JP2008528568A - Celecoxib of type IV crystals - Google Patents

Abstract

Novel crystalline form of celecoxib (4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide), process for its preparation and pharmaceutical composition containing it Things are listed.

Description

  The present invention is in the field of pharmaceuticals that are active as cyclooxygenase 2 inhibitors, more specifically 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H, which is a cyclooxygenase 2 inhibitor. -Pyrazol-1-yl] benzenesulfonamide ("celecoxib"). In particular, the present invention relates to a novel crystalline form of celecoxib.

  The use of non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of pain and swelling associated with inflammation can produce severe side effects, including life-threatening ulcers. Discovery of inducible enzymes related to inflammation ("Prostaglandin G / H Synthase II" or "Cyclooxygenase 2 (COX-2)") realizes more effectively reducing inflammation, less side effects and less intense Sexual inhibition targets have been provided.

  Compounds that selectively inhibit COX-2 have been described. For example, substituted pyrazolylbenzenesulfonamides described in US Pat. No. 5,466,823, incorporated herein by reference, include, for example, celecoxib.

  US Pat. No. 5,892,053, incorporated herein by reference, describes a method for preparing celecoxib.

  International patent publication WO 00/04021, incorporated herein by reference, illustrates the solvated crystalline form of celecoxib and its synthesis.

  Currently, four solid forms of celecoxib known as type I, type II, type III, and amorphous celecoxib are known.

  Type I and Type II celecoxib are described in International Patent Publication No. WO 01/42222, incorporated herein by reference. Type I celecoxib has X-ray powder diffraction (“PXRD”) pattern peaks at 2θ of about 5.5, 5.7, 7.2, and 16.6 degrees, and differential scanning calorimetry (“ DSC ") is a crystalline form of celecoxib with a maximum value of about 163.3 ° C when scanned at 0.5 ° C / min. Type II celecoxib has peaks in the PXRD pattern at 2θ of about 10.3, 13.8, and 17.7 degrees, and about 162.0 when the DSC maximum is scanned at 0.5 ° C./min. Celecoxib crystal form at ℃.

  International Patent Publication No. WO 01/42221, incorporated herein by reference, describes amorphous celecoxib and a method for preparing amorphous celecoxib using a crystallization inhibitor. Amorphous celecoxib exhibits a clear glass transition at 111.4 ° C. (onset).

  US Pat. No. 6,391,906 alleges that it describes another solid form of celecoxib, referred to therein as Form I.

  Celecoxib formulations for oral administration have hitherto been difficult due to the unique physical and chemical properties of celecoxib, particularly its low solubility, and factors related to its crystal structure, including stickiness, low bulk density, and low compressibility It was a thing. Celecoxib is extremely insoluble in aqueous media. For example, after oral administration in capsule form, unformulated celecoxib does not dissolve and disperse easily to be rapidly absorbed in the gastrointestinal tract. Furthermore, unformulated celecoxib, which has a crystalline form that tends to form long sticky acicular crystals, is usually fused and united into a lump when pressed into a tableting mold. Even when blended with other materials, the celecoxib crystals tend to separate from other materials and tend to agglomerate when mixing the composition, and a heterogeneously blended composition containing undesirably large celecoxib agglomerates. Bring things. Therefore, it is difficult to prepare a pharmaceutical composition comprising celecoxib having the desired blend uniformity.

  Suspension is the preferred form for many pharmaceutical administrations where rapid onset is desired. In suspensions, viscosity and settling rate are important factors when dealing with consumer preferences. If the viscosity is too high, the suspension will not flow easily and it will be difficult to achieve accurate dosing due to excessive hold-up in the dosing cup or spoon. If the particles in the suspension settle too quickly and form a cake at the bottom of the bottle, the settling rate will be much more difficult for the consumer to resuspend the particles by shaking vigorously. Is important.

  Celecoxib has a relatively high dosage requirement. For such high dose / low solubility drugs, the size of the capsule or volume of solution required to provide the dose is a limiting factor. For example, for a drug with a solubility in a given solvent of 10 mg / mL and a dosage of 400 mg / day, it may be necessary to take at least 40 mL of solution. Such a volume may be inconvenient or unacceptable for consumption in a drinking form, and capsules containing more than about 1.0 mL to about 1.5 mL of liquid are generally too large to be comfortably swallowed. As seen, this volume presents certain problems even when a capsule dosage form is desired. Thus, when administering a solution in capsule form, multiple capsules will need to be ingested to provide the required dose.

  Celecoxib as a selective inhibitor of COX-2 is in the treatment or prevention of disorders involving COX-2, such as inflammatory disorders (including, for example, arthritis), disorders associated with pain, disorders associated with fever, etc. Can be administered if desired to use a COX-2 selective inhibitor.

  For example, in the treatment of acute pain in headaches or migraines, a crystalline form of celecoxib with enhanced bioavailability may be useful in providing rapid pain relief. A form of celecoxib that is more soluble in an aqueous medium would be useful in providing new formulations with superior properties. These superior properties include, but are not limited to: (1) improved bioavailability, (2) improved solubility, (3) short disintegration time of the solid dosage form, (4) solid dosage form One or more of a short dissolution time and (5) an improved dissolution profile of the solid dosage form is included.

  As is the case with all compounds, the chemical and physical properties, including but not limited to the thermodynamic and pharmacokinetic properties of celecoxib formulations, are therapeutic and commercial. Important for development. Unfortunately, many useful drugs are poorly water soluble and are therefore difficult to formulate at convenient concentrations as solutions in aqueous media. Even if a suitable solvent is discovered as a vehicle for such drugs, especially poorly water soluble drugs such as celecoxib often precipitate out of solution and / or come into contact with water in the aqueous environment of the gastrointestinal tract, for example. Then, there is a tendency to recrystallize. Such precipitation and / or recrystallization may offset or reduce the benefit of rapid onset of therapeutic effect to be obtained by formulating the drug as a solution. Moreover, such precipitation or recrystallization can create regulatory objections during the new drug approval process.

  A novel crystalline form of celecoxib with enhanced bioavailability will provide greater flexibility with regard to the choice of pharmaceutical additives in pharmaceutical compositions. If such improved crystalline forms of celecoxib could be provided, significant advances in the treatment of conditions and disorders involving COX-2 would be a reality.

Now provided is a crystalline form of celecoxib, referred to herein as type IV crystalline celecoxib. Form IV crystalline celecoxib is a powder X-ray diffraction pattern comprising at least one peak with 2θ of about 4.46, 13.13, 18.29, 20.21, 18.83, or 26.24 degrees; Characterized by a differential scanning calorimetry profile with an endotherm between 144 ° C. and 149 ° C .; and at least one of the infrared spectra having at least one peak at about 3342, 3295, or 3213 cm ⁻¹ . In a more preferred embodiment, the type IV crystalline celecoxib comprises a powder X-ray containing peaks where 2θ is about 4.46, 13.13, 18.29, 20.21, 18.83, and 26.24 degrees. Characterized by at least one of a diffraction pattern; a differential scanning calorimetry profile with an endotherm between about 144 ° C. and 149 ° C .; and an infrared spectrum with peaks at about 3342, 3295, and 3213 cm ⁻¹ .

  Furthermore, a pharmaceutical composition comprising Form IV crystalline celecoxib and at least one pharmaceutically acceptable pharmaceutical additive is provided.

  Furthermore, a method for preparing a composition comprising cerecoxib type IV, wherein a first solution is prepared by dissolving a water-soluble polymer and a surfactant in an aqueous solvent to form a first solution; Dissolving celecoxib in liquid PEG to prepare a second solution; adding the second solution to the first solution to produce a mixture such that precipitation of Form IV crystalline celecoxib; and celecoxib from the mixture A method is provided comprising the step of isolating the precipitate.

  Still further, a method of preparing Form III celecoxib is provided, comprising heating the Form IV crystalline celecoxib to a temperature of about 150 ° C to about 162 ° C.

  Furthermore, a method of treating or preventing a condition or disorder involving COX-2 in a subject is provided, comprising administering to the subject a pharmaceutical composition comprising Form IV crystalline celecoxib.

  In one method of making Form IV crystalline celecoxib, celecoxib (produced as described in US Pat. No. 5,466,823) is dissolved in a solvent to produce a celecoxib solution. The celecoxib solution is contacted with an aqueous solution to produce a controlled precipitation mixture. The phase purity of the celecoxib precipitate in the controlled precipitation mixture is controlled by adjusting the starting reagent proportions and / or manufacturing techniques as taught below. In one embodiment of the invention, Form IV crystalline celecoxib constitutes substantially all celecoxib present in the controlled precipitation mixture. In another embodiment of the invention, the type III celecoxib comprises substantially all celecoxib present in the controlled precipitation mixture. In another embodiment of the invention, the blend of Form IV crystalline celecoxib and Form III celecoxib constitutes substantially all celecoxib present in the controlled precipitation mixture.

  An exemplary procedure for controlled deposition of Form IV crystalline celecoxib is described in Example 1.

  An exemplary celecoxib solution for controlled deposition of Form IV crystalline celecoxib may include celecoxib, PEG, and polysorbate 80. In one embodiment, a celecoxib solution is formed by slowly adding celecoxib to PEG or PEG and polysorbate 80 with stirring.

  In one embodiment, the controlled precipitation mixture is produced as follows. About 400 PEG containing celecoxib in the solution is added to an aqueous solution containing HPMC and optionally further PVP. Such optional PVP can be prepared, for example, in solution and then added to the aqueous solution before, simultaneously with, or after combining with the celecoxib solution. After an aqueous solution containing HPMC (or HPMC + PVP) is added to the celecoxib solution, type IV crystalline celecoxib precipitates. In optional embodiments, other agents can be added to one or more of the aqueous solution, celecoxib solution, or controlled precipitation mixture. Exemplary drugs are sucrose, citric acid, sodium citrate, and sodium benzoate.

  The controlled precipitation mixture may optionally be homogenized for several minutes with an emulsifier.

  In order to isolate the type IV crystalline celecoxib particles from the precipitation suspension, the controlled precipitation mixture is stored until the precipitation reaction reaches equilibrium. The precipitated type IV crystalline celecoxib particles are separated, for example, by a vacuum filtration device. When the type IV crystalline celecoxib particles are washed with water, water-soluble components can be removed from the particles. The type IV crystalline celecoxib particles can then be dried, for example, at room temperature under reduced pressure for 24 hours, and then placed in a desiccator until the particles are completely dry.

  One solvent useful for producing an aqueous solution according to the present invention is polyethylene glycol (PEG). Any liquid pharmaceutically acceptable PEG can be used. In one embodiment of the invention, the PEG has an average molecular weight of about 100 to about 800. In another embodiment, the PEG has an average molecular weight of about 200 to about 600. In another embodiment, the PEG has an average molecular weight of about 300 to about 500. Non-limiting examples of PEG that can be used as a solvent in the aqueous solutions of the present invention include PEG-200, PEG-350, PEG-400, PEG-540, and PEG-600. The presently preferred PEG has an average molecular weight of about 375 to about 450, such as PEG-400.

  In another embodiment, the aqueous solution of the present invention further comprises a polymer. Exemplary polymers are HPMC, PVP, and mixtures thereof, as described below.

  In another embodiment of the invention, the aqueous solution further comprises both HPMC and PVP. The PVP may include high viscosity PVP, medium viscosity PVP, or low viscosity PVP. Examples of useful PYPs according to the present invention include PVP K-17, PVP K-30, and PVP K-90.

  Without being bound by a particular theory, it is believed that the interaction between HPMC and polysorbate 80 may reduce the surfactant molecules available for drug solubilization. As shown below in Table 2, solids separated from suspensions (Lot C and Lot D) containing 5% HPMC and 1% polysorbate 80 have higher levels of type IV expressed by DSC ratio. Much higher than those isolated from suspensions containing low concentrations of HPMC and polysorbate 80 (Lot E) or surfactant-free suspensions (Lot F). The dissolution rate of samples containing high purity type IV is 2-3 times that of mainly containing type III, so improved precipitation suspensions prepared with appropriate levels of HPMC and polysorbate 80 Bioavailability appears to be due to both the new solid form of celecoxib, namely the presence of type IV and smaller particle size. Production of type IV celecoxib appears to be related to changes in diffusivity of celecoxib molecules, changes in surface tension, and supersaturation induced by the presence of both HPMC and polysorbate 80.

  In another embodiment of the invention, the aqueous solution further comprises a surfactant. It has been found that suspensions prepared without surfactant do not give detectable amounts of Form IV crystalline celecoxib. The surfactant may be, for example, sodium lauryl sulfate, polyoxyethylene alkyl ether, polyoxyethylene stearate, polysorbate 80, or a combination thereof. Without being bound to a particular theory, it is believed that the presence of surfactant rather than its amount results in the precipitation of type IV crystalline celecoxib.

  A useful amount of surfactant, such as polysorbate 80, is an amount of at least about 0.1% of the weight of the suspension. In another embodiment, polysorbate 80 is present in an amount from about 0.25% to about 50% of the weight of the suspension. In another embodiment, polysorbate 80 is present in an amount from about 0.3% to about 33% of the weight of the suspension. In another embodiment, polysorbate 80 is present in an amount from about 0.25% to about 25% of the weight of the suspension. In another embodiment, the polysorbate 80 is about. It is present in an amount of 3% to about 15%. In another embodiment, polysorbate 80 is present in an amount from about 0.35% to about 5% of the weight of the suspension. In another embodiment, polysorbate 80 is present in an amount from about 0.4% to about 1.5% of the weight of the suspension. In another embodiment, polysorbate 80 is present in an amount from about 0.45% to about 1% of the weight of the suspension. In another embodiment, polysorbate 80 is present in an amount from about 0.5% to about 0.55% of the weight of the suspension. In another embodiment, polysorbate 80 is present in an amount of about 0.54% of the weight of the suspension. Other surfactants referred to herein that are used in place of or in conjunction with polysorbate 80 may be used in amounts corresponding to the exemplary ranges of polysorbate 80 detailed above.

  Optional additional components, including but not limited to pharmaceutical additives, should be physically and chemically compatible with the other components of the composition and are harmful to the recipient Should not be. Importantly, some classes of pharmaceutical additives partially overlap each other. The compositions of the present invention can be adapted for administration by any suitable oral route by selecting appropriate solvent liquid components and drug dosages effective for the treatment intended. Thus, the component itself used in the solvent may be a solid, a liquid, or a combination thereof.

  Exemplary compositions of the present invention include pharmaceutical dosage forms and pharmaceutical dosage form intermediates, such as compositions useful for the manufacture of Form IV crystalline celecoxib.

  A pharmaceutical composition prepared in accordance with the present invention comprises Form IV crystalline celecoxib and at least one pharmaceutically acceptable pharmaceutical additive. Pharmaceutical dosage forms include liquid dosage forms and solid dosage forms.

  Liquid dosage forms may contain inert diluents commonly used in the art such as water. Liquid dosage forms may contain pharmaceutical additives such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, flavoring agents and the like. The liquid dosage forms of the present invention may be in the form of a concentrated solution, which may or may not be encapsulated as a separate article. When encapsulated, it is preferred that a single such article, or a small number of such articles up to about 10, more preferably about 4 or less, be sufficient to make a daily dose. Alternatively, the liquid dosage form may be in the form of a concentrated drinking liquid.

  Liquid dosage forms suitable for oral administration are becoming an important method for delivering drugs to subjects, particularly where rapid onset of therapeutic effect is desired. As an alternative to ready-to-drink liquid formulations of drugs, it is also known to encapsulate liquid formulations in, for example, soft or hard gelatin capsules to obtain individual dosage forms.

  Drugs administered as a drinking solution may be more highly absorbed than those that can only be absorbed in the gastrointestinal tract, such as the mouth and esophagus, after the carrier formulation is broken down in the stomach or intestine.

  The advantage of liquid dosage forms such as potable solutions and suspensions is that for many subjects these dosage forms are easy to swallow. Another advantage of a drinking liquid dosage form is that the dosage metering can be continuously changed and the dosage flexibility is much greater. The benefits of ease of swallowing and dose flexibility are particularly advantageous for children, children, and the elderly.

  Alternatively, the composition of the present invention has a wall in a separate unit dose article form, for example illustratively a cellulosic polymer such as gelatin and / or HPMC, each capsule being a predetermined amount in a solvent liquid. Can be prepared in the form of a capsule containing a liquid composition containing the drug. The liquid composition in the capsule is released as the wall collapses in contact with the digestive fluid. The detailed mechanism of capsule wall collapse is not critical, but mechanisms such as erosion, degradation, dissolution, etc. can be included.

  In such solid dosage forms, the compounds of the present invention usually contain one or more pharmaceutical additives suitable for the desired route of administration, such as lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc , Stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfuric acid, gelatin, gum acacia, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol, and then administered for convenience of administration. Lock or encapsulate. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents such as sodium citrate, citric acid, magnesium or calcium carbonate or bicarbonate. Tablets and pills may be prepared with an additional enteric coating.

  The pharmaceutical compositions of the present invention can be prepared by any suitable pharmaceutical method comprising combining the drug with at least one pharmaceutical additive.

  In general, the liquid dosage form of the present invention comprises a uniform and thorough mixing of celecoxib and a solvent solution in such a manner that at least a portion, preferably substantially all of the celecoxib is dissolved or suspended in the solvent solution, and then If desired, it is prepared by encapsulating the resulting solution, suspension, or solution / suspension in hard or soft capsules.

  In general, the solid dosage forms of the present invention are prepared by isolating type IV crystalline celecoxib particles and thoroughly mixing type IV crystalline celecoxib particles with at least one pharmaceutical additive.

  One skilled in the art will recognize that the amount of crystalline Form IV celecoxib that can be combined with pharmaceutical additives to produce a dosage form will vary depending on the mammalian host being treated and the particular mode of administration. Let's go. A particular dosage unit can be selected to match the desired frequency of administration used to achieve the specified daily dose. For example, a constant dose of 400 mg can be expedient by administering a 200 mg dose unit once or a 100 mg dose unit twice daily. The dosage is a ratio of the mass of the dosage form to the body weight of the subject, such as between about 1 mg / kg body weight to about 50 mg / kg body weight, between about 5 mg / kg body weight to about 45 mg / kg body weight, about 10 mg / kg body weight to It can also be expressed as between about 40 mg / kg body weight, between about 15 mg / kg body weight to about 35 mg / kg body weight, or about 30 mg / kg body weight.

  The amount of composition to be administered and the dosage regimen for treating the condition or disorder are selected as the subject's age, weight, sex, and medical condition, nature and severity of the condition or disorder, route of administration, frequency of administration, and It depends on a variety of factors, including the particular drug, and can therefore be diverse. However, in most cases, once-daily or twice-daily dosing regimens will provide the desired therapeutic effect.

  In one embodiment of the invention, the Form IV crystalline celecoxib is present in an amount of about 0.25% to about 90% of the total amount of all celecoxib present in the composition. In another embodiment of the invention, the Form IV crystalline celecoxib is about 0.05 grams to about 2 grams, about 0.1 grams to about 1.5 grams, 0.15 grams to about 1 gram, about 0.2 grams. Gram to about. Present in an amount of 5 grams, or about 0.3 grams.

  For certain therapeutic applications, blending type IV crystalline celecoxib with at least one other solid form of celecoxib selected from the group consisting of type I, type II, type III, and amorphous celecoxib desirable.

  In one embodiment of the invention, the composition comprises a blend of Form IV crystalline celecoxib and Form III celecoxib, wherein Form IV crystalline celecoxib is present in a detectable amount and the remaining celecoxib comprises Form III celecoxib. In another embodiment of the present invention, the composition has a percent of Form IV crystalline celecoxib of about 25%, about 50%, about 75%, or about 90% relative to the total amount of celecoxib present, and the rest The composition comprises a blend of type IV crystalline celecoxib and type III celecoxib, comprising type III celecoxib.

  The composition of the invention may comprise Form IV crystalline celecoxib in combination with a second selective COX-2 inhibitor such as valdecoxib, parecoxib, darecoxib, or rofecoxib.

  The term “polyethylene glycol” is abbreviated herein as “PEG”.

  The term “HPMC” refers herein to hydroxypropyl methylcellulose.

  The term “solvent” as used herein includes all of the components of a liquid medium that dissolve or solubilize a particular drug. Thus, a “solvent” is not only one or more solvents, but optionally additional pharmaceutical additives such as co-solvents, surfactants, co-surfactants, antioxidants, sweeteners, flavoring agents, coloring agents, etc. Also includes agents.

  The term “polyvinylpyrrolidone” is abbreviated herein as “PVP”.

  The term “pharmaceutical additive” as used herein is not itself a therapeutic agent, but is used as a carrier or excipient to deliver a therapeutic agent to a subject, or its handling, storage, disintegration, dispersion, Any substance added to the pharmaceutical composition to improve dissolution, release, or sensory irritation properties, or to enable or facilitate the dosage unit of the composition into a separate article such as a capsule suitable for oral administration. means. Examples of pharmaceutical additives include, but are not limited to, solvents, diluents, disintegrants, dispersants, binders, adhesives, wetting agents, lubricants, lubricants, crystallization inhibitors, stable Agents, antioxidants, substances added to mask or offset unpleasant taste or odor, flavoring agents, pigments, flavoring agents, preservatives can be included.

The term “AUC _(0−t) ” as used herein means the area under the plasma drug concentration time curve between time _{0 and t} .

The term “C _max ” as used herein means the highest drug concentration found in plasma.

The term “t _max ” or “T _max ” as used herein means the time of maximum drug concentration.

  The term “standard deviation” is abbreviated herein as “SD”.

  The term “expression rate” means the slope of the plasma concentration time curve from 0 to 0.5 hours.

  The expression “drinkable liquid” as used herein is substantially unencapsulated, such as a solution or solution / suspension, that can be orally administered and swallowed in liquid form, from which a single dosage unit can be measurablely separated. Used to refer to a homogeneous fluid mass.

  The term “substantially homogeneous” refers to a pharmaceutical composition comprising a plurality of components such that the individual components do not exist as separate layers and do not form a concentration gradient within the composition. Means that it is well mixed.

  The meaning of the term “celecoxib” (as distinguished from “type IV crystalline celecoxib”), as used in the examples below, varies depending on the context in which the term is used. For example, in the case where “celecoxib” is indicated as the starting material, the celecoxib is not type IV crystalline celecoxib, but instead is in the form of celecoxib in the form produced, for example, by the method taught in WO 95/15316 or WO 96/37476. is there.

  The term “liquid dosage form” includes pharmaceutically acceptable emulsions, solutions, suspensions, solutions / suspensions, syrups, and elixirs. The liquid dosage forms of the present invention may or may not be encapsulated as individual articles.

  The term “solid dosage form” includes capsules, tablets, pills, powders, and granules.

  The term “particle size” is used herein by conventional particle size measurement techniques well known in the art such as laser light scattering, sedimentation field flow fractionation, photon correlation spectroscopy, disc centrifugation, etc. Refers to the particle size being measured. One non-limiting example of a technique that can be used to measure the particle size is a liquid dispersion technique using a Sympatec Particle Size Analyzer.

  The term “DSC” means differential scanning calorimetry.

  The term “HPLC” means high pressure liquid chromatography.

  The term “IR” means infrared.

  The term “msec” means milliseconds.

  The term “PXRD” means X-ray powder diffraction.

  The term “TGA” means thermogravimetric analysis.

  The compounds of the present invention can be administered alone or in combination with one or more other drugs. In general, the compounds of the invention are administered as a formulation with one or more pharmaceutically acceptable pharmaceutical additives. The term “pharmaceutical additive” is used herein to describe any ingredient other than the compound of the invention. The choice of pharmaceutical additive is largely dependent on factors such as the particular mode of administration, the effect of the pharmaceutical additive on solubility and stability, and the nature of the dosage form.

  It goes without saying to those skilled in the art that pharmaceutical compositions suitable for delivery of the compounds of the invention and methods for their preparation. Such compositions and methods for their preparation can be found, for example, in “Remington's Pharmaceutical Sciences”, 19th Edition (Mack Publishing Company, 1995).

  The compounds of the present invention can be administered orally. Oral administration may be swallowed so that the compound enters the gastrointestinal tract, or buccal or sublingual administration where the compound enters the bloodstream directly from the mouth.

  Formulations suitable for oral administration include tablets, microparticles, liquid or powdered capsules, lozenges (including liquid-filled types), chewing agents, solid formulations such as multiparticulates and nanoparticles, gels, solid solutions, liposomes, films Vaginal suppositories, sprays, and liquid preparations.

  Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations can be used as fillers in soft or hard capsules, usually with a carrier such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil and one or more. Emulsifiers and / or suspending agents. A liquid formulation can also be prepared, for example, by reforming a solid from a sachet.

  The compounds of the present invention can be used in rapidly dissolving, rapidly disintegrating dosage forms such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents, Volume 11 (6), pages 981-986 (2001) May be.

  In tablet dosage forms, depending on dose, the drug may make up 1-80 wt% of the dosage form, more typically 5-60 wt% of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl substituted hydroxypropylcellulose, starch, pregelatinized Starch and sodium alginate are included. Generally, the disintegrant will comprise 1 to 25 wt%, preferably 5 to 20 wt% of the dosage form.

  Binders are commonly used to impart adhesive properties to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, saccharides, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose, and hydroxypropylmethylcellulose. Tablets are diluents such as lactose (monohydrate, spray-dried monohydrate, anhydride, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dicalcium phosphate dihydrate May be contained.

  Tablets may also optionally include surface active agents, such as sodium lauryl sulfate and polysorbate 80, and lubricants such as silicon dioxide and talc. When present, the surfactant may comprise 0.2-5 wt% of the tablet and the lubricant may comprise 0.2-1 wt% of the tablet.

  Tablets generally contain a lubricant, such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and a mixture of magnesium stearate and sodium lauryl sulfate. The lubricant generally occupies 0.25 to 10 wt%, preferably 0.5 to 3 wt% of the tablet.

  Other possible components include antioxidants, colorants, flavoring agents, preservatives, and flavoring agents.

  Exemplary tablets include up to about 80% drug, about 10 to about 90 wt% binder, about 0 to about 85 wt% diluent, about 2 to about 10 wt% disintegrant, and about 0.25 to about Contains 10 wt% lubricant.

  Tablet blends can be produced by compressing the tablet blend directly or by roller. Alternatively, the tablet blend or portion of the blend may be tableted after being wet, dry, or melt granulated, melt coagulated, or extruded. The final formulation may comprise one or more layers and may be coated, uncoated or even encapsulated.

  For tablet formulations, see H.C. Lieberman and L.L. Discussed in Lachman's “Pharmaceutical Dosage Forms: Tables”, Volume 1, (Marcel Dekker, New York, USA, 1980).

  Ingestible oral films for human or veterinary use are usually water-soluble or bendable thin film dosage forms that swell with water, and can be rapidly dissolving or mucoadhesive, usually containing a compound of formula I, Includes film-forming polymers, binders, solvents, wetting agents, plasticizers, stabilizers or emulsifiers, viscosity modifiers, and solvents. Some components of the formulation may serve multiple functions.

  The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is usually present in the range 0.01-99 wt%, more typically in the range 30-80 wt%.

  Other possible ingredients include: antioxidants, colorants, flavoring and umami seasonings, preservatives, salivary gland stimulants, cooling agents, cosolvents (including oils), relaxation agents, bulking agents, antifoaming Agents, surfactants, and flavoring agents.

  Films according to the present invention are usually prepared by evaporating and drying a thin water-soluble film coated on a peelable backing support or paper. This can be done in a drying oven or drying tunnel, usually a composite coating dryer, or by freeze drying or vacuum drying.

  Solid formulations for oral administration can be formulated for immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release.

  A modified release formulation suitable for the purposes of the present invention is described in US Pat. No. 6,106,864. Details of other suitable release technologies such as high energy dispersions, osmotic particles, coated particles can be found in Verma et al., Pharmaceutical Technology On-line, 25 (2), 1-14 (2001). . The use of chewing gum to achieve controlled release is described in PCT Publication No. WO 00/35298.

  The compounds of the present invention may be administered directly into the bloodstream, muscle, or viscera. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracerebral, intramuscular, subcutaneous. Suitable devices for parenteral administration include needle syringes (including fine needles), needleless syringes, and infusion techniques.

  Parenteral preparations are usually aqueous solutions that may contain pharmaceutical additives such as salts, carbohydrates, buffering agents (preferably at a pH of 3-9), but for some applications are sterile non-aqueous solutions. Or as a dry form for use with a suitable medium such as sterile water free of pyrogens.

  Preparation of parenteral formulations under sterile conditions, for example, by lyophilization, can be readily accomplished using standard pharmaceutical techniques well known in the art.

  The solubility of compounds of formula I used in the preparation of parenteral solutions can be increased by the use of appropriate formulation techniques such as mixing solubility improvers.

  Formulations for parenteral administration can be formulated for immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release. Thus, the compounds of the present invention can be formulated as solids, semisolids, or thixotropic liquids for administration as transplantation depots resulting in modified release of the active compound. Examples of such formulations include drug-coated stents and dl-lactic acid-glycolic acid copolymer (PGLA) microspheres.

  The compounds of the invention may be administered topically to the skin or mucosa, ie dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and Microemulsions are included. Liposomes may be used. Typical carriers include alcohol, water, mineral oil, liquid paraffin, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Permeation improvers may be incorporated, see, for example, Finnin and Morgan, J Pharm Sci, 88 (10), 955-958 (1999).

  Other means of topical administration include delivery by electroporation, iontophoresis, sonophoresis, ultrasound introduction, and microneedle or needle-free (eg, Powderject ™, Bioject ™, etc.) injection. included.

  Formulations for topical administration can be formulated for immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release.

  The compounds of the present invention are usually obtained from a dry powder inhaler (alone or as a mixture in a dry blend with, for example, lactose, or as mixed component particles, for example, with a phospholipid such as phosphatidylcholine). In the form or with or without a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. It can also be administered as an aerosol spray from a pressure vessel, pump, spray, atomizer (preferably an atomizer that produces a fine mist using electrohydraulics), as an aerosol spray, intranasally, or by inhalation. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

  Pressurized containers, pumps, sprays, atomizers, or nebulizers are, for example, ethanol, aqueous ethanol, or another agent suitable for dispersing, solubilizing, or extending the release of the active, propellant as a solvent As well as optional surfactants such as sorbitan trioleate, oleic acid, oligolactic acid or the like.

  Prior to use in a dry powder or suspension formulation, the formulation is micronized to a size suitable for delivery by inhalation (typically less than 5 μm). This can be achieved by any suitable comminuting method such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to produce nanoparticles, high pressure homogenization, spray drying and the like.

  Capsules (eg, made from gelatin or hydroxypropyl methylcellulose), blisters, and cartridges for use in an inhaler or infuser are suitable powder bases such as the compounds of the invention, lactose and starch, And a powder mixture of performance modifiers such as l-leucine, mannitol, or magnesium stearate. Lactose may be anhydrous or monohydrate, preferably the latter. Other suitable pharmaceutical additives include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

  A solution formulation suitable for use in an atomizer that produces a fine mist using electrohydraulics may contain from 1 μg to 20 mg of a compound of the invention per run, with an operating volume of 1-100 μL. And various. A typical formulation may comprise a compound of formula I, propylene glycol, sterile water, ethanol and sodium chloride. Other solvents that can be used in place of propylene glycol include glycerin and polyethylene glycol.

  Appropriate flavoring agents such as menthol or l-menthol, or sweetening agents such as saccharin or sodium saccharin may be added to the formulations of the invention intended to be administered by inhalation / nasal administration.

  Formulations for inhalation / intranasal administration can be formulated for immediate and / or modified release, for example using PGLA. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release.

  The compounds of the invention can be administered rectally or vaginally, for example, in the form of a suppository, vaginal suppository, or enema. Cocoa butter is a traditional suppository base, but various options can be used as appropriate.

  Formulations for rectal / vaginal administration can be formulated for immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release.

  The compounds of the invention may be administered directly to the eye or ear, usually in the form of a finely divided suspension or solution droplet in isotonic pH adjusted sterile saline. Other formulations suitable for ophthalmic and otic administration include ointments, biodegradable (eg absorbable gel sponges, collagen) and non-biodegradable (eg silicon resin) implants, wafers, lenses, and Fine particle systems such as niosomes and liposomes or vesicle systems are included. Cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid and other polymers, cellulosic polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, or heteropolysaccharide polymers such as gellan gum can be mixed with preservatives such as benzalkonium chloride. it can. Such formulations may be delivered by iontophoresis.

  Formulations for ocular / ear administration can be formulated for immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, or programmed release.

  The compounds of the present invention may be cyclodextrin and its suitable to improve its solubility, dissolution rate, taste-masking, bioavailability, and / or stability for use in any of the above modes of administration. It can be mixed with a soluble polymer entity such as a derivative or a polyethylene glycol-containing polymer.

  For example, drug-cyclodextrin complexes have generally been found useful for most dosage forms and administration routes. Either inclusion or non-inclusion complex may be used. As an alternative to direct complexation with the drug, cyclodextrins can be used as auxiliary additives, ie as carriers, diluents, or solubilizers. The most commonly used for these purposes are α, β, and γ cyclodextrins, examples of which are disclosed in PCT Publication Nos. WO 91/11172, WO 94/02518, and WO 98/55148. Can see.

  For example, since it may be desirable to administer a combination of active compounds for the purpose of treating a particular disease or condition, two or more pharmaceutical compositions, at least one of which contains a compound according to the invention, It is within the scope of the invention that they may be conveniently combined in the form of a kit suitable for co-administration of the composition.

  Such a kit comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula I according to the present invention, and a container, a divided bottle, a divided foil bag, etc. Means for holding the compositions separately. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.

  Such a kit is particularly suitable for administering different dosage forms, e.g. oral and parenteral dosage forms, administering separate compositions at different dosing intervals, or titrating separate compositions against each other. ing. To assist compliance, kits usually include directions for administration and may be provided with a so-called memory aid.

  For administration to human patients, the total daily dose of the compounds of the invention will usually be in the range of about 50 to about 400 mg, naturally depending on the mode of administration. Typical dosage units of the compositions of the invention are about 10, 20, 25, 37.5, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, or 400 mg of COX-2 Inhibitors, illustrative examples include celecoxib. In adults, the therapeutically effective amount of celecoxib per dosage unit of the composition of the invention is usually about 50 mg to about 400 mg. A particularly preferred amount of celecoxib per dosage unit is from about 100 mg to about 200 mg, such as about 100 mg or about 200 mg. The total daily dose can be administered in a single dose or in several doses, and may deviate from the typical ranges set forth herein at the physician's discretion.

  These dosages are based on an average human subject having a weight of about 60-70 kg. A physician can easily determine doses for subjects whose weight falls outside this range, such as children and the elderly.

  For the avoidance of doubt, references herein to “treatment” include references to therapeutic, palliative and prophylactic treatment.

Example 1
Preparation and Isolation of Type IV Celecoxib Hydroxypropylmethylcellulose (HPMC 2910 USP15, Dow Chemical) and polyvinylpyrrolidone (PVP) are dispersed in water with stirring to produce a homogeneous solution containing about 15% HPMC and 20% PVP did. These solutions were diluted with water as shown in Table 1 below. To produce a precipitate, a pre-made PEG-400 solution containing celecoxib powder (10-30%, micronized, manufactured by Pharmacia) and polysorbate 80 was added to the polymer solution with stirring. After adding the celecoxib mixture, sucrose and other pharmaceutical additives were added to the already precipitated celecoxib suspension. PEG400NF, polysorbate 80NF food grade, sodium benzoate NF, citrate USP, and sodium citrate USP were supplied by Brenntag Great Lakes. PVP K90 was purchased from ISP Technology and sucrose NF was purchased from Indiana Sugars. Typical formulations are listed in Table 1. The suspension was continuously stirred for an additional 10-30 minutes to dissolve the soluble pharmaceutical additives. Homogenization was applied for 3-5 minutes if necessary.

  The precipitated crystals were then separated from the suspension and the suspension was diluted with water and washed. Diluted samples were filtered using a Millipore vacuum filtration apparatus and a 0.8 μm MilliporeAA filter. The particles were then dried under vacuum at room temperature for 24 hours and then placed in a desiccator with anhydrous calcium sulfate for at least 72 hours to fully dry the crystals. The integrity of the isolation method was verified by analyzing the wet sample before filtration and comparing it to the filtered and dried solid after isolation by PXRD. These experiments showed that there was no change in crystal form after the isolation process was completed.

(Example 2)
Solubility and Particle Size The solubility of the aqueous phase of the suspension prepared according to Example 1 was measured using a centrifuge that separates the particles from the supernatant. Using a Beckman J2-21 centrifuge, the liquid supernatant was filtered and diluted with a 3: 1 ratio of methanol and water prior to analysis. Celecoxib concentration in the supernatant was analyzed using HPLC analysis by Hewlett Packard 1090 HPLC. Celecoxib was detected at 254 nm using an isocratic method and a pH 3.0 mobile phase.

  The particle size measurement of these samples was performed using single particle optical sensing (SPOS). After weighing about 50 mg of suspension into a 1.5 mL centrifuge tube, weigh enough 2% PVP-K30 / 0.15% sodium lauryl sulfate dilution to a final drug concentration of 0.20%. I put it in. The resulting suspension is vigorously stirred by vortex mixing, holding that portion of the tube containing the suspension under the 5 mm probe tip and immersing both in water, thereby Sonicate for 30 seconds with a sonicator. The output level setting of the sonicator (Sonifier 350, Branson, Danbury, Conn.) Was adjusted to “5” and the duty cycle was 40%. An additional vortex step was performed and the suspension was left for 15 minutes before the vortex-sonication-vortex process was repeated once. A scatter-occlusion sensor (Model LE400-0.5, Particle Sizing Systems, Santa Barbara, CA) equipped with a stepper motor controlled pump was used for size characterization. A stirred 300 mL beaker placed in a laminar flow hood was filled to overflow and then continuously flushed with 0.2 μm filtered MilliQ water. After an appropriate interval, the flow was stopped and the water volume was stabilized to a value between 270 and 280 mL. The sensor was passed through the water for 1 minute at 60 mL / min and the total particle count was measured to be less than 50 and there were no particles greater than 2 μm. To a stirred beaker, 9 μL of an aliquot of 0.2% suspension was added and dispersed, then another 60 mL was passed through the sensor.

  As shown in Table 2, the average particle size of celecoxib in the precipitated suspension was about half that of the control suspension. While the solubility of celecoxib in water was 5-10 μg / ml, the solubility in suspension was significantly increased in the presence of polysorbate 80, PEG400, and PVP. Solubility of celecoxib in suspension without HPMC was about 600 μg / ml and decreased with increasing HPMC concentration.

  As shown in Table 2, solids separated from suspensions (Lot C and Lot D) containing 5% HPMC and 1% polysorbate 80 have a lower concentration of type IV expressed by DSC ratio. It was much higher than that isolated from a suspension containing lots of HPMC and polysorbate 80 (lot E) or a suspension without surfactant (lot F).

(Example 3)
Melting Optical fiber rotating disk melting apparatus (IKA-Werke's Eurostar Power Control Visc; Analytical Instrument Services Inc. Model D1000 CE UV Light Source, Ocean Optics PC1000 UV / V spec test using a spectroscope). Pellets were prepared using Carver Laboratory Press (Fred S Carbular Equipment Inc.) with a sample surface area of 0.178 cm ² and minimal porosity. The dissolution medium was 150 ml of a 50% aqueous solution of isopropyl alcohol. The rotation speed was 300 RPM, and the temperature was controlled at 25 ° C. Calibration was performed by placing the probe in a 0.027 mg / ml celecoxib medium solution and measuring the absorbance at 260 nm. About 20 mg of the solid sample was placed in a pellet press and pressed for 1 minute at a pressure higher than 35000 psi to ensure a zero-porosity shaped body. The pellet was then suspended in the medium and rotated at 300 RPM. Approximately 200 data points were collected over 20 minutes and prepared for plotting and calculation.

  FIG. 12 shows the results of a rotating disk melting experiment. It is clear that Form IV celecoxib is less stable than Form III and therefore dissolves at a much faster rate. The data show that type IV solubility is about 2-3 times that of type III.

Example 4
Scanning electron microscopy (SEM-EDS) using energy dispersive X-ray spectroscopy
Microscopic images were collected in a high vacuum mode using an Everhart-Thornley secondary electron detector with a Philips XL30 ESEM equipped with an EDAX energy dispersive X-ray spectrometer. The microscopic image was generated at 10 kV with a spot size of 3.0 and an inclination of 0 °. The EDS spectrum was generated at 20 kV with a spot of 4.0 and a slope of 0 °. Samples were coated with gold / palladium using a Pelco SC-6 sputter coater.

Polarization microscopy of lot B and lot D precipitates revealed that both were clearly homogeneous crystalline materials. The crystallinity was confirmed by the appearance of birefringence at the crossed polar lines, but in Lot B the particles are often elongated with an extinction angle of approximately 45 °, and Lot D particles usually do not exhibit complete absorption. Aggregation / multiple crystal centers were suggested. Although no significant HPMC content or other amorphous structure was revealed, both lots contained a small population of lath or needle-like separate crystals. The particle size of both lots was fairly small, generally <10 μm, which made it difficult to measure optical properties. In the lot B, the refractive index, n _alpha approximately 1.56, was estimated at n _beta approximately 1.60 and n _gamma about 1.66. Further examination of the particle morphology using SEM revealed that the sample consisted mostly of massive stacked plates and laths. SEM micrographs of lot B and bulk celecoxib (type III) are shown in FIGS. 2A and 2B. The qualitative SEM-EDS element profile (for Z> 4) of lot B reveals carbon, oxygen, nitrogen, fluorine, and sulfur as expected for celecoxib, as shown in FIG. Other elements were not detected at the stoichiometric level.

(Example 5)
Infrared Spectroscopy (IR) and Hot Stage Microscopy Infrared spectra were collected using a Thermo Nicolet Nexus 670 FTIR spectrometer with a Continuum microscope accessory. Samples were flattened onto sodium chloride plates. Spectra, the spectral resolution of ^{4 cm -1,} in the spectral range of 4000～650Cm ^-1, were collected using an MCT detector.

The infrared spectra of lots B and D were similar to each other as shown in FIG. 7, and were not the same as the reference spectrum of type III celecoxib. The type III reference spectrum shows peaks at 3342 and 3236 cm ⁻¹ , which are attributed to the symmetric and asymmetric elongation of the sulfonamide N—H ₂ group. Precipitated celecoxib samples also show these two peaks, suggesting the presence of some type III, but further showing the appearance of peaks at 3295 and 3213 cm ⁻¹ that were not observed in the type III celecoxib spectrum ( The latter peak becomes more apparent after subtracting the type III contribution from the precipitation spectrum). Also, as is typical for polymorphic differences, several peak shifts and peak ratio differences are present throughout the fingerprint region of the precipitation spectrum compared to the type III reference spectrum. These differences cannot be attributed to any other compound present during precipitation, as shown in FIG. Although no reference spectra were available for celecoxib type I and type II, the precipitated celecoxib samples did not match the peak positions at 3256 and 3356 cm ⁻¹ of the published type I sulfonamides. Since celecoxib type II could only be made in a mixture with type III, the spectrum of the published type II / III mixture shows the same sulfonamide NH pattern as type III, thus 3295 and 3213 cm ^−1. There is no peak. That is, the infrared spectra of lots B and D can be clearly distinguished from the previously recognized celecoxib crystal form. Infrared spectra were also generated for the lot B sample held at 145 ° C. for 20 minutes. Hot stage testing showed that this temperature condition caused the transition to a higher melting point mold. The spectrum obtained was similar to that of type III celecoxib, as shown in FIG. That is, the transition observed in the hot stage experiment is the creation of type III celecoxib.

  In the hot stage microscope observation, various thermal behaviors were observed depending on the conditions. Experiments are often performed with samples immersed in silicone oil to improve contrast and show desolvation by the formation of gas bubbles. In samples of lot B or lot D performed in silicone oil, no gas evolution was observed up to 165 ° C. In silicone oil, both samples were completely converted to 145-150 ° C via a gradual transition to lath crystals starting from 90-100 ° C. Newly produced crystals, similar to the known celecoxib form, melted at 160-162 ° C. Looking back at the video of the prepared experiment, there was a smaller population of molds with higher melting points at the onset of both lots, which was observed lath / needle morphology as described in the polarization microscopy section. It became clear that it was. A hot stage experiment conducted in air also revealed a transition to a lath that melts around 160-162 ° C. with an extended ramp time (initially 50 ° C., 10 ° C./minute heating program). There was no difference from the silicone oil experiment. However, when rapidly heated to 138 ° C. and then ramped up at 10 ° C./min, most of the material does not migrate and instead melts at 148-150 ° C. and then (not all) of the molten phase A portion recrystallized into a lath which melted at 160-162 ° C. The conclusions from the hot stage experiments are that the sample does not appear to be a hydrate or solvate of celecoxib, that the material melts at 148-150 ° C. and changes to a higher melting type, as well as a small amount The higher melting point type was present in the sample at the start of the analysis.

(Example 6)
Raman Spectroscopy Raman spectra were obtained from Thermo using a 532 nm laser at 20% power, a 25 μm pinhole spectrometer aperture, and a 672 grating / mm grating blazing while obtaining a spectral resolution of 6-10 cm ^−1. Collected using a Nicolet Almega dispersion Raman microscope. A 10 × objective lens was used to analyze a large area of the sample, and a 100 × objective lens was used to analyze individual crystals.

Both Lot B and Lot D samples produced equivalent spectra that did not correspond to Type III celecoxib. The spectrum of the precipitate was not an exact copy, but was somewhat similar to the reference spectrum of amorphous celecoxib. The Raman spectrum is shown in FIG. Although there were no available reference samples or celecoxib type I and II spectra, celecoxib type II was reported to have a characteristic peak at 712 cm ⁻¹ that was not present in the precipitated sample. ing. In addition, a higher magnification (1 μm spatial resolution) was used to evaluate several single lath crystals in lot B, thereby confirming the presence of some type III celecoxib crystals in the sample. (FIG. 11).

(Example 7)
Differential scanning calorimetry (DSC)
About 1 mg of separated crystals were weighed into a saucer, and then the saucer was sealed with a corresponding lid to prepare a test sample. The sample weight was recorded and entered into the data collection software for use in calculating the energy per gram released when melting occurred. Data was collected on a DSC2920 Differential Scanning Calibrator supplied by TA Instruments. The software used for data collection and analysis was TA Instrument Control software for data collection and TA Universal Analysis for data analysis. Experimental conditions included balancing the sample at 25 ° C. and increasing it to 180.0 ° C. at 10 ° C. per minute.

  The results of differential scanning calorimetry for the same two lots are shown in FIG. These lots showed melt development at 148 ° C and 145 ° C, respectively. The flat baseline suggested that there was no phase transition or excess solvent content prior to the first melt. Form III melting (at about 160 ° C.) was also observed in these samples. PXRD analysis suggested that lot A contained about 30% type III and lot B contained about 5% type III. Since type III crystallizes from a type IV melt, the difference is not evident in DSC. In an attempt to compare formulations, the DSC ratio was calculated to determine the energy loss for type III due to melting of type IV. This ratio was simply the area of the lower melting peak relative to the total peak area of the scan. It was assumed that the closer this ratio was to 1, the more formula IV was present than the lower ratio formula. This ratio indicated that lot A had more type IV than lot B (see Table 2).

(Example 8)
Powder X-ray diffraction (PXRD)
Powder X-ray diffraction data was collected using a Scintag Advanced Diffraction System operating under Scintag DMS / NT ™ software. This system uses a Peltier cooled solid state detector and a copper X-ray source kept at 45 kV and 40 mA to obtain CuKα1 radiation at 1.5406 °. The beam aperture was controlled using 2 and 4 mm tube divergence and anti-scatter slits, respectively, and the detector anti-scatter and receiving slits were set to 0.5 and 0.3 mm, respectively. Data was collected where 2θ was between 2 ° and 35 ° using a scan step of 0.03 ° / point and an integration time of 1 second / point. Samples were prepared using a Scintag round top loading stainless steel sample cup (part number 1ZEO-20-0120-01) and fitted with a 12 mm diameter aluminum insert to facilitate small sample volumes.

  FIG. 5 shows a comparison of the three known crystal forms of lot B precipitate and celecoxib using the PXRD method. The powder pattern of the precipitated material did not match any of these known crystal forms. Type III celecoxib was present as approximately 5% of the sample. PXRD patterns of sodium benzoate, sodium citrate, citric acid, and sucrose were also collected to show that some pharmaceutical additives did not cause an unknown reflection in the powder pattern. These results (not shown) demonstrated that the unique PXRD pattern did not match any of the known pharmaceutical additives in the suspension. This was not surprising considering the material was analyzed and had a very high potency.

Example 9
Bioavailability study in dogs In a non-randomized crossover study, the bioavailability of type IV celecoxib was examined in 6 male beagle dogs. The target dose was 200 mg celecoxib for all formulations. The capsule formulation was taken orally, and the suspension formulation (Lot B, Example 1, administered 2 months after preparation) was administered by gastric intubation. A control suspension was prepared by dispersing bulk drug powder in an aqueous dispersion containing xanthan gum, colloidal silicon dioxide, sucrose, polysorbate 80, sodium benzoate, citric acid, and sodium citrate. After all formulations were dosed, a sufficient amount of water was delivered by gastric intubation to deliver 10 mL of water to the stomach. A drug withdrawal period of at least 1 week was given between treatments. Individual animals using EDTA potassium as an anticoagulant 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 5, and 8 hours after dosing before dosing A series of blood samples (approximately 2 ml) were collected from the jugular vein by puncture. After centrifuging the samples, plasma was collected and extracted directly in polypropylene LC vials by acetonitrile precipitation by mixing 1 part plasma and 2 parts acetonitrile. The vial was centrifuged and the supernatant was injected directly into the LC / MS / MS platform for analysis.

  Quantification of celecoxib in dog plasma was performed by liquid chromatography with detection by mass spectrometry after removing the protein by acetonitrile precipitation. The typical quantification range for this method was 10-10,000 ng / mL celecoxib.

  Chromatography uses a Perkin-Elmer Series 200 chromatography system, by injecting sample supernatant (10 mcL) onto a 2.1 x 100 mm, 5 μm Waters Xterra® RP18 column at a temperature and flow rate of 50 ° C. The initial mobile phase was performed as 5 mM aqueous ammonium formate at 0.5 ml / min. A 1 minute linear gradient (from the initial mobile phase to 5 mM ammonium formate in acetonitrile) was started at the time of sample injection and then maintained with acetonitrile w / 5 mM ammonium formate for 1.5 minutes. The column was then equilibrated with the initial mobile phase for 4 minutes. The total LC effluent was allowed to stand for 3.5 minutes after the sample was injected and then introduced into the Sciex API 3000 triple quadrupole mass spectrometer over 2 minutes. Ionization was achieved using atmospheric pressure chemical ionization (APCI) in an anionic manner. Analytes were monitored using a transition from m / z 380® 316. Celecoxib quantification calculates the peak area ratio of the analyte to the internal standard, and the calibration curve using a quadratic regression analysis that weights the ratio by 1 / x (x is the concentration of the standard sample). Realized by comparing with.

  Plasma time concentration profiles were analyzed using WinNonLin Professional software (ver 3.1) using a two-compartment pharmacokinetic model.

The resulting pharmacokinetic profile and parameters are shown in FIG. Surprisingly, the absorption of celecoxib from the precipitated suspension (Lot B, Example 1) was confirmed by the control suspension (control suspension) prepared by dispersing commercially available capsules and bulk drug powder in an aqueous solution. Much faster than absorption from the liquid). Although the T _max values calculated from these three formulations were nearly identical, the drug concentration in plasma at 0.5 hours from the precipitated suspension was determined from the capsule and control suspensions. The drug concentration was 7.5 times and 4.2 times, respectively, suggesting the possibility of rapid onset of the precipitated suspension. The precipitated suspension also showed at least 4 times better bioavailability than the other formulations tested.

(Example 10)
Isopropanol Slurry Experiment A 25 ° C. slurry experiment was completed to verify the thermodynamic stability of Form IV. A small sample was generated by slurrying approximately 30 mg / mL of an approximately equivalent amount of Form III celecoxib into a saturated solution of celecoxib in isopropanol. The powder pattern of the suspended particles after being slurried overnight is shown in FIG. Slurry conversion tests clearly showed that type IV was metastable with respect to type III, and under these conditions, it turned into type III celecoxib relatively quickly at ambient temperature.

  The examples herein can be carried out using the reactants and / or operating conditions of the present invention as generally or specifically described, instead of those used in the previous examples.

  In view of the above, it can be seen that several objects of the present invention are realized. Since various changes may be made to the above methods, combinations, and compositions of the present invention without departing from the scope of the present invention, all matters contained in the above description are limited. It should be interpreted as illustrative rather than meaning. All documents referred to in this application are specifically incorporated by reference as if fully set forth in detail.

  When introducing elements of the present invention or preferred embodiments thereof, the articles “a”, “an”, “the”, and “said” shall mean that one or more of the elements are present. . The terms “comprising”, “including”, and “having” are non-limiting, meaning that there may be additional elements other than the listed elements.

Graph showing pharmacokinetic profiles of type IV suspension (lot B) (top), celecoxib suspension (middle), and commercially available capsule (bottom) after oral dosing to dogs 2 months after preparation It is. It is a figure which shows the SEM micrograph of a type III celecoxib. It is a figure which shows the SEM micrograph of a lot B (type IV) celecoxib. FIG. 6 is a graph showing a qualitative SEM-EDS element profile (for Z> 4) of lot B. FIG. FIG. 4 is a graph showing DSC temperature records for Type III, Lot A, and Lot B celecoxib (from top to bottom). (From top to bottom) PXRD comparison of lot B celecoxib, type I celecoxib, type II celecoxib, and type III celecoxib. (Top to Bottom) FIG. 3 is a graph showing PXRD patterns of type III celecoxib, lot B celecoxib after the isopropanol slurry experiment of Example 11, and lot B celecoxib before the isopropanol slurry experiment. FIG. 4 is a graph showing IR spectra of lot D, lot B, and type III celecoxib (from top to bottom). (From top to bottom) Graph showing IR spectra of lot B celecoxib, HPMC, PVP, polysorbate 80, and PEG400. FIG. 4 is a graph showing IR spectra of type III celecoxib, lot B celecoxib after heating at 145 ° C. for 20 minutes, and lot B without heating. It is a graph which shows the Raman spectrum of amorphous celecoxib, lot B celecoxib, lot D, and type III celecoxib. FIG. 4 is a graph showing Raman spectra of type III celecoxib (from top to bottom), a single lath type III crystal recovered from lot B, and a type IV crystal from lot B. FIG. FIG. 4 is a graph showing plots of data obtained from rotating disk dissolution of type IV (top line) and type III (bottom two lines) celecoxib.

Claims (14)

  A celecoxib having an X-ray powder diffraction pattern including at least one peak selected from the group consisting of 2.46, 13.13, 18.29, 20.21, 18.83, and 26.24 degrees. Crystal form.   A crystalline form of celecoxib having a melting point in the range of about 144 ° C to about 149 ° C. A crystalline form of celecoxib having an infrared absorption band profile comprising at least one absorption band at about 3342, 3295, and 3213 cm ⁻¹ . An infrared absorption band profile comprising at least one absorption band at about 3342, 3295, and 3213 cm ⁻¹ , and 2θ of about 4.46, 13.13, 18.29, 20.21, 21.83, And a crystalline form of celecoxib having an X-ray powder diffraction pattern comprising at least one peak at 26.24 degrees. A method for producing a crystalline form of celecoxib according to any one of claims 1 to 4,
Dissolving celecoxib in a solvent to produce a celecoxib solution;
Contacting the celecoxib solution with an aqueous solution to form a controlled precipitation mixture and separating the crystalline form of celecoxib from the controlled precipitation mixture.   The method of claim 5, wherein the solvent is polyethylene glycol.   The method of claim 5 or claim 6, wherein the aqueous solution comprises a polymer selected from the group consisting of HPMC, PVP, and mixtures thereof.   5. A pharmaceutical composition comprising celecoxib and one or more pharmaceutically acceptable pharmaceutical additives, wherein the detectable amount of celecoxib is according to any one of claims 1, 2, 3, or 4. A pharmaceutical composition present as a crystalline form of celecoxib.   9. The pharmaceutical composition of claim 8, wherein at least about 50% of the celecoxib is present as a crystalline form of celecoxib according to any one of claims 1, 2, 3, or 4.   9. The pharmaceutical composition of claim 8, wherein at least about 90% of the celecoxib is present as a crystalline form of celecoxib according to any one of claims 1, 2, 3, or 4.   9. A pharmaceutical composition according to claim 8, wherein the celecoxib present in the composition is substantially a crystalline form of celecoxib according to any one of claims 1, 2, 3, or 4.   9. The pharmaceutical composition of claim 8, wherein the amount of celecoxib present in the composition is between about 0.1 mg to about 1000 mg.   14. The pharmaceutical composition of claim 13, wherein the amount of celecoxib present in the composition is between about 0.1 mg to about 500 mg.   9. A method of treating or preventing a condition involving COX-2, wherein a therapeutic or prophylactically effective amount of the composition of claim 8 is administered to a subject having or susceptible to such a condition or disorder A method comprising:

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