HK1055297B - Polymorphic crystalline forms of celecoxib - Google Patents

Description

Polymorphic crystalline forms of celecoxib

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application claims priority from U.S. provisional patent application serial No. 60/169856 filed on 9.12.1999.

Technical Field

The present invention relates to orally deliverable pharmaceutical compositions comprising a cyclooxygenase-2 inhibitor drug as the active ingredient, methods of making such compositions, methods of treating cyclooxygenase-2 mediated disorders, said methods comprising orally administering such compositions to a subject, and the use of such compositions in the manufacture of medicaments.

The present invention is in the field of cyclooxygenase-2 inhibitory agents and specifically relates to novel forms I and II of celecoxib, methods of making these celecoxib forms, pharmaceutical compositions containing these celecoxib forms, and methods of treating and/or preventing cyclooxygenase-2 mediated disorders and/or diseases, including disorders and diseases.

Background

A variety of compounds have been reported to have therapeutic and/or prophylactic effects for selective cyclooxygenase-2 inhibition, and the effects of these compounds in the treatment or prevention of specific cyclooxygenase-2 mediated diseases or such diseases in general have been disclosed. Among such compounds, Talley et al, in U.S. Pat. No. 5,760,068, report a number of substituted pyrazolyl benzenesulfonamides, including, for example, the compound 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -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. Celecoxib has the following structure:

delacoxib has the following structure:

other compounds reported to have therapeutic and/or prophylactic utility for selective cyclooxygenase-2 inhibition are substituted isoxazolyl benzene sulfonamides, as reported by Talley et al in U.S. Pat. No. 5,633,272, including, for example, the compound 4- [ 5-methyl-3-phenylisoxazol-4-yl ] benzene sulfonamide, also referred to herein as Valdecoxib, which has the following structure:

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. Pat. No. 5,474,995, including, for example, the compound 3-phenyl-4- [4- (methylsulfonyl) phenyl ] -5-H-furan-2-one, also referred to herein as Rofecoxib, which has the following structure:

balley et al, U.S. Pat. No. 5,981,576, disclose that additional (methylsulfonyl) phenyl furanones are 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-cyclopentamethylen-1-one useful as a cyclooxygenase-2 inhibitor.

Among other things, international publication No. WO99/55380 discloses compounds useful as cyclooxygenase-2 inhibitors having the following structure:

many selective cyclooxygenase-2 inhibitory compounds include celecoxib, delacoxib, weddecocoxib, and rofecoxib, which are hydrophobic and have low solubility in water. There are practical difficulties in formulating such compounds for oral administration, particularly where a rapid onset of therapeutic action is desired or required.

Illustratively, formulation of celecoxib into a formulation for effective oral administration to a subject is complicated by its unique physical and chemical properties, particularly its low solubility and factors associated with its crystalline structure, including cohesiveness, low bulk density, and low compressibility. Celecoxib is unusually insoluble in aqueous media. For example, when administered orally in capsule form, unformulated celecoxib is not readily dissolved and dispersed, and thus is not conducive to rapid absorption in the gastrointestinal tract. In addition, unformulated celecoxib, which has a crystalline state that tends to form long, tacky needle crystals, is readily fused into a monolithic mass when compressed on the die of a tablet press. Even when mixed with other substances, the crystals of celecoxib are easily separated from the other substances and agglomerate during mixing of the composition, producing a non-uniformly mixed composition containing unwanted large aggregates of celecoxib. Therefore, it is difficult to prepare a pharmaceutical composition containing celecoxib with the desired mixing uniformity. Furthermore, in the preparation of pharmaceutical compositions containing celecoxib, handling problems are encountered. For example, the low bulk density of celecoxib makes it difficult to handle the small amounts of material required in formulating pharmaceutical compositions. There are therefore a number of problems associated with the preparation of suitable pharmaceutical compositions and dosage forms containing celecoxib, particularly oral delivery dosage units.

In particular, oral delivery formulations containing a cyclooxygenase-2 inhibitory drug of low water solubility of celecoxib are required to have one or more of the following properties for use with unformulated celecoxib or other celecoxib compositions:

(1) improving solubility;

(2) the disintegration time is shortened;

(3) the dissolution time is shortened;

(4) the tablet crumbliness is reduced;

(5) increasing tablet hardness;

(6) improving the wettability;

(7) improving compressibility;

(8) improving the flowability of liquid and particulate solid compositions;

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

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

(11) the mixing uniformity is improved;

(12) dose uniformity is improved;

(13) improved control of weight variation during encapsulation and/or tableting;

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

(15) reducing the water requirement for wet granulation;

(16) the time for wet granulation is reduced; and

(17) the drying time of the wet granulation mixture is reduced.

Further, there is a particular need for oral delivery formulations containing celecoxib cyclooxygenase-2 inhibitory drugs of low water solubility that are able to act more rapidly than the corresponding unformulated drugs or known formulations of such drugs. To the extent that a rapid onset of therapeutic action is achieved, e.g. with a maximum serum concentration (C) of the drug_max) And the minimum time to reach maximum serum concentration (T) after oral administration_max) In particular, there is a need for oral delivery formulations containing celecoxib cyclooxygenase-2 inhibitory drugs of low water solubility that provide a C greater than the corresponding unformulated drug or known formulations of such drugs_maxAnd/or earlier T_max。

As noted herein below, treatment with selective cyclooxygenase-2 inhibitors including celecoxib is indicated or potentially indicated in a very broad range of cyclooxygenase-2 mediated conditions and diseases. It would be beneficial to provide formulations that exhibit 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 advancement in the treatment of cyclooxygenase-2 mediated conditions and disorders.

Cyclooxygenase-2 inhibitory drugs having low solubility in water, including celecoxib, are most commonly prepared as solid microgranules. The individual or primary particles of the drug may be dispersed in a liquid medium, such as in a suspension formulation, or may be agglomerated 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.

Preparation of a primary particle size having the desired range, or having the desired average particle size, or having a particle size distribution characterized by, for example, D₉₀Various methods of pharmaceutical formulation of the parameters of (a) are well known and commonly used in the art. Text D₉₀Wire defined as pair diameterSexually, 90% of the particles in the formulation have a volume value, in the longest dimension of the particle, that is less than that diameter. For practical purposes, D is measured on the basis of 90% by weight₉₀More generally than by volume.

For the sake of consistency with the prior disclosure, the terms "microparticle" and "nanoparticle" are defined herein consistent with the definition of Courteille et al in U.S. patent No. 5,384,124, referring to particles having a diameter between 1mm and 2000mm and a diameter of less than 1mm (1000nm), respectively. According to us patent No. 5,384,124, preparations of micro-and nanoparticles "primarily intended to delay dissolution of the active principle". However, Liversidge et al, in U.S. Pat. No. 5,145,684, disclose the nanoparticle compositions to provide drug "unexpectedly high bioavailability", particularly drugs having 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 (mean particle size 240-300nm) has a significantly higher rate of expression of absorption than administration of microparticles (mean particle size 20-30 mm).

Many methods of preparing nanoparticulate compositions of therapeutic agents are known. Typically these methods employ mechanical means, such as milling or grinding, to reduce the particle size to the millimetre (less than 1mm) range, or to precipitate the millimetre particles from solution. Exemplary methods are disclosed in the following independent documents: U.S. Pat. No. 4,826,689 to Violanto & Fischer, U.S. Pat. No. 5,145,684 to Liversidge et al, U.S. Pat. No. 5,298,262 to Na & Rajagopalan, U.S. Pat. No. 5,302,401 to Liversidge et al, U.S. Pat. No. 5,336,507 to Na & Rajagopalan, U.S. Pat. No. 5,340,564 to Illig & Sarcotdar, U.S. Pat. No. 5,346,702 to Na & Rajagopalan, U.S. Pat. No. 5,352,459 to Hollister et al, U.S. Pat. No. 5,354,560 to Lovrecic, U.S. Pat. No. 5,384,124 to Rurtelle et al, U.S. Pat. No. 5,429,824 to June, U.S. Pat. No. 5,510,118 to Bosch et al, U.S. Pat. 5,518,738 to Eickhokhoff et al, U.S. Pat. No. 5,826, 5,503,723 to Ruchy & Eichhokhoff, U.S. Pat. 5,737, U.S. Pat. No. 5,628,628 to Baverjetting et al, U.S. Pat. No. 5,565 to Baldong et al, U.S. No. 8284 to Baldong et al, U.S. Pat. No. 5,628,565 to Pub. 5,628,84 to Pub. No. 5,565, U.S. Pat. No. 5,573,783 to Desieno & Stetsko, U.S. Pat. No. 5,580,579 to Ruddy et al, U.S. Pat. No. 5,585,108 to Ruddy et al, U.S. Pat. No. 5,587,143 to Wong, U.S. Pat. No. 5,591,456 to Franson & Snyder, U.S. Pat. No. 5,662,883 to Bagchi et al, U.S. Pat. No. 5,665,331 to Bagchi et al, U.S. Pat. No. 5,718,919 to Ruddy & Roberts, U.S. Pat. No. 5,747,001 to Wiedmann et al, International patent publication No. WO93/25190, International patent publication No. WO96/24336, International patent publication No. WO 98/35666.

Summary of The Invention

According to the present invention, selective cyclooxygenase-2 inhibitory compounds that are poorly water soluble, such as celecoxib, delacoxib, weddecoxib or rofecoxib, if the compound exhibits pharmacokinetic properties that result in greater maximum serum concentrations (C)_max) And/or a shorter time to reach maximum serum concentration (T) after administration_max) Then a faster initial therapeutic effect is provided when the composition containing the compound is administered orally. Said larger C is obtained by reducing the particle size of solid particles containing the compound_maxAnd/or shorter T_maxSuch that the majority by weight of the particles is less than 1mm in diameter and in the longest dimension of the particles. Without being bound by theory, it is believed that the larger C is when the particle size is reduced to less than 1mm_maxAnd/or shorter T_maxCausing a faster dissolution of the compound.

Accordingly, there is now provided a pharmaceutical composition comprising one or more orally deliverable dose units, each comprising a therapeutically effective amount of a low water solubility compoundWherein the compound has a D of about 0.01 to about 200mm₉₀The presence of solid particles of a particle size, the majority of which are less than 1mm by weight, provides a sufficiently high C compared to other similar compositions in which substantially all of the particles are greater than 1mm_maxAnd/or sufficiently 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 is formulated to have a D of about 0.01 to about 200mm₉₀Solid particles of a size where about 25% to 100% by weight of the particles are less than 1mm are present.

The compositions may comprise dosage units in the form of discrete solid articles, such as tablets, pills, hard or soft capsules, lozenges, sachets or pastilles; in addition, the compositions may be presented as a substantially homogeneous flowable mass, such as a granular or granulated solid or liquid suspension, in which case the single dosage unit is suitably removable.

Also provided is a method of treating a medical condition or disorder in a subject, herein treated with a cyclooxygenase-2 inhibitor, comprising orally administering one or more dosage units of a composition of the present invention, once or twice daily. Such methods are particularly useful for medical conditions or diseases associated with acute pain.

The present invention also includes a novel solid form of celecoxib, form I celecoxib. The invention further includes another solid form of celecoxib, form II celecoxib. Each of these new solid forms includes solvated, unsolvated, and unhydrated forms.

The novel celecoxib compounds described herein have one or more of the beneficial chemical and/or physical properties described above in connection with other solid state forms described herein or disclosed in the literature.

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

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

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

In yet another embodiment, the present invention provides a process for preparing form I celecoxib comprising crystallizing celecoxib from a mixture comprising celecoxib and a solvent, wherein the crystallization is conducted at a temperature above the enantiomeric transition temperature of form I celecoxib thereby producing form I celecoxib.

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

In another embodiment, the present invention provides a method of preparing form I celecoxib wherein the method comprises milling or grinding form III celecoxib thereby producing form I celecoxib.

In yet another embodiment, the present invention provides a method of preparing form I celecoxib wherein the method comprises milling or grinding a solvate of celecoxib thereby producing form I celecoxib.

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

In another embodiment, the invention provides a method of preparing form I celecoxib wherein the method comprises melting form III celecoxib and cooling the melt, thereby producing form I celecoxib.

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

Another embodiment of the invention includes a novel crystalline form of celecoxib, for example, one embodiment of the invention includes a form II crystalline form of celecoxib, preferably a crystalline form having an X-ray powder diffraction pattern with peaks at about 10.3, 13.8, or 17.7 degrees 2 Θ.

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 invention provides a method of treating or preventing a cyclooxygenase-2-mediated condition or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of form II celecoxib.

Yet another embodiment of the present invention provides a method of preparing form II celecoxib comprising crystallizing celecoxib from a mixture comprising celecoxib and a solvent, wherein the crystallization is performed at a temperature at which the enantiomeric transition of form II celecoxib is increased, thereby producing form II celecoxib.

Yet another embodiment of the present invention provides a method of preparing a crystalline form of celecoxib wherein the method comprises heating a celecoxib solvate thereby producing form II celecoxib.

Another embodiment of the present invention provides a method of preparing form II celecoxib wherein the method comprises milling or grinding form III celecoxib thereby producing form II celecoxib.

Another embodiment of the invention provides a method of preparing form II celecoxib wherein the method comprises milling or grinding a celecoxib solvate thereby producing form II celecoxib.

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

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

Another embodiment of the invention provides a solid form of celecoxib comprising form I celecoxib and form II celecoxib.

Another embodiment of the invention provides a solid form of celecoxib comprising form I celecoxib and form III celecoxib.

Another embodiment of the invention provides a solid form of celecoxib comprising form II celecoxib and form III celecoxib.

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

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

Brief description of the drawings

FIG. 1 depicts controls for experimental PXRD patterns between form I celecoxib (FIG. 1a), a mixture of form II and form III celecoxib (FIG. 1b), and form III celecoxib (FIG. 1 c);

FIG. 2 depicts a comparison between IR spectra of form I celecoxib, a mixture of form II celecoxib and form III celecoxib;

figure 3 depicts a control of DSC thermograms of 0.5 ℃/min scans of each celecoxib form with coverage (below the endotherm).

Description of the preferred embodiments

The term "selective cyclooxygenase-2 inhibitor" or "selective cyclooxygenase-2 inhibiting compound" herein refers to a compound that inhibits cyclooxygenase-2 to a therapeutically effective degree, while causing a significant reduction in inhibition of cyclooxygenase-1 over conventional non-steroidal anti-inflammatory drugs (NSAIDs).

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

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

The term "orally-deliverable" is intended herein to mean suitable for oral administration.

By "subject" is meant herein a subject to which a therapeutic agent or composition thereof can be administered, including patients of either sex and of any age, and also including any non-human animal, particularly domestic animals or companion (companion) animals, exemplified by cats, dogs, or horses.

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

The term "in solid particles" as applied herein to a selective cyclooxygenase-2 inhibitory compound includes compositions wherein the solid particles consist essentially of the compound, and wherein the solid particles comprise the compound in intimate admixture with one or more other ingredients. These additional ingredients include one or more therapeutic agents in addition to the selective cyclooxygenase-2 inhibitory compound and/or one or more pharmaceutically acceptable excipients.

The term "excipient" herein refers to any carrier or excipient that is not a therapeutic agent itself, but rather is used as a vehicle or excipient for the delivery of a therapeutic agent to a patient or for incorporation into a pharmaceutical composition to improve its handling or storage properties or to allow or facilitate the formulation of a dosage unit of the composition into a discrete preparation such as a capsule or tablet suitable for oral administration. Excipients include, but are not limited to, diluents, disintegrants, binders, adhesives, wetting agents, lubricants, glidants, substances that mask or counteract an unpleasant taste or odor, flavoring agents, dyes, flavoring agents, and substances that improve the appearance of the composition.

The term "substantially homogeneous" with respect to a pharmaceutical composition comprising several ingredients means that the ingredients are mixed so well that each ingredient does not exist as a discrete layer and that no concentration gradient is formed within the composition.

The term "purity" means the chemical purity of celecoxib as obtained according to conventional HPLC analysis methods.

The term "phase purity" means the solid state purity of celecoxib relating to a particular crystalline or amorphous form of celecoxib obtained when measured by infrared spectroscopic analysis as described herein.

The term "enantiomeric 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 enantiomeric transition temperature, form a may be a thermodynamically stable form, but above this temperature form B is a thermodynamically stable form.

The novel pharmaceutical compositions according to the present invention comprise one or more orally deliverable dosage units. Each dosage unit includes a therapeutically effective amount of a selective cyclooxygenase-2 inhibitor, in the case of celecoxib, preferably a therapeutically effective amount of about 10mg to about 1000 mg.

It will be appreciated that the therapeutically effective amount of the selective cyclooxygenase-2 inhibitor for a subject will depend, inter alia, on the weight of the subject. For example, where the cyclooxygenase-2 inhibitor is celecoxib and the subject is a child or small animal (e.g., a dog), a relatively low amount of celecoxib in the preferred range of about 10mg to about 1000mg is suitable to provide a serum concentration consistent with a therapeutic effect. In the case where the subject is an adult human or a large animal (e.g., a horse), such serum concentrations of celecoxib are likely to be obtained in a dosage unit containing a relatively large amount of celecoxib.

In the case of celecoxib, typical dosage units in the compositions of the invention contain about 10, 20, 25, 37.5, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350 or 400mg of the cyclooxygenase-2-inhibitor. For adults, a therapeutically effective amount of celecoxib is typically about 50mg to about 400mg per dosage unit in the compositions of the invention. A particularly preferred amount of celecoxib is about 100mg to about 200mg, for example about 100mg or about 200mg, per dosage unit.

The compositions of the present invention containing a selective cyclooxygenase-2 inhibitor, such as celecoxib, alone or in intimate admixture with one or more excipients, are present in nanoparticulate form, i.e., in the form of solid particles having a diameter of less than 1mm, measured as the longest dimension of the particle.

The effect of reducing particle size from the microparticle range (greater than 1mm diameter) to the nanoparticle range on the pharmacokinetic properties of any particle size drug or class of drugs is generally unpredictable. According to the present invention, for selective cyclooxygenase-2 inhibitors of low water solubility, the nanoparticulate composition exhibits a higher C than the microparticulate composition_maxAnd/or shorter T_max. Thus, in one embodiment of the invention, the particles are compared to a control composition in which substantially all of the particles are greater than 1mmThe weight percentage of nanoparticles in the particles may be sufficient to provide a substantially higher C_maxAnd/or substantially shorter T_max. Preferred compositions in this embodiment have sufficient nanoparticle weight percent to provide substantially short T_maxAnd more preferably sufficient nanoparticle weight percent to provide a substantially higher C than the control composition_maxAnd shorter T_max。

When administered orally to a fasting adult, a 100mg dosage unit preferably exhibits a T of less than about 90 minutes_maxMore preferably T of less than about 60 minutes and less than about 45 minutes_max，C_maxAt least about 100ng/ml, more preferably at least about 200 ng/ml. Typically within 30 minutes of oral administration, the compositions of the invention provide a serum concentration of the selective cyclooxygenase-2 inhibitor of at least about 50 ng/ml; preferred compositions achieve such concentrations in as little as 15 minutes. It is believed that the early rise in serum concentration is associated with a rapid onset of action of the composition of the invention.

In another embodiment of the invention, the selective cyclooxygenase-2 inhibitor, e.g., celecoxib, is present as solid particles having a D of about 0.01 to about 200mm₉₀Particle size, wherein about 25% to 100% by weight of the particles are nanoparticles. When the weight percent of nanoparticles is low, e.g., about 25% to about 50%, D₉₀The particle size is preferably from about 0.01 to about 100mm, more preferably from about 0.01 to about 75mm, still more preferably from about 0.01 to about 40mm, even more preferably from about 0.01 to about 25 mm. The particle size may vary continuously along the nanoparticle and microparticle range, or the composition may have a bimodal or multimodal particle size distribution, one set of particles having a D of less than 1mm₉₀Particle size, another set of particles having a D substantially greater than 1mm₉₀Particle size. At least about 50% by weight of the nanoparticles are generally preferred, with at least about 75% by weight being particularly preferred. In one embodiment, substantially all of the particles are less than 1mm, i.e., the weight percent of the nanoparticles is 100% or close to 100%.

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

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

The compositions of the present invention containing a selective cyclooxygenase-2 inhibitor of low water solubility, such as celecoxib, optionally contain one or more excipients selected from diluents, disintegrants, binders, wetting agents and lubricants. In one embodiment, the selective cyclooxygenase-2 inhibitor-containing nanoparticle has a surface modifying agent adsorbed on its surface. In another embodiment, the nanoparticles of the selective cyclooxygenase-2 inhibitor are contained in a matrix formed of a polymer. 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 composition of the present invention is ingested. Preferably, both a water soluble diluent and a wetting agent are present.

The composition of the invention may be a substantially homogeneous flowable mass such as a particulate or granular solid or liquid, or it may be in the form of a dispersion, for example a capsule or tablet, each containing a single dosage unit.

In a composition which is a substantially homogeneous flowable mass, a single dose unit is measurably removable using a suitable volumetric metering device such as a teaspoon or cup. Suitable flowable materials include, but are not limited to, powders and granules. Alternatively, the flowable mass may be a suspension of the cyclooxygenase-2 inhibitor in a solid particulate phase dispersed in a liquid phase, preferably an aqueous phase. At least a portion of the particulate phase is nanoparticulate. In preparing such suspensions, it may be beneficial to employ a wetting agent such as polysorbate or the like. A suspension may be prepared by dispersing a nanoparticulate or partially nanoparticulate cyclooxygenase-2 inhibitor in a liquid phase; alternatively, the cyclooxygenase-2 inhibitor, such as celecoxib, may be precipitated from, for example, a solution in an alcohol, 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 present 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 to, treating inflammation in a subject, such as analgesics for use in the treatment of pain and headache, and antipyretics for the treatment of fever. For example, such compositions may be used to treat arthritic conditions, including (but not limited to) rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, and juvenile arthritis. Such compositions may also be used to treat asthma, bronchitis, dysmenorrhea, premature labor, tendinitis, bursitis, allergic neuritis, cytomegalovirus infection, apoptosis including HIV-induced apoptosis, lumbago, liver disease including hepatitis, skin-related diseases such as psoriasis, eczema, acne, ultraviolet injury, burns and dermatitis, and post-operative inflammation including inflammation following ophthalmic surgery such as cataract surgery or refractive surgery. The compositions of the invention are useful for 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 conditions such as migraine, adventitious arteritis nodosa, thyroiditis, aplastic anemia, lymphogranulomatosis, scleroderma, rheumatic fever, type I diabetes, neuromuscular junction disorders including myasthenia gravis, white matter disorders including multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's disease, polymyositis, gum disease, nephritis, allergy, swelling after injury including cerebral edema, myocardial ischemia, and the like. The composition is useful for treating ophthalmic diseases such as retinitis, conjunctivitis, retinopathy, uveitis, ocular photophobia, and acute injury of ocular tissue. The composition can be used for treating pneumonia, such as pneumonia associated with viral infection and bladder fibrosis, and for treating bone resorption diseases, such as bone resorption disease associated with osteoporosis. The compositions are useful for treating certain central nervous system disorders such as cortical dementias including Alzheimer's disease, neurodegenerative disorders, and central nervous system injury due to stroke, ischemia, and trauma. The term "treatment" as used herein includes the partial or total inhibition of dementias, including Alzheimer's disease, vascular dementia, multi-infarct dementia, Alzheimer's disease, alcoholic dementia and senile dementia.

The compositions of the present invention are particularly useful as anti-inflammatory agents, such as in the treatment of arthritis, and have the additional advantage that their toxic side effects are significantly lower than in conventional non-steroidal anti-inflammatory drug (NSAIDs) compositions.

The composition can be used for treating allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome and liver diseases. The compositions are useful for treating pain, including but not limited to post-operative pain, dental pain, muscle pain, and pain caused by cancer.

The composition can be used for (but is not limited to) treating and preventing myocardial diseases related to inflammation in a subject. The compositions are useful for treating and preventing vascular disease, coronary artery disease, aneurysm, vascular rejection, arteriosclerosis, atherosclerosis including heart transplant atherosclerosis, myocardial infarction, embolism, stroke, thrombosis including venous thrombosis, angina including unstable angina, coronary plaque inflammation, bacterial-induced inflammation including chlamydial-induced inflammation, viral-induced inflammation, and inflammation associated with surgical procedures including vascular grafting for coronary artery bypass surgery, revascularization procedures including angioplasty, placement of stents, endarterectomy, or other invasive procedures involving arteries, veins, and capillaries. The composition can be used for (but not limited to) treating a subject having a disease associated with angiogenesis. The compositions of the present invention may be administered to a subject in need of inhibition of angiogenesis. The composition can be used for treating tumor formation, including tumor metastasis; ophthalmic diseases such as corneal graft rejection, ocular neovascularization, retinal neovascularization including that following injury or infection, diabetic retinal disease, macular changes, retrolental fibroplasia, and neovascular glaucoma; ulcerative diseases such as gastric ulcer; pathological but non-malignant diseases such as hemangiomas including infantile hemangiomas, nasopharyngeal angiofibromas, and avascular necrosis of bone; and diseases of the female reproductive system such as endometriosis.

The compositions are useful for preventing or treating benign or malignant tumors/neoplasias, including cancers such as colon, brain, bone, epithelial-derived neoplasias (epithelial cancers) such as basal cell, adenocarcinoma, etc., gastrointestinal cancers such as lip, mouth, esophagus, small intestine, and stomach, colon, liver, bladder, pancreas, ovary, cervix, lung, breast, and skin cancers such as squamous cell and basal-low cell, prostate, renal cell, and other cancers known to affect epithelial cells throughout the body. Tumors in which the compositions of the present invention are particularly effective are gastrointestinal cancer, Barret's esophageal cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer, cervical cancer, lung cancer, breast cancer, and skin cancers such as squamous cell and basal cell carcinomas. The compositions of the present invention may also be used to treat fibrosis resulting from radiation therapy. The composition can be used for treating subjects with adenomatous polyposis, including Familial Adenomatous Polyposis (FAP). In addition, the compositions are 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 non-steroidal anti-inflammatory drug compositions. The compositions also inhibit hormone-induced uterine contractions and have potential anti-cancer effects, but have a reduced ability to cause some of the mechanical side effects of the common NSAIDs. In particular, the compositions of the invention have the potential to reduce gastrointestinal toxicity and gastrointestinal irritation, including upper gastrointestinal ulceration and bleeding, potential to reduce renal side effects such as reduced renal function leading to fluid retention and exacerbation of hypertension, potential to reduce the effects on bleeding time including inhibition of platelet function, and possibly the ability to induce asthma attacks in aspirin-sensitive asthma patients, as compared to conventional NSAIDs compositions.

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

The composition inhibits prostaglandin-induced smooth muscle contraction by preventing synthesis of contractile prostanoids and can therefore be used for the treatment of dysmenorrhea, premature labor, asthma and eosinophil-related diseases. They can also be used in the treatment of alzheimer's disease, for reducing bone loss, particularly in postmenopausal women (i.e. in the treatment of osteoporosis), and for the treatment of glaucoma.

Because of their high cyclooxygenase-2 (COX-2) inhibitor activity and/or their cyclooxygenase-2 inhibiting specificity over cyclooxygenase-1 (COX-1) inhibition, the compositions of the present invention are useful as a replacement for conventional NSAIDs, particularly when such NSAIDs are contraindicated, e.g., in patients with peptic ulcers, gastritis, regional enteritis, ulcerative conjunctivitis, diverticulitis, or patients with a history of recurrence of gastrointestinal damage; gastrointestinal bleeding, blood clotting diseases including anemia, such as hypohemagglutination, hemophilia, or other bleeding problems; renal disease; or a patient prior to surgery or a patient taking anticoagulant. A brief description of the potential utility of cyclooxygenase-2 inhibitors is given in John Vane, Nature (Nature), Vol.367.pp.215-216, 1994, and in Drug News and perspectives (Drug News and perspectives), Vol.7, pp.501-512, 1994.

Preferred utility of the pharmaceutical composition of the invention is for the treatment of rheumatoid arthritis and osteoarthritis, for the relief of pain (especially post-oral pain, post-general surgery pain, post-orthopedic pain and acute-onset osteoarthritis), the treatment of alzheimer's disease and the chemoprevention of colon cancer.

Because of the advantages of the rapid onset of action exhibited by the pharmaceutical compositions of the present invention, these compositions have particular advantages over previous formulations of cyclooxygenase-2 inhibitory compounds useful in the treatment of acute cyclooxygenase-2 mediated disorders, and in particular, in the relief of pain.

The compositions of the present invention may be used therapeutically in combination with opioids and other analgesics, including narcotic analgesics, Mu receptor antagonists, Kappa receptor antagonists, non-narcotic (i.e., addictive) analgesics, monoamine uptake inhibitors, adenosine modulators, cannabinoids derivatives, substance P antagonists, neurokinin-1 receptor antagonists, sodium channel blockers, and the like. Preferred combination therapies include the use of a composition of the present invention and a compound selected from the group consisting of: morphine, meperidine, codeine, pentazocine, buprenorphine, butorphanol, dezocine, meptazinol, hydrocodone, oxycodone, methadone, DuP-747, Dynorphine (Dynorphine) A, etazoline, RP-60180, HN-11608, E-2078, ICI-204448, acetaminophen (paracetamol), dextropropoxyphene, nalbuphine, E-4018, felbina, mirfentanyl, amitriptyline, DuP-631, GP-531, acadesine, AKI-1, AKI-2, GP-1683, GP-69, 4030W92, tramadol racemate and isolated (+) and enantiomer, AXC-3742, SNX-111, ADL2-1294, CT-3 and CP-99994.

Dosage units containing specific amounts of a cyclooxygenase-2 inhibitor such as celecoxib can be selected to provide any desired dosing frequency that has been employed to achieve the desired daily dosage. The daily dose and frequency of administration, and the appropriate dosage unit selected accordingly, will vary widely depending upon a number of factors including the age, weight, sex and medical condition of the subject, and the nature and severity of the condition or disease.

In the case of celecoxib, the once-daily or twice-daily oral administration method which provides the daily dose required for celecoxib, for the compositions of the invention, exhibits improved efficacy over other methods of administration. Thus, for therapeutically or prophylactically effective inhibition of cyclooxygenase-2 mediated diseases, it is preferred that the compositions of the present invention be administered orally once daily or twice daily.

For the treatment of rheumatoid arthritis, the compositions of the present invention may be used to provide a daily dosage of celecoxib of from about 50mg to about 1000mg, preferably from about 100mg to about 600mg, more preferably from about 150mg to about 500mg, and further preferably from about 175mg to about 400mg, for example about 200 mg. The dosage may be once daily, twice daily, three times daily, or more. For example, the dose may be 200mg twice daily. When the composition of the present invention is administered, a generally suitable daily dosage of celecoxib is from about 0.67 to about 13.3mg/kg body weight, preferably from about 1.33 to about 8.00mg/kg body weight, more preferably from about 2.00 to 6.67mg/kg body weight, and still more preferably from about 2.33 to 5.33mg/kg body weight, e.g., about 2.67mg/kg body weight. The daily dose may be administered in divided doses 1 to 4 times daily, preferably 1 or 2 times daily. For most patients, it is preferred to administer the drug at a rate of one 100mg dosage unit at a time, twice daily, but for some patients it may be advantageous to administer the drug at a rate of one 200mg dosage unit at a time, or two 100mg dosage units at a time, twice daily.

For the treatment of osteoarthritis, the compositions of the invention may be used to provide a daily dosage of celecoxib of about 50mg to about 1000mg, preferably about 100mg to about 600mg, more preferably about 150mg to about 500mg, and even more preferably about 175mg to about 400mg, for example about 200 mg. When the compositions of the present invention are administered, a generally suitable daily dosage of celecoxib is from about 0.67 to about 13.3mg/kg body weight, preferably from about 1.33 to about 8.00mg/kg body weight, more preferably from about 2.00 to 6.67mg/kg body weight, and still more preferably from about 2.33 to 5.33mg/kg body weight, e.g., about 2.67mg/kg body weight. The daily dosage may be given as 1-4 doses per day, preferably 1 or 2 doses per day. The compositions of the present invention are preferably administered at a rate of one 100mg dosage unit per day, twice per day, or one 200mg dosage unit or two 100mg dosage units per day.

For alzheimer's disease, the compositions of the invention may be used to provide a daily dosage of celecoxib of about 50mg to about 1000mg, preferably about 100mg to about 800mg, more preferably about 150mg to about 600mg, and further preferably about 175mg to about 400mg, for example about 400 mg. When the composition of the present invention is administered, a generally suitable daily dosage of celecoxib is from about 0.67 to about 13.3mg/kg body weight, preferably from about 1.33 to about 10.67mg/kg body weight, more preferably from about 2.00 to 8.00mg/kg body weight, and still more preferably from about 2.33 to about 5.33mg/kg body weight, e.g., about 5.33mg/kg body weight. The daily dosage may be given as 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 a rate of one 200mg dosage unit or two 100mg dosage units twice daily.

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

For the treatment of pain, the compositions of the invention may be used to provide a daily dosage of celecoxib of from about 50mg to about 1000mg, preferably from about 100mg to about 600mg, more preferably from about 150mg to about 500mg, and even more preferably from about 175mg to about 400mg, for example about 200 mg. When the compositions of the present invention are administered, a generally suitable daily dosage of celecoxib is from about 0.67 to about 13.3mg/kg body weight, preferably from about 1.33 to about 8.00mg/kg body weight, more preferably from about 2.00 to about 6.67mg/kg body weight, and still more preferably from about 2.33 to about 5.33mg/kg body weight, for example about 2.67mg/kg body weight. The daily dosage can be 1-4 times daily. The compositions of the present invention are preferably administered at a rate of one 50mg dosage unit at a time, four times daily, or one 100mg dosage unit at a time, or two 50mg dosage units at a time, twice daily, or one 200mg dosage unit at a time, or two 100mg dosage units or four 50mg dosage units at a time, once daily.

In general, it is preferred that the compositions of the present invention be administered at a dosage and frequency suitable to provide a dose that provides a mean serum concentration of celecoxib of at least about 100ng/ml in the subject over a period of about 24 hours after administration.

While the celecoxib content of the compositions of the invention is preferably within the ranges disclosed herein, the compositions may also be used for administration of celecoxib doses outside the disclosed dosage ranges. For other selective cyclooxygenase-2 inhibitors, appropriate dosages can be selected by reference to the above-cited patent literature.

The nanoparticles containing or consisting of a selective cyclooxygenase-2 inhibitory compound of low water solubility, such as celecoxib, delacoxib, weddecocoxib, or rofecoxib, may be prepared according to any of the methods previously applied to the formulation of other poorly water soluble drugs in nanoparticulate form. Suitable methods for such other drugs are disclosed by way of example, but not limitation, in the above-cited U.S. Pat. Nos. 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 and 5,747,001, and the above-cited International publications WO93/25190, WO96/24336 and WO98/35666, all of which are incorporated herein by reference. One of ordinary skill in the art will readily employ the methods described therein for preparing selective cyclooxygenase-2 inhibitors in the form of poorly water soluble nanoparticles, such as celecoxib, delacoxib, weddecocoxib, or rofecoxib.

Any excipient used in the compositions of the present invention may be solid or liquid or both. The compositions preferably contain from about 1% to about 95%, preferably from about 10% to about 90%, more preferably from about 25% to about 85%, and even more preferably from about 30% to about 80%, by weight of the selective cyclooxygenase-2 inhibitor, e.g., celecoxib. Compositions of the invention containing excipients may be prepared by generally any well-known pharmaceutical technique which involves mixing the excipient with the drug or therapeutic agent, except that the selective cyclooxygenase-2 inhibitor is prepared, at least in part, in the presence of the drug or therapeutic agent, optionally together with one or more excipients, in the nanoparticulate form indicated above.

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

For example, compositions of the invention suitable for buccal or sublingual administration include lozenges comprising celecoxib in a flavoured base such as sucrose and acacia or tragacanth, and pastilles comprising celecoxib in an inert base such as gelatin and glycerin or sucrose and acacia.

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

As noted above, the compositions of the present invention containing excipients may be prepared by any suitable pharmaceutical method that includes the step of combining the cyclooxygenase-2 inhibitor (at least partially in nanoparticulate form) with the excipient. In general, the compositions are prepared by uniformly and intimately admixing the cyclooxygenase-2 inhibitory compound (hereinafter sometimes referred to as "nanoparticulate compound") with a liquid or a finely divided diluent or both, and then, if necessary or desired, encapsulating the capsules or shaping the product. For example, tablets may be prepared by compressing or molding a powder or granules of the nanoparticulate compound with one or more excipients. Compressed tablets may be prepared by compressing, in a suitable machine, a free-flowing composition such as a powder or granules containing the nanoparticulate compound optionally in admixture with one or more binders, lubricants, inert diluents, wetting agents and/or dispersing agents. Molded tablets may be prepared by molding in a suitable machine the nanoparticulate compound moistened with an inert liquid diluent.

As noted above, each dosage unit of the compositions of the present invention comprises a therapeutically or prophylactically effective amount of a partially or fully nanoparticulate selective cyclooxygenase-2 inhibitory compound, such as celecoxib, in combination with one or more pharmaceutically acceptable excipients suitable for oral administration. The compositions of the present invention preferably comprise mixing the desired amount of the nanoparticulate compound with one or more excipients selected from the group consisting of pharmaceutically acceptable diluents, disintegrants, binders, wetting agents, lubricants, and anti-adherent agents. In addition, 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 compressed or encapsulated in immediate release capsules or tablets for conventional administration.

By appropriate selection and combination of excipients, compositions may be provided that exhibit improved performance in terms of other properties, efficacy, bioavailability, elimination time, stability, compatibility of the celecoxib with the carrier material, safety, dissolved form, disintegrated form, and/or other pharmacokinetic, chemical and/or physical properties. Preferred excipients are water-soluble or water-dispersible and have a wetting property, thereby counteracting the low water solubility and hydrophobicity of the cyclooxygenase-2 inhibitor. When the composition is formulated into a tablet, the combination of excipients selected provides, among other properties, a tablet improved in dissolved and disintegrating form, hardness, crushing strength and/or friability.

The compositions of the present invention 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; starch that can be directly tabletted; mannitol USP; sorbitol; glucose monohydrate; microcrystalline cellulose NF; dibasic calcium phosphate dihydrate NF; a sucrose-based diluent; sugar is commercially available; calcium sulfate monohydrate in the form of monobasic; calcium sulfate dihydrate NF; calcium lactate trihydrate particles NF; dextrates NF (e.g., Emedx); celutab; glucose (e.g., industrial glucose); inositol; hydrolyzed cereal solids such as Maitron and Mor-Rex; amylose starch; rexcel; powdered cellulose (e.g., Elcema); calcium carbonate; glycine; bentonite; polyvinylpyrrolidone, and the like. 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 selected to have suitable flow properties and, where tablets are desired, compressibility.

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

The compositions of the invention optionally contain one or more pharmaceutically acceptable disintegrants as excipients, particularly for tablets. Suitable disintegrants include, alone or in combination, starch, sodium starch glycolate, clays (e.g., Veegum HV), celluloses (e.g., pure cellulose, methyl cellulose, sodium carboxymethyl cellulose, and carboxymethyl cellulose), alginates, pregelatinized corn starch (e.g., National 1551 and National 1550), cross-linked povidone USP NF, and gums (e.g., agar, guar gum, locust bean gum, karaya gum, pectin, and tragacanth). The disintegrant may be added at any suitable step in the preparation of the composition, particularly at the lubrication step prior to granulation or prior to tableting. 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 total weight of the composition.

Croscarmellose sodium is a preferred disintegrant for tablet or capsule disintegration, and if present, preferably comprises from about 0.2% to about 10%, more preferably from about 0.2% to about 6%, and even more preferably from about 0.2% to about 5% by weight of the total composition. Croscarmellose sodium provides greater intragranular disintegration capabilities to the compositions of the present invention.

The compositions of the invention optionally contain one or more pharmaceutically acceptable binders or adhesives as excipients, particularly for tablets. Such binders and binders preferably provide the compressed powder with sufficient viscosity to allow normal processing operations such as sizing, lubrication, compression and packaging, and, when ingested, allow the tablet to disintegrate and the composition to be absorbed. Suitable binders and adhesives include acacia, tragacanth, sucrose, gelatin, glucose, starch, cellulosic materials such as, but not limited to, methylcellulose and sodium carboxymethylcellulose (e.g., Tylose), alginic acid and its alginates, magnesium aluminum silicate, polyethylene glycol, guar gum, gluconic acids, bentonite, polyvinylpyrrolidone, polymethacrylates, Hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (Klucel), ethylcellulose (Ethocel), pregelatinized starches (e.g., National 1551 and starch 1550), alone or in combination. 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 for providing viscosity to the cyclooxygenase-2 inhibitor and other excipient powder mixture during granulation. Polyvinylpyrrolidone, if present, preferably comprises from about 0.5% to about 10%, more preferably from about 0.5% to about 7%, and even more preferably from about 0.5% to 5% by weight of the total composition. Although it is preferred that the polyvinylpyrrolidone have a viscosity of about 6cPs or less, particularly about 3cPs or less, polyvinylpyrrolidones having viscosities of up to about 20cPs may also be used. Polyvinylpyrrolidone provides powder mixture cohesiveness and promotes the necessary binding in wet granulation to form granules.

The cyclooxygenase-2 inhibitory compounds employed in the present invention, particularly celecoxib, are extremely insoluble in aqueous solutions. Thus, 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 selected so as to maintain the cyclooxygenase-2 inhibitor in intimate association with water, which is believed to be a condition that improves the relative bioavailability of the pharmaceutical composition of the present invention. Suitable wetting agents include oleic acid, glycerol monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate and sodium lauryl sulfate, alone or in combination. Anionic surfactants are preferred as wetting agents. If present, the humectant constitutes 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 a preferred wetting agent. Sodium lauryl sulfate, if present, comprises from about 0.25% to about 7%, more preferably from about 0.4% to about 6%, and even more preferably from about 0.5% to about 5% by weight of the total composition.

The compositions of the invention optionally comprise one or more pharmaceutically acceptable lubricants and/or glidants as excipients. Suitable lubricants and/or glidants include glyceryl behapate (Compritol 888); stearates (magnesium, calcium and sodium stearate), stearic acid, hydrogenated vegetable oils (e.g. fully hydrogenated vegetable oil), talc, wax, stearever, boric acid, sodium benzoate, sodium acetate, sodium fumarate, sodium chloride, DL-leucine, polyethylene glycols (e.g. waxy polyethylene glycol and methoxypolyethylene glycol mixtures 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 for reducing friction between equipment and the granulation mixture during tableting.

Other excipients (e.g., anti-adherents, colorants, flavors, sweeteners, 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 form a yellow color.

In one embodiment of the invention, the composition is in the form of a capsule or tablet as a unit dose and comprises the required amounts, partially or wholly, of the nanoparticulate selective cyclooxygenase-2 inhibitor (e.g., celecoxib) and a binder. Preferably, the composition further comprises one or more excipients selected from the group consisting of pharmaceutically acceptable diluents, disintegrants, binders, wetting agents and lubricants. More preferably, the composition comprises one or more excipients selected from 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. Even more preferably, the composition further comprises one or more of the carrier materials sodium lauryl sulfate, magnesium stearate and microcrystalline cellulose.

Although the dosage unit capsule and tablet compositions of the present invention may be prepared, for example, by direct encapsulation of the capsule or direct compression, they are preferably wet granulated prior to encapsulation of the capsule and prior to compression. Wet granulation, among other effects, may provide an increase in density of the milled composition, thereby improving flowability, improving tableting properties and making it easier to meter or modify the weight distribution of the composition for encapsulation or tableting. The secondary particle size (i.e., particle size) obtained by granulation is not merely critical, it is only important in that the average particle size is preferred for ease of handling and processing, and for tablets, allows the formation of a directly compressible mixture that produces pharmaceutically acceptable tablets.

The desired bulk density and bulk density of the particles is generally from about 0.3g/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.

For tablet formulations, the entire mixture in an amount sufficient to produce a uniform batch of tablets is compressed in a conventional production scale tablet press using normal compression forces (e.g., using a compression force of about 1kN to about 50kN in a typical tablet compression die). Any tablet hardness suitable for handling, manufacture, storage, ingestion may be used. For a 100mg tablet, the hardness is preferably at least 4kP, more preferably at least about 5kP, and still more preferably at least about 6 kP. For a 200mg tablet, the hardness is preferably at least 7kP, more preferably at least about 9kP, and still more preferably at least about 11 kP. However, the mixture is not pressed to such an extent that difficulties in hydration may occur with exposure to gastric fluid.

For tablet formulations, tablet friability of less than about 1.0%, more preferably less than 0.8%, and even more preferably less than about 0.5% is preferred in standard testing.

The present invention also relates to a method of treating a condition or disorder in which treatment is effected 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 present invention. The dosage regimen used for prophylactic, palliative, or ameliorating a condition or disease is preferably equivalent to the once-or twice-daily treatment described above, but may be modified depending on various factors. These factors include type, age, weight, sex, diet, and the nature and severity of the condition and disease in the subject. Thus, 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 disorder with a cyclooxygenase-2 inhibitor may begin with the dosages described above. The treatment that is usually necessary lasts from weeks to months or years until the condition or disease is controlled or eliminated. Patients undergoing treatment with the compositions of the present invention may be routinely monitored for therapeutic efficacy by any method known in the art. Continuous analysis of these data enables the treatment regime to be modified during the course of treatment so that an optimally effective amount of the cyclooxygenase-2 inhibitor can be administered at any one time point and thus the duration of treatment can also be determined. In this way, the treatment regimen/dosage schedule can be varied reasonably over the course of treatment, thus enabling administration of the lowest amount of cyclooxygenase-2 inhibitor that exhibits satisfactory therapeutic efficacy, and administration is continued only for the time necessary for successful treatment of the disease.

The present invention also relates to methods of making compositions of the present invention containing a poorly water soluble cyclooxygenase-2 inhibitor, such as celecoxib, partially or wholly in nanoparticulate form. More particularly, the present invention relates to a method of preparing such compositions in the form of discrete unit dose tablets or capsules, whereby each tablet or capsule contains a sufficient amount of the cyclooxygenase-2 inhibitor to provide the above-mentioned rapid onset therapeutic effect, and preferably a sustained therapeutic effect for about 12 to 24 hours. Each tablet or capsule preferably contains from about 50mg to about 200mg, such as about 50mg, about 100mg or about 200mg of a cyclooxygenase-2 inhibitor, such as celecoxib. The present invention may use wet granulation, dry granulation or direct compression or encapsulation methods 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. In a wet granulation process, any portion of the cyclooxygenase-2 inhibitor(s) (which may be used with one or more carrier materials, if desired) not included in the nanoparticulate form is first milled or micronized to the desired particle size range of greater than 1 mm. While various conventional mills or granulators can be used to impact mill the drug substance, such as pin milling, provide improved homogeneity in achieving mixing of the final composition as compared to other means of milling. During the milling process, it may be necessary to cool the milled material, for example using liquid nitrogen, to avoid heating the cyclooxygenase-2 inhibitor to undesirable temperatures. In this milling step, D₉₀The particle size is preferably reduced to less than about 25 mm.

The milled or micronized cyclooxygenase-2 inhibitor, if any, is then mixed with the desired amount of cyclooxygenase-2 inhibitor in nanoparticulate form prepared by any of the methods known in the art described above to provide a partially or fully 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-walled mixer or sigma mixer, with one or more excipients, including excipients that have been milled with celecoxib, or in nanoparticulate form, to form a dry powder mixture. Typically, the nanoparticulate compound is mixed with one or more diluents, disintegrants and/or binders and, optionally, one or more wetting agents in this step, although alternatively, all or part of one or more excipients may 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 a portion of croscarmellose sodium during the mixing step (providing intragranular croscarmellose sodium) and the remainder after the drying step discussed below (providing extragranular croscarmellose sodium) can facilitate disintegration of the tablets produced. In this case, it is preferred to add from about 60% to about 70% croscarmellose sodium within the granule and from about 25% to about 40% croscarmellose sodium outside the granule. 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 made with such granules.

The mixing step of the method preferably comprises mixing the nanoparticulate compound, lactose, polyvinylpyrrolidone and croscarmellose sodium. It has been found that mixing times as short as 3 minutes can provide a dry powder mixture with a sufficiently uniform distribution of the cyclooxygenase-2 inhibitor.

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 granulation mixture. A wetting agent is preferably used and is preferably added to the water first and mixed for at least 15 minutes, preferably at least 20 minutes, before the water is added to the dry powder mixture. The water may be added to the mixture immediately, stepwise over a period of time, or in portions over a period of time. The water is preferably added stepwise over a period of time. Alternatively, a wetting agent may be added to the dry powder mixture and then water added to the resulting mixture. Preferably, the water is added followed by an additional mixing period to ensure 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 materials that form by-products during the wet granulation operation. If not removed, these agglomerates will prolong the subsequent fluid bed drying operation and increase the variation in moisture control.

The wet granulation or wet milled mixture is then dried, for example, in an oven or fluid bed dryer, preferably a fluid bed dryer, to form dried granules. If desired, the wet granulation mixture may be extruded or spheronized (sphenonize) prior to drying. For the drying process, operating conditions such as inlet air temperature and drying time may be adjusted to achieve the desired moisture content of the dried particles. For this drying step and subsequent process steps, it would be desirable to combine 2 or more pelletization processes.

To the extent necessary, the dried granules are then reduced in size in preparation for compression and encapsulation of the capsules. Conventional equipment for reducing the particle size such as a shaker or impact mill (e.g., Fitz mills) may be used.

A slight decrease in particle size can be observed with increasing mixing time for mixtures with low water content. Given that a too low water content does not activate the binder used sufficiently, the cohesion between the primary particles within the granules is not sufficient to make the granules unable to withstand the shear forces generated by the mixer blades, and the granulometry is therefore worn away rather than increased. Generally, increasing the moisture content to sufficiently activate the binder allows the bonding forces between the primary particles to withstand the shear forces generated by the mixer blades, while allowing the particles to grow rather than wear out with increasing mixing time and/or water addition. Changing the wet grinder screen size will result in greater impact on particle size than changing the feed rate and/or grinding rate.

The dry powder granules are then placed in a suitable mixer, such as a twin-wall mixer, optionally with the addition of a lubricant (e.g., magnesium stearate) and any additional carrier materials (e.g., extragranular microcrystalline cellulose and/or extragranular croscarmellose sodium in a tablet formulation) to form the final blended mixture. Where the diluent comprises microcrystalline cellulose, it has been found that the addition of a further portion of microcrystalline cellulose during this step increases the compressibility of the granules and tablet hardness. However, increasing the amount of magnesium stearate above about 1% -2% decreases tablet hardness and increases friability and dissolution time.

The final blended mixture is then encapsulated (or if tablets are to be made, the blend is compressed with a suitably sized tool into tablets of the desired weight and hardness). Conventional pressing and encapsulation 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 20mm to about 60mm, a compression device of about 0 to about 5mm, and a rate of about 60,000 capsules to about 130,000 capsules per hour. By using a minimum compression means capable of controlling the weight of the capsule, the formation of lumps can be reduced or eliminated. When coated tablets are desired, conventional coating techniques known to those of ordinary skill in the art may be employed.

The combination of the operating units produces homogeneous granules of a cyclooxygenase 2 inhibitor such as celecoxib in an amount that, at the unit dosage level, is rapidly disintegrated and subsequently sufficiently released so that weight variation can be reliably controlled during capsule filling or tableting and that are of sufficient density so that they can be mass produced in the selected equipment and are suitable for a single dose for molding of a particular capsule or tablet.

The invention also relates to the use of the compositions of the invention in the manufacture of a medicament for the treatment and/or prevention of cyclooxygenase-2 mediated conditions and disorders, in particular where a rapid onset of therapeutic effect is required or desired.

The present invention also includes a novel solid form of celecoxib, form I celecoxib. The invention further includes another solid form of celecoxib, form II celecoxib. Each of these new solid state forms includes solvated forms, unsolvated and unhydrated forms. These novel celecoxib compounds described herein have one or more of the foregoing advantageous chemical and/or physical properties as compared to other solid state forms described or otherwise disclosed in the literature herein.

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

Form I celecoxib is a crystalline form of celecoxib having an X-ray powder diffraction pattern with peaks at about 5.5, 5.7, 7.2, and 16.6 degrees 2 Θ. The form I celecoxib X-ray powder diffraction pattern is substantially as shown in the top panel of figure 1 a. Form I celecoxib has a melting point of about 162.5 ℃ to about 163 ℃, preferably about 162.8 ℃. Form I celecoxib has a differential scanning calorimetry endotherm maximum at about 163.3 ℃ when scanned at 0.5 ℃/minute as shown in figure 3. The infrared spectrum of form I celecoxib is shown in FIG. 2 and is characterized as being at about 3250cm^-1And 3260cm^-1Has one peak and the other peak is 3350cm^-1And 3360cm^-1Preferably the peak is 3256cm^-1And 3356cm^-1. The solid form of the present invention has a phase purity of at least about 5% form I celecoxib, preferably at least about 10% form I celecoxib, more preferably at least about 25% form I celecoxib, even more preferably at least about 50% form I celecoxib, even more preferably at least about 75% form I celecoxib, even more preferably at least about 90% form I celecoxib, and most preferably substantially form I celecoxib phase purity.

In another embodiment of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of solid form of celecoxib wherein the solid form of celecoxib comprises at least 2% form I and preferably 10% form I, or more preferably 50% form I, and even more preferably 98% form I, and at least one pharmaceutically acceptable carrier, adjuvant or diluent. In a preferred embodiment, the solid form of celecoxib is predominantly form I celecoxib.

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

Another embodiment of the invention is a process for preparing form I celecoxib wherein the process comprises crystallizing form I celecoxib from a mixture comprising celecoxib and a solvent wherein the crystallization is conducted at a temperature above the enantiomeric transition temperature of form I celecoxib. Prior to crystallization of form I celecoxib, form I celecoxib can be seeded with seed crystals of form I celecoxib in a solvent resulting in form I celecoxib having at least about 5 weight percent phase purity, preferably at least about 10 weight percent phase purity, more preferably at least about 25 weight percent phase purity, even more preferably at least about 50 weight percent phase purity, and even more preferably at least about 90 weight percent phase purity.

The present invention also relates to preparing a crystalline form of celecoxib wherein the process comprises heating a solvate of celecoxib thereby producing form I celecoxib. For example, the solvate may be heated to a temperature of from about 50 ℃ to about 160 ℃, preferably from about 60 ℃ to about 150 ℃, more preferably from about 70 ℃ to about 140 ℃, still more preferably from about 80 ℃ to about 130 ℃, still more preferably from about 85 ℃ to about 120 ℃, still more preferably from about 90 ℃ to about 110 ℃, and most preferably about 100 ℃. The heating can be for any conventional time, such as 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, and still more preferably about 4 hours or more. Additionally, the process can be carried out at any pressure, preferably below atmospheric pressure. The solvate used in the present invention contains celecoxib and a solvent. For example, the solvent may be an amide solvent. Useful amide solvents include N, N-dimethylformamide, 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. The preferred solvent is 1, 1, 3, 3-tetramethylurea. Another preferred solvent is 1, 3-dimethyl-3, 4,5, 6-tetrahydro-2 (1H) -pyrimidinone. Still another preferred solvent is 1-methyl-2-pyrrolidone. Yet another preferred solvent is N, N-dimethylformamide. Yet another preferred solvent is N, N-dimethylacetamide.

A method of preparing a solvate comprising mixing celecoxib with an amide solvent selected from the group consisting of: n, N-dimethylformamide, 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. The 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. Still another preferred solvent is N, N-dimethylformamide. Yet another preferred solvent is N, N-dimethylacetamide.

The present invention also relates to a process for preparing form I celecoxib wherein the process comprises milling or grinding form III celecoxib. Useful milling steps include, for example, wet milling or ball milling. Useful milling steps may include, for example, grinding or shaking.

The present invention also relates to a process for preparing form I celecoxib wherein the process comprises milling or grinding a celecoxib 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 invention is a method of preparing form I celecoxib wherein the method comprises melting form II celecoxib and cooling the melt, thereby producing form I celecoxib.

Another embodiment of the invention is a method of preparing form I celecoxib wherein the method comprises melting form III celecoxib and cooling the melt, thereby producing form I celecoxib.

The invention also relates to a process for preparing form I celecoxib wherein the process comprises evaporating the solvent from a solution of celecoxib. For example, the solvent may be an ether or a hydrocarbon, or a mixture of an ether and a hydrocarbon. Preferred solvents include ethyl acetate and heptane, preferably in a ratio of 15: 85. 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 ℃.

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

Form II celecoxib has an X-ray powder diffraction pattern with peaks at about 10.3, 13.8, 17.7 degrees 2 Θ. The peaks for the mixture of celecoxib form I and II are shown in the top graph of fig. 1 b. Form II celecoxib has a melting point of about 161 ℃ to about 162 ℃, preferably about 161.5 ℃. Form II celecoxib has a differential scanning calorimetry endotherm maximum at about 162.0 ℃ when scanned at 0.5 ℃/minute. Form II celecoxib is expected to have higher solubility and faster dissolution rate than form III celecoxib. The solid form of the present invention has a phase purity of at least about 5% form II celecoxib, preferably at least about 10% form II celecoxib, more preferably at least about 25% form II celecoxib, even more preferably at least about 50% form II celecoxib, yet even more preferably at least about 75% form II celecoxib, yet even more preferably at least about 90%, most preferably substantially form II celecoxib.

In another embodiment of the invention, there is provided a pharmaceutical composition comprising an effective amount of solid form of celecoxib wherein the solid form of celecoxib comprises at least 2% form II celecoxib, and preferably 10% form II celecoxib, or more preferably 50% form II celecoxib, and even more preferably 98% form II celecoxib, and at least one pharmaceutically acceptable carrier, adjuvant or diluent. In a preferred embodiment, the solid form of celecoxib is predominantly form II celecoxib.

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

Another embodiment of the invention is a process for preparing form II celecoxib from a mixture comprising celecoxib and a solvent wherein crystallization is effected at a temperature above the enantiomeric transition temperature of form II celecoxib thereby producing form II celecoxib. Prior to crystallization of form II celecoxib, the solvent may be seeded with seed crystals of form II celecoxib resulting in form II celecoxib having at least about 5 weight percent phase purity, preferably at least about 10 weight percent phase purity, more preferably at least about 25 weight percent phase purity.

The present invention also relates to a method of preparing a crystalline form of celecoxib wherein the method comprises heating a solvate of celecoxib thereby producing form II celecoxib. The solvate may be heated to a temperature of, for example, about 50 ℃ to about 160 ℃, preferably about 60 ℃ to about 145 ℃, more preferably about 70 ℃ to about 140 ℃, still preferably about 80 ℃ to about 140 ℃, further preferably about 90 ℃ to about 140 ℃, still further preferably about 100 ℃ to about 140 ℃, still further preferably about 110 ℃ to about 140 ℃, still further preferably about 120 ℃ to about 140 ℃, still further preferably about 125 ℃ to about 135 ℃, and most preferably about 130 ℃. The heating can be for any conventional time, such as for more than about 1 minute, preferably for more than about 5 minutes, more preferably for more than about 60 minutes, even more preferably for about 2 hours, preferably for about 4 hours or more. Additionally, the process can be carried out at any pressure, preferably below atmospheric pressure. The solvate used in the present invention contains celecoxib and a solvent. For example, the solvent may be an amide solvent. Useful amide solvents include N, N-dimethylformamide, 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. The 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. Still further preferred solvent is N, N-dimethylformamide. Still further preferred solvent is N, N-dimethylacetamide.

In another embodiment of the invention wherein form II celecoxib is prepared by heating a celecoxib solvate, the process for preparing the solvate comprises mixing celecoxib with an amide solvent selected from the group consisting of: n, N-dimethylformamide, 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. 1, 1, 3, 3-tetramethylurea is preferable, 1, 3-dimethyl-3, 4,5, 6-tetrahydro-2 (1H) -pyrimidinone is more preferable, 1-methyl-2-pyrrolidone is further preferable, N-dimethylformamide is further preferable, and N, N-dimethylacetamide is further more preferable.

Another embodiment of the invention is a solid form of celecoxib comprising form I and form II celecoxib.

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

Yet another embodiment of the present invention is a solid form of celecoxib comprising form I I and form ii I celecoxib.

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

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

The present invention also relates to a process for preparing form I celecoxib wherein the process comprises milling or grinding a celecoxib solvate. Useful milling steps include, for example, wet milling or ball milling. Useful milling steps may include, for example, grinding or shaking.

Another embodiment of the invention is a method of preparing form II celecoxib wherein the method comprises melting form I celecoxib and cooling the melt, thereby producing form II celecoxib.

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

Form III celecoxib is prepared by crystallizing celecoxib from a solvent comprising isopropanol and water (see, e.g., u.s.5,910,597).

Form III celecoxib has a complex differential scanning calorimetry melting transition. When scanned at 0.5 ℃/min, melting of form III celecoxib was observed at about 160.8 ℃, followed by recrystallization to form II celecoxib, followed by melting of form II celecoxib was observed at about 162.0 ℃. Form III celecoxib is a thermostable state of celecoxib.

Polymorphic crystalline forms characterizing celecoxib

Form I and form II celecoxib were characterized using X-ray powder diffraction (PXRD), infrared absorption spectroscopy (IR), Differential Scanning Calorimetry (DSC), and Raman (Raman) spectroscopy.

X-ray powder diffraction (PXRD)

Various forms of celecoxib can be analyzed using a Siemens (Siemens) D5000 powder diffractometer or an Inel multifunctional diffractometer. For the siemens D5000 powder diffractometer, the raw data for 2 ° to 5 ° 2- θ values can be determined with a gradient of 0.02 ° and a gradient period of 2 seconds. For the Inel multifunction diffractometer, the samples were placed in an aluminum sample container while raw data for all 2 θ values were collected for 30 minutes.

As shown in fig. 1, three crystal forms of celecoxib can be readily distinguished by PXRD. Using a CuX-ray source (1.54nm), characteristic diffraction was observed at 2-theta values of approximately 5.5 °, 5.7 °, 7.2 °, and 16.6 ° for form I celecoxib, while characteristic diffraction was observed at approximately 10.3 °, 13.8 °, and 17.7 ° for form II celecoxib.

Melting/decomposition temperature

The melting and/or decomposition temperatures of the unsolvated celecoxib crystalline form are measured using a TA instruments 2920 differential scanning calorimeter. Each sample (1-2mg) was placed in a closed or unsealed aluminum container and heated at a rate of 0.5 deg.C/minute. The melting/decomposition range is defined from the extrapolated starting point to the maximum of the melting/decomposition endotherm.

Three polymorphic crystalline forms of celecoxib have been identified. The polymorphic crystalline form I celecoxib melts at about 162.8 ℃; form II celecoxib melts at about 161.5 ℃; and form III celecoxib melts at about 160.8 ℃. Upon melting, partial recrystallization of form III celecoxib to form II or form I celecoxib is observed.

Three polymorphic crystal forms and solvates of N, N-Dimethylacetamide (DMA) and N, N-Dimethylformamide (DMF) are identified. The physical properties and identifying characteristics of the new polymorphic forms are shown in table 1.

TABLE 1

Crystal form	Melting Point (. degree.C.)	ΔH(J/G)	Identifying transformations
									IR	Raman spectroscopy	PXRD(2θ)
I	162.8	72	3256cm-13356cm-1	NA	5.5 °, 5.7 °, 7.2 ° and 16.6 °
						II**	161.5	＜84	Is free of	712cm-1	10.3 °, 13.8 ° and 17.7 °
III	160.8	91	---	---	---
						A pair ofNo characteristic transformation was observed for other forms and pure samples of form II celecoxib were prepared

Differential Scanning Calorimetry (DSC)

DSC was used to characterize polymorphic crystalline forms of celecoxib. Form I celecoxib is the highest melting polymorph at 162.8 ℃ with an endothermic maximum at 163.3 ℃. Form II celecoxib melts at 161.5 ℃ and has an endothermic maximum at 162.0 ℃. A complex shift in form III celecoxib was observed. The complexity of this transition, which can only be observed at slow scan speeds, represents melting of form III celecoxib, followed by recrystallization to form II celecoxib, which in turn melts. Form III celecoxib prefers to melt at 160.8 c with an endothermic maximum at 161.5 c for only initial endothermic conversion. DSC measures low levels of form I celecoxib in form III celecoxib.

Infrared absorption spectrum

IR identifies form I celecoxib from form II and form III celecoxib (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 to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

Examples

The following examples include detailed descriptions of the methods for preparing crystalline form I celecoxib and form II celecoxib as described herein. These detailed descriptions fall within the scope of the invention and are intended to be illustrative of the invention.

The detailed description is to be construed as illustrative only and is not intended to limit the scope of the invention. All parts are by weight and temperatures are in degrees celsius unless otherwise indicated. The starting material for celecoxib used in each of the following examples was prepared according to the method of U.S. 5910597.

Preparation examples

Preparation example 1: preparation of celecoxib DMA solvate (ratio 1: 1 celecoxib-DMA)

Method a. in a round bottom flask, 4.84g of celecoxib was mixed with about 125mL of DMA. The solvent was removed under reduced pressure at 60 ℃ to cause crystallization. The dry solid was collected on the filter. This procedure yielded a 5 gl: 1 solvate. Decomposition started at about 100 ℃ with a maximum at 148 ℃ with a total weight loss of 17% as determined by TGA at 10 ℃/min.

Method B. in a 1L beaker, 38.2g of celecoxib was added with stirring in about 1000mL of DMA. The resulting solution was transferred to a 2L beaker. Crystallization was initiated by the addition of about 400ml of water. The crystals were isolated by filtration. The wet yield was 5.44 g. Addition of water to the filtrate produced additional crystals obtained. TGA measurements at 10 deg.C/min showed decomposition at about 100 deg.C with a maximum at about 150 deg.C with a total weight loss of 18% solvent.

Preparation example 2: preparation of celecoxib DMF solvate (ratio 1: 1 celecoxib-DMF)

In a crystallization vessel, about 1g of celecoxib was dissolved in 50mL of DMF. The crystallization vessel was covered with a small perforated aluminum foil and placed in a hood, which was then evaporated to dryness. This process produced about 1.02g of product. TGA measurements at 10 deg.C/min showed two weight losses in the decomposition, starting at 75 deg.C and continuing to a second maximum at 156 deg.C. The total weight loss was 13.4%.

The operation example:

example 1: conventional Process for preparing form I celecoxib

A. Preparation of form I celecoxib by heating a celecoxib solvate:

the open container of celecoxib solvate was heated in an oven at the lowest temperature at which desolvation was observed. Briefly, 0.3g of celecoxib-DMA is heated in an oven at about 100 ℃ for about 48 hours. The resulting sample PXRD showed reflections of features caused by form I celecoxib, and celecoxib-DMA reflections; TGA showed a weight loss of 9.6% centered approximately at 147 ℃, indicating about 50% conversion to form I celecoxib.

B. Preparation of form I celecoxib by evaporation

A high purity sample of celecoxib was crystallized from ethyl acetate-heptane solvent by evaporation. Celecoxib (16.03g) was purified by preparative liquid chromatography using 15/85(v/v) ethyl acetate/heptane and a 150mm column of 40-63 mm silica gel (50.8 mm diameter). Fractions eluting between 270ml and 900ml were collected and pooled. The solvent was removed under vacuum at about 35 ℃ to cause crystallization and evaporated to dryness. This process produced 8.6g of form I celecoxib. The crystalline product was found to be solvent free by TGA determination and its form I celecoxib PXRD pattern is shown in figure 1 a.

C. Preparation of form I celecoxib by melting:

typically, celecoxib is placed in an open container and melted by heating, and then allowed to cool. In more detail, the beaker containing celecoxib is heated on a hot plate to about 170 ℃ and the celecoxib is completely melted. The molten celecoxib is then poured onto a crystal of watch crystal and allowed to cool. Melting of form I celecoxib was observed at about 163 ℃ as measured by DSC at 0.5 ℃/min scan. A melt of form III celecoxib, and recrystallization of form II celecoxib and its melt are also observed.

Example 2: conventional Process for preparing form II celecoxib

A. Preparation of form II celecoxib by heating a celecoxib solvate:

1. using DMA solvates

Typically, an open container of celecoxib-DMA solvate is heated in an oven and desolvation is observed near this peak temperature. Briefly, 0.3g of celecoxib-DMA is heated in an oven at about 130 ℃ for about 48 hours. The resulting sample PXRD showed characteristic reflections caused by form II and form III celecoxib; DSC at 0.5 deg.C/min shows a single melting endotherm with an onset point at 161.4 deg.C and a maximum at 161.9 deg.C; below 200 ℃, TGA shows no weight loss. The powder X-ray diffraction pattern of the mixture is shown in FIG. 1 b.

2. Solvates with DMF

Typically, an open container of celecoxib-DMA solvate is heated in an oven and desolvation is observed near this peak temperature. Briefly, about 0.2g of celecoxib-DMA is heated overnight in an oven at about 130 ℃. The resulting sample PXRD showed characteristic reflections caused by form II and form III celecoxib; DSC at 0.5 ℃/min showed a single melting endotherm with an onset point at 161.5 ℃, a maximum at 161.8 ℃, and a small endothermic transition (form I) with a maximum at about 163.8 ℃; below 200 ℃, TGA shows no weight loss.

B. Form II celecoxib is prepared from form III celecoxib by mechanical transformation:

typically, form III celecoxib is milled in a ball mill. Simply, using a creeper, form III celecoxib prefers milling at maximum intensity for 30 seconds. The resulting solid is a mixture of form III celecoxib and form II celecoxib, as determined by powder X-ray diffraction.

C. Preparation of form II celecoxib by melting:

celecoxib was melted in a test tube using an oil bath at 170 ℃. A teflon spatula was inserted into the molten celecoxib, the spatula was moved, scraped, and the dry solids on the spatula were collected. The dry solid is a mixture of form II and form III as determined by powder X-ray. DSC at 10 deg.C/min also showed the presence of form I celecoxib.

Claims (23)

1. A crystalline form I form of celecoxib having the following physical properties:

(1) an X-ray powder diffraction pattern having peaks at 5.5, 5.7, 7.2, and 16.6 degrees 2 Θ;

(2) having a melting region of 160 ℃ to 164 ℃;

(3) having a differential scanning calorimetry endotherm maximum in the range of 160.0 ℃ to 164.0 ℃;

(4) has a length of 3250 to 3260cm^-1Infrared spectrum having peaks and a peak length of 3350 to 3360cm^-1(iii) an infrared spectrum having peaks.

2. The crystalline form of claim 1 having a melting range of 162 ℃ to 163 ℃.

3. The crystalline form of claim 2 having a melting point of 162.8 ℃.

4. The crystalline form of claim 1 having a differential scanning calorimetry endotherm maximum of 163.3 ℃.

5. The crystalline form of claim 4 having a melting point of 162.8 ℃.

6. The crystalline form of claim 1 having a length of 3256cm^-1(iii) an infrared spectrum having peaks.

7. The crystalline form of claim 1 having a length of 3356cm^-1(iii) an infrared spectrum having peaks.

8. The crystalline form of claim 1 having a length of 3256cm^-1And 3356cm^-1A peaked infrared spectrum and a melting point of 162.8 ℃.

9. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of any one of claims 1 to 8 and at least one pharmaceutically acceptable carrier, adjuvant or diluent.

10. Use of form I celecoxib according to any one of claims 1-8 in the manufacture of a medicament for the treatment or prevention of a cyclooxygenase-2-mediated condition or disorder in a subject.

11. The use of claim 10, wherein the condition or disease is pain.

12. The use of claim 10, wherein the condition or disease is inflammation.

13. The use of claim 10, wherein the condition or disease is arthritis.

14. The use of claim 10, wherein the condition or disease is tumor growth.

15. The use of claim 10, wherein the condition or disease is tumor metastasis.

16. The use of claim 10, wherein the condition or disease is familial adenomatous polyposis.

17. A process for preparing form I crystalline form of celecoxib wherein the process comprises heating a solvate of celecoxib comprising celecoxib and an amide solvent wherein the amide solvent is N, N-dimethylacetamide, thereby producing form I celecoxib.

18. The method of claim 17 wherein the solvate is heated to a temperature of 100 ℃.

19. The process of claim 17 wherein the solvate is heated for 48 hours.

20. A process for preparing form I celecoxib crystalline form wherein the process comprises heat melting celecoxib and cooling the melt to a temperature of 163 ℃ thereby producing form I celecoxib.

21. A process for preparing form I crystalline form of celecoxib comprising evaporating the solvent from a solution of celecoxib and ethyl acetate and heptane in a ratio of 15: 85 to produce form I celecoxib.

22. The method of claim 21, wherein said evaporating is carried out at subatmospheric pressure.

23. The method of claim 21, wherein said evaporating is performed at a temperature of 35 ℃.