CN1216869C - Polymorphic crystalline forms of celecoxib - Google Patents

Abstract

Pharmaceutical compositions are provided comprising one or more orally deliverable dose units, each comprising a selective cyclooxygenase-2 inhibitory compound of low water solubility in a therapeutically effective amount, wherein the compound is present in the form of solid particles, about 25 % to 100 % by weight of which are smaller than 1 mm. The compositions 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. The novel Form I and Form II crystalline forms of celecoxib are described. The crystalline forms have unique chemical and physical properties relative to other solid state forms of celecoxib and are characterized by their powder x-ray diffraction (PXRD) patterns, differential scanning calorimetric (DSC) thermograms, and other physical characterizations.

Description

Delightful Polymorphic Forms of Sely

Related application reference

This patent application claims priority to US Provisional Patent Application Serial No. 60/169856, filed December 9, 1999.

field of invention

The present invention relates to orally releasable pharmaceutical compositions containing cyclooxygenase-2 inhibitor drugs as active ingredients, methods of preparing such compositions, methods of treating cyclooxygenase-2 mediated diseases, said Methods include oral administration of such compositions to a subject, and use of such compositions for the manufacture of a medicament.

The invention belongs to the field of cyclooxygenase-2 inhibitory agents, and specifically relates to new type I and type II crystal forms of celecoxib, methods for preparing these celecoxib crystal forms, and celecoxib containing these crystalline forms Pharmaceutical compositions and methods of treating and/or preventing cyclooxygenase-2 mediated disorders and/or diseases (including disorders and diseases).

Background of the invention

A variety of compounds have been reported for selective cyclooxygenase-2 inhibition in the treatment and/or prophylaxis and have been disclosed to be useful in the treatment or prevention of specific cyclooxygenase-2 mediated diseases or in general role in such diseases. Among such compounds, Talley et al. reported heavily substituted pyrazolylbenzenesulfonamides in U.S. Patent No. 5,760,068, including, for example, the compound 4-[5-(4-methylphenyl)-3-(trifluoromethane base)-1H-pyrazol-1-yl]benzenesulfonamide, also referred to herein as celecoxib, and the compound 4-[5-(3-fluoro-4-methoxyphenyl)-3- Difluoromethyl]-1H-pyrazol-1-yl]benzenesulfonamide, also referred to herein as deracoxib. Sally Kexi has the following structure:

Della Delight has the following structure:

Other compounds reported to have therapeutic and/or prophylactic effects for selective cyclooxygenase-2 inhibition are substituted isoxazolylbenzenesulfonamides as reported by Talley et al. in U.S. Patent No. 5,633,272, including for example compounds 4- [5-Methyl-3-phenylisoxazol-4-yl]benzenesulfonamide, also referred to herein as valdecoxib, has the following structure:

Still other compounds reported to have therapeutic and/or prophylactic effects for selective cyclooxygenase-2 inhibition are substituted (methylsulfonyl)phenylfuranones as reported by Ducharme et al. in U.S. Patent No. 5,474,995, for example including Compound 3-phenyl-4-[4-(methylsulfonyl)phenyl]-5-H-furan-2-one, also referred to herein as rofecoxib, has the following structure:

Balley et al. in U.S. Patent No. 5,981,576 disclose further (methylsulfonyl)phenylfuranones useful as cyclooxygenase-2-inhibitors, including 3-(1-cyclopropylmethoxy )-5,5-Dimethyl-4-[4-(methylsulfonyl)phenyl]-5-H-furan-2-one and 3-(1-cyclopropylethoxy)-5,5 -Dimethyl-4-[4-(methylsulfonyl)phenyl]-5-H-furan-2-one.

European Patent Application No. 0863134 discloses the compound 2-(3,5-difluorophenyl)-3-[4-(methylsulfonyl)phenyl]-2-cyclooxygenase-2 inhibitors Pentamethylene-1-one.

Compounds useful as cyclooxygenase-2 inhibitors are disclosed inter alia in International Publication No. WO99/55380:

A number of selective cyclooxygenase-2 inhibitory compounds, including Selykexi, Delakexi, Wardkexi and Roferkexi, are hydrophobic and have low solubility in water. There are practical difficulties in formulating such compounds for oral administration, particularly where rapid onset of therapeutic effect is desired or required.

Illustratively, due to the unique physical and chemical properties of Selyco, particularly its low solubility and factors related to its crystalline structure, including cohesiveness, low bulk density and low compressibility, it was formulated for use in Formulations for effective oral administration to a subject are complicated. Sally is remarkably insoluble in aqueous media. For example, when administered orally in the form of capsules, unformulated celecoxil is not readily soluble and dispersible, thus not conducive to rapid absorption in the gastrointestinal tract. In addition, unformulated celica, which has a crystalline state that tends to form viscous elongated needle crystals, tends to fuse into a monolithic mass when compressed on a tablet machine die. Even when mixed with other substances, the saliva crystals tend to separate from the other substances and agglomerate into lumps during mixing of the composition, resulting in an unevenly mixed composition containing unwanted large aggregates of saliva . Therefore, it is difficult to prepare a pharmaceutical composition containing celecoxan with the desired uniformity of mixing. Furthermore, handling problems are encountered in the preparation of pharmaceutical compositions containing celecoxane. For example, the desirably low bulk density of Celli makes it difficult to handle the small quantities of material required during the formulation of pharmaceutical compositions. Accordingly, there are a number of related problems to be solved in the preparation of suitable pharmaceutical compositions and dosage forms, particularly oral release dosage units, containing celecoxane.

In particular, an oral release formulation containing a cyclooxygenase-2 inhibitory drug of low water solubility of celecoxil needs to have one or more of the following properties for combination with unformulated celecoxil or other celecoxil :

(1) Improve solubility;

(2) shorten the disintegration time;

(3) shorten the dissolution time;

(4) reduce tablet friability;

(5) increase tablet hardness;

(6) Improve wettability;

(7) Improve compressibility;

(8) Improve the fluidity of liquid and granular solid compositions;

(9) Improve the physical stability of the finished composition;

(10) Reduce the size of the tablet or capsule;

(11) Improve mixing uniformity;

(12) Improve dose uniformity;

(13) Improve the control of weight differences during encapsulation and/or tabletting;

(14) Increase the particle density of the wet granulation composition;

(15) Reduce the water requirement of wet granulation;

(16) reduce the time of wet granulation; and

(17) Reduce the drying time of the wet granulation mixture.

Further, there is a particular need for oral release formulations containing Cyclooxygenase-2 inhibitory drugs of low water solubility that exhibit a faster onset of action than the corresponding unformulated drugs or known formulations of these drugs. The extent to which a rapid onset of therapeutic effect is achieved is related to pharmacokinetic parameters such as the maximum serum concentration of the drug (C _max ) and the shortest time to reach maximum serum concentration (T _max ) after oral administration, and such celecoxane-containing Oral release formulations of cyclooxygenase-2 inhibiting drugs of low water solubility which provide greater _Cmax and/or earlier _Tmax than corresponding unformulated drugs or known formulations of these drugs.

As noted herein below, a very wide range of cyclooxygenase-2 mediated conditions and diseases are indicated or potentially indicated for treatment with selective cyclooxygenase-2 inhibitors that include Cyliche. It would be beneficial to provide formulations exhibiting pharmacokinetics consistent with rapid onset of therapeutic action, particularly for the treatment of acute conditions where early relief of pain or other symptoms is desired or required.

Such formulations would show significant advances in the treatment of cyclooxygenase-2 mediated conditions and diseases.

Cyclooxygenase-2 inhibitory drugs with low solubility in water, including Celex, are most commonly formulated as solid microparticles. Individual or primary particles of drug may be dispersed in a liquid medium, such as in a suspension formulation, or may be aggregated to form secondary particles or granules that may be coated to provide a capsule dosage form, or compressed or molded to provide a tablet dosage form .

Various methods of preparing pharmaceutical formulations having a desired range of primary particle sizes, or having a desired average particle size, or having a particle size distribution characterized by parameters such as _D90 are well known and commonly used in the art. _D90 is defined herein as a linear measure of the diameter at which 90% of the volume of particles in a formulation has a volume value smaller than that diameter in the longest dimension of the particle. For practical purposes, _D90 measured on a 90% by weight basis is generally more appropriate than that measured by volume.

To be consistent with the priority publication, the terms "microparticle" and "nanoparticle" are defined herein to refer to particles having a diameter between 1 mm and 2000 mm and less than 1 mm ( 1000nm) diameter particles. According to US Patent No. 5,384,124, microparticles and nanoparticles are formulated "primarily to delay the dissolution of the active ingredient". However, U.S. Patent No. 5,145,684 by Liversidge et al. discloses such nanoparticulate compositions to provide "unexpectedly high bioavailability" of drugs, especially drugs with low solubility in liquid media such as water. International Publication No. WO93/25190 provides pharmacokinetic data from rat studies showing that oral administration of nanoparticles (average particle size 240-300 nm) has a significantly higher apparent rate of absorption than administration of microparticles (average particle size 20-30 mm) .

A number of methods are known for preparing nanoparticulate compositions of therapeutic agents. Typically these methods employ mechanical means, such as grinding or milling, to reduce the particle size to the nanoscale (less than 1 mm) range, or to precipitate nanoscale particles from solution. Illustrative methods are disclosed in the following independent documents: U.S. Patent No. 4,826,689 to Violanto & Fischer, U.S. Patent No. 5,145,684 to Liversidge et al. cited above, U.S. Patent No. 5,298,262 to Na & Rajagopalan, U.S. Patent No. to Liversidge et al. 5,302,401, U.S. Patent No. 5,336,507 to Na & Rajagopalan, U.S. Patent No. 5,340,564 to Illig & Sarpotdar, U.S. Patent No. 5,346,702 to Na & Rajagopalan, U.S. Patent No. 5,352,459 to Hollister et al., U.S. Patent No. 5,354,560 to Lovrecich, Courteille et al. cited above U.S. Patent No. 5,384,124 to Man, U.S. Patent No. 5,429,824 to June, U.S. Patent No. 5,510,118 to Bosch et al., U.S. Patent No. 5,518,738 to Eickhoff et al., U.S. Patent No. 5,503,723 to Ruddy & Eickhoff, U.S. Patent No. 5,534,270 to De Castro, Canal et al. U.S. Patent No. 5,536,508 to Liversidge 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 & 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. to Franson & Snyder No. 5,591,456, 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 & Roberts, U.S. Patent No. 5,747,001 to Wiedmann et al., International Patent Publication No. WO93/25190, International Patent Publication No. WO96/24336, International Patent Publication No. WO98/35666.

Summary of the invention

According to the present invention, a selective cyclooxygenase-2 inhibitory compound which is poorly water soluble, e.g. Selikexi, Delakexi, Wardkexi or Roverkexi, if the compound exhibits the following pharmacokinetic properties, which lead to more Larger maximum serum concentration ( _Cmax ) and/or shorter time to reach maximum serum concentration ( _Tmax ) after administration then provides a faster onset of therapeutic effect when a composition containing the compound is orally administered. Said greater _Cmax and/or shorter _Tmax are obtained by reducing the particle size of the solid particles containing the compound such that a majority by weight of the particles are less than 1 mm in diameter and in the longest dimension of the particles. Without being bound by theory, a larger _Cmax and/or shorter _Tmax is believed to result in faster dissolution of the compound when the particle size is reduced to less than 1 mm.

Accordingly, there is now provided a pharmaceutical composition comprising one or more oral release dosage units, each comprising a therapeutically effective amount of a selective cyclooxygenase-2 inhibitory compound of low water solubility, wherein the compound has a concentration of about 0.01 The presence of solid particles of D ₉₀ particle size to about 200 mm, the particles being mostly less than 1 mm by weight, provides a sufficiently high _Cmax and/or sufficient Short T _max .

Also provided is a pharmaceutical composition comprising one or more oral release dosage units, each comprising a therapeutically effective amount of a selective cyclooxygenase-2 inhibitory compound of low water solubility, wherein the compound has a concentration of about 0.01 to about Solid particles of a D ₉₀ particle size of 200 mm are present with about 25% to 100% by weight of the particles being smaller than 1 mm.

The dosage units comprised by the composition may be in the form of discrete solid articles such as tablets, pills, hard or soft capsules, lozenges, sachets or pastilles; alternatively, the composition may be in the form of a substantially uniform flowable Forms such as particles or granulated solids or liquid suspensions, wherein single dosage units are dispensed in moderation.

Also provided is a method of treating a medical condition or disease in a subject, herein referred to as treatment with a cyclooxygenase-2 inhibitor, comprising orally administering one or more dosage units of a composition of the invention once or twice daily. Second-rate. Such methods are particularly suitable for medical conditions or diseases accompanied by acute pain.

The present invention also includes a new solid-state type of sally, the type I sally. The present invention further includes another solid type Sally Kexi, type II Sally Kexi. Each of these new solid state forms includes solvated, unsolvated and nonhydrated forms.

These novel celicas described herein possess one or more of the beneficial chemical and/or physical properties described above in relation to other solid state forms described herein or disclosed in the literature.

Another embodiment of the present invention comprises a new crystalline form of sariga. For example, one embodiment of the present invention includes crystalline form I of celecox, preferably a crystalline form having an X-ray powder diffraction spectrum with peaks at 5.5, 5.7, 7.2 and 16.6 degrees 2Θ.

In another embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of crystalline form I of sariga and at least one pharmaceutically acceptable carrier, adjuvant or diluent.

In another embodiment, the present invention provides a method of treating or preventing a cyclooxygenase-2 mediated condition or disease, wherein the method comprises administering to the subject a therapeutically effective amount of saliva type I.

In yet another embodiment, the present invention provides a process for the preparation of sarikel, Form I, comprising crystallizing sarikel from a mixture comprising sarikel and a solvent, wherein enantiomerically Crystallization proceeds at the transition temperature, resulting in type I saliva.

In yet another embodiment, the present invention provides a method of preparing a crystalline form of sarike, wherein the method comprises heating a solvate of sarike, thereby producing sarikesi Form I.

In another embodiment, the present invention provides a method of preparing saliva type I, wherein the method comprises comminuting or milling saliva type III, thereby producing saliva type I.

In yet another embodiment, the present invention provides a process for the preparation of sarikeratin Form I, wherein the method comprises comminuting or milling a solvate of sarikeratin, thereby producing sarikeratin Form I.

In another embodiment, the present invention provides a method of preparing sariko Form I, wherein the method comprises melting sariko Form II and cooling the melt, thereby producing sariko Type I.

In another embodiment, the present invention provides a method of preparing sariko Form I, wherein the method comprises melting sariko Type III and cooling the melt, thereby producing sariko Type I.

In another embodiment, the present invention provides a method of preparing sarixiform I, wherein the method comprises evaporating the solvent from a sarixiform solution, thereby producing sarixiform I.

Another embodiment of the present invention includes a novel crystalline form of sarikh, for example, an embodiment of the invention includes crystalline form II of sarikh, preferably having Crystal form with peaked X-ray powder diffraction pattern.

Another embodiment of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the crystals and at least one pharmaceutically acceptable carrier, adjuvant or diluent.

Another embodiment of the present invention provides a method of treating or preventing a cyclooxygenase-2-mediated condition or disease in a subject, the method comprising administering to the subject a therapeutically effective amount of type II salikinase .

Yet another embodiment of the present invention provides a process for the preparation of saricerol Form II, comprising crystallizing sarikeratin from a mixture comprising sarikeratin and a solvent, wherein at the enantiomeric transition temperature of sarikeratin Form II The crystallization was carried out under, resulting in type II saliva.

Yet another embodiment of the present invention provides a process for the preparation of a crystalline form of sarikexi, wherein the method comprises heating sarikexi solvate, thereby producing sarikexi form II.

Another embodiment of the present invention provides a method of preparing sarikh type II, wherein the method comprises comminuting or milling salikini type III, thereby producing salikini type II.

Another embodiment of the present invention provides a process for the preparation of sarikeloids Form II, wherein the method comprises comminuting or milling sarikeratin solvate, thereby producing sarikeratin Form II.

Yet another embodiment of the present invention provides a method of preparing sariko Form II, wherein the method comprises melting sariko Form I and cooling the melt, thereby producing sariko Form II.

Yet another embodiment of the present invention provides a method of preparing sariko Form II, wherein the method comprises melting sariko Form III and cooling the melt, thereby producing sariko Form II.

Another embodiment of the present invention provides a solid form of sariko comprising sariko Type I and sariko Type II.

Another embodiment of the present invention provides a solid form of sariko comprising sariko Type I and sariko Type III.

Another embodiment of the present invention provides a solid form of sariko comprising sariko Form II and sariko Type III.

Another embodiment of the present invention provides a solid form of sariko comprising sariko Type I, sariko Type II and sariko Type III.

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

Brief description of the drawings

Figure 1 depicts a comparison of the experimental PXRD patterns between sarixi type I (figure 1a), a mixture of sarikiri type II and type III (figure 1b) and sariki type III (figure 1c);

Figure 2 depicts a comparison between the IR spectra of a mixture of sarixi type I, sariki type II and type III sariki and sariki type III;

Figure 3 depicts a comparison of the DSC thermograms scanned at 0.5°C/min for each of the crystalline forms of sarixi with overlay (below the endotherm).

Description of the preferred embodiment

The term "selective cyclooxygenase-2 inhibitor" or "selective cyclooxygenase-2 inhibitory compound" herein means inhibition of cyclooxygenase-2 to a therapeutically effective Inflammatory drugs (NSAIDs) inhibit compounds that significantly reduce cyclooxygenase-1.

The term "poor water solubility" or "low water solubility" in relation to a selective cyclooxygenase-2 inhibitor means herein a solubility in distilled water at 25°C of less than about 10 g/l, preferably less than about 1 g/l .

The term "oral administration" herein includes any form of delivery of a therapeutic agent or composition thereof to a subject wherein the therapeutic agent or composition is placed in the subject's mouth, whether or not the therapeutic agent or composition is swallowed. "Oral administration" thus includes buccal and sublingual as well as esophageal administration. Absorption of therapeutic agents can be found in any part or parts of the gastrointestinal tract, including the oral cavity, esophagus, stomach, duodenum, ileum, and colon.

The term "orally released" means herein suitable for oral administration.

"Subject" means herein a subject to which a therapeutic agent or composition thereof may be administered, including patients of either sex and of any age, and also includes any non-human animal, especially a livestock or companion animal, exemplified by cat, dog or horse.

The term "dosage unit" herein means a pharmaceutical composition containing an amount of a therapeutic moiety, suitable for single oral administration, in the presence of a selective cyclooxygenase-2 inhibitor, to provide a therapeutic effect. Typically one dosage unit, or a small number of multiple (up to about 4) dosage units, will provide a sufficient amount of therapeutic agent to produce the desired effect.

The term "present in a solid particle" as applied to a selective cyclooxygenase-2 inhibitory compound herein includes compositions wherein the solid particle consists essentially of the compound, and wherein the solid particle contains the compound in combination with one or more other ingredients. This compound forms an intimate mixture. These other ingredients include one or more therapeutic agents and/or one or more pharmaceutically acceptable excipients in addition to the selective cyclooxygenase-2 inhibitory compound.

As used herein, the term "excipient" refers to a therapeutic agent that is not itself a therapeutic agent, but is used to deliver a therapeutic agent to a patient or is added to a pharmaceutical composition to improve its handling or storage or to allow or facilitate the delivery of a dosage unit of the therapeutic agent. The composition is formulated with any carrier or adjuvant suitable for dispersible preparations such as capsules or tablets for oral administration. Excipients include, but are not limited to, diluents, disintegrants, binders, adhesives, wetting agents, lubricants, glidants, substances to mask or counteract unpleasant tastes or odors, flavoring agents, Dyes, fragrances and substances that improve the appearance of the composition.

The term "substantially homogeneous" in reference to a pharmaceutical composition comprising several ingredients means that the ingredients are thoroughly mixed such that each ingredient does not exist in a dispersed layer and no concentration gradients form within the composition.

The term "purity" means the chemical purity of celica according to conventional HPLC analysis.

The term "phase purity" means the resulting solid-state purity of celecity with respect to a particular crystalline or amorphous form of celecity when measured by infrared spectroscopic analysis as described herein.

The term "enantiotropic transition temperature" means the temperature at which a thermodynamically stable polymorph changes from one form to another. For example, for two polymorphs, Form A and Form B, below the enantiotropic transition temperature, Form A may be the thermodynamically stable crystalline form, but above this temperature, Form B is the thermodynamically stable crystalline form. stable crystal form.

The novel pharmaceutical compositions according to the invention comprise one or more dosage units for oral delivery. Each dosage unit contains a therapeutically effective amount of a selective cyclooxygenase-2 inhibitor, for example, Cylicoxime, and the preferred therapeutically effective amount is about 10 mg to about 1000 mg.

It will be appreciated that a therapeutically effective amount of a selective cyclooxygenase-2 inhibitor for a subject depends inter alia on the subject's body weight. Illustratively, where the cyclooxygenase-2 inhibitor is celica and the subject is a child or a small animal such as a dog, relatively low amounts of celica in the preferred range of about 10 mg to about 1000 mg Suitable to provide serum concentrations consistent with therapeutic effects. In cases where the subject is an adult human or a large animal (eg, a horse), obtaining such serum concentrations of celecil will likely require a dosage unit containing a relatively large amount of celecil.

Taking Saili Kexi as an example, the usual dosage units in the composition of the present invention contain about 10, 20, 25, 37.5, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350 or 400 mg of Cyclooxygenase-2-inhibitors. For an adult, a therapeutically effective amount of celecox will generally be from about 50 mg to about 400 mg per dosage unit in the compositions of the invention. A particularly preferred amount of celecoxil is about 100 mg to about 200 mg per dosage unit, eg about 100 mg or about 200 mg.

Compositions of the present invention comprising a selective cyclooxygenase-2 inhibitor, such as celica, alone or in intimate admixture with one or more excipients, are in the form of nanoparticles, that is, such solid particles are in the form of The particles are less than 1 mm in diameter based on their longest dimension.

The effect of particle size reduction from the microparticle range (greater than 1 mm diameter) to the nanoparticulate range on the pharmacokinetic properties of any particle size drug or any class of drug is generally unpredictable. According to the present invention, nanoparticle compositions exhibit higher _Cmax and/or shorter _Tmax than microparticle compositions for selective cyclooxygenase-2 inhibitors of low water solubility. Thus, in one embodiment of the invention, the weight percent of nanoparticles in the particles may be sufficient to provide a substantially higher _Cmax and/or substantially shorter C as compared to a control composition wherein substantially all of the particles are larger than 1 mm. T _max . Preferred compositions in this embodiment have a sufficient weight percent of nanoparticles to provide a substantially shorter _Tmax , and more preferably a sufficient weight percent of nanoparticles to provide a substantially higher _Cmax and a shorter Tmax than the control composition. _max .

When administered orally to fasting adults, the 100 mg dosage unit preferably exhibits a _Tmax of less than about 90 minutes, more preferably a _Tmax of less than about 60 minutes and less than about 45 minutes, and a _{Cmax of} at least about 100 ng/ml, More preferably at least about 200 ng/ml. Typically within 30 minutes of oral administration, the compositions of the present invention provide a serum concentration of a selective cyclooxygenase-2 inhibitor of at least about 50 ng/ml; preferred compositions achieve this in as little as 15 minutes. concentration. It is believed that the early rise in serum concentration is related to the rapid onset of action of the compositions of the invention.

In another embodiment of the invention, the selective cyclooxygenase-2 inhibitor, e.g., Celica, is present as solid particles having a _D90 particle size of from about 0.01 to about 200 mm, wherein about 25 mm by weight % to 100% of the particles are nanoparticles. When the weight percent of nanoparticles is lower, such as from about 25% to about 50%, the _D90 particle size is preferably from about 0.01 to about 100 mm, more preferably from about 0.01 to about 75 mm, still more preferably from about 0.01 to about 40 mm, even more preferably about 0.01 to about 25mm. The particle size may vary continuously along the nanoparticle and microparticle range, or the composition may have a bimodal or multimodal particle size distribution, with one set of particles having a _D90 particle size of less than 1 mm and another set of particles having a _D90 particle size substantially greater than 1 mm. At least about 50% by weight nanoparticles in the particles are generally preferred, with at least about 75% by weight being particularly preferred. In one embodiment, substantially all particles are smaller than 1 mm, ie, the weight percent of nanoparticles is at or near 100%.

Primary particles, for example by grinding or milling, or by precipitation in solution, can aggregate to form secondary aggregate particles. As used herein, unless the context indicates otherwise, the term "particle size" refers to the size of a primary particle in its longest dimension.

Considering only the nanoparticulate component of the compositions of the present invention, the average particle size is preferably from about 0.1 to about 0.8 mm (about 100 to about 800 nm), more preferably from about 0.15 to about 0.6 mm (about 150 to about 600 nm), preferably from about 0.2 to about 0.4mm (about 200 to about 400nm). Selective cyclooxygenase-2 inhibitors, such as Cylic, can be in crystalline or amorphous form in nanoparticles. Methods of preparing nanoparticles, including grinding and milling, generally provide the drug in crystalline form, while methods involving precipitation from solution generally provide the drug in amorphous form.

Compositions of the present invention containing a selective cyclooxygenase-2 inhibitor of low water solubility, such as Selyke, optionally contain one or more compounds selected from the group consisting of diluents, disintegrants, binders, moisturizers Excipient for wetting agents and lubricants. In one embodiment, nanoparticles containing a selective cyclooxygenase-2 inhibitor have a surface modifier adsorbed on their surface. In another embodiment, nanoparticles of a selective cyclooxygenase-2 inhibitor are contained in a polymer-forming matrix. At least one excipient is preferably a water-soluble diluent or wetting agent. Such water-soluble diluents or wetting agents facilitate dispersion and dissolution of the cyclooxygenase-2 inhibitor when the compositions of the invention are ingested. Preferably both water-soluble diluents and wetting agents are present.

The composition of the invention may be in the form of a substantially uniform flowable such as a particulate or granulated solid or a liquid, or it may be in the form of a dispersion such as capsules or tablets each containing a single dosage unit.

In a substantially uniform flowable composition, individual dosage units are measurably dispensed using a suitable volumetric metering device, such as a teaspoon or cup. Suitable flowables include, but are not limited to, powders and granules. Alternatively, the flowable may be a suspension having a cyclooxygenase-2 inhibitor dispersed in a liquid phase, preferably an aqueous phase, in a solid particulate phase. At least part of the particulate phase is nanoparticles. In preparing such suspensions it may well be beneficial to employ wetting agents such as polysorbates or the like. Suspensions can be prepared by dispersing nanoparticles or fractions of nanoparticulate cyclooxygenase-2 inhibitors in a liquid phase; alternatively, cyclooxygenase-2 inhibitors, such as Celex, are available from e.g. It is precipitated from a solution using an alcohol as a solvent, preferably ethanol. The aqueous phase preferably contains a palatable carrier such as water, syrup or fruit juice such as apple juice.

The compositions of the invention are useful in the treatment and prevention of a very wide range of cyclooxygenase-2 mediated diseases. The presently described compositions are useful, but not limited thereto, in the treatment of inflammation in a subject, such as analgesics in the treatment of pain and headache, and antipyretics in the treatment of fever. For example, such compositions are useful in the treatment of arthritic diseases including, but not limited to, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, systemic lupus erythematosus, and juvenile arthritis. Such compositions are also useful in the treatment of asthma, bronchitis, dysmenorrhea, premature labor, tendonitis, bursitis, allergic neuritis, cytomegalovirus infection, apoptosis including HIV-induced apoptosis, low back pain, including Liver disease including hepatitis, skin-related diseases such as psoriasis, eczema, acne, UV damage, burns and dermatitis, and post-operative inflammation including inflammation after eye surgery such as cataract surgery or refractive surgery. The compositions of the present invention are useful in the treatment of gastrointestinal disorders such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis. The composition is useful for treating inflammation in diseases such as migraine, adventitia nodosa, thyroiditis, aplastic anemia, lymphogranulomatous disease, scleroderma, rheumatic fever, I Type 2 diabetes, neuromuscular junction disorders including myasthenia gravis, white matter disorders including multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's disease, polymyositis, gingival disease, nephritis, allergies, post-injury The swelling includes cerebral edema, myocardial ischemia and so on. The composition can be used for the treatment of ophthalmic diseases, such as retinitis, conjunctivitis, retinopathy, uveitis, ocular photophobia and acute injury of ocular tissue. The composition is useful in the treatment of pneumonia, such as pneumonia associated with viral infection and fibrosis of the bladder, and in the treatment of bone resorptive diseases, such as bone resorptive diseases associated with osteoporosis. The composition can be used to treat certain central nervous system diseases such as cortical dementia including Alzheimer's disease, neurodegenerative diseases and central nervous system damage caused by stroke, local ischemia and trauma. The term "treating" as used herein includes partial or total inhibition of dementia, including Alzheimer's disease, vascular dementia, multi-infarct dementia, Alzheimer's disease, alcoholic dementia and senile dementia.

The composition of the present invention is particularly useful as an anti-inflammatory agent, such as treating arthritis, and has the additional advantage that its toxic side effects are significantly lower than conventional non-steroidal anti-inflammatory drug (NSAIDs) compositions.

The composition can be used to treat allergic rhinitis, respiratory distress syndrome, endotoxic shock syndrome and liver disease. The compositions are useful in the treatment of pain, including but not limited to post-surgical pain, dental pain, muscle pain, and pain caused by cancer.

The compositions are useful, but not limited to, for treating and preventing inflammation-related myocardial diseases in a subject. The composition is useful for the treatment and prevention of vascular disease, coronary artery disease, aneurysm, vascular rejection, arteriosclerosis, atherosclerosis including heart transplant atherosclerosis, myocardial infarction, embolism, stroke, atherosclerosis including venous thrombosis Thrombosis, colic including unstable angina, coronary plaque inflammation, bacterial-induced inflammation including chlamydia-induced inflammation, viral-induced inflammation, and inflammation associated with surgical procedures including vascular grafts for coronary artery bypass surgery , revascularization procedures including angioplasty, placement of stents, endarterectomy, or other invasive procedures involving arteries, veins, and capillaries. The compositions are useful, but not limited to, for treating a subject with an angiogenesis-related disease. Compositions of the present invention may be administered to a subject in need of inhibition of angiogenesis. The composition is useful in the treatment of tumor formation, including tumor metastasis; ophthalmic diseases such as corneal transplant rejection, ocular neovascularization, retinal neovascularization including neovascularization after injury or infection, diabetic retinopathy, macular changes, retro-lens fibers Tissue formation and neovascular glaucoma; ulcerative diseases such as gastric ulcers; morbid but non-malignant diseases such as hemangiomas including infantile hemangiomas, nasopharyngeal angiofibromas, and avascular necrosis of bone; and female reproductive system disorders such as endometrium Ectopic.

The composition can be used to prevent or treat benign or malignant tumors/neoplasias, including cancers, such as colon cancer, brain cancer, bone cancer, such as basal cell carcinoma, adenocarcinoma, etc. , such as lip cancer, oral cancer, esophageal cancer, small intestine cancer and gastric cancer, colon cancer and other gastrointestinal system cancers, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer and skin cancer, such as squamous cell and Low-cell carcinoma, prostate cancer, renal cell carcinoma, and other cancers known to affect epithelial cells throughout the body. The tumors for which the compositions of the present invention are particularly effective are gastrointestinal cancer, Barret's esophagus cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer, cervical cancer, lung cancer, breast cancer and skin cancers such as squamous and basal cell carcinomas. The compositions of the present invention are also useful in the treatment of fibrosis induced by radiation therapy. The compositions are useful for treating subjects with adenomatous polyposis, including familial adenomatous polyposis (FAP). Additionally, the composition is useful for preventing polyp formation in patients at risk of FAP.

The compositions of the present invention have anti-inflammatory, antipyretic and analgesic properties similar to or superior to conventional NSAID compositions. The composition also inhibits hormone-induced uterine contractions and has potential anticancer effects, but has a reduced ability to cause some of the mechanistic side effects of common NSAIDs. In particular, compared with conventional NSAIDs compositions, the composition of the present invention has the ability to potentially reduce gastrointestinal toxicity and gastrointestinal irritation including upper gastrointestinal ulceration and bleeding, and potentially reduce renal side effects such as causing fluid retention and high blood pressure. The ability of renal insufficiency to exacerbate blood pressure, potentially reducing the effect on bleeding time includes inhibition of platelet function, and may reduce the ability to induce asthma exacerbations in patients with aspirin-sensitive asthma.

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

The composition inhibits prostaglandin-induced smooth muscle contraction by preventing the synthesis of contractile prostanoids and thus can be used in the treatment of dysmenorrhea, premature labor, asthma and eosinophil-related diseases. They can also be used in the treatment of Alzheimer's disease, in the reduction of bone loss especially in postmenopausal women (ie in the treatment of osteoporosis) and in the treatment of glaucoma.

Due to their high cyclooxygenase-2 (COX-2) inhibitor activity and/or their specificity for inhibiting cyclooxygenase-2 over inhibition of cyclooxygenase-1 (COX-1), therefore, The composition of the present invention can be used as a substitute for conventional NSAIDs, especially when said NSAIDs are prohibited, such as patients suffering from peptic ulcer, gastritis, Crohn's disease, ulcerative conjunctivitis, diverticulitis or patients with gastrointestinal damage Patients with a history of; gastrointestinal bleeding, blood clotting disorders including anemia, such as hypoprothrombin, hemophilia, or other bleeding problems; kidney disease; or patients before surgery or patients taking anticoagulants. A simple Describe the potential utility of cyclooxygenase-2 inhibitors.

The preferred utility of the pharmaceutical composition of the present invention is to be used for the treatment of rheumatoid arthritis and osteoarthritis, for pain (particularly oral postoperative pain, general surgical postoperative pain, orthopedic postoperative pain and acute onset osteoarthritis) inflammation), the treatment of Alzheimer's disease and the chemoprevention of colon cancer.

Due to the advantages of the rapid onset of action exhibited by the pharmaceutical compositions of the present invention, these compositions have advantages over cyclooxygenase-2 previously used for the treatment of acute cyclooxygenase-2 mediated diseases, particularly for pain relief. A particular advantage of the formulation of inhibitory compounds.

The compositions of the present invention may be used in combination therapy with opioids and other analgesics including narcotic analgesics, Mu receptor antagonists, Kappa receptor antagonists, non-narcotic (i.e. addictive) sex) analgesics, monoamine uptake inhibitors, adenosine modulators, cannabis chemical constituent derivatives, substance P antagonists, neurokinin-1 receptor antagonists and sodium channel blockers, etc. A preferred combination therapy involves the use of the composition of the present invention and a compound selected from the group consisting of: morphine, meperidine, codeine, pentazocine, buprenorphine, butorphanol, dezocine, meprotamol, hydrogen Codone, Oxycodone, Methadone, DuP-747, Dynorphine A, Enadoline, RP-60180, HN-11608, E-2078, ICI-204448, Acetaminophen (Acetaminophen), Dextropropoxyphene, Nalbuphine, E-4018, Phrenadol, Mifentanil, Amitriptyline, DuP-631, GP-531, Acardisine, AKI-1, AKI-2, GP -1683, GP-3269, 4030W92, tramadol racemate and isolated (+) and (-) enantiomers, AXC-3742, SNX-111, ADL2-1294, CT-3 and CP- 99994.

Dosage units containing a particular amount of a cyclooxygenase-2 inhibitor, such as Cycloxan, may be selected to provide any desired dosing frequency that has been employed to achieve the desired daily dosage. The daily dosage and frequency of administration, and thus the selection of an appropriate dosage unit, will depend on many factors, including the age, weight, sex, and medical condition of the subject to be treated, and the nature and severity of the condition or disease, and thus can vary widely .

In the case of salikin, once-daily or twice-daily oral administration methods providing the desired daily dosage of salikin showed improved efficacy over other methods of administration for the compositions of the present invention. Therefore, in order to effectively inhibit cyclooxygenase-2-mediated diseases therapeutically or prophylactically, it is preferable to orally administer the composition of the present invention once a day or twice a day.

For the treatment of rheumatoid arthritis, the composition of the present invention can be used to provide a daily dose of Cylicoxime of about 50 mg to about 1000 mg, preferably about 100 mg to about 600 mg, more preferably about 150 mg to about 500 mg, and still more preferably about 175 mg to about 400 mg, such as about 200 mg. Doses can be once daily, twice daily, three times daily, or more. For example, the dosage may be 200 mg twice daily. When administering the composition of the present invention, a suitable daily dose of celecox is generally about 0.67 to about 13.3 mg/kg body weight, preferably about 1.33 to about 8.00 mg/kg body weight, more preferably about 2.00-6.67 mg/kg body weight , and further preferably about 2.33-5.33 mg/kg body weight, such as about 2.67 mg/kg body weight. The daily dose can be divided into 1-4 doses per day, preferably 1 or 2 doses per day. For most patients, dosing at the rate of one 100 mg dosage unit twice daily is preferred, but for some patients, one 200 mg dosage unit or two 100 mg dosage units twice daily Medicine is beneficial.

For the treatment of osteoarthritis, the composition of the present invention may be used to provide a daily dose of celecoxane of about 50 mg to about 1000 mg, preferably about 100 mg to about 600 mg, more preferably about 150 mg to about 500 mg, and further preferably about 175 mg to about 400 mg , such as about 200 mg. When administering the composition of the present invention, a suitable daily dose of celecox is generally about 0.67 to about 13.3 mg/kg body weight, preferably about 1.33 to about 8.00 mg/kg body weight, more preferably about 2.00-6.67 mg/kg body weight , and further preferably about 2.33-5.33 mg/kg body weight, such as about 2.67 mg/kg body weight. The daily dose can be 1-4 doses per day, preferably 1 or 2 doses per day. The compositions of the present invention are preferably administered at the rate of one 100 mg dosage unit per day, twice daily, or one 200 mg dosage unit or two 100 mg dosage units, once daily.

For Alzheimer's disease, the composition of the present invention can be used to provide a daily dose of Cylicoxime of about 50 mg to about 1000 mg, preferably about 100 mg to about 800 mg, more preferably about 150 mg to about 600 mg, and further preferably about 175 mg to about 400 mg, such as about 400 mg. When administering the composition of the present invention, a suitable daily dose of celecox is generally about 0.67 to about 13.3 mg/kg body weight, preferably about 1.33 to about 10.67 mg/kg body weight, more preferably about 2.00-8.00 mg/kg body weight , and further preferably about 2.33 to about 5.33 mg/kg body weight, such as about 5.33 mg/kg body weight. The daily dose can be 1-4 doses per day, preferably 1 or 2 doses per day. For most patients, it is preferred to administer the compositions of the present invention at the rate of one 200 mg dosage unit or two 100 mg dosage units each, twice daily.

For the treatment of cancer, the composition of the present invention may be used to provide a daily dose of Cylicor from about 50 mg to about 1000 mg, preferably from about 100 mg to about 800 mg, more preferably from about 150 mg to about 600 mg, and further preferably from about 175 mg to about 400 mg, e.g. About 400mg. When administering the composition of the present invention, a suitable daily dose of celecox is generally about 0.67 to about 13.3 mg/kg body weight, preferably about 1.33 to about 10.67 mg/kg body weight, more preferably about 2.00-8.00 mg/kg body weight , and further preferably about 2.33-5.33 mg/kg body weight, eg about 5.33 mg/kg body weight. The daily dose can be 1-4 doses per day, preferably 2 doses per day. For most patients, it is preferred to administer the compositions of the present invention at the rate of one 200 mg dosage unit or two 100 mg dosage units each, twice daily.

For the treatment of pain, the composition of the present invention may be used to provide a daily dose of celecoxan of about 50 mg to about 1000 mg, preferably about 100 mg to about 600 mg, more preferably about 150 mg to about 500 mg, and further preferably about 175 mg to about 400 mg, e.g. About 200mg. When administering the composition of the present invention, a suitable daily dosage of celecox is generally about 0.67 to about 13.3 mg/kg body weight, preferably about 1.33 to about 8.00 mg/kg body weight, more preferably about 2.00 to about 6.67 mg/kg body weight, and further preferably about 2.33 to about 5.33 mg/kg body weight, eg about 2.67 mg/kg body weight. The daily dose can be in the form of 1-4 doses per day. Preferably one 50 mg dosage unit each time, four times a day, or one 100 mg dosage unit each time, or two 50 mg dosage units each, twice a day, or one 200 mg dosage unit or two 100 mg dosage units or four times a day The composition of the present invention is administered at a rate of one 50 mg dosage unit once a day.

In general, the compositions of the present invention are preferably administered at a dosage and frequency such that the dosage provides a mean serum concentration of celecoxib in the subject of at least about 100 ng/ml for a period of about 24 hours after administration.

Whilst the amount of saliva in the composition of the invention is preferably within the ranges disclosed herein, the composition may also be used for administration of saliva in doses outside the disclosed dosage range. For other selective cyclooxygenase-2 inhibitors, appropriate dosages can be selected by reference to the patent literature cited above.

Nanoparticles containing or consisting of selective cyclooxygenase-2 inhibitory compounds of low water solubility, e.g., Selycoxi, Delacoxi, Wardcoxi or Rovercoxi, can be prepared according to any of the previous methods applied to other nanoparticulate forms. Process for the preparation of formulations of poorly water soluble drugs.对于这样的其它药物的适合方法，举例性地公开在以上引证的美国专利4,826,689、5,145,684、5,298,262、5,302,401、5,336,507、5,340,564、5,346,702、5,352,459、5,354,560、5,384,124、5,429,824、5,510,118、5,518,738、5,503,723、5,534,270、5,536,508 、5,552,160、5,560,931、5,560,932、5,565,188、5,569,448、5,571,536、5,573,783、5,580,579、5,585,108、5,587,143、5,591,456、5,662,883、5,665,331、5,718,919和5,747,001，以及以上引用的国际公布WO93/25190、WO96/24336和WO98/35666，但Without limitation, all of the above published texts are hereby incorporated by reference. One of ordinary skill in the art can readily adapt the methods described therein for the preparation of poorly water-soluble nanoparticles of selective cyclooxygenase-2 inhibitors, such as Celikexi, Delacoxi, Wardkexi, or Luoxixi. Fu Kexi.

Any excipient used in the compositions of the invention may be solid or liquid or both. The composition preferably contains, by weight of the selective cyclooxygenase-2 inhibitor, from about 1% to about 95%, preferably from about 10% to about 90%, more preferably from about 25% to about 85%, and still more preferably about 30% to about 80%, such as Sally gratifying. Compositions of the invention containing excipients may generally be prepared by any of the well-known techniques of pharmacy, which include admixing the excipient with the drug or therapeutic agent, except in the presence of the drug or therapeutic agent, i.e. at least in part. The cyclooxygenase-2 inhibitor, optionally together with one or more excipients, is in nanoparticulate form as indicated above.

The compositions of the present invention contain the desired amount of cyclooxygenase-2 inhibitor, such as Cylic, per dosage unit, and can be in the form of, for example, tablets, pills, hard or soft capsules, lozenges, sachets, dispersible powders, Granules, suspensions, elixirs, liquids, or any other suitable dosage form for oral administration may be used. Such compositions are preferably prepared as discrete dosage units, such as tablets or capsules, each containing a predetermined amount of a cyclooxygenase-2 inhibitor. These oral dosage forms may further include, for example, buffering agents. Tablets, pills, and other dosage forms can be coated or uncoated.

For example, compositions of the present invention suitable for buccal or sublingual administration include lozenges containing celica in a flavored base such as sucrose and acacia or tragacanth, and in an inert base such as gelatin and glycerin or sucrose. and pastilles with celery in gum arabic.

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

As noted above, compositions of the invention containing excipients may be prepared by any suitable method of pharmacy, which comprises combining a cyclooxygenase-2 inhibitor, at least in part in nanoparticulate form, with an excipient. The step of combining agents. In general, the compositions are prepared by uniformly and intimately mixing a cyclooxygenase-2 inhibitory compound (hereinafter sometimes referred to as "nanoparticulate compound") with a liquid or pulverized diluent or both, and then, if desired or Desirably, capsules are encapsulated or the product is shaped. For example, a tablet may be prepared by compressing or molding a powder or granules of the nanoparticulate compound together with one or more excipients. Compressed tablets may be prepared by combining, in a suitable machine, a free-flowing combination containing the nanoparticulate compound, optionally mixed with one or more binder, lubricant, inert diluent, wetting and/or dispersing agents. Substances such as powder or granular tableting. Molded tablets may be made by molding, in a suitable machine, the nanoparticulate compound moistened with an inert liquid diluent.

As mentioned above, each dosage unit of the composition of the present invention comprises a therapeutically or prophylactically effective amount of a partially or totally nanoparticulate selective cyclooxygenase-2 inhibitory compound, such as celecox, and one or more suitable for Pharmaceutically acceptable excipients for oral administration. The compositions of the present invention preferably comprise admixing the desired amount of the nanoparticulate compound with one or more excipients selected from pharmaceutically acceptable diluents, disintegrants, binders, Adhesives, wetting agents, lubricants and anti-adhesives. Furthermore, the nanoparticles themselves may optionally contain one or more matrix polymers and/or surface modifiers as disclosed in several of the documents cited above. More preferably, such compositions are tableted or encapsulated in immediate release capsule or tablet form for conventional administration.

Through proper selection and combination of excipients, among other properties, efficacy, bioavailability, elimination time, stability, compatibility of Cylic and carrier substances, safety, dissolved form, disintegrated form and/or Or other compositions showing improved performance in pharmacokinetic, chemical and/or physical properties. Preferred excipients are water soluble or dispersible and have wettability properties, thereby offsetting the low water solubility and hydrophobicity of cyclooxygenase-2 inhibitors. When the composition is prepared as a tablet, the selected combination of excipients provides a tablet with improved dissolution and disintegration form, hardness, crushing strength and/or friability, among other properties.

Compositions of the invention may optionally include one or more pharmaceutically acceptable diluents as excipients. Suitable diluents include lactose USP, alone or in combination; anhydrous lactose USP; spray-dried lactose USP; starch USP; direct compressible starch; Cellulose NF; dibasic calcium phosphate dihydrate NF; sucrose-based diluent; commercially available sugar; monobasic calcium sulfate monohydrate; calcium sulfate dihydrate NF; calcium lactate trihydrate granules NF; dextratesNF ( For example, Emedx); Celutab; Glucose (eg industrial dextrose); Inositol; Hydrolyzed cereal solids such as Maitrons and Mor-Rex; Amylose; Rexcel; Powdered cellulose (eg Elcema); Calcium carbonate; Glycine; Bentonite clay; polyvinylpyrrolidone, etc. If present, such diluents comprise from about 5% to about 99%, preferably from about 10% to about 85%, more preferably from about 20% to 80%, by weight of the total composition. Preferably, the diluent is chosen to have suitable flow properties and, when tablets are required, also compressibility.

Lactose and microcrystalline cellulose alone or in combination are effective diluents. Both diluents are chemically compatible with Celex. The use of extragranular microcrystalline cellulose (ie microcrystalline cellulose added to the wet granulation composition after the drying step) can be used to improve hardness (for tablets) and/or disintegration time. Lactose, especially lactose monohydrate, is particularly preferred. Typically, lactose provides a composition with a suitable cyclooxygenase-2 inhibitor release rate, stability, flowability and/or dryness prior to tableting at relatively low diluent cost. It provides a high density material which facilitates the granulation (if wet granulation is used) process by increasing the density of the composition and thus improving the flowability of the mixture.

Compositions of the invention may optionally contain one or more pharmaceutically acceptable disintegrants as excipients, especially for tablets. Suitable disintegrants include, alone or in combination, starches, sodium starch glycolate, clays (such as Veegum HV), celluloses (such as pure cellulose, methylcellulose, sodium carboxymethylcellulose, and carboxymethylcellulose alginate), pregelatinized corn starch (such as National 1551 and National 1550), cross-linked povidone USP NF, and gums (such as agar, guar gum, locust bean gum, karaya gum, Pectin and Tragacanth). The disintegrant can be added at any suitable step in the preparation of the composition, especially in the lubricating step before granulation or tablet compression. If present, such disintegrants comprise from about 0.20% to about 30%, preferably from about 0.20% to about 10%, and more preferably from about 0.2% to about 5%, by weight of the total composition.

Croscarmellose sodium is the preferred disintegrant for tablet or capsule disintegration and, if present, preferably comprises from about 0.2% to about 10% by weight of the total composition, more preferably from about 0.2% to About 6%, and more preferably about 0.2% to about 5%. The croscarmellose sodium makes the composition of the present invention have greater intragranular disintegration ability.

The compositions of the present invention may optionally contain one or more pharmaceutically acceptable binders or adhesives as excipients, especially for tablets. Such binders and adhesives preferably provide sufficient viscosity to the tableted powder to allow normal processing operations such as sizing, lubrication, tabletting and packaging, and when ingested, enable the tablet to collapse. solution and allow the composition to be absorbed. Suitable binders and sticking agents include acacia, tragacanth, sucrose, gelatin, dextrose, starch, cellulosic materials such as, but not limited to, methylcellulose and carboxymethylcellulose, alone or in combination. Sodium bismuth (eg, Tylose), alginic acid and its salts, magnesium aluminum silicate, polyethylene glycol, guar gum, polysaccharide acid, bentonite, polyvinylpyrrolidone, polymethacrylate, hydroxypropylmethyl Cellulose (HPMC), Hydroxypropyl Cellulose (Klucel), Ethyl Cellulose (Ethocel), Pregelatinized Starch (eg National 1551 and Starch 1550). If present, the binder and/or adhesive comprises from about 0.5% to about 25%, preferably from about 0.75% to about 15%, and more preferably from about 1% to about 10%, by weight of the total composition.

Polyvinylpyrrolidone is the preferred binder used to provide viscosity to the powder mixture of cyclooxygenase-2 inhibitor and other excipients in granulation. If present, polyvinylpyrrolidone preferably comprises from about 0.5% to about 10%, more preferably from about 0.5% to about 7%, and still more preferably from about 0.5% to 5%, by weight of the total composition. Although it is preferred that the polyvinylpyrrolidone has a viscosity of about 6 cPs or less, especially about 3 cPs or less, polyvinylpyrrolidone with a viscosity of up to about 20 cPs may also be used. Polyvinylpyrrolidone provides cohesiveness to the powder mixture and facilitates the necessary binding in wet granulation to form granules.

The cyclooxygenase-2 inhibitory compounds employed in the present invention, in particular selix, are very insoluble in aqueous solutions. Accordingly, the compositions of the present invention may optionally but preferably comprise one or more pharmaceutically acceptable wetting agents as excipients. Preferably, the wetting agent is chosen so as to keep the cyclooxygenase-2 inhibitor tightly bound to water, which is believed to be a condition for improving the relative bioavailability of the pharmaceutical compositions of the invention. Suitable wetting agents include oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan, alone or in combination. Sugar alcohol monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate and sodium lauryl sulfate. Anionic surfactants are preferred for wetting. If present, the humectant comprises from about 0.25% to about 15%, preferably from about 0.4% to about 10%, more preferably from about 0.5% to about 5%, by weight of the total composition.

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

The compositions of the present invention may optionally contain one or more pharmaceutically acceptable lubricants and/or glidants as excipients. Suitable lubricants and/or glidants include glyceryl behapate (Compritol 888), alone or in combination; stearates (magnesium, calcium and sodium stearate), stearic acid, hydrogenated vegetable oils (such as fully hydrogenated vegetable oils ), talc, wax, Stearowet, boric acid, sodium benzoate, sodium acetate, sodium fumarate, sodium chloride, DL-leucine, polyethylene glycol (such as waxy polyethylene glycol and methoxypolyethylene glycol Glycol Mixture 4000 and 6000), Sodium Oleate, Sodium Lauryl Sulfate and Magnesium Lauryl Sulfate. If present, such lubricants comprise from about 0.1% to about 10%, preferably from about 0.2% to about 8%, and more preferably from about 0.25% to about 5%, by weight of the total composition.

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

Other excipients such as anti-adherents, coloring agents, flavoring agents, sweetening agents and preservatives are known in the pharmaceutical art and may be included in the compositions of the present invention. For example iron oxide may be added to the composition to impart a yellow color.

In one embodiment of the invention, the composition is a capsule or tablet as a unit dose and contains a desired amount, partially or entirely, of a nanoparticulate selective cyclooxygenase-2 inhibitor (eg, Cyclooxygenase-2 inhibitor). gratifying) and binders. Preferably, the composition further comprises one or more excipients selected from pharmaceutically acceptable diluents, disintegrants, binders, wetting agents and lubricants. More preferably, the composition comprises one or more excipients selected from the group consisting of lactose, sodium lauryl sulfate, polyvinylpyrrolidone, croscarmellose sodium, magnesium stearate and microcrystalline cellulose . It is further preferred that the composition comprises lactose monohydrate and croscarmellose sodium. Still more preferably, the composition further comprises one or more carrier substances sodium lauryl sulfate, magnesium stearate and microcrystalline cellulose.

Although dosage unit capsule and tablet compositions of the present invention can be prepared, for example, by direct encapsulation or direct compression, they are preferably wet granulated prior to encapsulation and prior to tabletting. Among other effects, wet granulation can increase the density of the finely divided composition, thereby improving flowability, improving tabletability and making it easier to meter or improve the weight distribution of the composition for encapsulation or tableting. The secondary particle size (i.e. particle size) obtained by granulation is not only critical, it is only important in terms of optimizing the average particle size for ease of handling and processing and, in the case of tablets, to allow the formation of a pharmaceutically acceptable tablet. Directly compressible blend.

The desired bulk and bulk densities of the particles are generally from about 0.3 g/ml to about 1.0 g/ml.

The excipients used in the capsule and tablet compositions of the present invention are preferably selected to provide a disintegration time of less than about 30 minutes, preferably about 25 minutes or less, more preferably about 20 minutes or less, more preferably 15 minutes or less few.

For tablet formulations, an amount of the total blend sufficient to make a uniform batch of tablets is compressed in a conventional manufacturing-scale tablet press using normal pressures (e.g., about 1 kN to about 1 kN in a typical compression die). 50kN pressure). Any tablet hardness suitable for handling, manufacturing, storage, ingestion may be used. For a 100 mg tablet, the hardness is preferably at least 4 kP, more preferably at least about 5 kP, even more preferably at least about 6 kP. For a 200 mg tablet, the hardness is preferably at least 7 kP, more preferably at least about 9 kP, even more preferably at least about 11 kP. However, the mixture is not compressed to such an extent that hydration difficulties ensue when exposed to gastric fluids.

For tablet formulations, tablet friability is preferably less than about 1.0%, more preferably less than 0.8%, even more preferably less than about 0.5% in standard tests.

The invention also relates to a method of treating a condition or disease using a cyclooxygenase-2 inhibitor, the method comprising orally administering to a subject in need thereof one or more dosage units of a composition of the invention. Dosage regimens for prophylaxis, amelioration, or amelioration of a condition or disease are preferably equivalent to once-daily or twice-daily treatment as described above, but may vary according to various factors. These factors include type, age, weight, sex, diet, and the nature and severity of the condition and disease of the subject. Accordingly, the dosage regimen actually employed may vary widely and may deviate from the preferred dosage regimen set forth above.

Initial treatment of a subject with a condition or disease with a cyclooxygenase-2 inhibitor can begin at the doses described above. Treatment is usually necessary for weeks to months or years until the condition or disease is controlled or eliminated. Routine monitoring of patients undergoing treatment with the compositions of the present invention can be performed by any means well known in the art to determine the efficacy of the treatment. Continuous analysis of these data enables the improvement of the treatment regimen during the course of treatment, so that at any point in time the optimal effective dose of the cyclooxygenase-2 inhibitor can be administered, and thus also the duration of treatment can be determined. In this way, the treatment regimen/dosing schedule can be rationally varied during the course of treatment so that the lowest amount of cyclooxygenase-2 inhibitor that shows satisfactory efficacy can be administered and administered only for as long as necessary to successfully treat the disease.

The present invention also relates to a process for the preparation of the compositions of the present invention comprising a poorly water-soluble cyclooxygenase-2 inhibitor, such as celecoxil, partly or fully in the form of nanoparticles. More particularly, the present invention relates to methods of preparing such compositions in the form of discrete unit dosage tablets or capsules, whereby each tablet or capsule contains a sufficient amount of a cyclooxygenase-2 inhibitor to provide the above-mentioned Rapid onset of therapeutic effect, and preferably a sustained therapeutic effect of about 12 to 24 hours. Each tablet or capsule preferably contains from about 50 mg to about 200 mg, such as about 50 mg, about 100 mg or about 200 mg of a cyclooxygenase-2 inhibitor, such as Celex. The present invention may use wet granulation, dry granulation or direct compression or encapsulation to prepare tablets or capsules of the composition of the present invention.

Wet granulation is a preferred method of preparing the pharmaceutical compositions of the present invention. During wet granulation, any part of the cyclooxygenase-2 inhibitor that is not included in the nanoparticulate form (with one or more carrier substances, if desired) is first ground or micronized to the desired The particle size range is greater than 1mm. Although various conventional mills or granulators can be used, impact milling of pharmaceuticals, such as pin milling, provides improved uniformity of blending into the final composition compared to milling by other means . During milling, cooling of the milled material, such as with liquid nitrogen, may be necessary to avoid heating the cyclooxygenase-2 inhibitor to undesired temperatures. During this milling step, the _D90 particle size is preferably reduced to less than about 25mm.

Milled or micronized cyclooxygenase-2 inhibitor (little if any), is then mixed with the required amount of cyclooxygenase-2 inhibitor in nanoparticulate form prepared by any of the methods known in the art above. agent to provide some or all of the nanoparticulate cyclooxygenase-2 inhibitor compound ("nanoparticulate compound").

Simultaneously or subsequently, the nanoparticulate compound is mixed, such as in a high shear mixer/granulator, planetary mixer, double wall mixer or zigzag mixer, with one or more excipients including The excipients which have been co-milled with Celica, or excipients in nanoparticulate form together form a dry powder mixture. Typically, in this step, the nanoparticulate compound is mixed with one or more diluents, disintegrants and/or binders, and optionally, one or more wetting agents, but another may The method used is that all or part of one or more excipients can be added in a subsequent step. For example, in tablet formulations using croscarmellose sodium as a disintegrant, it has been found that the addition of partially croscarmellose during the mixing step (providing intragranular croscarmellose sodium) Sulfate sodium, and adding the remainder after the drying step discussed below (providing extragranular sodium carboxymethylcellulose), can facilitate the disintegration of the prepared tablet. In this case, it is preferred to add from about 60% to about 70% croscarmellose sodium intragranularly and from about 25% to about 40% croscarmellose sodium extragranularly. Similarly, for tablet formulations, it has been found that the addition of microcrystalline cellulose (extragranular microcrystalline cellulose) after the following drying step improves the compressibility of the granules and the hardness of tablets prepared from the granules.

The mixing step of the method preferably comprises mixing the nanoparticulate compound, lactose, polyvinylpyrrolidone and croscarmellose sodium. Mixing times as short as 3 minutes have been found to provide dry powder mixtures with sufficiently uniform distribution of cyclooxygenase-2 inhibitors.

Water, preferably purified water, is then added to the dry powder mixture and the mixture is further mixed for a period of time to form a wet granule mixture. A wetting agent is preferably used and is preferably added to the water and mixed for at least 15 minutes, preferably at least 20 minutes, before water is added to the dry powder mixture. Water can be added to the mixture at once, gradually over a period of time, or in portions over a period of time. Water is preferably added gradually over a period of time. Alternatively, a wetting agent can be added to the dry powder mixture and water can then be added to the resulting mixture. It is preferable to mix for an additional period of time after adding the water to ensure the uniformity of water distribution in the mixture.

The wet granulation mixture is then preferably subjected to wet milling, such as with a screen mill, to eliminate agglomerated material that forms a by-product during wet granulation operations. If not removed, these agglomerates will prolong subsequent fluid bed drying operations and increase humidity control variability.

The wet granulation or wet mill mixture is then dried, for example, in an oven or fluid bed drier, preferably a fluid bed drier, to form dry granules. If desired, the wet granule mixture can be extruded or spheronized prior to drying. For the drying process, operating conditions such as inlet temperature and drying time can be adjusted to achieve the desired moisture content of the dried granules. For this drying step and subsequent process steps, it would be ideal to combine 2 or more granulation steps.

The dried granules are then reduced in size to the desired extent in preparation for compression and encapsulation. Conventional particle size reduction equipment such as shakers or impact mills (eg Fitz mills) can be used.

A slight decrease in particle size was observed with increasing mixing time for the low water content mixture. Assuming that the moisture content is too low to sufficiently activate the binder used, the cohesion between the primary particles within the granule is not sufficient for the granule to withstand the shear forces generated by the mixer blades, and the granule size wears rather than increases. Generally, the water content is increased to sufficiently activate the binder so that the cohesion between the primary particles can withstand the shear force generated by the mixer blade, and the growth of the particles does not occur with the increase of mixing time and/or the amount of water added wear and tear. Changing wet mill screen size can have a greater impact on particle size than changing feed rate and/or grind rate.

The dry powder granules are then placed in a suitable mixer, such as a double-wall mixer, optionally with lubricants (such as magnesium stearate) and any additional carrier substances (such as granules in a tablet formulation). Extra microcrystalline cellulose and/or extragranular croscarmellose sodium) to form the final blended mixture. Where the diluent comprises microcrystalline cellulose, it has been found that adding an additional portion of microcrystalline cellulose at this step increases the compressibility of the granules and tablet hardness. However, increasing the amount of magnesium stearate beyond about 1%-2% reduces tablet hardness and increases friability and dissolution time.

The final blended mixture is then packaged (or if tablets are to be prepared, the mixture is compressed into tablets of the desired weight and hardness using suitably sized tooling). Conventional pressing and packaging techniques known to those of ordinary skill in the art may be employed. For capsules, suitable results can be obtained by using a bed height of about 20 mm to about 60 mm, a compression device of about 0 to about 5 mm, and a rate of about 60,000 capsules to about 130,000 capsules per hour. The formation of lumps can be reduced or eliminated by using a minimal compression device capable of controlling the weight of the capsule. When coated tablets are desired, conventional coating techniques known to those of ordinary skill in the art can be employed.

Combination of operating units yields cyclooxygenase 2 inhibitors such as Cycloxanthine homogeneous granules at unit dosage levels that disintegrate rapidly followed by adequate release, allowing reliable capsule filling or tablet compression. Controlled weight variation and sufficient density to be mass-produced in selected equipment and suitable for specific capsule or tablet molded single doses.

The present invention also relates to the use of the composition of the present invention in the preparation of a medicament for the treatment and/or prevention of conditions and diseases mediated by cyclooxygenase-2, especially where a rapid onset of therapeutic effect is required or desired .

The present invention also includes a new solid state version of Sallyco, Type I Sallyco. The present invention further includes another solid-state version of Salyco, Type II Salyco. Each of these new solid state forms includes solvated crystalline forms, unsolvated and nonhydrated crystalline forms. These novel celicas described in this application have one or more of the above-mentioned superior chemical and/or physical properties compared to other solid-state forms described in this document or otherwise disclosed.

In one embodiment of the invention, the solid state form comprises type I saliva. Without limiting the present invention, it is believed that type I sarikexi has higher solubility and faster dissolution rate than type III salikexi, because type III has better thermodynamic stability than type I, and because type III is more stable than type I have lower free energy. A fast dissolution rate is a useful property because increasing the dissolution rate of a drug generally increases its bioavailability.

Type I sarikexi is the crystalline form of sarikexi, and its X-ray powder diffraction pattern has peaks at about 5.5, 5.7, 7.2 and 16.6 degrees 2θ. The X-ray powder diffraction pattern of type I celecox is substantially as shown in the top pattern of Figure 1a. Celli Type I has a desirable melting point of about 162.5°C to about 163°C, preferably about 162.8°C. As shown in Fig. 3, when scanned at 0.5°C/min, the type I Celica had a differential scanning calorimetry endotherm maximum at about 163.3°C. The infrared spectrum of type I saliva is shown in Figure 2, which is characterized by peaks at about 3250cm ^-1 and 3260cm-1 and another peak between 3350cm ^-1 and 3360cm ^{- 1} , preferably at 3256cm-1 and 3256cm ^-1 respectively. 3356cm ^-1 . The solid state form of the present invention has a phase purity of at least about 5% celecium type I, preferably at least about 10% celecium type I, more preferably at least about 25% celecium type I, still more preferably at least about 50% celecium type I The sariko, still more preferably at least about 75% sariko Type I, still more preferably at least about 90% sariko Type I, and most preferably has a substantially Type I sariko phase purity.

In another embodiment of the present invention, a pharmaceutical composition is provided, which includes a therapeutically effective amount of solid-state celecoxil and at least one pharmaceutically acceptable carrier, adjuvant or diluent, wherein the solid-state The saliva contains at least 2% saliva type I, and preferably 10% saliva type I, or more preferably 50% saliva type I, still more preferably 98% saliva type I. In a preferred embodiment, the solid form of saliva is predominantly saliva type I.

In another embodiment of the invention, a method of treating or preventing a cyclooxygenase-2 mediated condition or disease in a subject is described, the method comprising administering to the subject a therapeutically effective amount of Type I Sally is happy. Preferably, the condition or disease mediated by cyclooxygenase-2 to be treated or prevented is pain, infection, arthritis, tumor growth, metastasis, or familial adenomatous polyposis.

Another embodiment of the present invention is a process for the preparation of salicyridine type I, wherein the method comprises crystallizing salicyril type 1 from a mixture comprising salicyril and a solvent, wherein the Crystallization takes place at a temperature of the enantiotropic transition temperature. Prior to crystallization of Cellica Type I, seed crystals of Cellicosanth Form I may be seeded in a solvent, resulting in Cellicosanth Form I having a phase purity of at least about 5% by weight, preferably at least about 10% by weight. Purity, more preferably at least about 25% by weight phase purity, still more preferably at least about 50% by weight phase purity, still more preferably at least about 90% by weight phase purity.

The present invention also relates to the preparation of a crystalline form of sarike, wherein the process comprises heating a solvate of sailyke solvate, thereby producing sarikexi Form I. For example, the solvate may be heated to a temperature of from about 50°C to about 160°C, preferably from about 60°C to about 150°C, more preferably from about 70°C to about 140°C, still more preferably from about 80°C to about 130°C, still more preferably about 85°C to about 120°C, more preferably about 90°C to about 110°C, most preferably about 100°C. The heating can be performed for any conventional period of time, such as heating for more than about 1 minute, preferably more than about 5 minutes, more preferably more than about 60 minutes, still more preferably about 2 hours, still more preferably about 4 hours or longer. Additionally, the process can be carried out at any pressure, preferably subatmospheric. The solvates used in the present invention contain celica and a solvent. For example the solvent may be an amide solvent. Useful amide solvents include N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone, 1,3-dimethyl-3,4,5,6- Tetrahydro-2(1H)-pyrimidinone and 1,1,3,3-tetramethylurea, or any mixture of these solvents. A preferred solvent is 1,1,3,3-tetramethylurea. Another preferred solvent is 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. Yet another preferred solvent is 1-methyl-2-pyrrolidone. Yet another preferred solvent is N,N-dimethylformamide. Yet another preferred solvent is N,N-dimethylacetamide.

The method for preparing the solvate comprises mixing Selicor with an amide solvent selected from the group consisting of: N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone, 1, 3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and 1,1,3,3-tetramethylurea, or any mixture of these solvents. A preferred solvent is 1,1,3,3-tetramethylurea. Another preferred solvent is 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. Yet another preferred solvent is 1-methyl-2-pyrrolidone. Yet another preferred solvent is N,N-dimethylformamide. Yet another preferred solvent is N,N-dimethylacetamide.

The present invention also relates to a method of preparing saliva type I, wherein the method comprises comminuting or milling saliva type III. Useful grinding steps include, for example, wet or ball milling. Useful milling steps may include, for example, grinding or shaking.

The present invention also relates to a process for the preparation of sariquel solvate Form I, wherein the process comprises comminuting or milling salicylic solvate. Useful milling steps may include, for example, wet milling or ball milling. Useful milling steps may include, for example, grinding or shaking.

Another embodiment of the present invention is a process for the preparation of sarikeratin type I, wherein the method comprises melting sarikeratin-type II and cooling the melt, thereby producing sarikeratin-type I.

Another embodiment of the present invention is a process for the preparation of Celliosilicate Type I, wherein the method comprises melting Cellicosanth III and cooling the melt, thereby producing Cellicosanth Type I.

The present invention also relates to a process for the preparation of salicylic acid Form I, wherein the process comprises evaporating the solvent from a salicylic acid solution. For example the solvent may be an ether or a hydrocarbon, or a mixture of ether and hydrocarbon. Preferred solvents include ethyl acetate and heptane, preferably in a 15:85 ratio. The process can be carried out at any pressure, preferably subatmospheric. The process can be carried out at a wide range of temperatures, preferably at about 35°C.

In another embodiment of the invention, the solid state form comprises a type II saliva. Without limiting the invention, it is believed that type II salicy has a higher solubility and a faster dissolution rate than type III salicy, because type III salicy has better thermodynamics than type II salicy stability, and because Type III Sally has lower free energy than Type II Sally. A fast dissolution rate is useful because increasing the dissolution rate of a drug generally increases its bioavailability.

Type II Celery has an X-ray powder diffraction pattern with peaks at about 10.3, 13.8, and 17.7 degrees 2Θ. The peaks for the mixture of Celecia Form I and Form II are shown in the top graph of Figure 1b. The desirable melting point of type II saliva is from about 161°C to about 162°C, preferably about 161.5°C. When scanned at 0.5°C/min, Celli Kexi Type II had a differential scanning calorimetry endotherm maximum at about 162.0°C. It is expected that Cylicoxime Type II has a higher solubility and a faster rate of dissolution than Cylicoxime Type III. The solid state forms of the present invention have a phase purity of at least about 5% celecium type II, preferably at least about 10% celecoxil type II, more preferably at least about 25% celecoxil type II, still more preferably at least about 50% celecoxil type II Type II saliva, still more preferably at least about 75% type II saliva, still more preferably at least about 90%, most preferably substantially type II saliva.

In another embodiment of the present invention, there is provided a pharmaceutical composition, which comprises an effective amount of solid-state Saili Kexi and at least one pharmaceutically acceptable carrier, adjuvant or diluent, wherein the solid-state Saili Kexi The saliva contains at least 2% saliva type II, and preferably 10% saliva II, or more preferably 50% saliva II, further preferably 98% saliva II. In a preferred embodiment, the solid form of sariko is predominantly sariko of type II.

In another embodiment of the present invention, a method of treating or preventing a condition or disease mediated by cyclooxygenase-2 in a subject is described, the method comprising administering to the subject a therapeutically effective amount of II The type of Sally is gratifying. Preferably, the condition or disease mediated by cyclooxygenase-2 to be treated or prevented is pain, infection, arthritis, tumor growth, metastasis, or familial adenomatous polyposis.

Another embodiment of the present invention is a process for the preparation of sariceratin II from a mixture containing sariceratin and a solvent, wherein the crystallization is carried out at a temperature higher than the enantiomeric transition temperature of sariceratin form II, The resulting type II sally is gratifying. Prior to the crystallization of Form II seracid, a seeding solvent for the Form II sellicid may be used, resulting in the formation of Form II sellicid having a phase purity of at least about 5% by weight, preferably at least about 10% by weight, and more A phase purity of at least about 25% by weight is preferred.

The present invention also relates to a process for the preparation of a crystalline form of sarikesi, wherein the method comprises heating a solvate of sarikexi to produce salikexi form II. The solvate can be heated, for example, to a temperature of from about 50°C to about 160°C, preferably from about 60°C to about 145°C, more preferably from about 70°C to about 140°C, still more preferably from about 80°C to about 140°C, still more preferably at about 90°C. °C to about 140°C, more preferably about 100°C to about 140°C, still more preferably about 110°C to about 140°C, still more preferably about 120°C to about 140°C, still more preferably about 125°C to about 135°C , most preferably about 130°C. The heating can be performed for any conventional time, such as heating for more than about 1 minute, preferably more than about 5 minutes, more preferably more than about 60 minutes, still more preferably about 2 hours, preferably about 4 hours or longer. Additionally, the process can be carried out at any pressure, preferably subatmospheric. The solvates used in the present invention contain celica and a solvent. For example the solvent may be an amide solvent. Useful amide solvents include N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone, 1,3-dimethyl-3,4,5,6- Tetrahydro-2(1H)-pyrimidinone, and 1,1,3,3-tetramethylurea, or any mixture of these solvents. A preferred solvent is 1,1,3,3-tetramethylurea. Another preferred solvent is 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. A further preferred solvent is 1-methyl-2-pyrrolidone. A still further preferred solvent is N,N-dimethylformamide. Another further preferred solvent is N,N-dimethylacetamide.

In another embodiment of the present invention, wherein the Form II sarike solvate is prepared by heating the sarike solvate, the process for preparing the solvate comprises mixing sarike with an amide solvent selected from the group consisting of: N,N -Dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)- pyrimidinone and 1,1,3,3-tetramethylurea, or any mixture of these solvents. Preferably 1,1,3,3-tetramethylurea, more preferably 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, further preferably 1-methyl- 2-Pyrrolidone, still further preferably N,N-dimethylformamide, and still further preferably N,N-dimethylacetamide.

Another embodiment of the present invention is a solid form of sariko comprising both types I and II.

Yet another embodiment of the present invention is a solid form of sariko comprising both types I and II.

Still another embodiment of the present invention is a solid form of saliva containing both type II and type III saliva.

Yet another embodiment of the present invention is a solid form of sariko comprising types I, II and III.

The present invention also relates to a process for the preparation of saliva form II, wherein the method comprises comminuting or milling saliva form III. Useful grinding steps include, for example, wet or ball milling. Useful milling steps may include, for example, grinding or shaking.

The present invention also relates to a process for the preparation of sariquel solvate Form I, wherein the process comprises comminuting or milling salicylic solvate. Useful grinding steps include, for example, wet or ball milling. Useful milling steps may include, for example, grinding or shaking.

Another embodiment of the present invention is a method of preparing sariko Form II, wherein the method comprises melting sariko Type I and cooling the melt, thereby producing sariko Form II.

Another embodiment of the present invention is a method of preparing sariko Form II, wherein the method comprises melting sariko Form III and cooling the melt, thereby producing sariko Form II.

Celyccid Form III is prepared by crystallizing Celyccid from a solvent containing isopropanol and water (see, eg, U.S. 5,910,597).

Type III celery has a complex DSC melting transition. When scanning at 0.5°C/min, the melting of Salicosanol Form III was observed at about 160.8°C, followed by recrystallization to Celicasia Form II, followed by the melting of Salicosanol Form II at about 162.0°C. Type III sally is the thermally stable state of sally.

Characterization of desirable polymorphic forms of Sely

The X-ray powder diffraction (PXRD), infrared absorption spectroscopy (IR), differential scanning calorimetry (DSC) and Raman (Raman) spectroscopy were used to characterize the type I and type II salycoxi.

X-ray Powder Diffraction (PXRD)

The various crystalline forms of Selyke can be analyzed with a Siemens D5000 powder diffractometer or an Inel multifunctional diffractometer. For a Siemens D5000 powder diffractometer, raw data for 2-theta values from 2° to 5° can be determined with a gradient of 0.02° and a gradient period of 2 seconds. For the Inel multifunctional diffractometer, the sample was placed in an aluminum sample container while raw data for all 2θ values were collected for 30 minutes.

As shown in Figure 1, the three crystalline forms of sera could be easily distinguished by PXRD. Using a CuX-ray source (1.54nm), characteristic diffractions were observed at 2-theta values of approximately 5.5°, 5.7°, 7.2° and 16.6° for Type I Cylic, and at approximately 10.3° for Type II Characteristic diffractions were observed at , 13.8° and 17.7°.

Melting/decomposition temperature

The melting and/or decomposition temperature of the non-solvated crystalline form of selecid was determined with a TA Instruments 2920 differential scanning calorimeter. Each sample (1-2 mg) was placed in a closed or uncovered aluminum container and heated at a rate of 0.5°C/min. The melting/decomposition range is defined from the extrapolated onset to the maximum value of the melting/decomposition endotherm.

Three polymorphic forms of celery have been identified. The polymorphic forms of Celica Form I melt at about 162.8°C; Celica Form II melt at about 161.5°C; and Celica Form III melt at about 160.8°C. Upon melting, part of the recrystallization of the type III sarik as either type II or type I sally was observed.

Three polymorphic crystal forms and solvates of N,N-dimethylacetamide (DMA) and N,N-dimethylformamide (DMF) were identified. The physical properties and identifying characteristics of the new polymorphic form are shown in Table 1.

Table 1 crystal form Melting point (°C) ΔH(J/G) Differential conversion IR Raman spectrum PXRD(2θ) I 162.8 72 3256cm ^-1 3356cm ^-1 NA 5.5°, 5.7°, 7.2° and 16.6° II** 161.5 <84 none 712cm ^-1 10.3°, 13.8° and 17.7° III 160.8 91 --- --- --- * No characteristic transitions were observed for other crystal forms ** No pure samples of Form II Selicor were prepared

Differential Scanning Calorimetry (DSC)

DSC was used to characterize the pleasing polymorphic form of Celli. Type I saliva is the polymorphic form with the highest melting point at 162.8°C, and has an endothermic maximum at 163.3°C. Type II Celery melts at 161.5°C and has an endothermic maximum at 162.0°C. A gratifying complex transition was observed for type III saliva. The complexity of this transition, which can only be observed at slow scan speeds, represents the melting of Celysian III, followed by recrystallization to Cellician II, followed by the melting of Celician II. As far as the initial endothermic transformation is concerned, type III Celli melts at 160.8°C and has an endothermic maximum at 161.5°C. DSC measures low levels of type I saliva in type III saliva.

Infrared absorption spectrum

IR distinguishes type I sarik from type II sariki and type III sariki (see Figure 2).

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred embodiments are only for illustration and not limiting the rest of the disclosure of the present invention in any way.

Example

The following examples include detailed descriptions of the methods for the preparation of crystalline saricid Form I and saricid Form II described in this application. These detailed descriptions are within the scope of the invention and serve to illustrate the invention.

These detailed descriptions are for illustration only and do not limit the scope of the invention. All parts are by weight and temperatures are in degrees Celsius unless otherwise indicated. The starting material for celecity used in each of the following examples was prepared according to the procedure of U.S. 5,910,597.

Preparation Example

Preparation Example 1: Preparation of Sailikexi DMA Solvate (Ratio 1:1 Sailikexi-DMA)

Method A. In a round bottom flask, mix 4.84 g of Selicor with about 125 mL of DMA. The solvent was removed under reduced pressure at 60°C to induce crystallization. The dry solid was collected on a filter. This procedure yielded the 5gl:1 solvate. Decomposition started at about 100°C and had a maximum at 148°C with a total weight loss of 17%, measured by TGA at 10°C/min.

Method B. In a 1L beaker, stir in about 1000mL of DMA and add 38.2g of Selycoxi. Transfer the resulting solution to a 2L beaker. Crystallization was induced by adding about 400 ml of water. Crystals were isolated by filtration. The wet yield was 5.44 g. Addition of water to the filtrate resulted in additional crystals obtained. TGA at 10°C/min showed decomposition at about 100°C with a maximum at about 150°C with a total weight loss of 18% solvent.

Preparation Example 2: Preparation of Sailikexi DMF Solvate (Ratio 1:1 Sailikexi-DMF)

In a crystallization vessel, dissolve approximately 1 g of celecoxil in 50 mL of DMF. The crystallization vessel was covered with perforated aluminum foil, placed in a protective hood, and allowed to evaporate to dryness. This process yielded about 1.02g of product. Measurements by TGA at 10°C/min showed two weight losses in decomposition, which started at 75°C and continued to a second maximum at 156°C. Total weight loss was 13.4%.

Example of operation:

Embodiment 1: the routine method of preparation I type Saili Kexi

A. Preparation of Cylyxanol Form I by Heating the Cylyxanol Solvate:

An open container of the Selicor solvate was heated in an oven at the lowest temperature at which desolvation was observed. Briefly, 0.3 g of Selicor-DMA was heated in an oven at about 100°C for about 48 hours. The PXRD of the resulting sample showed characteristic reflections due to Selycine type I, and that of Selycine-DMA; TGA showed a weight loss of 9.6% approximately centered at about 147°C, indicating approximately 50% conversion to Selycine type I Li Kexi.

B. Preparation of Type I Selycox by Evaporation

Crystallize a high-purity sample of celica from ethyl acetate-heptane solvent by evaporation. Selicor (16.03 g) was purified by preparative liquid chromatography using 15/85 (v/v) ethyl acetate/heptane and a 150 mm 40-63 mcm silica gel column (diameter 50.8 mm). Fractions eluting between 270ml and 900ml were collected and pooled. The solvent was removed under vacuum at about 35°C to cause crystallization and evaporated to dryness. This process yielded 8.6 g of type I saliva. It was found by TGA that the crystalline product contained no solvent, and the PXRD pattern of its type I sari kexi was shown in Figure 1a.

C. Preparation of type I saliva by melting:

Typically, sari keshi is placed in an open container and heated to melt, then allowed to cool. In more detail, the beaker containing the celek was heated to about 170° C. on a hot plate, and the celek was completely melted. The molten sally kebab is then poured over the watch glass and allowed to cool. Sweeping at 0.5°C/min, a gratifying melting of Celliform I was observed at about 163°C as determined by DSC. A gratifying melt of Cell type III, and a recrystallization of Celica type II and its melt were also observed.

Embodiment 2: the routine method of preparing type II Saili Kexi

A. Preparation of type II sarikh by heating sariki solvate:

1. Using DMA solvates

In general, an open container of the selix-DMA solvate was heated in an oven, and desolvation was observed near the peak temperature. Briefly, 0.3 g of Selicor-DMA was heated in an oven at about 130°C for about 48 hours. The PXRD of the resulting sample showed characteristic reflections caused by Type II and Type III Cylic; DSC at 0.5°C/min showed a single melting endotherm with an onset at 161.4°C and a maximum at 161.9°C; Below 200°C, TGA showed no weight loss. The powder X-ray diffraction pattern of the mixture is shown in Figure 1b.

2. Using the solvate of DMF

In general, an open container of the selix-DMA solvate was heated in an oven, and desolvation was observed near the peak temperature. Briefly, about 0.2 g of Selicor-DMA was heated in an oven at about 130°C overnight. The PXRD of the resulting sample showed characteristic reflections caused by type II and type III celecox; DSC at 0.5°C/min showed a single melting endotherm with an onset at 161.5°C and a maximum at 161.8°C, And has a small endothermic transition (Type I) with a maximum at about 163.8°C; below 200°C, TGA shows no weight loss.

B. Preparation of Type II Sally from Type III Sally by Mechanical Transformation:

Typically, type III saliva is milled in a ball mill. Briefly, using a peristaltic machine, the Type III Selyco was milled at maximum intensity for 30 seconds. The resulting solid was a mixture of cericosityl type III and sellicidin type II, as determined by powder X-ray diffraction.

C. Preparation of type II saliva by melting:

Melt the celica in a test tube at 170°C using an oil bath. Extend the Teflon spatula into the molten selecium, move the spatula, scrape, and collect the dried solids on the spatula. The dry solid was a mixture of Forms II and III as determined by powder X-ray. DSC at 10°C/min also showed the presence of type I saliva.

Claims (23)

1. the I type crystal formation of a YM 177, it has following physical behavior:

(1) has the X-ray powder diffraction that the peak is arranged at 5.5,5.7,7.2 and 16.6 degree, 2 θ places;

(2) having the melting range is 160 ℃ to 164 ℃;

(3) has differential scanning calorimetric heat absorption maximum value in 160.0 ℃ to 164.0 ℃;

(4) have 3250 to 3260cm ^-1The place infrared spectra at peak is arranged and 3350 to 3360cm ^-1There is the infrared spectra at peak at the place.

2. the crystal formation of claim 1, it has the melting range is 162 ℃ to 163 ℃.

3. the crystal formation of claim 2, it has fusing point is 162.8 ℃.

4. the crystal formation of claim 1, it has 163.3 ℃ of differential scanning calorimetric heat absorption maximum values.

5. the crystal formation of claim 4, it has 162.8 ℃ fusing point.

6. the crystal formation of claim 1, it has at 3256cm ^-1There is the infrared spectra at peak at the place.

7. the crystal formation of claim 1, it has at 3356cm ^-1There is the infrared spectra at peak at the place.

8. the crystal formation of claim 1, it has at 3256cm ^-1And 3356cm ^-1There is the infrared spectra at peak at the place, and has 162.8 ℃ fusing point.

9. pharmaceutical composition, it comprises each crystal formation and at least a pharmaceutically acceptable carrier, auxiliary agent or the thinner of claim 1 to 8 for the treatment of significant quantity.

Any described I type YM 177 of claim 1-8 preparation treatment or prevention curee by the application in the medicine of the illness of cyclooxygenase-2-mediation or disease.

11. the application of claim 10, wherein said illness or disease are pain.

12. the application of claim 10, wherein said illness or disease are inflammation.

13. the application of claim 10, wherein said illness or disease are sacroiliitis.

14. the application of claim 10, wherein said illness or disease are tumor growths.

15. the application of claim 10, wherein said illness or disease are metastases.

16. the application of claim 10, wherein said illness or disease are the adenoma polyposises of familial.

17. a method for preparing YM 177 I type crystal formation, wherein this method comprises heating YM 177 solvate, thereby produces I type YM 177, and described solvate comprises YM 177 and amide solvent, and described amide solvent is a N,N-dimethylacetamide.

18. the method for claim 17, wherein said solvate is heated to 100 ℃ temperature.

19. the method for claim 17 is wherein to described solvate heating 48 hours.

20. a method for preparing YM 177 I type crystal formation, wherein this method comprises the heat fused YM 177 and this melt is cooled to 163 ℃ temperature, thereby produces I type YM 177.

21. a method for preparing YM 177 I type crystal formation, this method comprise that from YM 177 and ratio be evaporating solvent the YM 177 solution formed of 15: 85 ethyl acetate and heptane, thereby produce I type YM 177.

22. the method for claim 21, wherein said evaporation are carried out being lower than under the normal atmosphere.

23. the method for claim 21, wherein said evaporation is carried out under 35 ℃ temperature.

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