.

European patent application No.0 863 134.

European patent application No.0 985 666.

The present composition is particularly useful for formula (VI) chemical compound:

R wherein ³Be methyl or amino, R ⁴Be hydrogen or C _1-4Alkyl or alkoxyl, X are N or CR ⁵, R wherein ⁵Be hydrogen or halogen, and Y and Z be carbon or nitrogen-atoms independently, what described carbon or nitrogen-atoms limited is the adjacent atom of 5-6 unit ring, and this 5-6 unit ring replaces or replaced by oxo, halogen, methyl or halogenated methyl in one or more positions.The first ring of preferred described 5-6 is to be no more than the substituted cyclopentenone in position, furanone, methylpyrazole, isoxazole and a pyridine ring.

For example; the present composition is applicable to celecoxib, deracoxib, valdecoxib, rofecoxib, 5-chloro-3-(4-methyl sulphonyl) phenyl-2-(2-methyl-5-pyridine radicals) pyridine, 2-(3; the 5-difluorophenyl)-3-[4-(methyl sulphonyl) phenyl]-2-cyclopentenes-1-ketone and (S)-6; 8-two chloro-2-(trifluoromethyl)-2H-1-.alpha.-5:6-benzopyran-3-carboxylic acid; more preferably celecoxib and valdecoxib, most preferably celecoxib.

Illustrate the present invention with particular reference to celecoxib in this article, should be appreciated that if necessary, any other low aqueous solubility selective COX-2-2 suppresses chemical compound can all or part of celecoxib that substitutes in the compositions described herein.

The present composition can be used for treating and prevents multiple disease by the COX-2 mediation, includes but not limited to it is characterized in that the disease of inflammation, pain and/or heating.The present composition is especially as antiinflammatory, the for example antiinflammatory of treatment of arthritis, and its additional advantage is that its deleterious side effect significantly is lower than conventional nonsteroidal anti-inflammatory drug (NSAIDs) (these nonsteroidal anti-inflammatory drugs lack the selectivity to COX-2 aspect COX-2 and COX-1).Particularly, compare with conventional NSAIDs compositions, gastrointestinal toxicity and GI irritation that the present composition has reduction comprise upper gastro-intestinal tract ulcer and hemorrhage, the decreased renal function that the kidney side effect that reduces for example causes fluid retention and hypertension to increase the weight of, reduction comprises the inhibition platelet function to the influence in bleeding time, and the ability that causes asthma attack in the irritated asthma individuality of aspirin that may reduce.Therefore the present composition is particularly suitable for for example replacing conventional NSAIDs NSAIDs taboo patient in following patient: suffer from the patient of peptic ulcer, gastritis, regional enteritis, ulcerative colitis, diverticulitis or have the patient of injury of gastrointestinal tract recurrent history; The gastrointestinal hemorrhage patient, the blood clotting disease comprises for example hypoprothrombinemia patient of anemia, hemophilia or other hemorrhage patient; The nephrotic; Or preoperative patient or the patient that takes anticoagulant.

The present composition can be used for treating multiple arthritis disease, includes but not limited to rheumatoid arthritis, spondyloarthropathy, gouty arthritis, osteoarthritis, systemic lupus erythematosus, adolescent arthritis.

The present composition can be used for treating asthma, bronchitis, menstruation spasm, premature labor, tendinitis, bursitis, allergic neuritis, cytomegalovirus is infected, and apoptosis comprises the inductive apoptosis of HIV-, lumbago, hepatic disease comprises hepatitis, skin associated conditions for example psoriasis, eczema, acne, burn, dermatitis and ultraviolet radiation injury comprises that sunburn and operation back inflammation comprise for example inflammation behind cataract operation or the refractive surgery of ophthalmologic operation.

The present composition can be used for treating gastroenteropathy for example inflammatory bowel, segmental enteritis, gastritis, zest bowel syndrome and ulcerative colitis.

The present composition can be used for treating the inflammation in the following disease: migraine, polyarteritis nodosa, thyroiditis, aplastic anemia, Hokdkin disease, sclerosis, rheumatic fever, type i diabetes, myoneural junction disease comprise that myasthenia gravis, white matter disease comprise that the expansion after multiple sclerosis, sarcoidosis, nephropathy syndrome, Behcet, polymyositis, gingivitis, nephritis, anaphylaxis, the injury comprises cerebral edema, myocardial ischaemia etc.

The present composition can be used for treating for example acute injury of retinitis, conjunctivitis, retinopathy, uveitis, eye photophobia and eye tissue of ophthalmic.

The present composition can be used for treating pneumonia for example relevant with viral infection pneumonia and Cystic fibrosis, and bone resorption is osteoarthritis for example.

The present composition can be used for treating some central nervous system disease, and for example the cortex dementia comprises Alzheimer, the central nervous system injury due to neural degeneration and apoplexy, ischemia and the wound.In this context, term " treatment " comprises that partially or completely inhibition is dull-witted, comprises Alzheimer, vascular dementia, multi-infarct dementia, presenile dementia, alcoholic dementia and senile dementia.

The present composition can be used for treating allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome and hepatic disease.

The present composition can be used for treating pain, includes but not limited to postoperative pain, has a toothache, the pain due to myalgia and the cancer.For example, the present composition can be used for alleviating pain, heating and the inflammation in the various diseases, and these diseases comprise that rheumatic fever, influenza and other viral infection comprise flu, back part and neck pain, dysmenorrhea, have a headache, have a toothache, sprain and strain, myositis, neuralgia, synovitis, arthritis comprise the wound after rheumatoid arthritis, degenerative joint disease (osteoarthritis), gout and ankylosing spondylitis, bursitis, burn and operation and the dental procedure.

The present composition can be used for treating and the cardiovascular disease of prevention and inflammation-related, comprise angiopathy, coronary artery disease, aneurysm, blood vessel repels, arteriosclerosis, atherosclerosis comprises the heart transplantation atherosclerosis, myocardial infarction, thromboembolism, apoplexy, thrombosis comprises venous thrombosis, angina pectoris comprises the instability angina pectoris, the coronary plaques inflammation, the inflammation of bacteria-induction comprises the inductive inflammation of clothing bacterium, the inflammation of virus induction and for example perform the operation that blood vessel transplantation comprises coronary bypass, revascularization comprises angioplasty, stent is placed, endarterectomy, or other relates to tremulous pulse, the inflammation that the intrusion operation of vein and blood capillary is caused.

The present composition can be used for treating in the individuality disease with associated angiogenesis, for example suppresses tumor-blood-vessel growth.The present composition can be used for treating tumor and forms, and comprises neoplasm metastasis; For example corneal graft rejection, eyes neovascularity generate eye conditions, the retina neovascularity generates and comprises operation or metainfective neovascularity generation, diabetic retinopathy, degeneration of macula, retrolental fibroplasia and neovascular glaucoma; Ulcer disease is gastric ulcer for example; Pathologic but non-malignant disorders be hemangioma for example, comprises infantile hemangioma, and nasopharyngeal fibrohemangioma and bone do not have the blood vessel necrosis; And disease in the female sexual system endometriosis for example.

The present composition can be used for prevention and treats optimum and malignant tumor and tumor formation, comprise for example colorectal carcinoma of cancer, the brain cancer, osteocarcinoma is derived from epithelial neoplasia (epithelial cancer) basal cell carcinoma for example, adenocarcinoma, gastrointestinal cancer is lip cancer, oral cancer, the esophageal carcinoma, carcinoma of small intestine, gastric cancer, colon cancer for example, hepatocarcinoma, bladder cancer, cancer of pancreas, ovarian cancer, cervical cancer, pulmonary carcinoma, breast carcinoma, skin carcinoma is squamous cell and basal cell carcinoma for example, carcinoma of prostate, renal cell carcinoma and other are by the systemic known cancer of epithelial cell.The neoplasia of present composition particularly suitable has gastrointestinal cancer, Barrette ' s esophagus, hepatocarcinoma, bladder cancer, cancer of pancreas, ovarian cancer, carcinoma of prostate, cervical cancer, pulmonary carcinoma, breast carcinoma and skin carcinoma especially.The present composition also can be used for treating the fibre modification that is taken place when adopting radiotherapy.The present composition can be used for treating the individuality of suffering from adenomatous polyp, comprises the individuality of suffering from familial adenomatous polyp (FAP).In addition, the present composition is used in and prevents to form polyp among the patient with FAP danger.

The present composition can suppress the inductive smooth muscle contraction of prostaglandins material by suppressing synthesizing of contractility prostaglandins material, and it is diseases related therefore to can be used for treating dysmenorrhea, premature labor, asthma and oxyphil cell.The present composition also can be used for alleviating bone loss (promptly treating osteoporosis) and the treatment glaucoma among bone loss, the particularly postmenopausal women.

The advantageous applications of the present composition is treatment rheumatoid arthritis and osteoarthritis, general pain control (particularly behind the operation on oral cavity after pain, the general surgery osteoarthritis of pain, hand orthosis postoperative pain and acute burst), treatment Alzheimer, and chemoprophylaxis colon cancer.

In order to treat rheumatoid arthritis or osteoarthritis, can use the present composition so that the about 1000mg of about 50mg-, the preferably about 600mg of about 100mg-, the more preferably from about about 500mg of 150mg-, the also more preferably from about about 400mg of 175mg-, the celecoxib of about 200mg daily dose for example to be provided.When using the present composition, the about 13mg/kg body weight of about 0.7-, preferably the about 8mg/kg body weight of about 1.3-, more preferably from about the about 6.7mg/kg body weight of 2-, also more preferably from about the about 5.3mg/kg body weight of 2.3-, for example the celecoxib of about 2.7mg/kg body weight daily dose generally is suitable.But this daily dose divides 1-every day to be used for about 4 times, preferred 1 or 2 time.

In order to treat Alzheimer or cancer, can use the present composition so that the about 1000mg of about 50mg-, the preferably about 800mg of about 100mg-, the more preferably from about about 600mg of 150mg-, the also more preferably from about about 400mg of 175mg-, the celecoxib of about 400mg daily dose for example to be provided.When using the present composition, the about 13mg/kg body weight of about 0.7-, preferably the about 10.7mg/kg body weight of about 1.3-, more preferably from about the about 8mg/kg body weight of 2-, also more preferably from about the about 5.3mg/kg body weight of 2.3-, for example the celecoxib of about 5.3mg/kg body weight daily dose generally is suitable.About 4 times, preferred 1 or 2 dosage are used but this daily dose divides 1-every day.

For pain management, can use the present composition so that the about 1000mg of about 50mg-, the preferably about 600mg of about 100mg-, the more preferably from about about 500mg of 150mg-, the also more preferably from about about 400mg of 175mg-, the celecoxib of about 200mg daily dose for example to be provided.When using the present composition, the about 13mg/kg body weight of about 0.7-, preferably the about 8mg/kg body weight of about 1.3-, more preferably from about the about 6.7mg/kg body weight of 2-, also more preferably from about the about 5.3mg/kg body weight of 2.3-, for example the celecoxib of about 2.7mg/kg body weight daily dose generally is suitable.But this daily dose divides about 4 dosage of 1-to use every day.With every day 4 times, every next 50mg dosage unit, every day 2 times, whenever next 100mg dosage unit or two 50mg dosage units, once a day, the speed administration of next 200mg dosage unit or two 100mg dosage units or four 50mg dosage units whenever is preferred.

Suppress medicine for the selective COX-2 except celecoxib-2, can select suitable dose with reference to the patent documentation of above quoting.

Except being used for the treatment of the people, the present composition also is used in the veterinary and goes up treatment house pet, external animal, agricultural animal etc., particularly mammal.The present composition can more be used in particular for the disease of treatment COX-2 mediation in horse, Canis familiaris L. and cat.

The invention still further relates to disease or the treatment of diseases method of treatment as the indication of Arcoxia thing, described method comprises the individual Orally administered present composition to the needs treatment.The dosage regimen that is used to prevent, alleviate or improves disease or disease preferably with once a day or twice treatment every day consistent, but can regulate according to several factors.These factors comprise type, age, body weight, sex, diet and the health of treatment target, and the character of disease and the order of severity.Therefore, the actual dosage regimen that adopts can in very large range change, and therefore can break away from above-mentioned preferred dosage regimen.

Can begin initial therapy according to above-mentioned dosage regimen.Continue treatment in generally as required during several weeks to several months or several years, controlled or eliminated until disease or disease.For the patient who treats with the present composition, can carry out routine monitoring to determine curative effect to it by any method well-known in the art.Continue to analyze the data that monitoring is obtained,, use optimum effective dose, and can determine the treatment time limit thereby can put at any time with adjustment of treatment scheme during treating.By this method, can be during treating reasonably adjustment of treatment scheme and treatment sequence, thereby can use the compositions of the minimum that can show satisfactory effect, as long as and can only proceed successfully to treat disease or the required administration of disease.

The present composition can carry out therapeutic alliance with opioid and other analgesic, and described opioid and analgesic comprise anesthesia class analgesic, Mu receptor antagonist, Kappa receptor antagonist, non-narcotic (being non-addiction) analgesic, monoamine uptake inhibitor, adenosine regulator, hemp biological alkali derivant, P substance antagonist, the preferred therapeutic alliance of antagonists of neurokinine-1 receptor and sodium channel blockers etc. comprises uses the present composition and one or more to be selected from following compound: Aceclofenac; Rantudil; E-acetylamino caproic acid; Paracetamol; Acetaminophen; Antifebrin; Acetylsalicylic acid (aspirin); SAM; Chlorophenol acid; Alfentanil; Alperidine; Alminoprofen; Aloxiprin; Alphameprodine; Dipyrocetyl aluminium; The ammonia phenolic acid; Aminochlorthenoxazin; 3-amino-4-hydroxybutyric acid; 2-amino-4-picolin; Aminopropylon; Aminopyridine; Amixetrine; Ammonium salicylate; Ampiroxicam; The ammonia tolmetin; Anileridine; Antipyrine; Salazon; Antrafenine; Ah bundle's hydrazone; Bendazac; Benorylate; Benoxaprofen; Benzpiperilone; Benzydamine; Benzylmorphine; Bermoprofen; Bezitramide; α-bisabol; The fragrant acid of bromine; Antisepsin; 5-acetyl bromide salicylic acid; Bromo ortho-oxybenzoic acid; Betadid; Bucloxic acid; BCP; Bufexamac; Bumadizon; Buprenorphine; Butacetin; Butibufen; Stadol; Calcium acetylsalicylate; Carbamazepine; Carbiphene; Carprofen; Baaprine; Chlorobutanol; Chlorthenoxazine; Choline Salicylate; Quinophan; Cinmetacine; Ciramadol; Clidanac; Clometacine; Clonitazene; Clonixin; Clopiran; Clove; Codeine; Codeine methyl bromide; Codeine phosphate; Codeine sulfate; Cropropamide; Crotethamide; Desomorphine; Relane; Loose pain; Dezocine; Diampromide; Diclofenac; Difenamizole; Difenax; Diflonid; Paracodin; Dihydrocodeinone enol acetate; Paramorphane; Dihydroxyaluminum acetylsalicylate; Lokarin; Dimepheptanol; Ohton; Amidalgon; Dipipanone; Diacetol; Analgin; Ageroplas; Droxicam; Emorfazone; The acid of phenyl ethylamine fennel; DA-398; Eptazocine; The Yi Teliu ester; Ethenzamide; Hydrogen nitrogen ethyl ester; Carmurit; Ethylmethiambutene; Dionin; Etodolac; Etofenamate; Etonitazene; Eugenol; Felbinac; Fenbufen; Fenclozic acid; Fendosal; Fenoprofen; Fentanyl; Fentiazac; Fepradinol; FEP; Floctafenine; Clofenamic acids; Flunoxaprofen; Bripadon; Flupirtine; Fluproquazone; Flurbiprofen; Menir; Gentianic acid; Glafenine; Glucametacin; Spirosal; Guaiazulene; The dichloro codeinone; Dilauid; Bemidone; Dytransin; Brufen; Ibuproxam; Imidazole salicylate; Indomethacin; Indoprofen; Isofezolac; Isoladol; Isomethadone; Isonixin; Oxygen acetic acid; Isoxicam; Cetobemidone; Ketoprofen; Ketorolac; P-lactophenetide; Lefetamine; Levorphan; Lofentanil; Lonazolac; Lornoxicam; Roseau the third sweet smell; Lysine acetylsalicylate; Magnesium acetylsalicylate; Meclofenamic acid; Mefenamic acid; Pethidine; First nitrogen phenol; Mesalamine; Metazocine; Methadone hydrochloride; Levomepromazine; Metiazic Acid; Methopholine; Methyldihydromorphinone; The toluene phenylbutazone; Mofezolac; Morazone; Morphine; Morphine hydrochloride; Morphine sulfate; Morphine salicylate; Myrophine; Nabumetone; Nalbuphine; L-naphthyl salicylate; Naproxen; Narceine; Benzoxazocine; Neopiran; Buddhist nun's oxygen fenamic acid; Aulin; 5 '-nitro-2 '-the third oxygen acetanilide; Norlevorphanol; Normethadone; Normorphine; Dipipanone; Olsalazine; Opium; N-acetylhydroxyproline; Flogar; Oxaprazine; Dihydrohydroxycodeinone; Numorphan; Crovaril; Papaveretum; Paranyline; Parsal; Pentazocine; Perisoxal; Non-that tincture; Phenadoxone; NIH-7519; Phenazopyridine hydrochloride; Phenocoll; Phenoperidine; Phenopyrazone; Acetylphenyl salicylate; Phenylbutazone; Phenyl salicytate; Phenyramidol; The pyrrole Ketoprofen; Piminodine esylate; Pipebuzone; Palerol; Piprofen; Pirazdac; Piritramide; Feldene; Pranoprofen; The scorching pain of junket; Proheptazine; Promedol; Propacetamol; Disopyramide; The third oxygen is fragrant; Propyphenazone; Proquanone; Pirocrid; Ramifenazone; Remifentanil; Prohon; Ethrisin; Salicin; Salicylamide; Salicyamide o-acetic acid; Bigcatkin willow sulfuric acid; Sasapyrin; Salverine; Sodium salicylate; Sufentanil; SASP; Sulindac; Superoxide dismutase; Sutoprofen see suprofen; Suxibuzone; Talniflumate; Tenidap; Tenoxicam; Terofenamate; Hanfangchin A; Thiazolinobutazone; Artiflam; Tiaramide; Tilidate; Tienoridine; Clotame; Tolectin; C16H25NO2; Tropesin; Diviminol; Xenbucine; Ximoprofen; Zaltoprofen; And zomepirac sodium is (referring to The Merck Index; 12th Edition; Therapeutic Category and Biological ActivityIndex; Ed.S.Budavari (1996); Pp.Ther-2 to Ther-3 and Ther-12 (Analgesic (Dental); Analgesic (Narcotic); Analgesic (Non-narcotic), Anti-inflammatory (Nonsteroidal)).

Particularly preferred therapeutic alliance comprises uses the present composition and opioid compounds, and more especially wherein opioid compounds is the described therapeutic alliance of codeine, Pethidine, morphine or derivatives thereof.

Celecoxib compositions of the present invention also can suppress for example administering drug combinations such as valdecoxib, rofecoxib of medicine with another kind of selective COX-2-2.

Can open preparation with the celecoxib branch with the chemical compound of celecoxib administering drug combinations, perhaps be formulated in the present composition with celecoxib.As celecoxib when for example opioid drug is prepared with another kind of medicine, described another kind of medicine can be mixed with promptly and release, begin rapidly, slow release or dual release dosage form.

Comprise or basically by low aqueous solubility selective COX-2-2 suppress nano-particle that medicine forms can according to be applicable in the prior art preparation form of nanoparticles a little less than other any means of water soluble drug prepare.Suitable method is such as but not limited to the disclosed method that is used for other such medicine in following patent and publication, and described patent and publication are introduced the present invention with for referencial use.

U.S. patent No.4,826,689to Violanto ﹠amp; Fischer.

Above-mentioned U.S. Patent No. 5,145,684.

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

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

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

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

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

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

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

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. patent No.5,510,118 to Bosch et al.

U.S. patent 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. patent 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 ﹠amp; 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 open No.WO93/25190. of above-mentioned international monopoly

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Those skilled in the art can be easy to improve the low aqueous solubility selective COX-2-2 inhibition medicine that wherein described method prepares form of nanoparticles.

In an embodiment of the present invention, the nano-particle that selective COX-2-2 suppresses medicine is by method for grinding, and preferably the wet grinding method in the presence of the surface conditioner that can suppress the coalescent and/or crystal growth of nano-particle (in case making) makes.In another embodiment of the present invention, the nano-particle that selective COX-2-2 suppresses medicine is by the sedimentation method, what preferably precipitation made in aqueous medium from the solution of medicine in nonaqueous solvent.Described nonaqueous solvent can be the supercritical gas that for example liquefies under pressure.Illustrate in greater detail the example that preparation selective COX-2-2 suppresses these and other method of medicine nano-particle hereinafter.

In a particular of the present invention, nano-particle is to make by the method that comprises following step: basic as above-mentioned United States Patent (USP) 5145684 is disclosed, (a) selective COX-2-2 inhibition medicine and surface conditioner are dispersed in the liquid dispersion medium; (b) the wet gained pharmaceutical dispersions of milling in the presence of the medium of milling, to obtain the medicament nano granule of crystal form, wherein granule is adsorbing in its surface and presents in an amount at least sufficient to make average particle size to be lower than the surface conditioner of about 400nm.Described surface conditioner suppresses the coalescent of nano-particle, and can be any polymer, low-molecular weight oligo thing, natural product, surfactant etc.In this embodiment and related embodiment, nano-particle is made up of nanocrystal medicine/surface conditioner complex.

In a relevant embodiment of the present invention, basically as above-mentioned United States Patent (USP) 5352459 is disclosed, the surface conditioner that the nanocrystal medicine/surface conditioner complex that makes as mentioned above comprises purification is the polymeric surfactant of purification for example, and is coalescent in sterilization steps subsequently to prevent granule.

In another relevant embodiment of the present invention, basically as above-mentioned United States Patent (USP) 5340564 is disclosed, the nanocrystal medicine/surface conditioner complex that makes as mentioned above comprise surfactant to different Nonylphenoxy poly-((+)-2,3-Epoxy-1-propanol) as surface conditioner.

In another relevant embodiment of the present invention, basically as described in above-mentioned United States Patent (USP) 5298262 (cation or anion surfactant are as the cloud point aromatics modifier), 5336507 (charged phospholipid is as the cloud point aromatics modifiers) or 5346702 (nonionic cloud point aromatics modifier), the nanocrystal medicine/surface conditioner complex that makes as mentioned above has anion or cation cloud point aromatics modifier to improve the cloud point of surface conditioner.

In another relevant embodiment of the present invention, basically as described in the above-mentioned United States Patent (USP) 5302401, nanocrystal medicine/surface conditioner the complex that makes as mentioned above also comprises cryoprotector for example hydrocarbon or sugar alcohol, and the amount of cryoprotector is enough to make nano-particle can carry out lyophilization.The preferred cryoprotector of this embodiment is a sucrose.Preparation has and is adsorbed on its lip-deep surface conditioner and with comprising with the method for the nano-particle of its compound cryoprotector nano-particle is contacted certain hour under certain condition with cryoprotector, so that nano-particle enough carries out lyophilization.

In another relevant embodiment of the present invention, the nano-particle drug particles that has the amount that is adsorbed on its lip-deep surface conditioner and surface conditioner and be enough to average particle size is kept below about 400nm is to make by the method that comprises following step: basically as above-mentioned United States Patent (USP) 5552160 is disclosed, (a) medicine is dispersed in this medicine and is insoluble in wherein the liquid dispersion medium; (b) abrasive media (for example in dispersion mill) in the presence of the rigidity abrasive media, the pH of its medium is maintained at about in the scope of 2-about 6.

In another relevant embodiment of the present invention, nano-particle is to make by the method that comprises following step: basically as above-mentioned United States Patent (USP) 5534270 disclosed, (a) provide selective COX-2-2 inhibition medicine; (b) the rigidity abrasive media is killed pyrogen, for example in baking oven, under about 200 ℃-Yue 300 ℃ of temperature, kill pyrogen about 6 to about 20 hours; Medicine and abrasive media are mixed, and in about 60 minutes of about 100 ℃-Yue 150 ℃ of about 10-of autoclaving; (c) surface conditioner (for example being selected from polymer, low-molecular weight oligo thing, natural product and surfactant) is added in the gained autoclaving medicine, carries out wet lapping then, to provide and to keep the average particle size that is lower than about 400nm.

In another relevant embodiment of the present invention, nano-particle makes by comprising following method of operating: basically as above-mentioned United States Patent (USP) 5429824 is disclosed, selective COX-2-2 is suppressed medicine to be contacted with surface conditioner under certain condition (for example by medicine being added in the liquid medium that comprises surface conditioner, and in dispersion mill wet lapping) certain hour, making is enough to provide and keep the average particle size that is lower than about 400nm.In this embodiment, surface conditioner is alkyl aryl polyether alcohol type nonionic liquid polymers, for example tyloxapol.Can choose wantonly and also have other surface conditioner.

In another relevant embodiment of the present invention, nano-particle is to make by the method that comprises the steps: as above-mentioned United States Patent (USP) 5510118 is disclosed, (a) forms selective COX-2-2 and suppress medicine and the premix of surface conditioner (for example being selected from polymer, low-molecular weight oligo thing, surfactant etc.) in liquid dispersion medium (for example water, saline solution, ethanol etc.) basically; (b) this premix is transferred in the microfluid device with the interaction chamber that can produce shearing, bump, cavitation and frictional force; (c) being no more than under the fluid pressure of about 40 ℃ of temperature and the about 200000kPa of about 20000-, come to apply these active forces, with the granularity of reduction medicine and obtain its homogeneous slurry to premix by this premix being flow through the interaction chamber; (d) serosity is collected the receiving tank from the interaction chamber; (e) serosity is introduced again in the interaction chamber with further reduction granularity; (f) repeated collection and introduce step again and be lower than about 400nm until the average particle size of medicine.

In another relevant embodiment of the present invention, nano-particle is to make by the method that comprises the steps: basically as United States Patent (USP) 5560931 is disclosed, (a) in the presence of surface conditioner (for example gelatin, casein, lecithin, polyvinylpyrrolidone, tyloxapol, poloxamer, other block copolymer etc.), and choose wantonly in the presence of oil, (for example in the dispersion mill) selective COX-2-2 of milling suppresses medicine.In this embodiment, drug particles has and is adsorbed on its lip-deep uncrosslinked regulator, and is suspended in emulsive aqueous phase in oil-continuous phase.Average particle size is lower than about 1000nm.As disclosed in the above-mentioned United States Patent (USP) 5571536, oil phase can be an oleic acid.

In another relevant embodiment of the present invention, nano-particle is to make by the method that comprises the steps: (block copolymer is as surface conditioner as above-mentioned United States Patent (USP) 5565188 basically, wherein said block copolymer contains one or more polyoxyethylene blocks and one or more polyoxy (senior alkylidene) block, and some block links together by oxygen methylene linking group at least) and 5587143 (block copolymer of ethylene oxide and butylene oxide is as surface conditioners) disclosed like that, (a) selective COX-2-2 is suppressed medicine, liquid medium, abrasive media, place grinding container with surface conditioner; (b) wet lapping is brought down below about 1000nm with the average particle size with medicine.

In another relevant embodiment of the present invention, the invention provides compositions, wherein comprise nano-particle selective COX-2-2 depressant composition granule, and granule is adsorbing the block copolymer that is connected at least one anionic group in its surface as surface conditioner.Said composition is to make by the method that comprises the steps: basically as disclosed in the above-mentioned United States Patent (USP) 5569448, (a) preparation particle form, preferred size is less than the medicine of the particle form of about 100 μ m; (b) medicine is added in its undissolved basically liquid medium to form premix; (c) this premix is carried out machining so that the particle mean size in the premix is brought down below about 1000nm.Preferably, in premix, there is surface conditioner.

In another relevant programme of the present invention, the method preparation of nano-particle by comprising the following steps: (a) (for example with selective COX-2-2 suppressive drug and surface modifier, aseptic stabilizing agent, as gelatin, casein, lecithin, arabic gum, cholesterol, tragacanth, Isosorbide Dinitrate, Polyethylene Glycol, polyxyethylated ester, Myrj 45 etc.) be added to a kind of pre-composition of formation in the insoluble liquid of its Chinese medicine, (b) to pre-composition adopt mechanical means (as, in dispersion mill), make its particle mean size be decreased to about 400nm (disclosed with above-mentioned United States Patent (USP) 5573783 basically).

In another relevant programme of the present invention, the method preparation of nano-particle by comprising the following steps: (a) (for example with selective COX-2-2 suppressive drug and surfactant, molecular weight is about 1000-about 15000 daltonian poloxamers, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropyl methylcellulose and polyethenoxy sorbitan monooleate) be distributed in the relatively poor liquid dispersion medium of medicine dissolution, use mechanical means (for example dispersion mill) that the medicine particle mean size is decreased to less than about 400nm (disclosed with above-mentioned United States Patent (USP) 5585108 basically) then.

In another relevant programme of the present invention, the method preparation of nano-particle by comprising the following steps: (a) be added to selective COX-2-2 suppressive drug with as the hydroxypropyl cellulose of surface modifier and form a kind of pre-composition in the insoluble basically liquid medium of its Chinese medicine, and the use mechanical means (as, in dispersion mill), the medicine particle mean size is decreased to less than about 1000nm, preferably less than about 400nm (disclosed with above-mentioned United States Patent (USP) 5591456 basically).

In another related embodiment of the present invention, nano-particle uses the surface modifier preparation by methods described herein, the selection of surface modifier makes the hydrophile-lipophile balance value (HLB) of resulting composition for about 4 to about 9, basically as the disclosed method of above-mentioned international monopoly publication NO.WO00/30615 carry out.

In special embodiment of the present invention, the method preparation of nano-particle by comprising the following steps: (a) with selective COX-2-2 suppressive drug and a kind of support material, preferred a kind of crosslinked water-swellable polymer mixes; (b) the gained mixture is ground in the vapour-saturated grinding chamber of solvent (as water, ethanol, isopropyl alcohol, chloroform, methanol etc.); (c) mixture after the drying and grinding under vacuum; (d) exsiccant milled mixtures is sieved remove any aggregation (method basically as above-mentioned United States Patent (USP) 5354560 disclosed) of formation.

In another particular of the present invention, the method preparation of nano-particle by comprising the following steps: (a) form a kind of pastel that contains following ingredients: (i) nano-particle of selective COX-2-2 suppressive drug, (ii) at least a thickening agent or binding agent are (for example, be selected from polypeptide, high molecular polymer, colloid etc.) and/or extender, (iii) be used to avoid nano grain surface to sink or protruding one or more stabilizing agents and (iv) in order to adjust the suitable quantity of water of viscosity; And (b) this pastel of lyophilizing (disclosed with above-mentioned United States Patent (USP) 5384124 basically).

In another specified scheme of the present invention, the method preparation of nano-particle by comprising the following steps: (a) selective COX-2-2 suppressive drug of preparation particle form, described particulate granularity is preferably less than about 100 μ m; (b) drug prepared is added in the insoluble basically liquid medium of its Chinese medicine (preferably contain and show modifier), to form pre-composition as hygroscopicity sugar; (c) this pre-composition is adopted mechanical means, the granularity of pre-composition is reduced to less than about 1000nm (disclosed as above-mentioned United States Patent (USP) 5518738 basically).Preferably also contain polyvinylpyrrolidone and/or wetting agent in the pre-composition, as sodium lauryl sulfate.Adopt the compositions of this method preparation to preferably have the film of one deck attached to nano grain surface, this film contains polyvinylpyrrolidone, hygroscopicity sugar and sodium lauryl sulfate.

In another specified scheme of the present invention, the method preparation of nano-particle by comprising the following steps: (a) choose wantonly in the presence of one or more solvents, material with a kind of modification interfacial property is total to one or more component of polymer of solubilising, comprise, the biological example degradable polymer (for example, polylactic acid, polyglycolic acid or their copolymer, poly butyric, polycaprolactone, poe etc.), gel polysaccharide and/or bioadhesive polymer and/or amphiphilic polymers (as, Polyethylene Glycol, polyvinylpyrrolidone or polyvinyl alcohol), form the polymer pre-composition; (b) with selective COX-2-2 suppressive drug dissolving or be suspended in this polymeric blends; (c) by emulsifying, extrude, spray drying or the spraying technology of congealing forms by the material of polymer, modification interfacial property and the granule that medicine is formed (disclosed as above-mentioned United States Patent (USP) 5536508 basically).Adopting the preferred weight average particle mean size of the nano-particle of this method preparation is about 0.1 μ m-150 μ m.

In another specified scheme of the present invention, the method preparation of nano-particle by comprising the following steps: (a) the mixable organic solvent of water prepares the solution of selective COX-2-2 suppressive drug; (b) liquid with precipitation (as water, inorganic salt solution or surfactant solution) of aqueous is injected into as described in the solution, produce the suspension of the sedimentary amorphous solid medicine of non-aggregated particle form; (c) separating particles and use cleaning mixture washing from sedimentary liquid (basically as disclosed in the above-mentioned United States Patent (USP) 4826689).

In another specified scheme of the present invention, the method preparation of nano-particle by comprising the following steps: (a) under agitation, selective COX-2-2 suppressive drug is dissolved in (as NaOH, KOH, CsOH etc.) formation solution in the alkaline aqueous solution; (b) add surface modifier (as various polymer, surfactant, low-molecular-weight oligomer etc.), form clear and bright solution; (c) stir down, with suitable acid solution (as HCl, HNO ₃, HClO ₄, H ₂SO ₄, formic acid, propanoic acid, acetic acid, butanoic acid etc.) and neutralization this clear and bright solution (disclosed as above-mentioned United States Patent (USP) 5560932 and 5580579 basically).

In another relevant programme of the present invention, the method preparation of nano-particle by comprising the following steps: (a) selective COX-2-2 suppressive drug is dissolved in the akaline liquid medium that contains the relatively poor avirulence solvent of medicine dissolution wherein (as NaOH, KON, CsOH, trialkylamine, pyridine etc.), form solution; (b) add the aqueous solution of one or more surface modifiers (as anion or non-ionic surface active agent, polymer or oligomer), (c) in and the gained alkaline solution, with acid (HCl, HNO ₃, HClO ₄, H ₂SO ₄, formic acid, propanoic acid, acetic acid, butanoic acid etc.) form dispersion, wherein the Z-particle mean size of measuring by the light quantum correlation spectroscopy is preferably less than about 100nm (disclosed as above-mentioned United States Patent (USP) 5662883 basically).

In another relevant programme of the present invention, the method preparation of nano-particle by comprising the following steps: (a) (promptly with selective COX-2-2 suppressive drug and crystalline growth modifier, with the isostructural basically chemical compound of medicine) be dissolved in alkaline aqueous solution (as NaOH, KOH, CsOH, trialkylamine, pyridine etc.), form solution; (b) add the aqueous solution of one or more surface modifiers (as the mixture of anion surfactant, non-ionic surface active agent, polymer or oligomer); With the gained alkaline solution with acid (as HCl, HNO ₃, HClO ₄, H ₂SO ₄, formic acid, propanoic acid, acetic acid, butanoic acid etc.) and neutralization, form dispersion, the Z-particle mean size of the preferred drug particles of wherein measuring by the light quantum correlation spectroscopy is less than about 400nm (disclosed as above-mentioned United States Patent (USP) 5665331 basically).

In another particular of the present invention, average particle size less than the nano-particle of about 400nm by comprising selective COX-2-2 suppressive drug and surface modifier with first kind of particle size distribution, as the dispersion preparation of poly-sulphuric acid tyloxapol, the method preparation of described dispersion by comprising the steps: (a) dispersion is placed between first electrode and second electrode; (b) discard part dispersion between first electrode and second electrode, this part dispersion has second particle size distribution (disclosed as United States Patent (USP) 5503723 basically) less than first particle size distribution.

In another particular of the present invention, average particle size is not higher than the method preparation of nano-particle by comprising the steps of about 300nm: (a) selective COX-2-2 suppressive drug is dissolved in solvent, forms solution; (b) in the presence of the surface modifier that disperses or be soluble in the aqueous phase, with this solution spray (disclosed as the open NO.WO97/14407 of international monopoly basically) in liquid gas or supercritical liq.

In another related embodiment of the present invention, average particle size is not higher than the method preparation of nano-particle by comprising the steps of about 300nm: (a) selective COX-2-2 suppressive drug is dissolved in liquid gas or the supercritical liq, forms solution; (b) preparation contains the water of surface modifier; (c) with this solution spray to aqueous phase (disclosed as the open NO.WO97/14407 of international monopoly basically).

In another related embodiment of the present invention, the method preparation of nano-particle by comprising the following steps: (a) selective COX-2-2 suppressive drug and surface modifier are dissolved in liquid gas or the supercritical liq, form solution; (b) this solution is added to (disclosed as the open NO.WO99/13755 of international monopoly basically) in the aqueous medium.

The excipient that comprises in the compositions of the present invention can be that solid or liquid or two have concurrently.The present composition that contains excipient can comprise that near small part is selective COX-2-2 suppressive drug and the excipient of previously prepared aforesaid form of nanoparticles, randomly with one or more mixed with excipients according to any pharmaceutical technology preparation.

The compositions that is suitable for cheek or sublingual administration comprises, for example, and in flavoring substrate, as containing the dragee of selective COX-2-2 suppressive drug in sucrose and arabic gum or the tragacanth; With at inert base, as containing the lozenge of medicine in gelatin and glycerol or sucrose and the arabic gum.

The liquid dosage form of oral administration comprises pharmaceutically acceptable suspension, syrup and elixir, wherein contains this area inert diluent commonly used, for example water.This based composition also can contain, for example wetting agent, emulsifying agent and suspending agent, and sweeting agent, correctives and aromatic.

The solid unit dosage form that is used for oral administration contains the selective COX-2 of form of nanoparticles-2 suppressive drug and tablet or the most frequently used excipient of capsule preparation.Following nonrestrictive excipient example can be used for preparing pharmaceutical composition of the present invention.

Compositions of the present invention can randomly contain one or more pharmaceutically acceptable diluents as excipient.Suitable diluent comprises following a kind of or its combination: lactose comprises Lactis Anhydrous and lactose monohydrate; Starch comprises that directly compacted starch and hydrolyzed starch are (as Celutab ^TMAnd Emdex ^TM); Mannitol; Sorbitol; Xylitol; Glucose is (as Cerelose ^TM2000) and Dextrose monohydrate; The biphosphate calcium dihydrate; Diluent, confection sugar, calcium bisulfate monohydrate, calcium sulfate dihydrate based on sucrose; Calcium lactate trihydrate granule; Dextrates; The frumentum solid of inositol, hydrolysis; Amylose; Cellulose comprises microcrystalline Cellulose, the α in food stage source-and amorphous cellulose (as Rexcel ^TM) and cellulose powder; Calcium carbonate; Glycerol; Bentonite; Polyvinylpyrrolidone etc.If there is this class diluent, it is about 99% that its total amount accounts for about 5-of composition total weight, and preferably about 10-is about 85%, and more preferably from about 20-about 80%.Diluent preferably selects to have suitable flowing property and (as if needing tablet) is compressible.

Preferable absorbent is lactose and microcrystalline Cellulose or its mixture.These two kinds of diluent and celecoxib are that chemistry is compatible.Extra granule microcrystalline Cellulose (that is, behind drying steps microcrystalline Cellulose being added in the wet particulate composition) can be used for improving hardness (tablet) and/or disintegration time.Lactose, especially lactose monohydrate are particularly preferred.Lactose can provide the compositions with suitable celecoxib release rate, stability, precommpression flowability and/or drying property with relatively low diluent cost usually.It provides the high density substrate that helps close mode during granulating (when adopting wet granulation), has therefore improved the flow behavior of mixture.

Compositions of the present invention can randomly contain one or more pharmaceutically acceptable disintegrating agents as excipient, and is especially true for tablet.Suitable disintegrating agent comprises following a kind of or its combination: starch comprises that sodium starch glycolate is (as the Explotab of Pen West ^TM) and pregelatinized corn starch (as National ^TM1551, National ^TM1550 and Colocorn ^TM1500); Clay is (as Veegum ^TMHV); Cellulose, as purifying cellulose, microcrystalline Cellulose, methylcellulose, carboxymethyl cellulose and sodium carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose (as the Ac-Di-Sol of FMC ^TM); Alginate; Polyvinylpolypyrrolidone; With the glue class, as agar, guar gum, tracasol, karaya, pectin and tragacanth.

During preparation of compositions, can add disintegrating agent in any suitable step, especially before granulation or during the lubricated step before the compression.If there is this class disintegrating agent, it is about 30% that its total amount accounts for about 0.2-of composition total weight, and preferably about 0.2-is about 10%, and more preferably from about 0.2-about 5%.

For tablet or capsular disintegrate, cross-linked carboxymethyl cellulose (croscarmellose) sodium is preferred disintegrating agent, and if present, it is about 10% that it preferably accounts for about 0.2-of composition total weight, and more preferably from about 0.2-is about 7%, and most preferably from about 0.2-about 5%.Cross-linking sodium carboxymethyl cellulose is given particulate composition of the present invention with super granule disintegrating property.

Compositions of the present invention can randomly contain one or more pharmaceutically acceptable binding agents or adhesive as excipient, and is especially true to tablet.This class binding agent and adhesive preferably give the film-making powder with enough viscosity so that it can carry out conventional process operation, for example sieve, lubricate, suppress and pack, the while tablet is disintegratable still, component is through digesting and assimilating.Suitable binding agent and adhesive comprise following a kind of or its combination: arabic gum; Tragacanth; Sucrose; Gelatin; Glucose; Starch for example, but is not limited to pregelatinized Starch (as National ^TM1511 and National ^TM1500); Cellulose for example, but is not limited to methylcellulose and carboxymethyl cellulose (as Tylose ^TM); Alginic acid and alginate; Magnesiumaluminumsilicate; PEG; Guar gum; Polysaccharide acid; Bentonite; Polyvidone, for example 30 POVIDONE K 30 BP/USP-15, K-30 and K-29/32; Polymethacrylates; HPMC; Hydroxypropyl cellulose is (as Klucel ^TM); And ethyl cellulose is (as Ethocel ^TM).If there is this class binding agent and/or adhesive, it is about 25% that its total amount accounts for about 0.5-of composition total weight, and preferably about 0.75-is about 15%, and more preferably from about 1-about 10%.

Compositions of the present invention can randomly contain one or more pharmaceutically acceptable wetting agent as excipient.This class wetting agent is preferably selected to keep the material that selective COX-2-2 suppressive drug and water are combined closely, and condition is the bioavailability that they are considered to improve compositions.

In compositions of the present invention, the example that can be used as the non-limiting surfactant of wetting agent comprises quaternary ammonium compound, for example benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, dioctyl sodium sulfosuccinate, polyoxyethylene alkyl phenyl ether, for example nonoxynol 9, nonoxynol 10 and octoxynol 9; Poloxamer (polyoxyethylene and polyoxypropylene block copolymers); Polyoxyethylene fatty acid glyceride and oil, for example polyoxyethylene (8) caprylic/capric one and two glyceride are (as the Labrasol of Gattefoss é ^TM), polyoxyethylene (35) Oleum Ricini, polyoxyethylene (40) castor oil hydrogenated; Polyoxyethylene alkyl ether is as polyoxyethylene (20) cetyl stearyl ether; Polyoxyethylene fatty acid ester, for example polyoxyethylene (40) stearate, Sorbitan ethoxylate, as polysorbate20 and Spheron MD 30/70 (as the soil temperature of ICI ^TM80); Methyl glycol fatty acid ester, as the propylene glycol laurate (as the Lauroglycol of Gattefoss é ^TM); Sodium lauryl sulfate; Fatty acid and its salt, for example oleic acid, enuatrol and triethanolamine oleate; Fatty acid glyceride is as monostearin; Isosorbide Dinitrate is as anhydro sorbitol one lauric acid ester, anhydro sorbitol monooleate, anhydro sorbitol monopalmitate and anhydro sorbitol monostearate; Tyloxapol and their mixture.Described wetting agent, if present, account for altogether composition total weight about 0.25% to about 15%, preferred about 0.4% to about 10%, more preferably from about 0.5% to about 5%.

The anion surfactant wetting agent is preferred.Sodium lauryl sulfate is particularly preferred wetting agent.If present, sodium lauryl sulfate, it is about 7% to account for about 0.25-of composition total weight, and more preferably from about 0.4-is about 4%, and more preferably from about 0.5-about 2%.

Compositions of the present invention can randomly contain one or more pharmaceutically acceptable lubricants (comprising antiplastering aid and/or antiseize paste) as excipient.Suitable lubricant comprises following a kind of or its combination: behapate glyceride is (as Compritol ^TM888); Stearic acid and salt thereof comprise stearic magnesium salt, calcium salt and sodium salt; Hydrogenated vegetable oil is (as Sterotex ^TM); Colloidal silica; Talcum; Wax; Boric acid; Sodium benzoate; Sodium acetate; Fumaric acid acid; Sodium chloride; The DL-leucine; PEG is (as Carbowax ^TM4000 and Carbowax ^TM6000); Enuatrol; Sodium lauryl sulfate; And lauryl magnesium sulfate.If there is this series lubricant agent, it is about 10% that its total amount accounts for about 0.1-of composition total weight, and preferably about 0.2-is about 8%, and more preferably from about 0.25-about 5%.

Magnesium stearate is a kind of lubricant of preferred use, is used for, and for example reduces the friction between the equipment and granulate mixture during the tabletting.

Suitable antiplastering aid comprises Talcum, corn starch, DL-leucine, sodium lauryl sulfate and stearic slaine.Talcum is preferred antiplastering aid or antiseize paste, is used for, and for example reduces the preparation that is bonded at equipment surface, also reduces the static property of mixture simultaneously.If there is Talcum, it is about 10% that it accounts for about 0.1-of composition total weight, and preferred 0.25-is about 5%, and more preferably 0.5-about 2%.

Other excipient is that drug world is known as coloring agent, aromatic and sweeting agent, can be used in the compositions of the present invention.Tablet can carry out coating, for example with the enteric coating coating or do not carry out coating.Compositions of the present invention also can contain, for example buffer agent.

One or more effervescents also can randomly be used as disintegrating agent and/or be used to strengthen the special sense of the present composition.When containing the dosage form that promotes the dosage form disintegrate in the compositions of the present invention, it is about 75% that the total amount of one or more effervescents preferably accounts for about 30-of composition weight, and preferably about 45-about 70%, for example about 60%.

In one embodiment of the invention, compositions is the capsule of unit dose or tablet form and the part that contains aequum is or all be the selective COX-2-inhibitor 2 of form of nanoparticles, as celecoxib and one or more excipient, described excipient is selected from acceptable diluents, disintegrating agent, binding agent, wetting agent and lubricant.Compositions more preferably contains one or more and is selected from following excipient: lactose (most preferably lactose monohydrate), sodium lauryl sulfate, polyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, magnesium stearate and microcrystalline Cellulose.Compositions more preferably contains lactose monohydrate and cross-linking sodium carboxymethyl cellulose.This based composition especially preferably also contains one or more carrier materials: sodium lauryl sulfate, magnesium stearate and microcrystalline Cellulose.

The excipient that is used for capsule of the present invention and tablet composition is preferably selected from the material that following performance can be provided: the disintegrate in standard is analyzed, disintegration time is less than about 30 minutes, preferably be less than about 25 minutes or shorter time, more preferably less than about 20 minutes or shorter time, most preferably be less than about 15 minutes or shorter time.

For tablet is illustrated, the mixture that consumption is enough to prepare all the components of a collection of even tablet carries out tabletting (for example, using the power of the about 50kN of about 1kN-on typical tabletting drift) with normal pressure in the production-scale tablet machine of routine.Can obtain to be convenient to any tablet hardness of processing, make, storing and digesting.For the tablet of 100mg, hardness is preferably 4kP at least, more preferably at least about 5kP, more preferably at least about 6kP.For the tablet of 200mg, hardness is preferably 7kP at least, more preferably at least about 9kP, most preferably at least about 11kP.Yet mixture should not be pressed into and make it be difficult to realize the degree of aquation when contacting with gastric juice subsequently.

It is about 1.0% that the fragility of tablet preferably is lower than in code test, more preferably less than 0.8%, most preferably is lower than about 0.5%.

Wet granulation, dry granulation or direct compression or encapsulation process all can be used for preparing tablet of the present invention or capsule composition.

Though the capsule of unit dose of the present invention and tablet composition can, for example, preferably before encapsulation or tabletting, carry out wet granulation by the preparation of direct encapsulation or direct compression.Except other effect, wet granulation can make the compositions of grinding combine closely, and the result has improved flowability, has improved tabletting characteristics and has made compositions be easy to metering or weight dispersion in encapsulation or tabletting.The second kind of granularity (that is, particle size) that obtains for granulation do not have strict restriction, only importantly this particle mean size should preferably be convenient to operation and processing and, for tablet, mixture directly should be pressed into pharmaceutically acceptable tablet.

In representational wet granulation method, at first any drug moiety (if desired, with one or more carrier materials) with the non-nano particle form grinds or is micronized to the desired particle size range greater than 1 μ m.Although can use the mill or the pulverizer of various routines, for the mill of other type, impact type is ground, and grinds medicine as the bolt formula higher final mixture uniformity can be provided.During grinding, be heated to undesirable temperature for avoiding medicine, may need, for example use the cooled with liquid nitrogen milled mixtures.D during this grinding steps ₉₀Granularity preferably is reduced to less than about 25 μ m.

If contain grinding or micronized medicine, as implied above, with the nano-particle medicament mixed of itself and aequum, obtain part and be or all be the drug substance of form of nanoparticles.Simultaneously or afterwards; for example in high speed shear blender/granulator, planetary mixer, bivalve blender or Sigma's blender; with drug substance and one or more excipient; comprise the mixed with excipients that contains in the excipient that grinds with celecoxib or the nano-particle, obtain powder mixture.Typically, with drug substance and one or more diluent, disintegrating agent and/or binding agent, and one or more optional wetting agent mix in this step; Perhaps in step subsequently, add one or more excipient all or part.For example, in using the tablet of cross-linking sodium carboxymethyl cellulose as disintegrating agent, find during blend step, (to provide cross-linking sodium carboxymethyl cellulose granule in) and add partial cross-linked sodium carboxymethyl cellulose and below behind the drying steps discussed its remainder of adding (receiving) as super granule cross-linked carboxymethyl cellulose can improve the disintegrative of production tablet.In this case, preferably in granule, add the cross-linking sodium carboxymethyl cellulose of about 60-about 75%, outside granule, add the cross-linking sodium carboxymethyl cellulose of about 25-about 40%.The same discovery for tablet, adds microcrystalline Cellulose (super granule microcrystalline Cellulose) and can improve particulate compressibility and the raising hardness by the tablet of these preparation of granules behind the drying steps below.

The blend step of this method preferably includes hybrid medicine material, lactose, polyvinylpyrrolidone and cross-linking sodium carboxymethyl cellulose.Find that incorporation time is as short as 3 minutes and can obtains the powder mixture that medicine is evenly distributed to is enough to obtain the marketed tablet degree.

Then, with water, preferred pure water is added in this powder mixture, with this mixture restir a period of time, forms wet granulate mixture.Preferably use wetting agent, wetting agent preferably adds add entry in powder mixture before and stirred at least 15 minutes, preferably at least 20 minutes, add entry at once in mixture then, or progressively add in a period of time, or branch adds in a period of time several times.Preferred water in a period of time, progressively add or, wetting agent can be added in the powder mixture, water is added in the mixture of gained then.It is preferred adding and fully mixing a period of time after the entry again, to guarantee water uniform distribution in mixture.

Then, the preferred granulate mixture that will wet for example carries out wet grinding with grinding sieve, with remove the wet granulation operation subsidiary form than the large crumb material.If do not remove, these agglomerates will prolong dry run subsequently, increase the difference of moisture Control.

For example the mixture of dry wet pelletize or wet grinding obtains dried granule in baking box or fluidized bed dryer, the preferred latter.If desired, can before dry, wet granulate mixture be extruded and nodularization.For dry run, adjust drying condition, as inlet air temperature and drying time to obtain the dried granule of desired moisture content.For this drying steps and procedure of processing subsequently, may need two or more granulations partially mixed.

As needs, can will do particulate particle size reduction to prepare tabletting and encapsulation.Can use the conventional device that reduces granularity for example agitator or impact grinding (for example Fitz mill).

For the lower mixture of water content, prolong incorporation time and can observe slightly reducing of particle size.By inference, when the concentration of water is too low and can not activate used binding agent fully the time, the bonding force between the intragranular primary granule can not bear the shearing force that is produced by hybrid blade, particulate granularity will reduce and can not increase.On the contrary, the content that increases water can make the bonding force between the primary granule can bear the shearing force that is produced by hybrid blade with complete activated adhesive, and along with incorporation time and/or add the increase of water speed, granule will become greatly and not and can reduce.The screen size that changes wet grinding is bigger than the influence that changes charging rate and/or grinding rate to the influence of grain graininess.

Dried granule is placed in suitable mixer instance such as the bivalve body blender then, and optional lubricant (for example magnesium stearate) and other the extra carrier material (for example super granule microcrystalline Cellulose in some tablet formulation and/or super granule cross-linking sodium carboxymethyl cellulose) of adding is to form final mixture.When diluent comprises microcrystalline Cellulose, find in this step, to add the hardness that a part of microcrystalline Cellulose can increase particulate compressibility and tablet largely.But the amount of magnesium stearate increases to and can reduce the hardness of tablet and increase fragility and dissolution time to about 2% o'clock more than 1% approximately.

Then with finally mixed mixture encapsulation (or if the preparation tablet, the instrument of use suitable dimension is pressed into the tablet of required weight and hardness).Can adopt conventional tabletting known in the art and encapsulation techniques.By the height of bed scope that adopts the about 60mm of about 20mm-, the about 5mm of about 0-compress the scope of setting and about 60000 capsules/hour-Yue 130000 capsules/hour the capsule of speed preparation can obtain suitable result.But minimum when using the retentive control capsules weight compresses setting and can reduce or eliminate fritter to greatest extent and form.During the need of coating sheet, can adopt the conventional packaging technique that is known in the art.

This operative combination produces the granule that single dose of drug content is uniform, be easy to disintegrate, this granule enough flows easily so that control weight change reliably when capsule filling or tabletting, and has enough density so that preparation in quantity under the selected device that specific capsule or tablet mould are installed and each dosage.

The present invention also relates to the present composition and can be used for treating and/or preventing that application, particularly these diseases and disease in the medicine of the disease of COX-2 mediation and disease needs or when requiring the therapeutical effect quick acting in preparation.

The description of particularly preferred embodiment

Relate to patent and other teach literatures of nanoparticle pharmaceutical compositions, drug particle size is more little, in general helps the onset speed of oral back therapeutical effect or the performance of other pharmacodynamics advantages more.For example, following at least patent proposes particle size reduction to about 400nm or littler.

The U.S. Patent No. of above quoting as proof 5,145,684.

The U.S. Patent No. of above quoting as proof 5,298,262.

The U.S. Patent No. of above quoting as proof 5,302,401.

The U.S. Patent No. of above quoting as proof 5,336,507.

The U.S. Patent No. of above quoting as proof 5,340,564.

The U.S. Patent No. of above quoting as proof 5,346,702.

The U.S. Patent No. of above quoting as proof 5,352,459.

The U.S. Patent No. of above quoting as proof 5,429,824.

The U.S. Patent No. of above quoting as proof 5,503,723.

The U.S. Patent No. of above quoting as proof 5,510,118.

The U.S. Patent No. of above quoting as proof 5,534,270.

The U.S. Patent No. of above quoting as proof 5,552,160.

The U.S. Patent No. of above quoting as proof 5,573,783.

The U.S. Patent No. of above quoting as proof 5,585,108.

The U.S. Patent No. of above quoting as proof 5,591,456.

The U.S. Patent No. of above quoting as proof 5,662,883.

The U.S. Patent No. of above quoting as proof 5,665,331.

Yet drug particle size is more little, produce this granule and in general require long more grinding or pulverizing time, and more energy and work, and therefore make this process cost higher lower with efficient.So producing a certain amount of drug particles less than nano-scale has obviously high price and labor intensity than the drug particles greater than nano-scale usually.

Surprised is, we find to have the weight average granularity now and are about the about 1000nm of the 450nm-selective COX-2 of (this paper is called " submicron " preparation and granularity)-inhibitor 2 pharmaceutical composition and equal the reference composition that the weight average granularity is about the about 400nm of 200nm-in fact through external and in-vivo measurement demonstration onset time and bioavailability.The submicron preparation is that the preparation of the littler nano-particle of 200-400nm requires short milling time and the energy that lacks than containing the weight average particle size range.

Also watch the submicron relative attentively and can obtain some advantages except that saving money with small grain size more.For example, ultramicro powder is tending towards condensing or can not be in gastro-intestinal Fluid under the dispersive situation, and bigger submicron particles can show enhanced dispersibility.

Therefore, in particularly preferred embodiment of the present invention, provide a kind of contain one or more can be oral the pharmaceutical composition of releasing agent amount unit, each dosage unit contains the selective COX-2-inhibitor 2 medicine of the low aqueous solubility for the treatment of effective dose, its Chinese medicine is with the D of the about 1000nm of about 450nm- ₂₅The solid particle of granularity exists, and the solid granularity about 900nm of 500nm-more preferably from about, with D ₂₅Granularity is compared less than other analogous composition of 400nm, and the present composition provides at least in fact similarly C _MaxAnd/or similar in fact at the most T _Max, and/or and D ₂₅Granularity is compared greater than other analogous composition of 1000nm, and the present composition provides bigger in fact C _MaxAnd/or shorter in fact T _Max

Also provide a kind of contain one or more can be oral the pharmaceutical composition of releasing agent amount unit, each dosage unit contains the selective COX-2-inhibitor 2 medicine of the low aqueous solubility for the treatment of effective dose, its Chinese medicine exists with solid particle, and approximately the particulate granularity of 25%-100% weight is at the about 1000nm of about 450nm-, more preferably from about the about 900nm of 500nm-.

Also provide a kind of contain one or more can be oral the pharmaceutical composition of releasing agent amount unit, each dosage unit contains the selective COX-2-inhibitor 2 medicine of the low aqueous solubility for the treatment of effective dose, its Chinese medicine exists with the solid particle of the weight average granularity of the about 1000nm of about 450nm-, and the solid granularity is the about 900nm of 500nm-more preferably from about, compare less than other analogous composition of 400nm with the weight average granularity, the present composition provides at least in fact similarly C _MaxAnd/or similar in fact at the most T _Max, and/or compare greater than other analogous composition of 1000nm with the weight average granularity, the present composition provides bigger in fact C _MaxAnd/or shorter in fact T _MaxFor convenience of description, " weight average granularity " can be considered to D ₅₀The synonym of granularity.

The submicron particles of selective COX-2-inhibitor 2 medicine can be by improving the method described in the preparation of nanoparticles above or preparing by the method for describing for example among the embodiment 1 hereinafter.

Embodiment

Embodiment 1

The dispersion D1-D4 that contains the celecoxib of 5% weight ratio by method preparation hereinafter described.Dispersion only has difference on the particle size range of celecoxib.

1, with celecoxib in aerojet mill micronization to form drug powder.

2, drug powder is added in the aqueous solution that contains 2.5% low-viscosity hydroxypropylcelluloand (HPC-SL) and 0.12% sodium lauryl sulphate to form suspension.

3, press following method wet grinding suspension to form an intermediate section prose style free from parallelism.Bead that sample size 6.0ml suspension (containing 20% celecoxib), magnetic stirring bar, 8ml is unleaded and the defoamer (Sigma Antifoam A concentrate) of 50 μ l are added in the 20ml scintillation vial.To have the target particle size range be the 6-7 μ m intermediate section prose style free from parallelism of (particle size range that promptly reaches in micronization step is used to provide reference composition) in order to provide, with scintillation vial jolting 2 minutes.For the prose style free from parallelism of the intermediate section with littler target particle size range is provided, scintillation vial is suspended on the high strength rotary magnet so that provide magnetic stirring bar rotation stirred glass pearl to grind.Change the target particle size range by table 1 control magnet rotary speed, milling time and/or bead size.Take out sample aliquot at interval so that detect the progress of particle size reduction.

The intermediate section prose style free from parallelism that 4, will at every turn obtain is transferred in the bigger bottle and with fresh carrier and is diluted to form final dispersion.Normal celecoxib concentration is 5% weight ratio in the final dispersion.Table 1. is used to produce the grinding condition of celecoxib dispersion D1-D4

Dispersion	Target magnitude range (μ m)	Bead size (mm)	Milling time (min)	Grinding rate (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

Embodiment 2

By laser (Fraunhofer) diffraction with measure the granularity of celecoxib among the embodiment 1 prepared dispersion D1-D4 by light microscopy.

Measure static dispersion samples Fraunhofer scattering situation with the Sympatec spectrometer.Samples with water is diluted to the static pond that keeps laser intensity to reduce about 20% concentration.Selecting the specimen camera lens is to determine that by the big material sum that exists in the suspension therefore this selection is different concerning each sample.Yet the suitable minimum Focus length of eyes is applicable to various situations.Do not carry out the Mie scatter correction.Result shown among Fig. 1 shows, D ₅₀Granularity is consistent with the target particle size range.Believe, for the celecoxib dispersion of 0.2-0.4 μ m, the D that Fig. 1 is shown ₅₀Overestimate with other grain size parameters, because this particle size range is the detectable limit of this technology.

In order to determine granularity, use light microscopy with vision.Observe with the Olympus BH-2 microscope that connects television camera.Then, with image digitazation (Snappy4.0; Play Inc., Rancho Cordova, CA) and (the Paint Shop Pro6.02 that deals with on the merits of each case; JASC, Eden Prairie, MN).Fig. 2 shows the non-polarized light (left side) and polarized light (right side) microphotograph of celecoxib dispersion D1-D4 sample.Bar is represented 10 μ m.Observe important Brownian movement at dispersion D3 and D4, observed result with exist minimum nano-particle consistent.Notice that on the contrary dispersion D2 only has slight Brownian movement and dispersion D1 not to have at all.

Embodiment 3

The crystalline dissolution characteristic of celecoxib among the assessment embodiment 1 dispersion D1-D4 in external stripping as described below is measured.Fig. 4 is the graphic representation of this test institute operative installations.The stripping container is a 600ml chuck beaker.Chuck is connected on the temperature control water cycle machine, and this circulator plays the effect that the temperature of dissolution fluid is remained on 37 ℃.Utilize standard USP II stripping oar to stir dissolution fluid.This oar drives by computer-controlled constant speed engine, in whole mensuration process, this oar is transferred to rotation speed operation with 75rpm.

Dispersion samples is expelled to makes it in the stripping container just under the dissolution fluid surface.Introducing a sample in the method makes particle aggregation be reduced to minimum in the probability of liquid surface.Simultaneously, obtaining data program brings into operation.Between test period, at 30 seconds and per afterwards 30 seconds collected specimens points.For each study sample, process in leaching continues 60 minutes.Monitor stripping drug concentrations in the container on the spot by the fiber optics probe that is used for measuring dissolution fluid stripping medicine optical absorption degree.In whole mensuration process, probe keeps being immersed in the liquid.According to the Beer-Lambert formula, stripping drug concentrations from measured trap pH-value determination pH liquid $c=\frac{A}{1\·\mathrm{\ϵ}}$ The trap of A wherein for recording at 254nm, l is for being the path of unit with cm, ε be the absorptance at 254nm, is unit with ml/ (μ gcm), and c is to be the drug level of unit with μ g/ml.The path stuck-at-cm of fiber optics probe.A kind of typical step with the calibration of standard celecoxib solution is used for measuring absorptance at 254nm.

Assembling one additional PC is used for trap value of per 30 seconds records.Such battery of tests data are made of on the spot per 30 seconds trap values at interval in the entire test.The trap value is converted into drug level by above-mentioned Beer-Lambert formula then.

Before analyzing dispersion of the present invention, add 500ml dissolution fluid (deionized water) in the stripping container, and 37 ℃ of following balances.With the stripping oar with fiber optics probe is put in the container and also 37 ℃ of following balances.About 5 minutes of Celecoxib dispersion D1-D4 sonication before mensuration of embodiment 1 preparation.Each dispersion is drawn 40 μ l dispersion samples with micropipet immediately then and is put in the above-mentioned dissolution fluid with hand moving.

Fig. 3 shows the dissolution rate of dispersion D1-D4.For relatively convenient, in the time of 60 minutes, all stripping traces are normalized into identical value.When more similar stripping figure, this normalization step is that compensation sample fine difference is essential.Stripping figure shows the standardization percentage ratio as the stripping celecoxib of time function.

Generally speaking, the stripping of reference dispersion D1 than the stripping of dispersion D2 of the present invention, D3 and D4 slowly many, all dispersions are with basic similarly speed stripping.This results suggest is compared at the celecoxib of 450nm-1000nm scope granule with average particle size, is lower than the dissolution rate that 400nm obtains and does not have significant functional advantage by the celecoxib granule being ground to average particle size.Compare with micronized celecoxib dispersion, all nanoparticle dispersions demonstrate significant advantage on dissolution rate. Embodiment 4

In the body of Canis familiaris L., assessed the pharmaco-kinetic properties of the celecoxib dispersion liquid D1-D4 of embodiment 1 preparation in the research.

To one of 8 male four kinds of celecox ib of ratio brother hunting dog administration dispersion liquid D1-D4, dosage is 10mg/kg.0.25,0.5,0.75,1,1.5,2,3,5,8 and 24 hour collection venous blood before administration and after the administration.By the centrifugal blood plasma of from blood, isolating, then by the high-performance liquid chromatogram determination plasma drug level.The pharmacokinetic data available that obtains is as shown in table 2.

The pharmacokinetic parameters of table 2:celecoxib dispersion liquid D1-D4

	Dispersion
					????D1	????D2	????D3	????D4
	?T max(h)	????1.2	????0.84	????0.72					????0.72
?C max(ng/m1)					????1400	????4850	????6120	????6310
	?AUC(h *ng/ml)	????14600	????32700	????37500					????43500

The T of dispersion D3 (targeted particle size scope 0.5-0.9 μ m) and D4 (targeted particle size scope 0.2-0.4 μ m) _Max, C _MaxAnd AUC (total bioavailability) value is closely similar.Compare with D3 with dispersion liquid D4, dispersion liquid D2 (targeted particle size scope 1-3 μ m) shows the T that prolongs slightly _MaxC with the moderate reduction _MaxWith the AUC value.The T of dispersion liquid D1 _MaxMuch longer, and C _MaxAlso much lower than dispersion liquid D2, D3 and D4 with AUC.

These results show, when the therapeutic effect of the rapid onset of needs, use to be ground to the targeted particle size scope and to be 0.5-0.9 μ m and the D that measures by Fraunhofer scattering (Fig. 1) ₅₀Granularity is that the celecoxib of about 0.9 μ m can obtain good bioavailability.Cost more time and energy are ground to targeted particle size scope 0.2-0.4 μ m with the celecoxib granule and do not produce obvious benefit.

Claims (18)

1. the pharmaceutical composition that comprises one or more oral dosage units, each dosage unit comprise the low aqueous solubility selectivity COX-2 for the treatment of effective dose and suppress medicine, and wherein said medicine is present in D ₉₀Granularity is in the solid particle of the about 200 μ m of about 0.01 μ m-, and the granule that enough wt parts are arranged is less than 1 μ m, has the C that essence increases to provide all to compare greater than other analogous compositions of 1 μ m with all granules basically _MaxAnd/or the T of essence shortening _Max

2. the pharmaceutical composition that comprises one or more oral dosage units, each dosage unit comprise the low aqueous solubility selectivity COX-2 for the treatment of effective dose and suppress medicine, and wherein said medicine is present in D ₉₀Granularity is in the solid particle of the about 200 μ m of about 0.01 μ m-, and the granule of the 25%-100% weight of wherein having an appointment is less than 1 μ m.

3. claim 1 or 2 compositions, wherein basically all granules all less than 1 μ m.

4. each compositions of claim 1-3, wherein said dosage unit is the form of discontinuous solid product.

5. the compositions of claim 4, wherein said solid product is tablet or capsule.

6. each compositions of claim 1-3, wherein said compositions are can be by measuring the even form of flowable mass basically of taking out single dosage unit.

7. the compositions of claim 6, wherein said basically evenly flowable mass be liquid suspension.

8. each compositions of claim 1-7, wherein solid particle has the D of the about 1000nm of about 450nm- ₂₅Granularity.

9. each compositions of claim 1-7, the solid particle of the 25%-100% weight of wherein having an appointment has the granularity of the about 1000nm of about 450nm-.

10. each compositions of claim 1-7, wherein solid particle has the average particle size of the about 1000nm of about 450nm-.

11. each compositions of claim 1-10, it is following formula: compound that wherein said selectivity COX-2 suppresses medicine

R wherein ³Be methyl or amino, R ⁴Be hydrogen or C _1-4Alkyl or alkoxyl, X are N or CW ⁵, R wherein ⁵Be hydrogen or halogen, and Y and Z be carbon or nitrogen-atoms independently, what described carbon or nitrogen-atoms limited is the adjacent atom of 5-6 unit ring, and this 5-6 unit ring replaces or replaced by oxo, halogen, methyl or halogenated methyl in one or more positions.

12. the compositions of claim 11, the first ring of wherein said 5-6 is selected from and is being no more than substituted cyclopentenone, furanone, methylpyrazole, isoxazole and pyridine ring on the position.

13. each compositions of claim 1-10; wherein said selectivity COX-2 suppresses medicine and is selected from celecoxib, deracoxib, valdecoxib, rofecoxib, 5-chloro-3-(4-methyl sulphonyl) phenyl-2-(2-methyl-5-pyridine radicals) pyridine, 2-(3; the 5-difluorophenyl)-3-[4-(methyl sulphonyl) phenyl]-2-cyclopentenes-1-ketone and (S)-6,8-two chloro-2-(trifluoromethyl)-2H-1-.alpha.-5:6-benzopyran-3-carboxylic acid.

14. the compositions of claim 13, it is celecoxib that wherein said selectivity COX-2 suppresses medicine.

15. the compositions of claim 14 wherein comprises the about 1000mg celecoxib of about 10mg-in each dosage unit.

16. treat in the individuality as the disease of COX-2 inhibitors indication or the method for disease for one kind, this method comprises each the dosage unit of compositions of Orally administered one or more claim 1-15, about 6 times of administration every day 1-.

17. the method for claim 16, wherein said disease or disease are with acute pain.

18. the solid particle that low aqueous solubility selectivity COX-2 suppresses medicine is used for the treatment of or prevent application process in the medicine of disease that COX-2 mediates or disease in preparation, wherein said solid particle has the D of the about 200 μ m of about 0.01 μ m- ₉₀Granularity, and the solid particle of the 25%-100% weight of having an appointment is less than 1 μ m.

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