US 2004O156872A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0156872 A1 Bosch et al. (43) Pub. Date: Aug. 12, 2004

(54) NOVEL NMESULIDE COMPOSITIONS application No. 09/572,961, filed on May 18, 2000, now Pat. No. 6,316,029. (75) Inventors: H. William Bosch, Bryn Mawr, PA (US); Christian F. Wertz, Brookhaven, Publication Classification PA (US) (51) Int. Cl...... A61K 9/14; A61K 9/00 Correspondence Address: FOLEY AND LARDNER (52) U.S. Cl...... 424/400; 424/489 SUTE 500 3000 KSTREET NW WASHINGTON, DC 20007 (US) (57) ABSTRACT (73) Assignee: Elan Pharma International Ltd. The present invention provides nanoparticulate nimeSulide (21) Appl. No.: 10/697,703 compositions. The compositions preferably comprise nime (22) Filed: Oct. 31, 2003 Sulide and at least one Surface Stabilizer adsorbed on or asSociated with the Surface of the nimeSulide particles. The Related U.S. Application Data nanoparticulate nimeSulide particles preferably have an effective average particle size of less than about 2000 nm. (63) Continuation-in-part of application No. 10/276,400, The invention also provides methods of making and using filed on Jan. 15, 2003, which is a continuation of nanoparticulate nimeSulide compositions. US 2004/O156872 A1 Aug. 12, 2004

NOVEL NMESULIDE COMPOSITIONS tion;' U.S. Pat. Nos. 5,399,363 and 5,494,683, both for “Surface Modified Anticancer Nanoparticles; U.S. Pat. No. RELATED APPLICATIONS 5,401,492 for “Water Insoluble Non-Magnetic Manganese Particles as Magnetic Resonance Enhancement Agents,” 0001. This application is a continuation-in-part of U.S. U.S. Pat. No. 5,429,824 for “Use of Tyloxapol as a Nano application Ser. No. 10/276,400, filed on Jan. 15, 2003, particulate Stabilizer;” U.S. Pat. No. 5,447,710 for “Method which is a continuation of U.S. application Ser. No. 09/572, for Making Nanoparticulate X-Ray Blood Pool Contrast 961, filed on May 18, 2000, now U.S. Pat. No. 6,316,029. Agents. Using High Molecular Weight Non-ionic Surfac FIELD OF THE INVENTION tants;" U.S. Pat. No. 5,451,393 for “X-Ray Contrast Com positions Useful in Medical Imaging; U.S. Pat. No. 5,466, 0002 The present invention relates to nanoparticulate 440 for “Formulations of Oral Gastrointestinal Diagnostic compositions comprising nimeSulide. The nimeSulide par X-Ray Contrast Agents in Combination with Pharmaceuti ticles in these compositions preferably have an effective cally Acceptable Clays;” U.S. Pat. No. 5,470,583 for average particle size of less than about 2000 nm. “Method of Preparing Nanoparticle Compositions Contain ing Charged Phospholipids to Reduce Aggregation; U.S. BACKGROUND OF THE INVENTION Pat. No. 5,472,683 for “Nanoparticulate Diagnostic Mixed Carbamic Anhydrides as X-Ray Contrast Agents for Blood 0.003 I. Background Regarding Nanoparticulate Active Pool and Lymphatic System Imaging; U.S. Pat. No. 5,500, Agent Compositions 204 for “Nanoparticulate Diagnostic Dimers as X-Ray Con 0004 Nanoparticulate active agent compositions, first trast Agents for Blood Pool and Lymphatic System Imag described in U.S. Pat. No. 5,145,684 (“the 684 patent”), ing.” U.S. Pat. No. 5,518,738 for “Nanoparticulate NSAID contain particles of a poorly Soluble therapeutic or diagnos Formulations;” U.S. Pat. No. 5,521,218 for “Nanoparticu tic agent having adsorbed onto, or associated with, the late Iododipamide Derivatives for Use as X-Ray Contrast Surface thereof a non-crosslinked Surface Stabilizer. Such Agents; U.S. Pat. No. 5,525,328 for “Nanoparticulate Diag compositions provide Superior bioavailability, which can be nostic Diatrizoxy Ester X-Ray Contrast Agents for Blood affected by factorS Such as dosage form and the dissolution Pool and Lymphatic System Imaging; U.S. Pat. No. 5,543, rate of a drug. Poor bioavailability constitutes a significant 133 for “Process of Preparing X-Ray Contrast Compositions problem encountered in developing of pharmaceutical com Containing Nanoparticles;” U.S. Pat. No. 5,552,160 for positions, particularly those containing an active ingredient “Surface Modified NSAID Nanoparticles;” U.S. Pat. No. that is poorly Soluble in water. By decreasing the particle 5,560,931 for “Formulations of Compounds as Nanoparticu Size of an active agent, the Surface area of the composition late Dispersions in Digestible Oils or Fatty Acids; U.S. Pat. is increased, which generally results in increased bioavail No. 5,565,188 for “Polyalkylene Block Copolymers as ability. The 684 patent does not teach nanoparticulate Surface Modifiers for Nanoparticles;” U.S. Pat. No. 5,569, compositions of nimeSulide. 448 for “Sulfated Non-ionic Block Copolymer Surfactant as Stabilizer Coatings for Nanoparticle Compositions; U.S. 0005 Methods of making nanoparticulate active agent Pat. No. 5,571,536 for “Formulations of Compounds as compositions are described in, for example, U.S. Pat. Nos. Nanoparticulate Dispersions in Digestible Oils or Fatty 5,518,187 and 5,862.999, both for “Method of Grinding Pharmaceutical Substances; U.S. Pat. No. 5,718,388, for Acids;” U.S. Pat. No. 5,573,749 for “Nanoparticulate Diag “Continuous Method of Grinding Pharmaceutical Sub nostic Mixed Carboxylic Anydrides as X-Ray Contrast stances;” and U.S. Pat. No. 5,510,118 for “Process of Agents for Blood Pool and Lymphatic System Imaging,” Preparing Therapeutic Compositions Containing Nanopar U.S. Pat. No. 5,573,750 for “Diagnostic Imaging X-Ray Contrast Agents;” U.S. Pat. No. 5,573,783 for “Redispers ticles.” ible Nanoparticulate Film Matrices With Protective Over 0006 Nanoparticulate active agent compositions are also coats;” U.S. Pat. No. 5,580,579 for “Site-specific Adhesion described, for example, in U.S. Pat. No. 5,298,262 for “Use Within the GI Tract Using Nanoparticles Stabilized by High of Ionic Cloud Point Modifiers to Prevent Particle Aggre Molecular Weight, Linear Poly(ethylene Oxide) Polymers;” gation During Sterilization; U.S. Pat. No. 5,302,401 for U.S. Pat. No. 5,585,108 for “Formulations of Oral Gas “Method to Reduce Particle Size Growth During Lyophiliza trointestinal Therapeutic Agents in Combination with Phar tion;” U.S. Pat. No. 5,318,767 for “X-Ray Contrast Com maceutically Acceptable Clays; U.S. Pat. No. 5,587,143 for positions Useful in Medical Imaging; U.S. Pat. No. 5,326, “Butylene Oxide-Ethylene Oxide Block Copolymers Sur 552 for “Novel Formulation For Nanoparticulate X-Ray factants as Stabilizer Coatings for Nanoparticulate Compo Blood Pool Contrast Agents Using High Molecular Weight sitions;” U.S. Pat. No. 5,591,456 for “Milled Naproxen with Non-ionic Surfactants; U.S. Pat. No. 5,328,404 for Hydroxypropyl Cellulose as Dispersion Stabilizer; U.S. “Method of X-Ray Imaging Using Iodinated Aromatic Pro Pat. No. 5,593,657 for “Novel Barium Salt Formulations panedioates;” U.S. Pat. No. 5,336,507 for “Use of Charged Stabilized by Non-ionic and Anionic Stabilizers; U.S. Pat. Phospholipids to Reduce Nanoparticle Aggregation; U.S. No. 5,622,938 for “Sugar Based Surfactant for Nanocrys Pat. No. 5,340,564 for “Formulations Comprising Olin 10-G tals;” U.S. Pat. No. 5,628,981 for “Improved Formulations to Prevent Particle Aggregation and Increase Stability; U.S. of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents Pat. No. 5,346,702 for “Use of Non-Ionic Cloud Point and Oral Gastrointestinal Therapeutic Agents; U.S. Pat. No. Modifiers to Minimize Nanoparticulate Aggregation During 5,643,552 for “Nanoparticulate Diagnostic Mixed Carbonic Sterilization;” U.S. Pat. No. 5,349,957 for “Preparation and Anhydrides as X-Ray Contrast Agents for Blood Pool and Magnetic Properties of Very Small Magnetic-Dextran Par Lymphatic System Imaging; U.S. Pat. No. 5,718,388 for ticles; U.S. Pat. No. 5,352,459 for “Use of Purified Surface “Continuous Method of Grinding Pharmaceutical Sub Modifiers to Prevent Particle Aggregation During Steriliza stances;” U.S. Pat. No. 5,718,919 for “Nanoparticles Con US 2004/O156872 A1 Aug. 12, 2004 taining the R(-)Enantiomer of Ibuprofen;” U.S. Pat. No. 5,747,001 for “Aerosols Containing Beclomethasone Nano particle Dispersions;” U.S. Pat. No. 5,834,025 for “Reduc tion of Intravenously Administered Nanoparticulate Formu lation Induced Adverse Physiological Reactions; U.S. Pat. No. 6,045,829 “Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors. Using Cellulosic Surface Stabilizers; U.S. Pat. No. 6,068,858 for “Methods of Making Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors NO Using Cellulosic Surface Stabilizers;” U.S. Pat. No. 6,153, 225 for “Injectable Formulations of Nanoparticulate Naproxen;” U.S. Pat. No. 6,165,506 for “New Solid Dose 0010 Nimesulide has a molecular weight of 308.31 Form of Nanoparticulate Naproxen; U.S. Pat. No. 6,221, g/mol and is practically insoluble in water, having a half-life 400 for “Methods of Treating Mammals Using Nanocrys of about 4 hours. It operates by selectively inhibiting talline Formulations of Human Immunodeficiency Virus cyclooxygenase-2 (COX-2). (HIV) Protease Inhibitors;” U.S. Pat. No. 6,264,922 for 0011. Therapeutic concentrations of nimeSulide cause “Nebulized Aerosols Containing Nanoparticle Dispersions;” Several actions, including the following: (a) inhibition of 6,267,989 for “Methods for Preventing Crystal Growth and prostaglandin Synthesis, (b) inhibition of toxic oxygen Particle Aggregation in Nanoparticle Compositions, U.S. metabolite formation, (c) inhibition of cytokine release, (d) Pat. No. 6,270.806 for “Use of PEG-Derivatized Lipids as inhibition of histamine release, and (e) inhibition of cartilage Surface Stabilizers for Nanoparticulate Compositions; U.S. degradation. In accord with these actions, nimeSulide exerts Pat. No. 6,316,029 for “Rapidly Disintegrating Solid Oral anti-inflammatory, analgesic and anti-pyretic activities, and Dosage Form,” U.S. Pat. No. 6,375,986 for “Solid Dose Nanoparticulate Compositions Comprising a Synergistic therefore effectively treats a wide range of disorders. Combination of a Polymeric Surface Stabilizer and Dioctyl 0012 One drawback of nimeSulide is that it can be Sodium SulfoSuccinate; U.S. Pat. No. 6,428,814 for “Bio difficult to administer, due to its near insolubility in water. adhesive Nanoparticulate Compositions Having Cationic The art has addressed Several ways to render nimeSulide Surface Stabilizers; U.S. Pat. No. 6,431,478 for “Small more bioavailable. U.S. Pat. No. 5,756,546 to Pirotte et al. Scale Mill,” and 6,432,381 for “Methods for Targeting Drug discloses a water-Soluble Salt formed from equimolar Delivery to the Upper and/or Lower Gastrointestinal Tract,” amounts of nimeSulide and L-lysine, but the Salt can be all of which are specifically incorporated by reference. In contaminated with exceSS L-lysine or insoluble nimeSulide addition, U.S. Patent Application No. 20020012675 A1, upon any variation from the 1:1 molar ratio. U.S. Pat. No. published on Jan. 31, 2002, for “Controlled Release Nano 5,744,165 Geczy et al. relates to alkali and alkaline earth particulate Compositions,” and WO 02/098565 for “System Salts of nimeSulide that, when combined with a cyclodextrin and Method for Milling Materials,” describe nanoparticulate to form inclusion complexes, can be dissolved in water. active agent compositions, and are specifically incorporated However, compositions of this type can deliver unwanted by reference. None of these references describe nanopar amounts of cyclodextrin and Sodium ion to a patient. U.S. ticulate nimeSulide compositions. Pat. No. 6,194,462 to Giorgetti discloses soluble formula tions of nimeSulide achieved by dissolving the drug in a 0007 Amorphous small particle compositions are mixture of water at basic pH and one or more alcohols Such described, for example, in U.S. Pat. No. 4,783,484 for as ethanol. In contrast, U.S. Pat. No. 6,288,121 to Bader et “Particulate Composition and Use Thereof as Antimicrobial al. discloses emulsions of nimeSulide in liquid crystal form Agent;” U.S. Pat. No. 4,826,689 for “Method for Making for the controlled release of the drug, while U.S. Pat. No. Uniformly Sized Particles from Water-Insoluble Organic 5,998,480 to Giorgetti relates to bioavailable formulations of Compounds;" U.S. Pat. No. 4,997,454 for “Method for nimeSulide, a phospholipid, and an organic or inorganic Making Uniformly-Sized Particles From Insoluble Com acid. pounds;” U.S. Pat. No. 5,741,522 for “Ultrasmall, Non 0013 Nimesulide has been marketed under numerous aggregated Porous Particles of Uniform Size for Entrapping trade names, including Ainex(R), Aulin(R), Donulide(R), Edri Gas Bubbles Within and Methods;” and 5,776,496, for gyl(R), Eskaflam(R, FansidolE), FlogoVital(R), Guaxan(R), “Ultrasmall Porous Particles for Enhancing Ultrasound Heugan(R), Mesulid(R), Nemil(R), Nexen(R), Nide(R), Nidol(R), Back Scatter.” Nimed(R), Nimedex(E), Nisulid(R), Plarium(E), Scaflam(E), Scaflan(E), and SulidenedE). 0008 II. Background Regarding NimeSulide 0014. There is a need in the art for nimeSulide composi 0009 Nimesulide, also known as N-(4-Nitro-2-phenoxy tions which can decrease frequency of dosing, improve phenyl)-methaneSulfonamide, is a non-Steroidal anti-inflam clinical efficacy, and potentially reduce Side effects. The matory drug (NSAID) having the following structure: present invention Satisfies these needs. US 2004/O156872 A1 Aug. 12, 2004

SUMMARY OF THE INVENTION administering to a Subject a therapeutically effective amount of a nanoparticulate nimeSulide composition in combination 0.015 The present invention provides nanoparticulate nimeSulide compositions. The compositions preferably com with one or more non-nimeSulide active agents. prise nimeSulide and at least one Surface Stabilizer adsorbed 0023. Both the foregoing general description and the on or associated with the Surface of the nimeSulide particles. following detailed description are exemplary and explana The nanoparticulate nimeSulide particles preferably have an tory, and are intended to provide further explanation of the effective average particle size of less than about 2000 nm. invention as claimed. Other objects, advantages, and novel features will be readily apparent to those skilled in the art 0016. The invention also provides pharmaceutical com from the following detailed description of the invention. positions that comprise nanoparticulate nimeSulide. The pharmaceutical compositions preferably comprise nime DETAILED DESCRIPTION OF THE Sulide, at least one Surface Stabilizer, and at least one INVENTION pharmaceutically acceptable carrier, as well as any desired excipients known to those in the art. The compositions can 0024. The present invention relates to nanoparticulate be formulated into any desired dosage form. nimeSulide compositions. The compositions preferably com 0.017. In another aspect, the invention includes nanopar prise nimeSulide and at least one Surface Stabilizer adsorbed ticulate nimeSulide compositions having improved pharma on or associated with the Surface of the nimeSulide particles. cokinetic profiles, Such as improved Ta, Ca, and AUC The nanoparticulate nimeSulide particles preferably have an parameters, relative to conventional Solubilized, microcryS effective average particle size of less than about 2000 nm. talline or non-nanoparticulate nimeSulide formulations. 0025 The present invention also relates to pharmaceuti 0.018. In yet another aspect, the invention encompasses a cal compositions that comprise a nanoparticulate nimeSulide nimeSulide composition having a pharmacokinetic profile active agent. The pharmaceutical compositions preferably that is not substantially affected by the fed or fasted State of comprise nimeSulide, at least one Surface Stabilizer, and at a Subjectingesting the composition, preferably as defined by least one pharmaceutically acceptable carrier. Non-toxic C and AUC guidelines given by the U.S. Food and Drug physiologically acceptable carriers, adjuvants, and Vehicles Administration and/or the corresponding European regula are collectively referred to as carriers herein. tory agency (EMEA). 0026. The pharmaceutical compositions may be formu 0019. Other aspects of the invention include, but are not lated for parenteral injection, including intravenous, intra limited to, nanoparticulate nimeSulide compositions that, as muscular, or Subcutaneous, oral administration in Solid, compared to conventional non-nanoparticulate formulations liquid, or aerosol form; or vaginal, nasal, rectal, ocular, local of nimeSulide, preferably have one or more of the following (Such as in powders, ointments or drops), buccal, intracis properties: (1) Smaller dosage form size; (2) Smaller doses of ternal, intraperitoneal, or topical administration, and the like. drug required to obtain the same pharmacological effect; (3) 0027 Solid dosage forms are preferred, though any phar increased bioavailability; (4) an increased rate of dissolution maceutically acceptable dosage form may be employed. for the nanoparticulate nimeSulide compositions; and (5) Exemplary Solid dosage forms include, but are not limited bioadhesive nimeSulide compositions. to, tablets, capsules, Sachets, lozenges, powders, pills, or 0020. This invention further discloses methods of making granules. A Solid dosage form may be, for example, a fast a nanoparticulate nimeSulide composition. The methods melt dosage form, controlled release dosage form, lyo comprise contacting nimeSulide and at least one Surface philized dosage form, delayed release dosage form, Stabilizer for a time and under conditions Sufficient to extended release dosage form, pulsatile release dosage form, provide a nanoparticulate nimeSulide composition. The one mixed immediate release and controlled release dosage or more Surface Stabilizers can be contacted with nimeSulide form, or a combination thereof. Solid dose tablet formula before, preferably during, or after size reduction of the tions are preferred. nimeSulide. 0028) I.Technical Challenges Overcome by the Inventors 0021. The present invention also includes methods of 0029 AS taught in the 684 patent, not every combination using nanoparticulate nimeSulide compositions for treating a of Surface Stabilizer and active agent will result in a stable wide range of conditions and disorders mediated by COX-2, nanoparticulate composition. Thus, the discovery that Stable including, but not limited to, disorders characterized by nanoparticulate nimeSulide formulations can be made was inflammation, pain, and/or fever. Thus, compositions of the Surprising. invention are useful for indications where anti-inflammatory agents, anti-angiogenesis agents, antitumorigenic agents, 0030. In general, the rate of dissolution of a particulate immunosuppressive agents, NSAIDs, COX-2 inhibitors, drug increases with increasing Surface area, e.g., decreasing analgesic agents, anti-thrombotic agents, narcotic or antife particle size. Consequently, methods of making finely brile agents are typically used. divided drugs have been studied and efforts have been made to control the size and Size range of drug particles in 0022. The methods comprise administering to a subject a pharmaceutical compositions. Nanoparticulate active agent therapeutically effective amount of a nanoparticulate nime formulations Suitable for administration as pharmaceuticals Sulide pharmaceutical composition according to the inven require formulation of the active ingredient into a colloidal tion. Additionally, a Subject may be administered a thera dispersion that exhibits the acceptable nanoparticle size peutic amount of a pharmaceutical composition that range and the Stability to maintain Such size range without comprises both nanoparticulate nimeSulide and non-nano agglomerating. Thus, merely increasing Surface area by particulate nimeSulide. Alternatively, the methods comprise decreasing particle size does not assure Success. Further US 2004/O156872 A1 Aug. 12, 2004

challenges include forming Solid dose forms that are redis about 2 microns' means that at least 50% of the particles of persible into nanoparticle form upon administration to a the composition have a size of greater than about 2 microns. patient, to maintain the benefit of nanoparticle nimeSulide over a traditional microparticulate or Solubilized nimeSulide 0038 “Pharmaceutically acceptable” as used herein dosage form. refers to those compounds, materials, compositions, and/or dosage forms which are, within the Scope of Sound medical 0.031 II. Summary of Advantages of Nanoparticulate judgment, Suitable for use in contact with the tissues of NimeSulide Formulations human beings and animals without excessive toxicity, irri 0032) Advantages of nanoparticulate nimeSulide formu tation, allergic response, or other problem or complication, lations, relative to conventional non-nanoparticulate or Solu commensurate with a reasonable benefit/risk ratio. bilized formulations of nimeSulide include, but are not 0039) “Pharmaceutically acceptable salts' as used herein limited to: (1) faster onset of action; (2) a potential decrease refers to derivatives wherein the parent compound is modi in the frequency of dosing; (3) Smaller tablet (or other Solid fied by making acid or base Salts thereof. Examples of dosage form) size or liquid dose volumes; (4) Smaller doses pharmaceutically acceptable Salts include, but are not lim of drug required to obtain the same pharmacological effect; ited to, mineral or organic acid Salts of basic residues Such (5) increased bioavailability; (6) an increased rate of disso as amines, alkali or organic Salts of acidic residues Such as lution; (7) high redispersibility of the nanoparticulate nime carboxylic acids, and the like. The pharmaceutically accept Sulide particles present in the compositions of the invention able Salts include the conventional non-toxic Salts or the following administration; (8) improved performance char quaternary ammonium Salts of the parent compound formed, acteristics for oral, intravenous, Subcutaneous, or intramus for example, from non-toxic inorganic or organic acids. For cular injection, Such as higher dose loading; (9) improved example, Such conventional non-toxic Salts include those pharmacokinetic profiles, Such as improved Ta, Ca, and derived from inorganic acids Such as hydrochloric, hydro AUC profiles; (10) substantially similar or bioequivalent bromic, Sulfuric, Sulfamic, phosphoric, nitric, and the like; pharmacokinetic profiles of the nanoparticulate nimeSulide and the Salts prepared from organic acids Such as acetic, compositions when administered in the fed versus the fasted propionic, Succinic, glycolic, Stearic, lactic, malic, tartaric, State; (11) bioadhesive nimeSulide compositions; (12) low citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylace Viscosity liquid nanoparticulate nimeSulide dosage forms tic, glutamic, benzoic, Salicylic, Sulfanilic, 2-acetoxyben can be made; (13) for liquid nanoparticulate nimeSulide Zoic, fumaric, toluenesulfonic, methaneSulfonic, ethane dis compositions having a low viscosity-better Subject com ulfonic, oxalic, isethionic, and the like. pliance due to the perception of a lighter formulation which is easier to consume and digest, (14) for liquid nanoparticu 0040) “Poorly water soluble drugs” as used herein means late nimeSulide compositions having a low Viscosity—ease drugs having a Solubility of less than about 30 mg/ml, of dispensing because one can use a cup or a Syringe; (15) preferably less than about 20 mg/ml, preferably less than the nanoparticulate nimeSulide compositions can be Sterile about 10 mg/ml, or preferably less than about 1 mg/ml. Such filtered; (16) the nanoparticulate nimeSulide compositions drugs tend to be eliminated from the gastrointestinal tract can be used in conjunction with other active agents; (17) the before being absorbed into the circulation. Moreover, poorly nanoparticulate nimeSulide compositions are Suitable for water Soluble drugs tend to be unsafe for intravenous parenteral administration; and (18) the nanoparticulate administration techniques, which are used primarily in con nimeSulide compositions do not require organic Solvents or junction with highly water Soluble drug Substances. pH extremes. 0041 AS used herein with reference to stable nimeSulide 0.033 Moreover, nanoparticulate nimeSulide formula particles, “stable' includes, but is not limited to, one or more tions do not possess the Sedative and addictive properties of of the following parameters: (1) that the nimeSulide particles narcotic analgesics. Because nimeSulide does not cause do not appreciably flocculate or agglomerate due to inter drowsineSS and is not addictive, it is a preferred analgesic particle attractive forces, or otherwise significantly increase when ambulation is important or when treatment is pro in particle size over time; (2) that the physical structure of tracted and chemical dependency could result from pro the nimeSulide particles is not altered over time, Such as by longed use of narcotic analgesics. conversion from an amorphous phase to crystalline phase; (3) that the nimeSulide particles are chemically stable; 0034) III. Definitions and/or (4) where the nimeSulide has not been Subject to a 0035. The present invention is described herein using heating Step at or above the melting point of the nimeSulide several definitions that are set forth below and throughout in the preparation of the nanoparticles of the invention. the Specification. 0042 “Therapeutically effective amount” as used herein 0.036 “About” will be understood by persons of ordinary with respect to a drug dosage, means a dosage that provides skill in the art and will vary to Some extent on the context the Specific pharmacological response for which the drug is in which the term is used. If there are uses of the term that administered in a significant number of Subjects in need of are not clear to perSons of ordinary skill in the art given the Such treatment. A “therapeutically effective amount,” context in which it is used, “about” will mean up to plus or administered to a particular Subject in a particular instance, minus 10% of the particular term. will not always effectively treat the diseases described herein, even though Such dosage is deemed a “therapeuti 0037 “Conventional” or “non-nanoparticulate active cally effective amount” by those skilled in the art. Through agent’ means an active agent that is Solubilized or that has out this description, drug dosages are, in particular an effective average particle size of greater than about 2 instances, measured as oral dosages, or with reference to microns. "Effective average particle size of greater than drug levels as measured in blood. US 2004/O156872 A1 Aug. 12, 2004

0043 IV. Preferred Characteristics of Nanoparticulate 0053. The desirable pharmacokinetic profile, as used NimeSulide Compositions herein, is the pharmacokinetic profile measured after an initial dose of nimeSulide. The dose can be formulated in any 0044 A. Fast Onset of Activity way as described below and as known to those skilled in the 0.045. Of particular importance, conventional formula art. tions of nimeSulide are inappropriate for managing acute 0054) A preferred nanoparticulate nimeSulide composi pain due to delayed onset of action, as conventional nime tion exhibits, in comparative pharmacokinetic testing with a Sulide formulations have a T of 4-6 hours, which is more non-nanoparticulate formulation of nimeSulide administered than five times as long as most narcotic analgesic drugs. See at the same dosage, a T not greater than about 90%, not The Physician 's Desk Reference, 56" Ed., pp. 446 and 1054. greater than about 80%, not greater than about 70%, not Unlike conventional nimeSulide formulations, nanoparticu greater than about 60%, not greater than about 50%, not late nimeSulide formulations, which exhibit faster onset of greater than about 30%, not greater than about 25%, not action, are useful for treating acute pain where fast pain greater than about 20%, not greater than about 15%, or not relief is required. greater than about 10% of the T, exhibited by the 0.046 B. Increased Bioavailability and Lower Dosages non-nanoparticulate formulation of nimeSulide. 0047 Relative to conventional nimeSulide formulations, 0055. A preferred nanoparticulate nimeSulide composi the inventive nanoparticulate nimeSulide compositions pref tion exhibits, in comparative pharmacokinetic testing with a erably exhibit increased bioavailability, require Smaller non-nanoparticulate formulation of nimeSulide administered doses, and Show longer plasma half-life. at the Same dosage, a C that is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least 0.048. As another advantage, nanoparticulate formula about 50%, at least about 60%, at least about 70%, at least tions of nimeSulide also provide a longer duration of pain about 80%, at least about 90%, or at least about 100% relief relative to traditional narcotic analgesic drugs. While greater than the C exhibited by the non-nanoparticulate traditional narcotics provide fast onset of action, the dura formulation of nimeSulide. tion of pain relief is short. Nanoparticulate nimeSulide 0056. A preferred nanoparticulate nimeSulide composi formulations combine the fast onset of traditional narcotics tion exhibits, in comparative pharmacokinetic testing with a with the duration of pain relief of conventional NSAIDs. non-nanoparticulate formulation of nimeSulide administered The long half-life of nimeSulide, approximately 20 hours as at the same dosage, an AUC that is at least about 10%, at compared to 2-3 hours for most narcotics, confers a long least about 20%, at least about 30%, at least about 40%, at duration of action and thus requires leSS frequent dosing. least about 50%, at least about 60%, at least about 70%, at 0049 Enhanced bioavailability enables the use of lower least about 80%, at least about 90%, or at least about 100% doses, which also results in decreased toxicity associated greater than the AUC exhibited by the non-nanoparticulate with nimeSulide. In this regard, lower doses of nanoparticu formulation of nimeSulide. late nimeSulide can achieve the same or better therapeutic 0057 According to the invention, any formulation that effects as larger doses of conventional nimeSulide. Such provides the desired pharmacokinetic profile is Suitable for lower doses can be realized due to the greater bioavailability administration. Exemplary types of formulations that give of nanoparticulate drug formulations as compared to con Such profiles are liquid dispersions, gels, aerosols, oint ventional drug formulations. NimeSulide, like any drug, can ments, creams and Solid dose forms. have adverse side effects. Therefore, the ability to administer lower doses of it translates into fewer adverse side effects. 0.058 D. The Pharmacokinetic Profiles are not Affected by the Fed or Fasted State of the Subject Ingesting the 0050 Enhanced bioavailability also can enable the use of Compositions a Smaller dosage size. This is significant for certain patient populations, Such as the elderly, juvenile and infant. 0059 Certain drugs have been shown to have signifi cantly lower plasma levels when administered under fasting 0051) C. Improved Pharmacokinetic Profiles conditions as when administered immediately after a stan 0.052 The inventive nanoparticulate nimeSulide compo dard test meal. This significant difference is undesirable. Sitions also preferably exhibit a desirable pharmacokinetic 0060 Nanoparticulate nimeSulide formulations of the profile when administered to mammalian Subjects. The invention preferably alleviate this problem. That is, they desirable pharmacokinetic profile preferably includes, but is preferably reduce the differences in, or more preferably do not limited to: (1) that the T of nimeSulide, when assayed not produce Significantly different, absorption levels when in the plasma of a mammalian Subject following adminis administered under fed as compared to fasting conditions. tration, is preferably less than the T for a conventional, non-nanoparticulate form of nimeSulide administered at the 0061 Thus, the invention encompasses a nimeSulide same dosage; (2) that the C of nimeSulide, when assayed composition having a pharmacokinetic profile that is not in the plasma of a mammalian Subject following adminis substantially affected by the fed or fasted State of a subject tration, is preferably greater than the C for a conven ingesting the composition. This means that there is no tional, non-nanoparticulate form of nimeSulide administered Substantial difference in the quantity of drug absorbed or the at the same dosage; and/or (3) that the AUC of nimeSulide, rate of drug absorption when the nanoparticulate nimeSulide when assayed in the plasma of a mammalian Subject fol compositions are administered in the fed versus the fasted lowing administration, is preferably greater than the AUC State. for a conventional, non-nanoparticulate form of nimeSulide 0062) The invention also encompasses animeSulide com administered at the same dosage. position for which administration to a Subject in a fasted US 2004/O156872 A1 Aug. 12, 2004

State is bioequivalent to administration to a Subject in a fed administration, the nanoparticulate nimeSulide compositions state. “Bioecquivalency” is preferably established by a 90% did not redisperse to a Substantially nanoparticulate particle Confidence Interval (CI) of between 0.80 and 1.25 for both size, then the dosage form might lose the benefits of a C, and AUC under U.S. Food and Drug Administration nanoparticulate formulation. regulatory guidelines, or a 90% CI for AUC of between 0.80 0071. This is because nanoparticulate active agent com to 1.25 and a 90% CI for C of between 0.70 to 1.43 under positions benefit from the Small particle size of the active the European EMEA regulatory guidelines (T is not agent. If the active agent does not redisperse into Small relevant for bioeduivalency determinations under USFDA particle sizes upon administration, then "clumps' or and EMEA regulatory guidelines). agglomerated active agent particles are formed, owing to the 0.063 Benefits of a dosage form that substantially elimi extremely high Surface free energy of the nanoparticulate nates the effect of food include an increase in convenience, System and the thermodynamic driving force to achieve an which increases patient compliance, as a patient does not overall reduction in free energy. With the formation of Such need to ensure that they are taking a dose either with or agglomerated particles, the bioavailability of the dosage without food. This is significant, as poor patient compliance form may fall well below that observed with a liquid can defeat the purpose of administering a drug. dispersion form of the nanoparticulate active agent. 0064. The difference in absorption of the inventive nime 0072 Moreover, the inventive nanoparticulate nime Sulide compositions, when administered in a fed verSuS a Sulide compositions preferably exhibit dramatic redispersion fasted State, preferably is less than about 100%, less than upon administration to a mammal, Such as a human or about 90%, less than about 80%, less than about 70%, less animal. This can be demonstrated by reconstitution/redis than about 60%, less than about 50%, less than about 40%, persion in a biorelevant acqueous medium Such that the less than about 30%, less than about 25%, less than about effective average particle size of the redispersed nimeSulide 20%, less than about 15%, less than about 10%, less than particles is less than about 2 microns. Biorelevant aqueous about 5%, or less than about 3%. media include any aqueous media that exhibit representative ionic Strength and pH. The desired pH and ionic strength is 0065 E. Rapid Dissolution Profiles one that represents physiological conditions found in the 0.066 Nanoparticulate nimeSulide compositions of the human body. Such biorelevant acqueous media can be, for invention preferably have rapid dissolution profiles. Rapid example, aqueous electrolyte Solutions or aqueous Solutions dissolution of an administered active agent is desirable, as of any salt, acid, base, or a combination thereof. faster dissolution generally leads to faster onset of action and greater bioavailability. To maximize the dissolution 0073 Biorelevant pH is well known in the art. For profile and bioavailability of nimeSulide, it would be useful example, in the Stomach, the pH ranges from Slightly leSS to increase the drugs dissolution So that it could attain a than 2 (but typically greater than 1) up to 4 or 5. In the Small level close to 100%. intestine the pH can range from 4 to 6, and in the colon it can range from 6 to 8. Biorelevant ionic Strength is also well 0067. The inventive nimeSulide compositions preferably known in the art. Fasted State gastric fluid has an ionic have a dissolution profile in which at least about 20% of the strength of about 0.1M, while fasted state intestinal fluid has composition is dissolved within 5 minutes. In other embodi an ionic Strength of about 0.14. See e.g., Lindahl et al., ments, at least about 30% or about 40% of the nimeSulide “Characterization of Fluids from the Stomach and Proximal composition is dissolved within about 5 minutes. In yet other Jejunum in Men and Women.” Pharm. Res., 14(4): 497-502 embodiments, preferably at least about 40%, about 50%, (1997). about 60%, about 70%, or about 80% of the nimeSulide composition is dissolved within about 10 minutes. Finally, in 0074. It is believed that the pH and ionic strength of a test Solution are more critical than the Specific chemical content. another embodiment, preferably at least about 70%, about Accordingly, appropriate pH and ionic strength values can 80%, about 90%, or about 100% of the nimeSulide compo be obtained through numerous combinations of Strong acids, sition is dissolved within about 20 minutes. Strong bases, Salts, Single or multiple conjugate acid-base 0068 Dissolution is preferably measured in a medium pairs (i.e., weak acids and corresponding salts of that acid), that is discriminating. Such a dissolution medium will monoprotic and polyprotic electrolytes, etc. produce two different dissolution curves for two products having different dissolution profiles in gastric juices, i.e., the 0075 Representative electrolyte solutions can be, but are dissolution medium is predictive of in vivo dissolution of a not limited to, HCl Solutions, ranging in concentration from composition. An exemplary dissolution medium is an aque about 0.001 to about 0.1 M, and NaCl solutions, ranging in ous medium containing the Surfactant Sodium lauryl Sulfate concentration from about 0.001 to about 0.1M, and mixtures at 0.025 M. Determination of the amount dissolved can be thereof. For example, electrolyte Solutions can be, but are performed by Spectrophotometry. The rotating blade method not limited to, about 0.1M HCl or less, about 0.01 M HCl (European Pharmacopoeia) can be used to measure disso or less, about 0.001M HCl or less, about 0.1M NaCl or less, lution. about 0.01 M NaCl or less, about 0.001M NaCl or less, and mixtures thereof. Of these electrolyte solutions, 0.01 M HCl 0069. F. Redispersion of Nanoparticulate Nimesulide and/or 0.1M NaCl, are most representative of fasted human Dosage Forms to Nanoparticulate Particle Size physiological conditions, owing to the pH and ionic Strength 0070 The inventive nanoparticulate nimeSulide compo conditions of the proximal gastrointestinal tract. Sitions preferably redisperse Such that the effective average 0.076 Electrolyte concentrations of 0.001M HCl, 0.01 M particle Size of the redispersed nimeSulide particles is leSS HCl, and 0.1M HCl correspond to pH 3, pH 2, and pH 1, than about 2 microns. This is significant because if, upon respectively. Thus, a 0.01 M HCl solution simulates typical US 2004/O156872 A1 Aug. 12, 2004

acidic conditions found in the stomach. A Solution of 0.1 M which is specifically incorporated by reference. Bioadhesive NaCl provides a reasonable approximation of the ionic formulations of nimeSulide exhibit exceptional bioadhesion Strength conditions found throughout the body, including the to biological Substrates. gastrointestinal fluids, although concentrations higher than 0084 Bioadhesive nimeSulide compositions are useful in 0.1 M may be employed to simulate fed conditions within any situation where it is desirable to apply the compositions the human GI tract. to a biological Surface. Bioadhesive nimeSulide composi 0.077 Exemplary solutions of salts, acids, bases or com tions coat the targeted Surface in a continuous and uniform binations thereof, that exhibit the desired pH and ionic film, which is invisible to the naked human eye. Strength include, but are not limited to, phosphoric acid/ 0085 Bioadhesion slows transit of a nimeSulide compo phosphate Salts+Sodium, potassium and calcium Salts of Sition, and Some nimeSulide particles inevitably adhere to chloride, acetic acid/acetate Salts+Sodium, potassium and tissue other than the mucous cells. This provides a prolonged calcium Salts of chloride, carbonic acid/bicarbonate Salts+ exposure to nimeSulide, thereby increasing absorption and Sodium, potassium and calcium Salts of chloride, and citric bioavailability of the administered dosage. acid/citrate SaltS+Sodium, potassium and calcium Salts of chloride. 0086. H. Low Viscosity Liquid Nanoparticulate Nime Sulide Compositions 0078. In other embodiments of the invention, the redis persed nimeSulide particles (redispersed in an aqueous, 0087 Aliquid dosage form of a conventional microcrys biorelevant, or any other Suitable media) have an effective talline or non-nanoparticulate or Solubilized nimeSulide average particle size of less than about 1900 nm, less than composition would be expected to be a relatively large about 1800 nm, less than about 1700 nm, less than about volume, highly viscous substance which would not be well 1600 nm, less than about 1500 nm, less than about 1400 nm, accepted by patient populations. This is significant, as liquid less than about 1300 nm, less than about 1200 nm, less than dosage forms can be particularly useful for patient popula about 1100 nm, less than about 1000 nm, less than about 900 tions Such as the elderly and infant. nm, less than about 800 nm, less than about 700 nm, less 0088 Liquid dosage forms of the nanoparticulate nime than about 600 nm, less than about 500 nm, less than about Sulide compositions of the invention provide significant 400 nm, less than about 300 nm, less than about 250 nm, less advantages over a liquid dosage form of a conventional than about 200 nm, less than about 150 nm, less than about microcrystalline or Solubilized nimeSulide composition. The 100 nm, leSS than about 75 nm, or leSS than about 50 nm, as low viscosity and silky texture of liquid dosage forms of the measured by light-Scattering methods, microScopy, or other nanoparticulate nimeSulide compositions of the invention appropriate methods. result in advantages in both preparation and use. These 0079. By “an effective average particle size of less than advantages include, for example: (1) better Subject compli about 2000 nm it is meant that at least 50% of the ance due to the perception of a lighter formulation which is nimeSulide particles have a particle Size leSS than the effec easier to injest; (2) ease of dispensing as compared to a tive average, by weight, i.e., less than about 2000 nm, 1900 highly viscous formulation; (3) potential for formulating a nm, 1800 nm, etc., when measured by the above-noted higher concentration of nimeSulide resulting in a Smaller techniques. Preferably, at least about 70%, about 90%, about dosage Volume and thus leSS Volume for the Subject to 95%, or about 99% of the nimeSulide particles have a consume; and (4) easier overall formulation concerns. particle Size less than the effective average, i.e., less than 0089. The viscosities of liquid dosage forms of nanopar about 2000 nm, 1900 nm, 1800 nm, 1700 nm, etc. ticulate nimeSulide according to the invention are preferably 0080 Redispersibility can be tested using any suitable less than about/200, less than about/175, less than about/150, means known in the art. See e.g., the example Sections of less than about /125, less than about /100, leSS than about /75, U.S. Pat. No. 6,375,986 for “Solid Dose Nanoparticulate less than about /SO, or less than about /25 of a topical liquid Compositions Comprising a Synergistic Combination of a dosage form of a non-nanoparticulate nimeSulide composi Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuc tion, at about the same concentration per ml of nimeSulide. cinate.” 0090 Typically the viscosity of liquid nanoparticulate nimeSulide dosage forms of the invention, at a shear rate of 0.081 G. Bioadhesive Nanoparticulate Nimesulide Com 0.1 (1/s) and measured at 20° C., is from about 2000 mPa's positions to about 1 mPats, from about 1900 mPa's to about 1 mPats, 0082 Nanoparticulate nimeSulide compositions of the from about 1800 mPa is to about 1 mPas, from about 1700 invention can exhibit bioadhesive properties. Such compo mPa's to about 1 mPas, from about 1600 mPa's to about 1 Sitions comprise one or more cationic Surface Stabilizers, mPas, from about 1500 mPa's to about 1 mPats, from about which are described in more detail below. 1400 mPa's to about 1 mPats, from about 1300 mPa is to about 1 mPas, from about 1200 mPa's to about 1 mPats, 0.083. The term bioadhesion refers to any attractive inter from about 1100 mPa's to about 1 mPats, from about 1000 action between two biological Surfaces or between a bio mPa's to about 1 mPats, from about 900 mPa is to about 1 logical and a Synthetic Surface. In the case of bioadhesive mPas, from about 800 mPa is to about 1 mPats, from about nanoparticulate nimeSulide compositions, the term bioadhe 700 mPa's to about 1 mPas, from about 600 mPa is to about Sion describes the adhesion between nanoparticulate nime 1 mPas, from about 500 mPa's to about 1 mPas, from about Sulide compositions and a biological Substrate (e.g., gas 400 mPa's to about 1 mPas, from about 300 mPa is to about trointestinal mucin, lung tissue, nasal mucosa, etc.). See, 1 mPas, from about 200 mPa's to about 1 mPas, from about e.g., U.S. Pat. No. 6,428,814 for “Bioadhesive Nanoparticu 175 mPa's to about 1 mPas, from about 150 mPa's to about late Compositions Having Cationic Surface Stabilizers,” 1 mPas, from about 125 mPa's to about 1 mPas, from about US 2004/O156872 A1 Aug. 12, 2004

100 mPa's to about 1 mPa's, from about 75 mPa's to about 0100 If the second nimeSulide composition has a nano 1 mPas, from about 50 mPa is to about 1 mPas, from about particulate particle size, then preferably the nimeSulide 25 mPa's to about 1 mPas, from about 15 mPa's to about 1 particles of the Second composition have at least one Surface mPats, from about 10 mPa is to about 1 mPats, or from about Stabilizer associated with the Surface of the drug particles. 5 mPa is to about 1 mPars. The one or more Surface Stabilizers can be the same as or 0.091 Viscosity is concentration and temperature depen different from the surface stabilizer(s) present in the first dent. Typically, a higher concentration results in a higher nimeSulide composition. Viscosity, while a higher temperature results in a lower 0101 Preferably where co-administration of a “fast-act Viscosity. Viscosity as defined above refers to measurements ing formulation and a “longer-lasting formulation is taken at about 20° C. (The viscosity of water at 20° C. is 1 desired, the two formulations are combined within a Single mPas.) The invention encompasses equivalent Viscosities composition, for example a dual-release composition. measured at different temperatures. 0102 K. Combination Active Agent Compositions 0092. The liquid formulations of this invention can be formulated for dosages in any Volume but preferably equiva 0103) The invention encompasses the nanoparticulate lent or Smaller Volumes than a liquid dosage form of a nimeSulide compositions of the invention formulated or non-nanoparticulate or Solubilized nimeSulide composition. co-administered with one or more non-nimeSulide active agents. Methods of using Such combination compositions 0093. I. Sterile Filtered Nanoparticulate Nimesulide are also encompassed by the invention. The non-nimeSulide Compositions active agents can be present in a crystalline phase, an 0094. The nanoparticulate nimeSulide compositions of amorphous phase, a Semi-crystalline phase, a Semi-amor the invention can be sterile filtered. This obviates the need phous phase, or a mixture thereof. for heat Sterilization, which can harm or degrade nimeSulide, 0104. The compound to be administered in combination as well as result in crystal growth and particle aggregation. with a nanoparticulate nimeSulide composition of the inven 0.095 Sterile filtration can be difficult because of the tion can be formulated Separately from the nanoparticulate required Small particle size of the composition. Filtration is nimeSulide composition or co-formulated with the nanopar an effective method for Sterilizing homogeneous Solutions ticulate nimeSulide composition. Where a nanoparticulate when the membrane filter pore size is less than or equal to nimeSulide composition is co-formulated with a Second about 0.2 microns (200 nm) because a 0.2 micron filter is active agent, the Second active agent can be formulated in sufficient to remove essentially all bacteria. Sterile filtration any Suitable manner, Such as immediate-release, rapid-onset, is normally not used to Sterilize Suspensions of micron-sized Sustained-release, or dual-release form. nimeSulide because the nimeSulide particles are too large to 0105 Such non-nimeSulide active agents can be, for pass through the membrane pores. example, a therapeutic agent. A therapeutic agent can be a 0.096 Asterile nanoparticulate nimeSulide dosage form is pharmaceutical agent, including a biologic, Such as proteins, particularly useful in treating immunocompromised peptides, and nucleotides, or a diagnostic agent, Such as a patients, infants or juvenile patients, and the elderly, as these contrast agent, including X-ray contrast agents. The active patient groups are the most Susceptible to infection caused agent can be Selected from a variety of known classes of by a non-Sterile liquid dosage form. drugs, including, for example, amino acids, proteins, pep tides, nucleotides, anti-obesity drugs, central nervous System 0097. Because the nanoparticulate nimeSulide composi Stimulants, carotenoids, corticosteroids, elastase inhibitors, tions of the invention, formulated into a liquid dosage form, anti-fungals, oncology therapies, anti-emetics, analgesics, can be Sterile filtered, and because the compositions can cardiovascular agents, anti-inflammatory agents, Such as have a very Small nimeSulide effective average particle Size, NSAIDs and COX-2 inhibitors, anthelmintics, anti-arrhyth the compositions are Suitable for parenteral administration. mic agents, antibiotics (including penicillins), anticoagul 0098. J. Combination Pharmacokinetic Profile Composi lants, antidepressants, antidiabetic agents, antiepileptics, tions antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, 0099. In one embodiment of the invention, a first nime immunosuppressants, antithyroid agents, antiviral agents, Sulide formulation providing the pharmacokinetic profile anxiolytics, Sedatives (hypnotics and neuroleptics), astrin described above is co-administered with at least one other gents, alpha-adrenergic receptor blocking agents, beta nimeSulide formulation that generates a different pharma adrenoceptor blocking agents, blood products and Substi cokinetic profile, Specifically one exhibiting slower absorp tutes, cardiac inotropic agents, contrast media, tion into the bloodstream, and therefore a longer T and corticosteroids, cough Suppressants (expectorants and typically a lower C. For example, the Second nimeSulide mucolytics), diagnostic agents, diagnostic imaging agents, formulation can have a conventional particle size, which diuretics, dopaminergics (antiparkinsonian agents), haemo produces a longer Ta, and typically a lower C. Alter Statics, immunological agents, lipid regulating agents, natively, a Second, third or fourth nimeSulide formulation muscle relaxants, parasympathomimetics, parathyroid cal can differ from the first, and from each other, in the effective citonin and biphosphonates, prostaglandins, radio-pharma average particle sizes of each composition. The difference ceuticals, Sex hormones (including Steroids), anti-allergic particle sizes produce different T values. The combina agents, Stimulants and anoretics, Sympathomimetics, thyroid tion of fast pain relief provided by the first formulation and longer-lasting pain relief provided by the Second (or third, agents, vasodilators, vasomodulators, and Xanthines. fourth, etc.) formulation can reduce the dose frequency 0106 Examples of representative active agents useful in required. this invention include, but are not limited to, acyclovir, US 2004/O156872 A1 Aug. 12, 2004

alprazolam, altretamine, amiloride, amiodarone, benz 2-amino-4-picoline, aminopropylon, aminopyrine, amix tropine meSylate, bupropion, cabergoline, candesartan, etrine, ammonium Salicylate, ampiroXicam, amtolimetin cerivastatin, chlorpromazine, ciprofloxacin, cisapride, guacil, anilleridine, antipyrine, antipyrine Salicylate, antrafe clarithromycin, clonidine, clopidogrel, cyclobenzaprine, nine, apaZone, bendazac, benorylate, benoxaprofen, benz cyproheptadine, delavirdine, desmopressin, diltiazem, dipy piperylon, benzydamine, benzylmorphine, bermoprofen, ridamole, dolasetron, enalapril maleate, enalaprilat, famoti bezitramide, C.-bisabolol, bromfenac, p-bromoacetanilide, dine, felodipine, furazolidone, glipizide, irbesartan, keto 5-bromoSalicylic acid acetate, bromosaligenin, bucetin, conazole, lanSoprazole, loratadine, loxapine, mebendazole, bucloxic acid, bucolome, bufeXamac, bumadizon, buprenor mercaptopurine, milrinone lactate, minocycline, mitox phine, butacetin, butibufen, butophanol, calcium acetylsali antrone, nelfinavir meSylate, nimodipine, norfloxacin, olan Zapine, omeprazole, penciclovir, pimozide, tacolimus, cylate, carbamazepine, carbiphene, carprofen, carSalam, quazepam, raloxifene, rifabutin, rifampin, risperidone, riza chlorobutanol, chlorthenoxazin, choline Salicylate, cin triptan, Saquinavir, Sertraline, Sildenafil, acetyl-Sulfisox chophen, cinmetacin, ciramadol, clidanac, clometacin, azole, temazepam, thiabendazole, thioguanine, trandolapril, clonitaZene, clonixin, clopirac, clove, codeine, codeine triamterene, trimetrexate, troglitaZone, trovafloxacin, Vera methyl bromide, codeine phosphate, codeine Sulfate, cro pamil, vinblastine Sulfate, mycophenolate, atovaquone, propamide, crotethamide, desomorphine, deXOXadrol, dex tromoramide, dezocine, diampromide, diclofenac Sodium, atovaquone, proguanil, ceftazidime, cefuroxime, etoposide, difenamizole, difenpiramide, diflunisal, dihydrocodeine, terbinafine, thalidomide, fluconazole, amsacrine, dacarba dihydrocodeinone enol acetate, dihydromorphine, dihy Zine, teniposide, and acetylsalicylate. droxyaluminum acetylsalicylate, dimenoxadol, dimephep 0107 A description of these classes of active agents and tanol, dimethylthiambutene, dioxaphetyl butyrate, dipi a listing of Species within each class can be found in panone, diprocetyl, dipyrone, ditaZol, droxicam, Martindale's The Extra Pharmacopoeia, 31 Edition (The emorfaZone, enfenamic acid, epirizole, eptazocine, eter Pharmaceutical Press, London, 1996), specifically incorpo Salate, ethenZamide, ethoheptazine, ethoxazene, ethylmeth rated by reference. The active agents are commercially ylthiambutene, ethylmorphine, etodolac, etofenamate, eto available and/or can be prepared by techniques known in the nitaZene, eugenol, felbinac, fenbufen, fenclozic acid, art. fendosal, fenoprofen, fentanyl, fentiazac, fepradinol, fepra Zone, floctafenine, flufenamic acid, flunoxaprofen, fluo 0108 Exemplary nutraceuticals or dietary supplements resone, flupirtine, flu.proquaZone, flurbiprofen, fosfosal, gen include, but are not limited to, lutein, folic acid, fatty acids tisic acid, glafenine, glucametacin, glycol Salicylate, (e.g., DHA and ARA), fruit and vegetable extracts, Vitamin guaiaZulene, hydrocodone, hydromorphone, hydroxypethi and mineral Supplements, phosphatidylserine, lipoic acid, dine, ibufenac, ibuprofen, ibuproxam, imidazole Salicylate, melatonin, glucosamine/chondroitin, Aloe Vera, Guggul, indomethacin, indoprofen, isofeZolac, isoladol, isometha glutamine, amino acids (e.g., arginine, iso-leucine, leucine, done, isonixin, isoxepac, isoxicam, ketobemidone, ketopro lysine, methionine, phenylanine, threonine, tryptophan, and fen, ketorolac, p-lactophenetide, lefetamine, levorphanol, valine), green tea, lycopene, whole foods, food additives, lofentanil, lonazolac, lomoxicam, loxoprofen, lysine acetyl herbs, phytonutrients, antioxidants, flavonoid constituents of Salicylate, magnesium acetylsalicylate, meclofenamic acid, fruits, evening primrose oil, flax Seeds, fish and marine mefenamic acid, meperidine, meptazinol, meSalamine, animal oils, and probiotics. Nutraceuticals and dietary metazocine, methadone hydrochloride, methotrimeprazine, Supplements also include bio-engineered foods genetically metiaZinic acid, metofoline, metopon, mofebutaZone, mof engineered to have a desired property, also known as “phar eZolac, moraZone, morphine, morphine hydrochloride, mor mafoods.” phine Sulfate, morpholine Salicylate, myrophine, nabume 0109 Exemplary nutraceuticals and dietary supplements tone, nalbuphine, 1-naphthyl Salicylate, naproxen, narceline, are disclosed, for example, in Roberts et al., Nutraceuticals. nefopam, nicomorphine, nifenaZone, niflumic acid, nime The Complete Encyclopedia of Supplements, Herbs, Vita Sulide, 5'-nitro-2'-propoxyacetanilide, norlevorphanol, mins, and Healing Foods (American Nutraceutical ASSocia normethadone, normorphine, norpipanone, olSalazine, tion, 2001), which is specifically incorporated by reference. opium, oxaceprol, Oxametacine, Oxaprozin, Oxycodone, Dietary Supplements and nutraceuticals are also disclosed in Oxyrnorphone, oxyphenbutaZone, papaveretum, paranyline, Physicians' Desk Reference for Nutritional Supplements, 1st parSalmide, pentazocine, perisoxal, phenacetin, phenadox Ed. (2001) and The Physicians' Desk Reference for Herbal one, phenazocine, phenaZopyridine hydrochloride, pheno Medicines, 1st Ed. (2001), both of which are also incorpo coll, phenoperidine, phenopyrazone, phenyl acetylsalicy rated by reference. A nutraceutical or dietary Supplement, late, phenylbutaZone, phenyl Salicylate, phenyramidol, also known as a phytochemical or functional food, is gen piketoprofen, piminodine, pipebuZone, piperylone, piprofen, erally any one of a class of dietary Supplements, Vitamins, piraZolac, piritramide, piroXicam, pranoprofen, proglu meta minerals, herbs, or healing foods that have medical or cin, proheptazine, promedol, propacetamol, propiram, pro pharmaceutical effects on the body. poxyphene, propyphenaZone, proguaZone, protizinic acid, ramifenaZone, remifentanil, rimazolium metilsulfate, Salac 0110 Preferred combination therapies comprise a com etamide, Salicin, Salicylamide, Salicylamide O-acetic acid, position useful in methods of the invention with one or more Salicylsulfuric acid, Salsalte, Salverine, Simetride, Sodium compounds Selected from aceclofenac, acemetacin, e-aceta Salicylate, Sufentanil, SulfaSalazine, Sulindac, Superoxide midocaproic acid, acetaminophen, acetaminoSalol, acetanil dismutase, Suprofen, SuxibuZone, talniflumate, tenidap, ide, acetylsalicylic acid (aspirin), S-adenosylmethionine, tenoxicam, terofenamate, tetrandrine, thiazolinobutaZone, alclofenac, alfentanil, allylprodine, alminoprofen, aloxiprin, tiaprofenic acid, tiaramide, tilidine, tinoridine, tolfenamic alphaprodine, aluminum bis(acetylsalicylate), amfenac, acid, tolmetin, tramadol, tropesin, Viminol, Xenbucin, Ximo aminochlorthenoxazin, 3-amino-4-hydroxybutyric acid, profen, Zaltoprofen, and Zomepirac. See The Merck Index, US 2004/O156872 A1 Aug. 12, 2004

12th Edition (1996), Therapeutic Category and Biological composition of the invention include, but are not limited to, Activity Index, lists therein headed “Analgesic”, “Anti celecoxib (SC-58635, CELEBREX(R), Pharmacia/Searle & inflammatory”, and “Antipyretic'). Co.), rofecoxib (MK-966, L-748731, VIOXX(R), Merck & 0111. In a particularly preferred embodiment of the Co.), meloxicam (MOBIC(R), co-marketed by Abbott Labo invention, the nanoparticulate nimeSulide composition is ratories, Chicago, Ill., and Boehringer Ingelheim Pharma ceuticals), Valdecoxib (BEXTRACE), G.D. Searle & Co.), combined with at least one analgesic. Useful analgesics parecoxib (G.D. Searle & Co.), etoricoxib (MK-663; include, for example, NSAIDS and non-nimeSulide COX-2 Merck), SC-236 (chemical name of 4-5-(4-chlorophenyl)- inhibitors. 3-(trifluoromethyl)-1H-pyrazol-1-yl) benzenesulfonamide; 0112 Particularly preferred combination therapies com G.D. Searle & Co., Skokie, Ill.); NS-398 (N-(2-cyclohexy prise use of a nanoparticulate nimeSulide composition of the loxy-4-nitrophenyl)methane sulfonamide; Taisho Pharma invention with an opioid compound, more particularly ceutical Co., Ltd., Japan); SC-58125 (methyl sulfone where the opioid compound is codeine, meperidine, mor spiro(2.4)hept-5-ene I; Pharmacia/Searle & Co.); SC-57666 phine, or a derivative thereof. (Pharmacia/Searle & Co.); SC-558 (Pharmacia/Searle & 0113. In an embodiment of the invention, particularly Co.); SC-560 (Pharmacia/Searle & Co.); etodolac (Lodine(R), where a COX-2 mediated condition is headache or migraine, Wyeth-Ayerst Laboratories, Inc.); DFU (5,5-dimethyl-3-(3- the nanoparticulate nimeSulide composition is administered fluorophenyl)-4-(4-methylsulfonyl)phenyl 2(5H)-furanone); in combination therapy with a vasomodulator, preferably a monteleukast (MK-476), L-745337 ((5-methanesulphona Xanthine derivative having vasomodulatory effect, more mide-6-(2,4-difluorothio-phenyl)-1-indanone), L-761066, preferably an alkylxanthine compound. L-761000, L-748780 (all Merck & Co.); DUP-697 (5-Bromo-2-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl; 0114 Combination therapies wherein an alkylxanthine DuPont Merck Pharmaceutical Co.); PGV 20229 (1-(7-tert.- compound is co-administered with a nanoparticulate nime butyl-2,3-dihydro-3,3-dimethylbenzo(b)furan-5-yl)-4-cy Sulide composition as provided herein are embraced by the clopropylbutan-1-one; Procter & Gamble Pharmaceuticals); present embodiment of the invention whether or not the iguratimod (T-614; 3-formylamino-7-methylsulfonylamino alkylxanthine is a vasomodulator and whether or not the 6-phenoxy-4H-1-benzopyran-4-one; Toyama Corp., Japan); therapeutic effectiveness of the combination is to any degree BF 389 (Biofor, USA); CL 1004 (PD 136095), PD 136005, attributable to a vasomodulatory effect. The term “alkylx PD 142893, PD 138387, and PD 145065 (all Parke-Davis/ anthine' herein embraces Xanthine derivatives having one or Warner-Lambert Co.); flurbiprofen (ANSAID(R); Pharmacia more C alkyl substituents, preferably methyl, and phar & Upjohn); nabumetone (FELAFENE); SmithKline Bee maceutically acceptable Salts of Such Xanthine derivatives. cham, plc); flosulide (CGP 28238; Novartis/Ciba Geigy); Dimethylxanthines and trimethylxanthines, including caf piroXicam (FELDANE(R); Pfizer); diclofenac feine, theobromine, and theophylline, are especially pre (VOLTARENCE and CATAFLAM(R), Novartis); lumiracoxib ferred. Most preferably, the alkylxanthine compound is (COX-189; Novartis); D 1367 (Celltech Chiroscience, plc); caffeine. R 807 (3 benzoyldifluoromethane sulfonanilide, diflumi 0115 Exemplary NSAIDS that can be formulated in done); JTE-522 (Japan Tobacco, Japan); FK-3311 (4'- combination with the nanoparticulate nimeSulide composi Acetyl-2'-(2,4-difluorophenoxy)methanesulfonanilide), FK tion of the invention include, but are not limited to, Suitable 867, FR 140423, and FR 115068 (all Fujisawa, Japan); GR nonacidic and acidic compounds. Suitable nonacidic com 253035 (Glaxo Wellcome); RWJ 63556 (Johnson & pounds include, for example, nabumetone, tiaramide, pro Johnson); RWJ 20485 (Johnson & Johnson); ZK 38997 quaZone, bufeXamac, flumizole, epirazole, tinoridine, tim (Schering); S 2474 (E)-(5)-(3,5-di-tert-butyl-4-hydroxy egadine, and dapsone. benzylidene)-2-ethyl-1,2-isothiazolidine-1,1-dioxide 0116 Exemplary acidic NSAID compounds that can be indomethacin; Shionogi & Co., Ltd., Japan), Zomepirac formulated in combination with the nanoparticulate nime analogs, such as RS 57067 and RS 104897 (Hoffmann La Sulide composition of the invention include, but are not Roche); RS 104894 (Hoffmann La Roche); SC 41930 (Mon limited to, carboxylic acids and enolic acids. Suitable car santo); pranlukast (SB 205312, Ono-1078, ONONGR), boxylic acid NSADs include, for example: (1) salicylic acids ULTAIRM; SmithKline Beecham); SB 2.09670 (SmithKline and esters thereof, Such as aspirin, diflunisal, benorylate, and Beecham); and APHS (heptinylsulfide). fosfosal; (2) acetic acids, including phenylacetic acids Such 0118 L. Miscellaneous Benefits of the Nanoparticulate as diclofenac, alclofenac and fenclofenac; (3) carbo- and Nimesulide Compositions of the Invention heterocyclic acetic acids Such as etodolac, indomethacin, Sulindac, tolmetin, fentiazac, and tilomisole; (4) propionic 0119) The nanoparticulate nimeSulide compositions pref acids, Such as carprofen, fenbufen, flurbiprofen, ketoprofen, erably exhibit an increased rate of dissolution as compared Oxaprozin, Suprofen, tiaprofenic acid, ibuprofen, naproxen, to microcrystalline or non-nanoparticulate forms of nime fenoprofen, indoprofen, pirprofen; and (5) fenamic acids, Sulide. In addition, the nanoparticulate nimeSulide compo Such as flufenamic, mefenamic, meclofenamic and niflumic. Sitions preferably exhibit improved performance character Suitable enolic acid NSAIDs that can be formulated in istics for oral, intravenous, Subcutaneous, or intramuscular combination with the nanoparticulate nimeSulide composi injection, Such as higher dose loading and Smaller tablet or tion of the invention include, but are not limited to: (1) liquid dose volumes. Moreover, the nanoparticulate nime pyrazolones Such as oxyphenbutaZone, phenylbutaZone, Sulide compositions of the invention do not require organic apaZone, and feprazone; and (2) oxicams Such as piroxicam, Solvents or pH extremes. Sudoxicam, iSoxicam, and tenoxicam. 0120 V. Compositions 0117 Exemplary COX-2 inhibitors that can be formu 0121 The present invention includes nanoparticulate lated in combination with the nanoparticulate nimeSulide active agent compositions that comprise nimeSulide. The US 2004/O156872 A1 Aug. 12, 2004 compositions preferably comprise nimeSulide and at least recurrent history of gastrointestinal lesions, gastrointestinal one Surface Stabilizer adsorbed on, or associated with, the bleeding, coagulation disorders including anemia Such as Surface of the nimeSulide. The nanoparticulate nimeSulide hypoprothrombinemia, hemophilia, or other bleeding prob particles preferably have an effective average particle Size of lems, kidney disease, or in patients prior to Surgery or less than about 2000 nm. In another aspect, the invention patients taking anticoagulants. provides novel combinations of nimeSulide and other active agents. 0128 Because of the rapid onset of therapeutic effect observed with the compositions of the invention, these 0122) The invention also provides nanoparticulate nime compositions have particular advantages over prior conven Sulide compositions together with one or more non-toxic tional formulations for treatment of acute COX-2 mediated physiologically acceptable carriers, adjuvants, or vehicles, disorders, especially for relief of pain, for example in collectively referred to as carriers. The compositions can be headache, including Sinus headache and migraine. formulated for various routes of administration including, but not limited to, oral, vaginal, rectal, nasal, ocular, 0.129 Nimesulide is also useful in treating and/or pre parenteral injection (e.g., intravenous, intramuscular, or Sub venting, for example, arthritic disorders, gastrointestinal cutaneous), local (e.g., in powder, ointment or drop form), conditions, inflammatory conditions, pulmonary inflamma buccal, intracisternal, intraperitoneal, or topical administra tion, opthalmic diseases, central nervous Systems disorders, pain, inflammation-related cardiovascular disorders, angio tion, and the like. genesis-related disorders, benign and malignant tumors, 0123 A. Nimesulide Particles adenomatous polyps, disorders of the female reproductive System Such as endometriosis, osteoporosis, dySmenorrhea, 0124. As used herein “nimeSulide” means N-(4-Nitro-2- premature labor, asthma, eosinophil-related disorders, pyr phenoxy-phenyl)-methaneSulfonamide, which has the fol exia, bone resorption, nephrotoxicity, hypotension, arthro lowing Structure: sis, joint Stiffness, kidney disease, liver disease including hepatitis, acute mastitis, diarrhea, colonic adenomas, bron chitis, allergic neuritis, cytomegalovirus infectivity, apopto O sis including HIV-induced apoptosis, lumbago; skin-related N4MyH conditions Such as psoriasis, eczema, acne, burns, dermati O tis, and ultraViolet radiation damage including Sunburn; allergic rhinitis, respiratory distress Syndrome, and endot OXin Shock Syndrome. Nanoparticulate nimeSulide is also useful as an immunosuppressive agent. 0.130 Exemplary forms of arthritic disorders that can be treated include, but are not limited to, Osteoarthritis, rheu NO matoid arthritis, spondyloarthropathies, gouty arthritis,juve nile arthritis, gout, ankylosing spondylitis, Systemic lupus erythematosus, burSitis, tendinitis, myofascial pain, carpal 0.125 or an analog or salt thereof. The nimeSulide may be in a crystalline phase, an amorphous phase, a Semi-crystal tunnel Syndrome, fibromyalgia Syndrome, infectious arthri line phase, a Semi-amorphous phase, or a mixture thereof. tis, psoriatic arthritis, Reiter's Syndrome, and Scleroderma 0.126 Nanoparticulate nimeSulide compositions are con 0131 Exemplary gastrointestinal conditions or ulcerative templated to be useful for treating and/or preventing a wide diseases that can be treated include, but are not limited to, range of conditions and disorders mediated by COX-2, inflammatory bowel disease, Crohn's disease, gastritis, irri including but not limited to, disorders characterized by table bowel Syndrome, ulcerative colitis, gastric ulcer, inflammation, pain, and/or fever. Such compositions are pathological but non-malignant conditions Such as heman especially useful as anti-inflammatory agents, Such as in giomas, including infantile hemaginomas, angiofibroma of treatment of arthritis, with the additional benefit of having the nasopharynx, and avascular necrosis of bone. Significantly leSS harmful Side effects than compositions of 0132) Exemplary inflammation conditions that can be conventional NSAIDs that lack selectivity for COX-2 over treated include, but are not limited to, migraine headaches, COX-1. In particular, Such compositions have reduced periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin’s potential for gastrointestinal toxicity and gastrointestinal disease, Sclerodoma, rheumatic fever, type I diabetes, neu irritation including upper gastrointestinal ulceration and romuscular junction disease including myasthenia gravis, bleeding, reduced potential for renal Side effects Such as white matter disease including multiple Sclerosis, Sarcoido reduction in renal function leading to fluid retention and sis, nephrotic Syndrome, Behcet's Syndrome, polymyositis, exacerbation of hypertension, reduced effect on bleeding gingivitis, nephritis, hyperSensitivity, Swelling occurring times including inhibition of platelet function, and possibly after injury including brain edema, myocardial ischemia, a lessened ability to induce asthma attacks in aspirin post-operative inflammation including that following oph Sensitive asthmatic Subjects, by comparison with composi thalmic Surgery Such as cataract Surgery or refractive Sur tions of conventional NSAIDs. gery, and the like. 0127 Thus, nanoparticulate nimeSulide compositions of 0.133 Exemplary pulmonary inflammation conditions the invention are particularly useful as an alternative to that can be treated include, but are not limited to, inflam conventional NSAIDs where Such NSAIDs are contraindi mation associated with viral infections and cystic fibrosis, cated, for example in patients with peptic ulcers, gastritis, and in bone resorption Such as that associated with regional enteritis, ulcerative colitis, diverticulitis, or with a Osteoporosis. US 2004/O156872 A1 Aug. 12, 2004

0134 Exemplary opthalmic diseases or conditions that with familial adenomatous polyposis (FAP). Additionally, can be treated include, but are not limited to, retinitis, Such compositions can be used to prevent polyps from conjunctivitis, retinopathies, uveitis, ocular photophobia, forming in patients at risk of FAP. acute injury to the eye tissue, corneal graft rejection, ocular neovascularization, retinal neovascularization including 0140. Because the nimeSulide compositions of the inven neovascularization following injury or infection, diabetic tion inhibit proStanoid-induced Smooth muscle contraction retinopathy, macular degeneration, retrolental fibroplasia, by inhibiting Synthesis of contractile proStanoids, the com positions can be used in the treatment of dysmenorrhea, glaucoma, and neovascular glaucoma. premature labor, asthma, and eosinophil-related disorders. 0135 Exemplary central nervous system disorders that can be treated include, but are not limited to, cortical 0.141. The compositions of the invention are also useful dementias including Alzheimer's disease, neurodegenera in treating indications where anti-inflammatory agents, anti tion, and central nervous System damage resulting from angiogenesis agents, antitumorigenic agents, immunoSup Stroke, ischemia, and trauma. The term “treatment' in the pressive agents, NSAIDs, COX-2 inhibitors, analgesic present context includes partial or total inhibition of demen agents, anti-thrombotic agents, narcotics, or antifebrile tias, including Alzheimer's disease, vascular dementia, agents are typically used. multi-infarct dementia, pre-Senile dementia, alcoholic dementia, and Senile dementia. 0142 B. Surface Stabilizers 0.136 Exemplary pain conditions that can be treated 0.143 Surface stabilizers especially useful herein physi include, but are not limited to, postoperative pain, pain cally adhere on or associate with the Surface of nanopar resulting from battle field wounds, dental pain, muscular ticulate nimeSulide particles, but do not chemically react pain, pain resulting from cancer, headaches, including Sinus with the nimeSulide particles or themselves. Preferably, headache and migraine, menstrual cramps, and pain associ individual molecules of the Surface Stabilizer are essentially ated with inflammation. free of intermolecular cross-linkages. 0.137 Exemplary inflammation-related cardiovascular 0144) Combinations of more than one surface stabilizer disorders that can be treated or prevented using composi can be used in the invention. Useful Surface stabilizers tions of the invention include, but are not limited to, Vascular include, but are not limited to, known organic and inorganic diseases, coronary artery disease, aneurysm, Vascular rejec pharmaceutical excipients. Such excipients include various tion, arteriosclerosis, atherOSclerosis including cardiac trans polymers, low molecular weight oligomers, natural prod plant atherOSclerosis, myocardial infarction, embolism, ucts, and Surfactants. Preferred Surface Stabilizers include Stroke, thrombosis including venous thrombosis, angina nonionic, ionic, anionic, cationic, and Zwitterionic Surfac including unstable angina, coronary plaque inflammation, tantS. bacterial-induced inflammation including Chlamydia-in duced inflammation, Viral induced inflammation, and 0145 Representative examples of Surface stabilizers inflammation associated with Surgical procedures Such as include hydroxypropylmethylcellulose, hydroxypropylcel vascular grafting including coronary artery bypass Surgery, lulose, polyvinylpyrrollidone, Sodium lauryl Sulfate, dioctyl revascularization procedures including angioplasty, Stent SulfoSuccinate, gelatin, casein, lecithin (phosphatides), dex placement, endarterectomy, or other invasive procedures tran, gum acacia, cholesterol, tragacanth, Stearic acid, benzalkonium chloride, calcium Stearate, glycerol involving arteries, veins, and capillaries. monoStearate, cetoStearyl alcohol, cetomacrogol emulsify 0138 Exemplary angiogenesis-related disorders for ing wax, Sorbitan esters, polyoxyethylene alkyl ethers (e.g., which the inventive compositions are useful include, but are macrogol etherS Such as cetomacrogol 1000), polyoxyeth not limited to, inhibition of tumor angiogenesis. Such com ylene castor oil derivatives, polyoxyethylene Sorbitan fatty positions also are useful for treating neoplasia, including acid esters (e.g., the commercially available TweenS(R) Such metastasis, benign and malignant tumors, and neoplasia as e.g., Tween 2008) and Tween 808) (ICI Speciality Chemi including cancer, Such as colorectal cancer, brain cancer, cals)); polyethylene glycols (e.g., CarbowaXS 3550(R) and bone cancer, epithelial cell-derived neoplasia (epithelial 934(R) (Union Carbide)), polyoxyethylene stearates, colloi carcinoma) Such as basal cell carcinoma, adenocarcinoma, dal Silicon dioxide, phosphates, carboxymethylcellulose cal gastrointestinal cancer Such as lip cancer, mouth cancer, cium, carboxymethylcellulose Sodium, methyl cellulose, esophageal cancer, Small bowel cancer, Stomach cancer, hydroxyethylcellulose, hydroxypropylmethylcellulose colon cancer, liver cancer, bladder cancer, pancreas cancer, phthalate, noncrystalline cellulose, magnesium aluminium OVary cancer, cerVical cancer, lung cancer, breast cancer, silicate, triethanolamine, polyvinyl alcohol (PVA), 4-(1,1,3, skin cancer Such as Squamous cell and basal cell cancers, 3-tetramethylbutyl)-phenol polymer with ethylene oxide and prostate cancer, renal cell carcinoma, and other known formaldehyde (also known as tyloxapol, Superione, and cancers that effect epithelial cells throughout the body. triton), poloxamers (e.g., Pluronics F68(R) and F1086, which Neoplasias for which compositions of the invention are are block copolymers of ethylene oxide and propylene contemplated to be particularly useful are gastrointestinal oxide); poloxamines (e.g., Tetronic 9080E, also known as cancer, Barrett's esophagus, liver cancer, bladder cancer, Poloxamine 9080E), which is a tetrafunctional block copoly pancreatic cancer, OVarian cancer, prostate cancer, cerVical mer derived from Sequential addition of propylene oxide and cancer, lung cancer, breast cancer and skin cancer. The ethylene oxide to ethylenediamine (BASF Wyandotte Cor nanoparticulate nimeSulide compositions of the invention poration, Parsippany, N.J.)); Tetronic 15086) (T-1508) can also be used to treat fibrosis that occurs with radiation (BASF Wyandotte Corporation), Triton X-2008), which is therapy. an alkylaryl polyether sulfonate (Dow Chemical); Crodestas 0.139. The compositions of the invention can be used to F-10(E), which is a mixture of Sucrose Stearate and Sucrose treat Subjects having adenomatous polyps, including those distearate (Croda Inc.), p-isononylphenoxypoly-(glycidol), US 2004/O156872 A1 Aug. 12, 2004 also known as Olin-IOG(R) or Surfactant 10-G(R) (Olin POLYOUAT 10TM, tetrabutylammonium bromide, benzyl Chemicals, Stamford, Conn.); Crodestas SL-40E (Croda, trimethylammonium bromide, choline esters (such as cho Inc.); and SA9OHCO, which is CH, CHC(O)N(CH4)- line esters of fatty acids), benzalkonium chloride, Stearalko CH(CHOH)(CHOH) (Eastman Kodak Co.); decanoyl nium chloride compounds (such as Stearyltrimonium chlo N-methylglucamide; n-decyl 3-D-glucopyranoside; n-decyl ride and Di-Stearyldimonium chloride), cetyl pyridinium B-D-maltopyranoside; n-dodecyl B-D-glucopyranoside; bromide or chloride, halide Salts of quaternized polyoxy n-dodecyl 3-D-maltoside; heptanoyl-N-methylglucamide; ethylalkylamines, MIRAPOLTM and ALKAQUATTM n-heptyl-B-D-glucopyranoside; n-heptyl B-D-thioglucoside; (Alkaril Chemical ComPany), alkyl pyridinium salts; n-hexyl B-D-glucopyranoside; nonanoyl-N-methylglucam amines, Such as alkylamines, dialkylamines, alkanolamines, ide; n-noyl B-D-glucopyranoSide; octanoyl-N-methylgluca polyethylenepolyamines, N,N-dialkylaminoalkyl acrylates, mide; n-octyl-B-D-glucopyranoside, octyl B-D-thioglucopy and vinyl pyridine, amine Salts, Such as lauryl amine acetate, ranoside; PEG-derivatized phospholipid, PEG-derivatized Stearyl amine acetate, alkylpyridinium Salt, and alkylimida cholesterol, PEG-derivatized cholesterol derivative, PEG Zolium Salt, and amine oxides, imide azolinium Salts, pro derivatized vitamin A, PEG-derivatized vitamin E, tonated quaternary acrylamides, methylated quaternary lysozyme, random copolymers of vinyl pyrrollidone and polymers, Such as polydiallyl dimethylammonium chlo vinyl acetate, and the like such as Plasdone(R) S630 in a ride and poly-N-methyl vinyl pyridinium chloride; and 60:40 ratio of the pyrrolidone and vinyl acetate. cationic guar. 0146 More examples of useful surface stabilizers 0.148 Such exemplary cationic surface stabilizers and include, but are not limited to, polymers, biopolymers, other useful cationic Surface Stabilizers are described in J. polysaccharides, cellulosics, alginates, phospholipids, and CroSS and E. Singer, Cationic Surfactants. Analytical and nonpolymeric compounds, Such as Zwitterionic Stabilizers, Biological Evaluation (Marcel Dekker, 1994); P and D. poly-n-methylpyridinium, anthryul pyridinium chloride, Rubingh (Editor), Cationic Surfactants. Physical Chemistry cationic phospholipids, chitosan, polylysine, polyvinylimi (Marcel Dekker, 1991); and J. Richmond, Cationic Surfac dazole, polybrene, polymethylmethacrylate trimethylammo tants. Organic Chemistry, (Marcel Dekker, 1990). niumbromide bromide (PMMTMABr), hexadecyltrimethy lammonium bromide (HDMAB), and polyvinylpyrrollidone 0149 Nonpolymeric surface stabilizers include nonpoly 2-dimethylaminoethyl methacrylate dimethyl sulfate. meric compounds, Such benzalkonium chloride, a car bonium compound, a phosphonium compound, an oxonium 0.147. Other useful cationic stabilizers include, but are not compound, a halonium compound, a cationic organometallic limited to, cationic lipids, sulfonium, phosphonium, and compound, a quartemary phosphorous compound, a pyri quartemary ammonium compounds, Such as Stearyltrim dinium compound, an anilinium compound, an ammonium ethylammonium chloride, benzyl-di(2-chloroethyl)ethylam compound, a hydroxylammonium compound, a primary monium bromide, coconut trimethyl ammonium chloride or ammonium compound, a Secondary ammonium compound, bromide, coconut methyl dihydroxyethyl ammonium chlo a tertiary ammonium compound, and quarternary ammo ride or bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride or bromide, nium compounds of the formula NRRRR''. For com C-dimethyl hydroxyethyl ammonium chloride or bro pounds of the formula NR. R.R.R.'": mide, coconut dimethyl hydroxyethyl ammonium chloride 0150 (i) none of R-R are CH; or bromide, myristyl trimethyl ammonium methyl Sulphate, lauryl dimethyl benzyl ammonium chloride or bromide, 0151 (ii) one of R-R is CH; lauryl dimethyl (ethenoxy) ammonium chloride or bro 0152 (iii) three of R-R are CH; mide, N-alkyl (Cs)dimethylbenzyl ammonium chloride, N-alkyl (Cs)dimethyl-benzyl ammonium chloride, 0153 (iv) all of R-R are CH; N-tetradecylidmethylbenzyl ammonium chloride monohy 0154 (v) two of R-R are CH, one of R-R is drate, dimethyl didecyl ammonium chloride, N-alkyl and CHCH, and one of R-R is an alkyl chain of (C2) dimethyl 1-napthylmethyl ammonium chloride, tri Seven carbon atoms or less, methylammonium halide, alkyl-trimethylammonium Salts and dialkyl-dimethylammonium Salts, lauryl trimethyl 0155 (vi) two of R-R are CH, one of R-R is ammonium chloride, ethoxylated alkyamidoalkyldialkylam CHCH, and one of R-R is an alkyl chain of monium Salt and/or an ethoxylated trialkyl ammonium Salt, nineteen carbon atoms or more; dialkylbenzene dialkylammonium chloride, N-didecyldim 0156 (vii) two of R-R are CH and one of R-R ethyl ammonium chloride, N-tetradecyldimethylbenzyl is the group CH3(CH2), where n>1; ammonium, chloride monohydrate, N-alkyl(C) dim ethyl 1-naphthylmethyl ammonium chloride and dode 0157 (viii) two of R-R are CH, one of R-R is cyldimethylbenzyl ammonium chloride, dialkyl benzene CHCH, and one of R-R comprises at least one alkyl ammonium chloride, lauryl trimethyl ammonium heteroatom; chloride, alkylbenzyl methyl ammonium chloride, alkyl 0158 (ix) two of R-R are CH, one of R-R is benzyl dimethyl ammonium bromide, C2, Cs, C7 trim CHCH, and one of R-R comprises at least one ethyl ammonium bromides, dodecylbenzyl triethyl ammo halogen; nium chloride, poly-diallyldimethylammonium chloride (DADMAC), dimethyl ammonium chlorides, alkyldimethy 0159 (x) two of R-R are CH, one of R-R is lammonium halogenides, tricetyl methyl ammonium chlo CHCH, and one of R-R comprises at least one ride, decyltrimethylammonium bromide, dodecyltriethylam cyclic fragment; monium bromide, tetradecyltrimethylammonium bromide, 0160 (xi) two of R-R are CH and one of R-R is methyl trioctylammonium chloride (ALIQUAT 336 TM), a phenyl ring; or US 2004/O156872 A1 Aug. 12, 2004

0161 (xii) two of R-R are CH and two of R-R 0170 Examples of Sweeteners are any natural or artificial are purely aliphatic fragments. Sweetener, Such as Sucrose, Xylitol, Sodium Saccharin, cycla mate, aspartame, and acSulfame. Examples of flavoring 0162 Such compounds include, but are not limited to, agents are Magnasweet(R) (trademark of MAFCO), bubble behenalkonium chloride, benzethonium chloride, cetylpyri gum flavor, and fruit flavors, and the like. dinium chloride, behentrimonium chloride, lauralkonium chloride, cetalkonium chloride, cetrimonium bromide, cet 0171 Examples of preservatives are potassium Sorbate, rimonium chloride, cethylamine hydrofluoride, chlorallyl methylparaben, propylparaben, benzoic acid and its Salts, methenamine chloride (Quatemium-15), distearyldimonium other esters of parahydroxybenzoic acid Such as butylpara chloride (Quaternium-5), dodecyl dimethyl ethylbenzyl ben, alcohols Such as ethyl or benzyl alcohol, phenolic ammonium chloride (Quaternium-14), Quaternium-22, compounds Such as phenol, and quarternary compounds Quatemium-26, Quaternium-18 hectorite, dimethylaminoet Such as benzalkonium chloride. hylchloride hydrochloride, cysteine hydrochloride, dietha 0172 Suitable diluents include pharmaceutically accept nolammonium POE (10) oletyl ether phosphate, diethano able inert fillers, Such as microcrystalline cellulose, lactose, lammonium POE (3)oleyl ether phosphate, tallow alkonium dibasic calcium phosphate, Saccharides, and/or mixtures of chloride, dimethyl dioctadecylammoniumbentonite, Stear any of the foregoing. Examples of diluents include micro alkonium chloride, domiphen bromide, denatonium ben crystalline cellulose, such as Avice1(R) PH101 and Avicel(R) Zoate, myristalkonium chloride, laurtrimonium chloride, PH102; lactose Such as lactose monohydrate, lactose anhy ethylenediamine dihydrochloride, guanidine hydrochloride, drous, and Pharmatose(RDCL21; dibasic calcium phosphate pyridoxine HCl, iofetamine hydrochloride, meglumine Such as Emcompress(E); mannitol, Starch, Sorbitol; Sucrose; hydrochloride, methylbenzethonium chloride, myrtrimo and glucose. nium bromide, oleyltrimonium chloride, polyguaternium-1, procainehydrochloride, cocobetaine, Stearalkonium bento 0173 Suitable disintegrants include lightly crosslinked nite, Stearalkoniumhectonite, Stearyl trihydroxyethyl propy polyvinyl pyrrollidone, corn Starch, potato Starch, maize lenediamine dihydrofluoride, tallowtrimonium chloride, and Starch, and modified Starches, croScarmelloSe Sodium, croSS hexadecyltrimethyl ammonium bromide. poVidone, Sodium Starch glycolate, and mixtures thereof. 0.174 Examples of effervescent agents are effervescent 0163 Most of these surface stabilizers are known phar couples, Such as an organic acid and a carbonate or bicar maceutical excipients and are described in detail in the bonate. Suitable organic acids include, for example, citric, Handbook of Pharmaceutical Excipients, published jointly tartaric, malic, fumaric, adipic, Succinic, and alginic acids by the American Pharmaceutical Association and The Phar and anhydrides and acid Salts. Suitable carbonates and maceutical Society of Great Britain (The Pharmaceutical bicarbonates include, for example, Sodium carbonate, Press, 2000), which is specifically incorporated herein by Sodium bicarbonate, potassium carbonate, potassium bicar reference. bonate, magnesium carbonate, Sodium glycine carbonate, L-lysine carbonate, and arginine carbonate. Alternatively, 0164 Particularly preferred surface stabilizers include, only the Sodium bicarbonate component of the effervescent but are not limited to, a copoVidone, Such as Plasdone(R) couple may be present. S-630 (ISP) and Kollidon(R) VA 64 (BASF), which are random copolymers of vinyl pyrrollidone and vinyl acetate in 0175 D. Nanoparticulate Nimesulide Particle Size a 60:40 ratio, hydroxypropylmethyl cellulose, or tyloxapol. 0176 Compositions of the invention contain nimeSulide nanoparticles that have an effective average particle size of 01.65 Each of these surface stabilizers is commercially less than about 2000 nm (i.e., 2 microns). In preferred available and/or can be prepared by techniques known in the embodiments of the invention, the nimeSulide nanoparticles art. have an effective average particle size of less than about 0166 C. Other Pharmaceutical Excipients 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than 0167 Pharmaceutical compositions of the invention may about 1400 nm, less than about 1300 nm, less than about also comprise one or more binding agents, filling agents, 1200 nm, less than about 1100 nm, less than about 1000 nm, lubricating agents, Suspending agents, Sweeteners, flavoring less than about 900 nm, less than about 800 um, less than agents, preservatives, buffers, wetting agents, disintegrants, about 700 nm, less than about 600 nm, less than about 500 effervescent agents, and other excipients depending upon the nm, less than about 400 nm, less than about 300 nm, less route of administration and the dosage form desired. Such than about 250 nm, less than about 200 nm, less than about excipients are well known in the art. 150 nm, less than about 100 nm, less than about 75 nm, or less than about 50 nm, as measured by light-Scattering 01.68 Examples of filling agents are lactose monohy methods, microScopy, or other appropriate methods. drate, lactose anhydrous, and various Starches, examples of binding agents are various celluloses and croSS-linked poly 0177. An “effective average particle size of less than Vinylpyrrolidone, microcrystalline cellulose, Such as about 2000 nm” means that at least 50% of the nimeSulide Avice1(R) PH101 and Avicel(R) PH102, microcrystalline cel particles have a particle size less than the effective average, lulose, and silicified microcrystalline cellulose (ProSolv by weight, i.e., less than about 2000 nm, about 1900 nm, about 1800 nm, etc., when measured by the above-noted SMCCTM). techniques. Preferably, at least about 70%, at least about 0169 Suitable lubricants, including agents that act on the 90%, at least about 95%, or at least about 99% of the flowability of the powder to be compressed, are colloidal nimeSulide particles have a particle Size leSS than the effec Silicon dioxide, Such as AeroSilf) 200, talc, Stearic acid, tive average, i.e., less than about 2000 nm, about 1900 nm, magnesium Stearate, calcium Stearate, and Silica gel. about 1800 rn, etc. US 2004/O156872 A1 Aug. 12, 2004

0178. In the present invention, the value for D50 of a Preparing Nanoparticle Compositions Containing Charged nanoparticulate nimeSulide composition is the particle size Phospholipids to Reduce Aggregation,” all of which are below which 50% of the nimeSulide particles fall, by weight. Specifically incorporated herein by reference. Similarly, D90 is the particle size below which 90% of the 0186 The resultant nanoparticulate nimeSulide composi nimeSulide particles fall, by weight. tions or dispersions can be utilized in Solid, Semi-Solid, or 0179 If the compositions of the invention also comprise liquid dosage formulations, Such as liquid dispersions, gels, microparticulate nimeSulide or non-nimeSulide active aeroSols, ointments, creams, controlled release formulations, agents, then the particles of Such compounds have an fast melt formulations, lyophilized formulations, tablets, effective average particle size greater than about 2 microns, capsules, delayed release formulations, extended release which means that at least 50% of the particles have a size formulations, pulsatile release formulations, mixed imme greater than about 2 microns. In other embodiments of the diate release and controlled release formulations, etc. Solid invention, at least about 70%, at least about 90%, at least dose forms of the dispersions of novel nimeSulide formula about 95%, or at least about 99% of the nimeSulide micro tions according to the present invention can be made as particulate or non-nimeSulide microparticulate particles described in U.S. Pat. No. 6,375,986. have a particle Size greater than about 2 microns. 0187 A. Milling to Obtain Nanoparticulate Nimesulide 0180 E. Concentration of Nanoparticulate Nimesulide Dispersions and Surface Stabilizers 0188 Milling nimeSulide to obtain a nanoparticulate 0181. The relative amounts of at least one nimeSulide and nimeSulide dispersion comprises dispersing nimeSulide par one or more Surface Stabilizers can vary widely. The optimal ticles in a liquid dispersion media in which the nimeSulide amount of the individual components depends, for example, is poorly Soluble, followed by applying mechanical means in upon physical and chemical attributes of the Surface Stabi the presence of grinding media to reduce the particle size of lizer(s) selected, Such as the hydrophilic lipophilic balance the nimeSulide to the desired effective average particle size. (HLB), melting point, and the Surface tension of water The dispersion media can be, for example, water, Safflower Solutions of the Stabilizer, etc. oil, ethanol, t-butanol, glycerin, polyethylene glycol (PEG), 0182 Preferably, the concentration of nimeSulide can hexane, or glycol. Water is a preferred dispersion media. vary from about 99.5% to about 0.001%, from about 95% to 0189 The nimeSulide particles can be reduced in size about 0.1%, or from about 90% to about 0.5%, by weight, preferably in the presence of at least one Surface Stabilizer. based on the total combined weight of the nimeSulide and at Alternatively, the nimeSulide particles can be contacted with least one Surface Stabilizer, not including other excipients. one or more Surface Stabilizers after attrition. Other com Higher concentrations of the active ingredient are generally pounds, Such as a diluent, can be added to the nimeSulide/ preferred from a dose and cost efficiency Standpoint. Surface Stabilizer composition during the particle Size reduc 0183 Preferably, the concentration of Surface stabilizer tion process. Dispersions can be manufactured continuously can vary from about 0.5% to about 99.999%, from about or in a batch mode. 5.0% to about 99.9%, or from about 10% to about 99.5%, by 0190. B. Precipitation to Obtain Nanoparticulate Nime weight, based on the total combined dry weight of nime Sulide Compositions Sulide and at least one Surface Stabilizer, not including other excipients. 0191 Another method of forming a nanoparticulate nimeSulide composition is microprecipitation. This involves 0184 VI. Methods of Making Nanoparticulate Nime preparing Stable dispersions of poorly Soluble active agents Sulide Compositions in the presence of one or more Surface Stabilizers and one or 0185. Nanoparticulate nimeSulide compositions can be more colloid Stability enhancing Surface active agents free of made using any Suitable method known in the art Such as, for any trace toxic Solvents or Solubilized heavy metal impuri example, milling, homogenization, or precipitation tech ties. Such a method comprises, for example: (1) dissolving niques. Exemplary methods of making nanoparticulate com nimeSulide in a Suitable Solvent; (2) adding the formulation positions are described in the 684 patent. Methods of from Step (1) to a Solution comprising at least one Surface making nanoparticulate compositions are also described in Stabilizer; and (3) precipitating the formulation from Step (2) U.S. Pat. No. 5,518,187 for “Method of Grinding Pharma using an appropriate non-Solvent. The method can be fol ceutical Substances; U.S. Pat. No. 5,718,388 for “Continu lowed by removal of any formed salt, if present, by dialysis ous Method of Grinding Pharmaceutical Substances; U.S. or diafiltration and concentration of the dispersion by con Pat. No. 5,862,999 for “Method of Grinding Pharmaceutical ventional means. Substances;” U.S. Pat. No. 5,665,331 for “Co-Microprecipi 0.192 C. Homogenization to Obtain NimeSulide Nano tation of Nanoparticulate Pharmaceutical Agents with Crys particulate Compositions tal Growth Modifiers; U.S. Pat. No. 5,662.883 for “Co Microprecipitation of Nanoparticulate Pharmaceutical 0193 Exemplary homogenization methods of preparing Agents with Crystal Growth Modifiers; U.S. Pat. No. active agent nanoparticulate compositions are described in 5,560,932 for “Microprecipitation of Nanoparticulate Phar U.S. Pat. No. 5,510,118, for “Process of Preparing Thera maceutical Agents;" U.S. Pat. No. 5,543,133 for “Process of peutic Compositions Containing Nanoparticles.” Such a Preparing X-Ray Contrast Compositions Containing Nano method comprises dispersing nimeSulide particles in a liquid particles;” U.S. Pat. No. 5,534.270 for “Method of Preparing dispersion media in which the nimeSulide is poorly Soluble, Stable Drug Nanoparticles;” U.S. Pat. No. 5,510,118 for followed by Subjecting the dispersion to homogenization to “Process of Preparing Therapeutic Compositions Containing reduce the particle size of the nimeSulide to the desired Nanoparticles;” and U.S. Pat. No. 5,470,583 for “Method of effective average particle size. The nimeSulide particles can US 2004/O156872 A1 Aug. 12, 2004

be reduced in size in the presence of at least one Surface as agar-agar, calcium carbonate, potato or tapioca Starch, Stabilizer. Alternatively, the nimeSulide particles can be alginic acid, certain complex Silicates, and Sodium carbon contacted with one or more Surface Stabilizers either before ate, (f) Solution retarders, Such as paraffin, (g) absorption or after attrition. Other compounds, Such as a diluent, can be accelerators, Such as quaternary ammonium compounds, (h) added to the nimeSulide/Surface Stabilizer composition wetting agents, Such as cetyl alcohol and glycerol either before, during, or after the Size reduction process. monostearate; (ii) adsorbents, Such as kaolin and bentonite; Dispersions can be manufactured continuously or in a batch and () lubricants, Such as talc, calcium Stearate, magnesium mode. Stearate, Solid polyethylene glycols, Sodium lauryl Sulfate, or 0194 VII. Methods of Using Nimesulide Formulations of mixtures thereof. For capsules, tablets, and pills, the dosage the Invention forms may also comprise buffering agents. 0.195 Nimesulide compositions of the invention can be 0201 Liquid dosage forms for oral administration administered to a Subject via any conventional means include pharmaceutically acceptable dispersions, emulsions, including, but not limited to, preferably orally, vaginally, Solutions, Suspensions, Syrups, and elixirs. In addition to the rectally, ocularly, parenterally (e.g., intravenous, intramus active agent, the liquid dosage forms may comprise inert cular, or Subcutaneous), intracisternally, pulmonary, intrav diluents commonly used in the art, Such as water or other aginally, intraperitoneally, topically, locally (e.g., powders, Solvents, Solubilizing agents, and emulsifiers. Exemplary ointments or drops), or as a buccal or nasal spray. AS used emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl car herein, the term “Subject' is used to mean an animal, bonate, ethyl acetate, benzyl alcohol, benzyl benzoate, pro preferably a mammal, including a human or non-human. pyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, The terms patient and Subject may be used interchangeably. Such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and Sesame oil, glycerol, tetrahydrofurfuryl 0196. The present invention provides a method of pro alcohol, polyethyleneglycols, fatty acid esters of Sorbitan, or longing plasma levels of nimeSulide in a Subject while mixtures of these Substances, and the like. achieving the desired therapeutic effect. 0202 Besides such inert diluents, the composition can 0197). In one aspect, compositions of the invention are also include adjuvants, Such as wetting agents, emulsifying administered for treating conditions characterized by pain, and Suspending agents, Sweetening, flavoring, and perfum inflammation, or fever. Many Such conditions are Set forth ing agents. above. 0203 Effective amounts of the inventive nimeSulide 0198 Compositions suitable for parenteral injection may compositions can be determined empirically. The composi comprise physiologically acceptable Sterile aqueous or non tions can be employed in pure form or, where Such forms aqueous Solutions, dispersions, Suspensions or emulsions, exist, in pharmaceutically acceptable Salt, ester, or prodrug and Sterile powders for reconstitution into Sterile injectable form. Actual dosage levels of nimeSulide in the inventive Solutions or dispersions. Examples of Suitable aqueous and nanoparticulate compositions may be varied to obtain an nonaqueous carriers, diluents, Solvents, or vehicles include amount of nimeSulide that is effective to obtain a desired water, ethanol, polyols (propyleneglycol, polyethylenegly therapeutic response for a particular composition, method of col, glycerol, and the like), Suitable mixtures thereof, veg administration and condition to be treated. The Selected etable oils (Such as olive oil) and injectable organic esters dosage level therefore depends upon the desired therapeutic Such as ethyl oleate. Proper fluidity can be maintained, for effect, the route of administration, the potency of the admin example, by the use of a coating Such as lecithin, by the istered nimeSulide, the desired duration of treatment, and maintenance of the required particle size in the case of other factors. dispersions, and by the use of Surfactants. 0204 Dosage unit compositions may contain Such 0199 The nanoparticulate nimeSulide compositions may amounts of Such Submultiples thereof as may be used to also contain adjuvants Such as preserving, wetting, emulsi make up the daily dose. It will be understood, however, that fying, and dispensing agents. Prevention of the growth of the Specific dose level for any particular patient will depend microorganisms can also be ensured by various antibacterial upon a variety of factors: the type and degree of the cellular and antifungal agents, Such as parabens, chlorobutanol, or physiological response to be achieved; activity of the phenol, Sorbic acid, and the like. It may also be desirable to Specific agent or composition employed; the Specific agents include isotonic agents, Such as Sugars, Sodium chloride, and or composition employed; the age, body weight, general the like. Prolonged absorption of the injectable pharmaceu health, Sex, and diet of the patient; the time of administra tical form can be brought about by the use of agents delaying tion, route of administration, and rate of excretion of the absorption, Such as aluminum monoStearate and gelatin. agent; the duration of the treatment; drugs used in combi 0200 Solid dosage forms for oral administration are nation or coincidental with the Specific agent; and like preferred and include, but are not limited to, capsules, factors well known in the medical arts. tablets, pills, powders, caplets, and granules. In Such Solid dosage forms, the active agent (i.e. the composition of this 0205 A. Treatment Applications invention) is admixed with at least one of the following: (a) 0206 Nanoparticulate nimeSulide compositions are use one or more inert excipients (or carriers), Such as Sodium ful for treating and/or preventing a wide range of conditions citrate or dicalcium phosphate; (b) fillers or extenders, Such and disorders mediated by COX-2, including but not limited as Starches, lactose, Sucrose, glucose, mannitol, and Silicic to, disorders characterized by inflammation, pain, and/or acid; (c) binders, Such as carboxymethylcellulose, alignates, fever. Such compositions are especially useful as anti gelatin, polyvinylpyrrolidone, Sucrose, and acacia; (d) inflammatory agents, Such as in treatment of arthritis, with humectants, Such as glycerol; (e) disintegrating agents, Such the additional benefit of having Significantly leSS harmful US 2004/O156872 A1 Aug. 12, 2004

side effects than compositions of conventional NSAIDs that periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin’s lack selectivity for COX-2 over COX-1. In particular, such disease, Sclerodoma, rheumatic fever, type I diabetes, neu compositions have reduced potential for gastrointestinal romuscular junction disease including myasthenia gravis, toxicity and gastrointestinal irritation including upper gas white matter disease including multiple Sclerosis, Sarcoido trointestinal ulceration and bleeding, reduced potential for sis, nephrotic Syndrome, Behcet's Syndrome, polymyositis, renal side effects Such as reduction in renal function leading gingivitis, nephritis, hyperSensitivity, Swelling occurring to fluid retention and exacerbation of hypertension, reduced after injury including brain edema, myocardial ischemia, effect on bleeding times including inhibition of platelet post-operative inflammation including that following oph function, and possibly a lessened ability to induce asthma thalmic Surgery Such as cataract Surgery or refractive Sur attacks in aspirin-Sensitive asthmatic Subjects, by compari gery, and the like. son with compositions of conventional NSAIDs. 0213 Exemplary pulmonary inflammation conditions 0207 Thus, nanoparticulate nimeSulide compositions of that can be treated include, but are not limited to, inflam the invention are particularly useful as an alternative to mation associated with viral infections and cystic fibrosis, conventional NSAIDs where Such NSAIDs are contraindi and in bone resorption Such as that associated with cated, for example in patients with peptic ulcers, gastritis, Osteoporosis. regional enteritis, ulcerative colitis, diverticulitis, or with a recurrent history of gastrointestinal lesions, gastrointestinal 0214) Exemplary opthalmic diseases or conditions that bleeding, coagulation disorders including anemia Such as can be treated include, but are not limited to, retinitis, hypoprothrombinemia, hemophilia, or other bleeding prob conjunctivitis, retinopathies, uveitis, ocular photophobia, lems, kidney disease, or in patients prior to Surgery or acute injury to the eye tissue, corneal graft rejection, ocular patients taking anticoagulants. neovascularization, retinal neovascularization including neovascularization following injury or infection, diabetic 0208 Because of the rapid onset of therapeutic effect retinopathy, macular degeneration, retrolental fibroplasia, observed with the compositions of the invention, these glaucoma, and neovascular glaucoma. compositions have particular advantages over prior conven tional formulations for treatment of acute COX-2 mediated 0215 Exemplary central nervous system disorders that disorders, especially for relief of pain, for example in can be treated include, but are not limited to, cortical headache, including Sinus headache and migraine. dementias including Alzheimer's disease, neurodegenera 0209 NimeSulide is also useful in treating and/or pre tion, and central nervous System damage resulting from venting, for example, arthritic disorders, gastrointestinal stroke, ischemia, and trauma. The term “treatment' in the conditions, inflammatory conditions, pulmonary inflamma present context includes partial or total inhibition of demen tion, opthalmic diseases, central nervous Systems disorders, tias, including Alzheimer's disease, vascular dementia, pain, inflammation-related cardiovascular disorders, angio multi-infarct dementia, pre-Senile dementia, alcoholic genesis-related disorders, benign and malignant tumors, dementia, and Senile dementia. adenomatous polyps, disorders of the female reproductive 0216 Exemplary pain conditions that can be treated System Such as endometriosis, osteoporosis, dySmenorrhea, include, but are not limited to, postoperative pain, pain premature labor, asthma, eosinophil-related disorders, pyr resulting from battle field wounds, dental pain, muscular exia, bone resorption, nephrotoxicity, hypotension, arthro pain, pain resulting from cancer, headaches, including Sinus sis, joint Stiffness, kidney disease, liver disease including headache and migraine, menstrual cramps, and pain associ hepatitis, acute mastitis, diarrhea, colonic adenomas, bron ated with inflammation. chitis, allergic neuritis, cytomegalovirus infectivity, apopto sis including HIV-induced apoptosis, lumbago; skin-related 0217 Exemplary inflammation-related cardiovascular conditions Such as psoriasis, eczema, acne, burns, dermati disorders that can be treated or prevented using composi tis, and ultraViolet radiation damage including Sunburn; tions of the invention include, but are not limited to, Vascular allergic rhinitis, respiratory distreSS Syndrome, and endot diseases, coronary artery disease, aneurysm, vascular rejec OXin Shock Syndrome. Nanoparticulate nimeSulide is also tion, arteriosclerosis, atherosclerosis including cardiac trans useful as an immunosuppressive agent. plant atherosclerosis, myocardial infarction, embolism, Stroke, thrombosis including venous thrombosis, angina 0210 Exemplary forms of arthritic disorders that can be including unstable angina, coronary plaque inflammation, treated include, but are not limited to, Osteoarthritis, rheu bacterial-induced inflammation including Chlamydia-in matoid arthritis, spondyloarthropathies, gouty arthritis,juve duced inflammation, Viral induced inflammation, and nile arthritis, gout, ankylosing spondylitis, Systemic lupus inflammation associated with Surgical procedures Such as erythematosus, burSitis, tendinitis, myofascial pain, carpal vascular grafting including coronary artery bypass Surgery, tunnel Syndrome, fibromyalgia Syndrome, infectious arthri revascularization procedures including angioplasty, Stent tis, psoriatic arthritis, Reiter's Syndrome, and Scleroderma placement, endarterectomy, or other invasive procedures 0211 Exemplary gastrointestinal conditions or ulcerative involving arteries, Veins, and capillaries. diseases that can be treated include, but are not limited to, 0218 Exemplary angiogenesis-related disorders for inflammatory bowel disease, Crohn's disease, gastritis, irri which the inventive compositions are useful include, but are table bowel Syndrome, ulcerative colitis, gastric ulcer, not limited to, inhibition of tumor angiogenesis. Such com pathological but non-malignant conditions Such as heman positions also are useful for treating neoplasia, including giomas, including infantile hemaginomas, angiofibroma of metastasis, benign and malignant tumors, and neoplasia the nasopharynx, and avascular necrosis of bone. including cancer, Such as colorectal cancer, brain cancer, 0212 Exemplary inflammation conditions that can be bone cancer, epithelial cell-derived neoplasia (epithelial treated include, but are not limited to, migraine headaches, carcinoma) Such as basal cell carcinoma, adenocarcinoma, US 2004/O156872 A1 Aug. 12, 2004 18 gastrointestinal cancer Such as lip cancer, mouth cancer, EXAMPLE 2 esophageal cancer, Small bowel cancer, Stomach cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, 0226. The purpose of this example was to prepare a OVary cancer, cerVical cancer, lung cancer, breast cancer, nanoparticulate composition of nimeSulide. skin cancer Such as Squamous cell and basal cell cancers, 0227. An aqueous solution of 1% (w/w) Plasdone(R) prostate cancer, renal cell carcinoma, and other known S-630 (International Specialty Products, Wayne, N.J.) and cancers that effect epithelial cells throughout the body. 0.2% (w/w) docusate sodium (DOSS; Cytec Industries Inc., Neoplasias for which compositions of the invention are West Paterson, N.J.) was prepared by dissolving 0.85g of contemplated to be particularly useful are gastrointestinal Plasdone(R) S-630 and 0.17 g of DOSS in 79.73 g of cancer, Barrett's esophagus, liver cancer, bladder cancer, deionized water. The Surface Stabilizer Solution was com pancreatic cancer, OVarian cancer, prostate cancer, cerVical bined with 4.25 g of nimeSulide (5% w/w) and PolyMillTM cancer, lung cancer, breast cancer and skin cancer. The 200 Polystyrene Milling Media (Dow Chemical, Midland, nanoparticulate nimeSulide compositions of the invention Mich.) and charged into the 150 cc batch chamber of a can also be used to treat fibrosis that occurs with radiation DYNO(E)-Mill Type KDL media mill (Willy Bachofen AG, therapy. Basel, Switzerland). The mill was operated for 2 hours at 0219. The compositions of the invention can be used to 4200 rpm with chilled water (101C) recirculated through the treat Subjects having adenomatous polyps, including those milling chamber. with familial adenomatous polyposis (FAP). Additionally, 0228. The process yielded a colloidal dispersion of nime Such compositions can be used to prevent polyps from Sulide with a mean particle size of 131 nm, a D50 of 111 nm, forming in patients at risk of FAP. a D90 of 216 nm, and a D95 of 253 nm, as measured using 0220 Because the nimeSulide compositions of the inven a Horiba LA-910 Laser Scattering Particle Size Distribution tion inhibit proStanoid-induced Smooth muscle contraction Analyzer ((Horiba Instruments, Irvine, Calif.). by inhibiting Synthesis of contractile prostanoids, the com EXAMPLE 3 positions can be used in the treatment of dysmenorrhea, premature labor, asthma, and eosinophil-related disorders. 0229. The purpose of this example was to prepare a nanoparticulate composition of nimeSulide. 0221) The compositions of the invention are also useful in treating indications where anti-inflammatory agents, anti 0230. An aqueous solution of 1% (w/w) Plasdone(R) angiogenesis agents, antitumorigenic agents, immunoSup S-630 (International Specialty Products, Wayne, N.J.) and pressive agents, NSAIDs, COX-2 inhibitors, analgesic 0.05% (w/w) sodium lauryl sulfate (SLS) was prepared by agents, anti-thrombotic agents, narcotics, or antifebrile dissolving 0.85g of Plasdone(R) S-630 and 0.04 g of SLS in agents are typically used. 79.9 g of deionized water. The surface stabilizer Solution was combined with 4.25 g of nimeSulide (5% w/w) and 0222. The following examples are provided to illustrate PolyMillTM-200 Polystyrene Milling Media (Dow Chemical, the present invention. It should be understood, however, that Midland, Mich.) and charged into the 150 cc batch chamber the invention is not to be limited to the Specific conditions of a DYNO(E)-Mill Type KDL media mill (Willy Bachofen or details described in these examples. Throughout the AG, Basel, Switzerland). The mill was operated for 2 hours Specification, any and all references to a publicly available at 4200 rpm with chilled water (110° C.) recirculated document, including a U.S. patent, are specifically incorpo through the milling chamber. rated by reference. 0231. The process yielded a colloidal dispersion of nime Sulide with a mean particle size of 116 nm, a D50 of 104 nm, EXAMPLE 1. a D90 of 175 nm, and a D95 of 212 nm, as measured using 0223) The purpose of this example was to prepare a a Horiba LA-910 Laser Scattering Particle Size Distribution nanoparticulate composition of nimeSulide (Sigma, St. Analyzer ((Horiba Instruments, Irvine, Calif.). Louis, Mo.), a COX-2 inhibitor. EXAMPLE 4 0224) An aqueous solution of 1% (w/w) Plasdone(R) S-630 (International Specialty Products, Wayne, N.J.), 0232 The purpose of this example was to prepare a which is a random copolymer of vinyl acetate and Vinyl nanoparticulate composition of nimeSulide. pyrrollidone, was prepared by dissolving 0.85 g of Plas 0233. An aqueous solution of 2% (w/w) hydroxypropy done(R) S-630 in 79.9 g of deionized water. The surface lmethyl cellulose (HPMC, Shin Etsu) was prepared by stabilizer solution was combined with 4.25 g of nimeSulide dissolving 1.7 g of HPMC in 74.8g of deionized water. The (5% w/w) and PolyMillTM-200 Polystyrene Milling Media surface stabilizer solution was combined with 8.5 g of (Dow Chemical, Midland, Mich.) and charged into the 150 nimeSulide (10% w/w) and PolyMillTM-200 Polystyrene cc batch chamber of a DYNO(E)-Mill Type KDL media mill Milling Media (Dow Chemical, Midland, Mich.) and (Willy Bachofen AG, Basel, Switzerland). The mill was charged into the 150 cc batch chamber of a DYNO(E)-Mill operated for 1 hour at 4200 rpm with chilled water (10° C.) Type KDL media mill (Willy Bachofen AG, Basel, Swit recirculated through the milling chamber. zerland). The mill was operated for 2 hours at 4200 rpm with 0225. The process yielded a colloidal dispersion of nime chilled water (110° C) recirculated through the milling Sulide with a mean particle size of 150 nm, a D50 of 124 nm, chamber. a D90 of 256 nm, and a D95 of 293 nm, as measured using 0234. The process yielded a colloidal dispersion of nime a Horiba LA-910 Laser Scattering Particle Size Distribution Sulide with a mean particle size of 110 nm, a D50 of 103 nm, Analyzer ((Horiba Instruments, Irvine, Calif.). a D90 of 157 nm, and a D95 of 183 nm, as measured using US 2004/O156872 A1 Aug. 12, 2004

a Horiba LA-910 Laser Scattering Particle Size Distribution mulations, extended release formulations, pulsatile release Analyzer ((Horiba Instruments, Irvine, Calif.). formulations, and mixed immediate release and controlled release formulations. EXAMPLE 5 6. The composition of claim 1, wherein the composition 0235. The purpose of this example was to prepare a further comprises one or more pharmaceutically acceptable nanoparticulate composition of nimeSulide. excipients, carriers, or a combination thereof. 7. The composition of claim 1, wherein the nimeSulide or 0236 An aqueous solution of 2% (w/w) tyloxapol a Salt thereof is present in an amount Selected from the group (Organichem Corp.) was prepared by dissolving 1.7 g of consisting of from about 99.5% to about 0.001%, from about tyloxapol in 74.8g of deionized water. The surface stabilizer 95% to about 0.1%, and from about 90% to about 0.5%, by solution was combined with 8.5g of nimeSulide (10% w/w) weight, based on the total combined dry weight of the and PolyMillTM-200 Polystyrene Milling Media (Dow nimeSulide or a Salt thereof and at least one Surface Stabi Chemical, Midland, Mich.) and charged into the 150 cc lizer, not including other excipients. batch chamber of a DYNO(E)-Mill Type KDL media mill 8. The composition of claim 1, wherein the at least one (Willy Bachofen AG, Basel, Switzerland). The mill was Surface Stabilizer is present in an amount Selected from the operated for 2 hours at 4200 rpm with chilled water (10°C.) group consisting of from about 0.5% to about 99.999% by recirculated through the milling chamber. weight, from about 5.0% to about 99.9% by weight, and 0237) The process yielded a colloidal dispersion of nime from about 10% to about 99.5% by weight, based on the Sulide with a mean particle size of 141 nm, a D50 of 127 nm, total combined dry weight of the nimeSulide or a salt thereof a D90 of 222 nm, and a D95 of 250 nm, as measured using and at least one Surface Stabilizer, not including other a Horiba LA-910 Laser Scattering Particle Size Distribution excipients. Analyzer ((Horiba Instruments, Irvine, Calif.). 9. The composition of claim 1, comprising two or more Surface Stabilizers. 0238. It will be apparent to those skilled in the art that 10. The composition of claim 1, wherein the surface various modifications and variations can be made in the Stabilizer is Selected from the group consisting of an anionic methods and compositions of the present invention without Surface Stabilizer, a cationic Surface Stabilizer, a Zwitterionic departing from the Spirit or Scope of the invention. Thus, it Surface Stabilizer, and an ionic Surface Stabilizer. is intended that the present invention cover the modifications 11. The composition of claim 10, wherein the at least one and variations of this invention provided they come within Surface stabilizer is selected from the group consisting of the Scope of the appended claims and their equivalents. cetyl pyridinium chloride, gelatin, casein, phosphatides, dextran, glycerol, gum acacia, cholesterol, tragacanth, We claim: Stearic acid, benzalkonium chloride, calcium Stearate, glyc 1. A nimeSulide composition comprising: erol monoStearate, cetoStearyl alcohol, cetomacrogol emul (a) particles of nimeSulide or a Salt thereof, wherein the Sifying wax, Sorbitan esters, polyoxyethylene alkyl ethers, particles have an effective average particle Size of leSS polyoxyethylene castor oil derivatives, polyoxyethylene Sor than about 2000 nm, and bitan fatty acid esters, polyethylene glycols, dodecyl trim ethyl ammonium bromide, polyoxyethylene Stearates, col (b) at least one Surface Stabilizer. loidal Silicon dioxide, phosphates, Sodium dodecylsulfate, 2. The composition of claim 1, wherein the nimeSulide is carboxymethylcellulose calcium, hydroxypropyl celluloses, Selected from the group consisting of a crystalline phase, an hypromellose, carboxymethylcellulose Sodium, methylcel amorphous phase, a Semi-crystalline phase, a Semi-amor lulose, hydroxyethylcellulose, hypromellose phthalate, non phous phase, and mixtures thereof. crystalline cellulose, magnesium aluminum Silicate, trietha 3. The composition of claim 1, wherein the effective nolamine, polyvinyl alcohol, polyvinylpyrrolidone, 4-(1,1, average particle size of the nimeSulide particles is Selected 3,3-tetramethylbutyl)-phenol polymer with ethylene oxide from the group consisting of less than about 1900 nm, leSS and formaldehyde, poloxamers, poloxamines, a charged than about 1800 nm, less than about 1700 nm, less than phospholipid, dioctylsulfoSuccinate, dialkylesters of Sodium about 1600 nm, less than about 1500 nm, less than about SulfoSuccinic acid, Sodium lauryl Sulfate, alkyl aryl poly 1400 nm, less than about 1300 nm, less than about 1200 nm, ether Sulfonates, mixtures of Sucrose Stearate and Sucrose less than about 1100 nm, less than about 1000 nm, less than distearate, p-isononylphenoxypoly-(glycidol), decanoyl-N- about 900 nm, less than about 800 nm, less than about 700 methylglucamide; n-decyl B-D-glucopyranoside; n-decyl nm, less than about 600 nm, less than about 500 nm, less B-D-maltopyranoside; n-dodecyl B-D-glucopyranoside; than about 400 nm, less than about 300 nm, less than about n-dodecyl 3-D-maltoside; heptanoyl-N-methylglucamide; 250 nm, less than about 200 nm, less than about 100 nm, less n-heptyl-B-D-glucopyranoside; n-heptyl P-D-thioglucoside; than about 75 nm, and less than about 50 nm. n-hexyl B-D-glucopyranoside; nonanoyl-N-methylglucam 4. The composition of claim 1, wherein the composition ide; n-noyl B-D-glucopyranoSide; octanoyl-N-methylgluca is formulated for administration Selected from the group mide; n-octyl-B-D-glucopyranoside; octyl B-D-thioglucopy consisting of oral, pulmonary, rectal, opthalmic, colonic, ranoside; lysozyme, PEG-phospholipid, PEG-cholesterol, parenteral, intracisternal, intravaginal, intraperitoneal, local, PEG-cholesterol derivative, PEG-vitamin A, and random buccal, nasal, and topical administration. copolymers of vinyl acetate and Vinyl pyrrolidone. 5. The composition of claim 1 formulated into a dosage 12. The composition of claim 10, wherein the at least one form Selected from the group consisting of liquid disper cationic Surface Stabilizer is Selected from the group con Sions, oral Suspensions, gels, aerosols, ointments, creams, Sisting of a polymer, a biopolymer, a polysaccharide, a controlled release formulations, fast melt formulations, lyo cellulo Sic, an alginate, a nonpolymeric compound, and a philized formulations, tablets, capsules, delayed release for phospho lipid. US 2004/O156872 A1 Aug. 12, 2004

13. The composition of claim 10, wherein the surface 17. The composition of claim 16, wherein the T is Stabilizer is Selected from the group consisting of cationic Selected from the group consisting of not greater than about lipids, polymethylmethacrylate trimethylammonium bro 90%, not greater than about 80%, not greater than about mide, Sulfonium compounds, polyvinylpyrrollidone-2-dim 70%, not greater than about 60%, not greater than about ethylaminoethyl methacrylate dimethyl Sulfate, hexadecyl 50%, not greater than about 30%, not greater than about trimethyl ammonium bromide, phosphonium compounds, 25%, not greater than about 20%, not greater than about quarternary ammonium compounds, benzyl-di(2-chloroeth 15%, and not greater than about 10% of the T, exhibited yl)ethylammonium bromide, coconut trimethyl ammonium by a non-nanoparticulate formulation of nimeSulide, admin chloride, coconut trimethyl ammonium bromide, coconut istered at the Same dosage. methyl dihydroxyethyl ammonium chloride, coconut methyl 18. The composition of claim 1, wherein the C of the dihydroxyethyl ammonium bromide, decyl triethyl ammo nimeSulide, when assayed in the plasma of a mammalian nium chloride, decyl dimethyl hydroxyethyl ammonium Subject following administration, is greater than the C for chloride, decyl dimethyl hydroxyethyl ammonium chloride a conventional, non-nanoparticulate form of nimeSulide, bromide, C2-sdimethyl hydroxyethyl ammonium chloride, administered at the same dosage. C-dimethyl hydroxyethyl ammonium chloride bromide, 19. The composition of claim 18, wherein the C is coconut dimethyl hydroxyethyl ammonium chloride, coco Selected from the group consisting of at least about 10%, at nut dimethyl hydroxyethyl ammonium bromide, myristyl least about 20%, at least about 30%, at least about 40%, at trimethyl ammonium methyl Sulphate, lauryl dimethylben least about 50%, at least about 60%, at least about 70%, at Zyl ammonium chloride, lauryl dimethylbenzyl ammonium least about 80%, at least about 90%, and at least about 100% bromide, lauryl dimethyl (ethenoxy) ammonium chloride, greater than the C exhibited by a non-nanoparticulate lauryl dimethyl (ethenoxy) ammonium bromide, N-alkyl (Cs)dimethylbenzyl ammonium chloride, N-alkyl (C- formulation of nimeSulide, administered at the same dosage. 1s)dimethyl-benzyl ammonium chloride, N-tetradecylidm 20. The composition of claim 1, wherein the AUC of the ethylbenzyl ammonium chloride monohydrate, dimethyl nimeSulide, when assayed in the plasma of a mammalian didecyl ammonium chloride, N-alkyl and (C-1) dimethyl Subject following administration, is greater than the AUC for 1-napthylmethyl ammonium chloride, trimethylammonium a conventional, non-nanoparticulate form of nimeSulide, halide, alkyl-trimethylammonium Salts, dialkyl-dimethy administered at the same dosage. lammonium Salts, lauryl trimethyl ammonium chloride, 21. The composition of claim 20, wherein the AUC is ethoxylated alkyamidoalkyldialkylammonium Salt, an Selected from the group consisting of at least about 10%, at ethoxylated trialkyl ammonium Salt, dialkylbenzene dialky least about 20%, at least about 30%, at least about 40%, at lammonium chloride, N-didecyldimethyl ammonium chlo least about 50%, at least about 60%, at least about 70%, at ride, N-tetradecyldimethylbenzyl ammonium, chloride least about 80%, at least about 90%, and at least about 100% monohydrate, N-alkyl(C-1) dimethyl 1-naphthylmethyl greater than the AUC exhibited by a non-nanoparticulate ammonium chloride, dodecyldimethylbenzyl ammonium formulation of nimeSulide, administered at the same dosage. chloride, dialkyl benzenealkyl ammonium chloride, lauryl 22. The composition of claim 1 which does not produce trimethyl ammonium chloride, alkylbenzyl methyl ammo Significantly different absorption levels when administered nium chloride, alkylbenzyl dimethyl ammonium bromide, under fed as compared to fasting conditions. C. trimethyl ammonium bromides, Cs trimethyl ammo 23. The composition of claim 22, wherein the difference nium bromides, C, trimethyl ammonium bromides, dode in absorption of the nimeSulide composition of the inven cylbenzyl triethyl ammonium chloride, poly-diallyldimethy tion, when administered in the fed versus the fasted State, is lammonium chloride (DADMAC), dimethyl ammonium Selected from the group consisting of less than about 100%, chlorides, alkyldimethylammonium halogenides, tricetyl less than about 90%, less than about 80%, less than about methyl ammonium chloride, decyltrimethylammonium bro 70%, less than about 60%, less than about 50%, less than mide, dodecyltriethylammonium bromide, tetradecyltrim about 40%, less than about 30%, less than about 25%, less ethylammonium bromide, methyl trioctylammonium chlo than about 20%, less than about 15%, less than about 10%, ride, POLYQUAT 10TM, tetrabutylammonium bromide, less than about 5%, and less than about 3%. benzyl trimethylammonium bromide, choline esters, benza 24. The composition of claim 1, wherein administration of Ikonium chloride, Stearalkonium chloride compounds, cetyl the composition to a Subject in a fasted State is bioeduivalent pyridinium bromide, cetyl pyridinium chloride, halide Salts to administration of the composition to a Subject in a fed of quaternized polyoxyethylalkylamines, MIRAPOLTM, State, when administered to a human. ALKAQUATTM, alkyl pyridinium salts; amines, amine salts, 25. The composition of claim 24, wherein “bioeduiva amine oxides, imide azolinium Salts, protonated quaternary lency” is established by a 90% Confidence Interval of acrylamides, methylated quaternary polymers, and cationic between 0.80 and 1.25 for both C, and AUC, when guar. administered to a human. 14. The composition of claim 1, comprising as a Surface 26. The composition of claim 24, wherein “bioeduiva Stabilizer a random copolymer of vinyl acetate and Vinyl lency” is established by a 90% Confidence Interval of pyrrollidone, hydroxypropylmethyl cellulose, or tyloxapol. between 0.80 and 1.25 for AUC and a 90%. Confidence

15. The composition of any of claims 10, 12, or 13, Interval of between 0.70 to 1.43 for C lax when adminis wherein the composition is bioadhesive. tered to a human. 16. The composition of claim 1, wherein the T of the 27. The composition of claim 1, further comprising at nimeSulide, when assayed in the plasma of a mammalian least one additional nimeSulide composition having an effec Subject following administration, is less than the T for a tive average particle size which is different that the effective conventional, non-nanoparticulate form of nimeSulide, average particle size of the nimeSulide composition of claim administered at the same dosage. 1. US 2004/O156872 A1 Aug. 12, 2004

28. The composition of claim 1, wherein upon adminis than about /200, less than about /100, less than about /50, leSS tration the composition redisperses Such that the nimeSulide than about 1/35, and less than about /10 of the viscosity of a particles have an effective average particle Size of less than liquid dosage form of conventional non-nanoparticulate about 2000 nm. nimeSulide at about the same concentration per ml of 29. The composition of claim 28, wherein upon admin nimeSulide. istration the composition redisperses Such that the nime 35. The composition of claims 32, wherein the viscosity Sulide particles have an effective average particle size of the dosage form is Selected from the group consisting of selected from the group consisting of less than about 1900 less than about 5%, less than about 10%, less than about nm, less than about 1800 nm, less than about 1700 nm, less 15%, less than about 20%, less than about 25%, less than than about 1600 nm, less than about 1500 nm, less than about 30%, less than about 35%, less than about 40%, less about 1400 nm, less than about 1300 nm, less than about than about 45%, less than about 50%, less than about 55%, 1200 run, less than about 1100 nm, less than about 1000 nm, less than about 60%, less than about 65%, less than about less than about 900 nm, less than about 800 nm, less than 70%, less than about 75%, less than about 80%, less than about 700 nm, less than about 600 nm, less than about 500 about 85%, and less than about 90% of the viscosity of a nm, less than about 400 nm, less than about 300 run, less liquid dosage form of conventional, non-nanoparticulate than about 250 nm, less than about 200 nm, less than about nimeSulide at about the same concentration per ml of 150 nm, less than about 100 nm, less than about 75 nm, and nimeSulide. less than about 50 mm. 36. The composition of claim 1, additionally comprising 30. The composition of claim 1, wherein the composition one or more non-nimeSulide active agents. redisperses in a biorelevant media Such that the nimeSulide 37. The method of claim 36, wherein said non-nimeSulide particles have an effective average particle Size of less than active agent is Selected from the group consisting of an about 2 microns. analgesic, an anti-inflammatory, an antipyretic, and a vaso 31. The composition of claim 30, wherein the composi modulator. tion redisperses in a biorelevant media Such that the nime 38. The composition of claim 36, wherein said non Sulide particles have an effective average particle size nimeSulide active agent is Selected from the group consisting selected from the group consisting of less than about 1900 of nutraceuticals, proteins, peptides, nucleotides, amino nm, less than about 1800 nm, less than about 1700 nm, less acids, anti-obesity drugs, central nervous System Stimulants, than about 1600 nm, less than about 1500 nm, less than carotenoids, corticosteroids, elastase inhibitors, anti-fun about 1400 nm, leSS than about 1300 nm, leSS than about gals, oncology therapies, anti-emetics, analgesics, cardio 1200 nm, less than about 1100 nm, less than about 1000 nm, vascular agents, anti-inflammatory agents, NSAIDS, non less than about 900 nm, less than about 800 nm, less than nimeSulide COX-2 inhibitors, anthelmintics, anti about 700 nm, less than about 600 nm, less than about 500 arrhythmic agentS, antibiotics, anticoagulants, nm, less than about 400 nm, less than about 300 nm, less antidepressants, antidiabetic agents, antiepileptics, antihis than about 250 nm, less than about 200 nm, less than about tamines, antihypertensive agents, antimuscarinic agents, 150 nm, less than about 100 nm, less than about 75 nm, and antimycobacterial agents, antineoplastic agents, immuno less than about 50 nm. SuppreSSants, antithyroid agents, antiviral agents, anxiolyt 32. The composition of claim 1 formulated into a liquid ics, Sedatives, astringents, alpha-adrenergic receptor block dosage form, wherein the dosage form has a Viscosity of leSS ing agents, beta-adrenoceptor blocking agents, blood than about 2000 mPats, measured at 20° C., at a shear rate products and Substitutes, cardiac inotropic agents, contrast of 0.1 (1/s). media, corticosteroids, cough Suppressants, diagnostic 33. The composition of claim 32, having a Viscosity at a agents, diagnostic imaging agents, diuretics, dopaminergics, Shear rate of 0.1 (1/s) selected from the group consisting of haemostatics, immunological agents, lipid regulating agents, from about 2000 mPa is to about 1 mPa's, from about 1900 muscle relaxants, parasymPathomimetics, parathyroid cal mPa's to about 1 mPas, from about 1800 mPa's to about 1 citonin and biphosphonates, prostaglandins, radio-pharma mPats, from about 1700 mPa's to about 1 mPats, from about ceuticals, SeX hormones, anti-allergic agents, Stimulants and 1600 mPa's to about 1 mPats, from about 1500 mPa is to anoretics, SymPathomimetics, thyroid agents, vasodilators, about 1 mPas, from about 1400 mPa's to about 1 mPats, vasomodulators, and Xanthines. from about 1300 mPa's to about 1 mPa-s, from about 1200 39. The composition of claim 38, wherein said nutraceu mPa's to about 1 mPats, from about 1100 mPa-S to about 1 tical is Selected from the group consisting of lutein, folic mPats, from about 1000 mPa's to about 1 mPats, from about acid, fatty acids, fruit extracts, vegetable extracts, Vitamin 900 mPa's to about 1 mPas, from about 800 mPa is to about Supplements, mineral Supplements, phosphatidylserine, 1 mPats, from about 700 mPa's to about 1 mPats, from about lipoic acid, melatonin, glucosamine/chondroitin, Aloe Vera, 600 mPa's to about 1 mPas, from about 500 mPa is to about Guggul, glutamine, amino acids, green tea, lycopene, whole 1 mPats, from about 400 mPa's to about 1 mPats, from about foods, food additives, herbs, phytonutrients, antioxidants, 300 mPa's to about 1 mPas, from about 200 mPa is to about flavonoid constituents of fruits, evening primrose oil, flax 1 mPats, from about 175 mPa's to about 1 mPats, from about Seeds, fish oils, marine animal oils, and probiotics. 150 mPa's to about 1 mPas, from about 125 mPa is to about 40. The composition of claim 36, wherein said non 1 mPats, from about 100 mPa's to about 1 mPats, from about nimeSulide active agent is Selected from the group consisting 75 mPa's to about 1 mPas, from about 50 mPa's to about 1 of aceclofenac, acemetacin, e-acetamidocaproic acid, mPats, from about 25 mPa is to about 1 mPats, from about 15 acetaminophen, acetaminoSalol, acetanilide, acetylsalicylic mPa's to about 1 mPats, from about 10 mPa's to about 1 acid, S-adenosylmethionine, alclofenac, alfentanil, allylpro mPats, and from about 5 mPa's to about 1 mPas. dine, alminoprofen, aloxiprin, alphaprodine, aluminum 34. The composition of claim 32, wherein the viscosity of bis(acetylsalicylate), amfenac, aminochlorthenoxazin, the dosage form is Selected from the group consisting of leSS 3-amino-4-hydroxybutyric acid, 2-amino-4-picoline, amino US 2004/O156872 A1 Aug. 12, 2004 22 propylon, aminopyrine, amiXetrine, ammonium Salicylate, 41. The composition of claim 38, in which the vasomodu ampiroXicam, amtolimetin guacil, anilleridine, antipyrine, lator is Selected from the group consisting of caffeine, antipyrine Salicylate, antrafenine, apaZone, bendazac, beno theobromine, and theophylline. rylate, benoxaprofen, benzpiperylon, benzydamine, benzyl 42. The composition of claim 38, in which the NSAID is morphine, bermoprofen, beZitramide, C.-bisabolol, bro Selected from the group consisting of nabumetone, tiara mfenac, p-bromoacetanilide, 5-bromosalicylic acid acetate, mide, produaZone, bufeXamac, flumizole, epirazole, tinori bromosaligenin, bucetin, bucloxic acid, bucolome, bufeX dine, timegadine, dapSone, aspirin, diflunisal, benorylate, amac, bumadizon, buprenorphine, butacetin, butibufen, fosfosal, diclofenac, alclofenac, fenclofenac, etodolac, indomethacin, Sulindac, tolmetin, fentiazac, tilomisole, car butophanol, calcium acetylsalicylate, carbamazepine, carbi profen, fenbufen, flurbiprofen, ketoprofen, oxaprozin, phene, carprofen, carSalam, chlorobutanol, chlorthenoxazin, Suprofen, tiaprofenic acid, ibuprofen, naproxen, fenoprofen, choline Salicylate, cinchophen, cinmetacin, ciramadol, clid indoprofen, pirprofen, flufenamic, mefenamic, meclofe anac, clometacin, clonitaZene, clonixin, clopirac, clove, namic, niflumic, oxyphenbutaZone, phenylbutaZone, apa codeine, codeine methyl bromide, codeine phosphate, Zone, feprazone, piroXicam, Sudoxicam, iSoxicam, and codeine Sulfate, cropropamide, crotethamide, desomor tenoxicam. phine, deXOXadrol, dextromoramide, dezocine, diampro 43. The composition of claim 38, in which the COX-2 mide, diclofenac Sodium, difenamizole, difenpiramide, inhibitor is Selected from the group consisting of celecoxib, diflunisal, dihydrocodeine, dihydrocodeinone enol acetate, rofecoxib, meloxicam, Valdecoxib, parecoxib, etoricoxib, dihydromorphine, dihydroxyaluminum acetylsalicylate, SC-236, NS-398, SC-58125, SC-57666, SC-558, SC-560, dimenoxadol, dimepheptanol, dimethylthiambutene, diox etodolac, DFU, monteleukast, L-745337, L-761066, aphetylbutyrate, dipipanone, diprocetyl, dipyrone, ditazol, L-761000, L-748780, DUP-697, PGV 20229, iguratimod, droxicam, emorfaZone, enfenamic acid, epirizole, eptaZO BF 389, CL 1004, PD 136005, PD 142893, PD 138387, PD cine, etersalate, ethenZamide, ethoheptazine, ethoxazene, 145065, flurbiprofen, nabumetone, flosulide, piroxicam, ethylmethylthiambutene, ethylmorphine, etodolac, etofe diclofenac, lumiracoxib, D 1367, R 807, JTE-522, FK-3311, namate, etonitaZene, eugenol, felbinac, fenbufen, fenclozic FK 867, FR 140423, FR 115068, GR 253035, RWJ 63556, acid, fendosal, fenoprofen, fentanyl, fentiazac, fepradinol, RWJ 20485, ZK 38997, S 2474, Zomepirac analogs, RS feprazone, floctafenine, flufenamic acid, flunoxaprofen, 104894, SC 41930, pranlukast, SB 2.09670, and APHS fluoresone, flupirtine, flu.proquaZone, flurbiprofen, fosfosal, 44. The composition of claim 1, which has been sterile gentisic acid, glafenine, glucame tacin, glycol Salicylate, filtered. guaiaZulene, hydrocodone, hydromorphone, hydroxypethi 45. A method of making a nimeSulide composition com prising contacting particles of nimeSulide or a Salt thereof dine, ibufenac, ibuprofen, ibuproxam, imidazole Salicylate, with at least one Surface Stabilizer for a time and under indomethacin, indoprofen, isofeZolac, isoladol, isometha conditions Sufficient to provide a nimeSulide composition done, isonixin, isoxepac, isoxicam, ketobemidone, ketopro having an effective average particle size of less than about fen, ketorolac, p-lactophenetide, lefetamine, levorphanol, 2000 nm. lofentanil, lonazolac, lomoxicam, loxoprofen, lysine acetyl 46. The method of claim 45, wherein said contacting Salicylate, magnesium acetylsalicylate, meclofenamic acid, comprises grinding. mefenamic acid, meperidine, meptazinol, meSalamine, 47. The method of claim 46, wherein said grinding metazocine, methadone hydrochloride, methotrimeprazine, comprises wet grinding. metiazinic acid, metofoline, metopon, mofebutaZone, mof 48. The method of claim 45, wherein said contacting eZolac, moraZone, morphine, morphine hydrochloride, mor comprises homogenizing. phine Sulfate, morpholine Salicylate, myrophine, nabume 49. The method of claim 45, wherein said contacting tone, nalbuphine, 1-naphthyl Salicylate, naproxen, narceline, comprises: nefopam, nicomorphine, nifenaZone, niflumic acid, nime Sulide, 5'-nitro-2'-propoxyacetanilide, norlevorphanol, (a) dissolving the particles of nimeSulide or a Salt thereof normethadone, normorphine, norpipanone, olSalazine, in a Solvent; opium, oxaceprol, Oxametacine, Oxaprozin, Oxycodone, Oxymorphone, oxyphenbutaZone, papaveretum, paranyline, (b) adding the resulting nimeSulide Solution to a Solution parSalmide, pentazocine, perisoxal, phenacetin, phenadox comprising at least one Surface Stabilizer; and one, phenazocine, phenazopyridine hydrochloride, pheno (c) precipitating the Solubilized nimeSulide having at least coll, phenoperidine, phenopyrazone, phenyl acetylsalicy one Surface Stabilizer adsorbed on the Surface thereof late, phenylbutaZone, phenyl Salicylate, phenyramidol, by the addition thereto of a non-solvent. piketoprofen, piminodine, pipebuZone, piperylone, piprofen, 50. The method of claim 45, wherein the nimeSulide or a piraZolac, piritramide, piroXicam, pranoprofen, proglu meta Salt thereof is Selected from the group consisting of a cin, proheptazine, promedol, propacetamol, propiram, pro crystalline phase, an amorphous phase, a Semi-crystalline poxyphene, propyphenaZone, produaZone, protizinic acid, phase, a Semi-amorphous phase, and mixtures thereof. ramifenaZone, remifentanil, rimazolium metilsulfate, Salac 51. The method of claim 45, wherein the effective average etamide, Salicin, Salicylamide, Salicylamide O-acetic acid, particle size of the nimeSulide particles is Selected from the Salicylsulfuric acid, Salsalte, Salverine, Simetride, Sodium group consisting of less than about 1900 nm, less than about Salicylate, Sufentanil, SulfaSalazine, Sulindac, Superoxide 1800 nm, less than about 1700 nm, less than about 1600 nm, dismutase, Suprofen, SuxibuZone, talniflumate, tenidap, less than about 1500 nm, less than about 1000 nm, less than tenoxicam, terofenamate, tetrandrine, thiazolinobutaZone, about 1400 nm, less than about 1300 nm, less than about tiaprofenic acid, tiaramide, tilidine, tinoridine, tolfenamic 1200 nm, less than about 1100 nm, less than about 900 nm, acid, tolmetin, tramadol, tropesin, Viminol, Xenbucin, Ximo less than about 800 nm, less than about 700 nm, less than profen, Zaltoprofen, and Zomepirac. about 600 nm, less than about 500 nm, less than about 400 US 2004/O156872 A1 Aug. 12, 2004 23 nm, less than about 300 nm, less than about 250 nm, less 59. The method of claim 57, wherein the at least one than about 200 nm, less than about 100 nm, less than about cationic Surface Stabilizer is Selected from the group con 75 nm, and less than about 50 nm. Sisting of a polymer, a biopolymer, a polysaccharide, a 52. The method of claim 45, wherein the composition is cellulosic, an alginate, a nonpolymeric compound, and a formulated for administration Selected from the group con phospholipid. Sisting of oral, pulmonary, rectal, opthalmic, colonic, 60. The method of claim 57, wherein the Surface stabilizer parenteral, intracisternal, intravaginal, intraperitoneal, local, is Selected from the group consisting of cationic lipids, buccal, nasal, and topical administration. polymethylmethacrylate trimethylammonium bromide, Sul 53. The method of claim 45, wherein the composition fonium compounds, polyvinylpyrrollidone-2-dimethylami further comprises one or more pharmaceutically acceptable noethyl methacrylate dimethyl sulfate, hexadecyltrimethyl excipients, carriers, or a combination thereof. ammonium bromide, phosphonium compounds, quarternary 54. The method of claim 45, wherein the nimeSulide or a ammonium compounds, benzyl-di(2-chloroethyl)ethylam Salt thereof is present in an amount Selected from the group monium bromide, coconut trimethyl ammonium chloride, consisting of from about 99.5% to about 0.001%, from about coconut trimethyl ammonium bromide, coconut methyl 95% to about 0.1%, and from about 90% to about 0.5%, by dihydroxyethyl ammonium chloride, coconut methyl dihy weight, based on the total combined dry weight of the droxyethyl ammonium bromide, decyl triethyl ammonium nimeSulide or a Salt thereof and at least one Surface Stabi chloride, decyl dimethyl hydroxyethyl ammonium chloride, lizer, not including other excipients. decyl dimethyl hydroxyethyl ammonium chloride bromide, 55. The method of claim 45, wherein the at least one C-dimethyl hydroxyethyl ammonium chloride, C Surface Stabilizer is present in an amount Selected from the 15 dimethyl hydroxyethyl ammonium chloride bromide, group consisting of from about 0.5% to about 99.999%, coconut dimethyl hydroxyethyl ammonium chloride, coco from about 5.0% to about 99.9%, and from about 10% to nut dimethyl hydroxyethyl ammonium bromide, myristyl about 99.5% by weight, based on the total combined dry trimethyl ammonium methyl Sulphate, lauryl dimethylben weight of the nimeSulide or a Salt thereof and at least one Zyl ammonium chloride, lauryl dimethylbenzyl ammonium Surface Stabilizer, not including other excipients. bromide, lauryl dimethyl (ethenoxy) ammonium chloride, 56. The method of claim 45, comprising at two surface lauryl dimethyl (ethenoxy) ammonium bromide, N-alkyl stabilizers. (Cs)dimethylbenzyl ammonium chloride, N-alkyl (C- 57. The method of claim 45, wherein the Surface stabilizer 1s)dimethyl-benzyl ammonium chloride, N-tetradecylidm is Selected from the group consisting of an anionic Surface ethylbenzyl ammonium chloride monohydrate, dimethyl Stabilizer, a cationic Surface Stabilizer, a Zwitterionic Surface didecyl ammonium chloride, N-alkyl and (C-1) dimethyl Stabilizer, and an ionic Surface Stabilizer. 1-napthylmethyl ammonium chloride, trimethylammonium 58. The method of claim 57, wherein the at least one halide, alkyl-trimethylammonium Salts, dialkyl-dimethy Surface Stabilizer is Selected from the group consisting of lammonium Salts, lauryl trimethyl ammonium chloride, cetyl pyridinium chloride, gelatin, casein, phosphatides, ethoxylated alkyamidoalkyldialkylammonium Salt, an dextran, glycerol, gum acacia, cholesterol, tragacanth, ethoxylated trialkyl ammonium Salt, dialkylbenzene dialky Stearic acid, benzalkonium chloride, calcium Stearate, glyc lammonium chloride, N-didecyldimethyl ammonium chlo erol monoStearate, cetostearyl alcohol, cetomacrogol emul ride, N-tetradecyldimethylbenzyl ammonium, chloride Sifying wax, Sorbitan esters, polyoxyethylene alkyl ethers, monohydrate, N-alkyl(C-1) dimethyl 1-naphthylmethyl polyoxyethylene castor oil derivatives, polyoxyethylene Sor ammonium chloride, dodecyldimethylbenzyl ammonium bitan fatty acid esters, polyethylene glycols, dodecyl trim chloride, dialkyl benzenealkyl ammonium chloride, lauryl ethyl ammonium bromide, polyoxyethylene Stearates, col trimethyl ammonium chloride, alkylbenzyl methyl ammo loidal Silicon dioxide, phosphates, Sodium dodecylsulfate, nium chloride, alkylbenzyl dimethyl ammonium bromide, carboxymethylcellulose calcium, hydroxypropyl celluloses, C. trimethyl ammonium bromides, Cs trimethyl ammo hypromellose, carboxymethylcellulose Sodium, methylcel nium bromides, C7 trimethyl ammonium bromides, dode lulose, hydroxyethylcellulose, hypromellose phthalate, non cylbenzyl triethyl ammonium chloride, poly-diallyldimethy crystalline cellulose, magnesium aluminum Silicate, trietha lammonium chloride (DADMAC), dimethyl ammonium nolamine, polyvinyl alcohol, polyvinylpyrrolidone, 4-(1,1, chlorides, alkyldimethylammonium halogenides, tricetyl 3,3-tetramethylbutyl)-phenol polymer with ethylene oxide methyl ammonium chloride, decyltrimethylammonium bro and formaldehyde, poloxamers, poloxamines, a charged mide, dodecyltriethylammonium bromide, tetradecyltrim phospholipid, dioctylsulfoSuccinate, dialkylesters of Sodium ethylammonium bromide, methyl trioctylammonium chlo SulfoSuccinic acid, Sodium lauryl Sulfate, alkyl aryl poly ride, POLYQUAT 10TM, tetrabutylammonium bromide, ether Sulfonates, mixtures of Sucrose Stearate and Sucrose benzyl trimethylammonium bromide, choline esters, benza distearate, p-isononylphenoxypoly-(glycidol), decanoyl-N- Ikonium chloride, Stearalkonium chloride compounds, cetyl methylglucamide; n-decyl B-D-glucopyranoside; n-decyl pyridinium bromide, cetyl pyridinium chloride, halide Salts B-D-maltopyranoside; n-dodecyl B-D-glucopyranoside; of quaternized polyoxyethylalkylamines, MIRAPOLTM, n-dodecyl 3-D-maltoside; heptanoyl-N-methylglucamide; ALKAQUATTM, alkylpyridinium salts; amines, amine salts, n-heptyl-B-D-glucopyranoside; n-heptyl B-D-thioglucoside; amine oxides, imide azolinium Salts, protonated quaternary n-hexyl B-D-glucopyranoside; nonanoyl-N-methylglucam acrylamides, methylated quaternary polymers, and cationic ide; n-noyl B-D-glucopyranoSide; octanoyl-N-methylgluca guar. mide; n-octyl-B-D-glucopyranoside, octyl B-D-thioglucopy 61. The method of claim 45, utilizing as a surface stabi ranoside; lysozyme, PEG-phospholipid, PEG-cholesterol, lizer a random copolymer of vinyl acetate and Vinyl pyr PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin rolidone, hydroxypropylmethyl cellulose, or tyloxapol. E, and random copolymers of vinyl acetate and Vinyl pyr 62. The method of any of claims 57,59, or 60, wherein the rolidone. composition is bioadhesive. US 2004/O156872 A1 Aug. 12, 2004 24

63. A method of treating a Subject in need comprising dextran, glycerol, gum acacia, cholesterol, tragacanth, administering to the Subject an effective amount of a com Stearic acid, benzalkonium chloride, calcium Stearate, glyc position comprising: erol monoStearate, cetoStearyl alcohol, cetomacrogol emul (a) particles of nimeSulide or a Salt thereof, wherein the Sifying wax, Sorbitan esters, polyoxyethylene alkyl ethers, nimeSulide particles have an effective average particle polyoxyethylene castor oil derivatives, polyoxyethylene Sor bitan fatty acid esters, polyethylene glycols, dodecyl trim size of less than about 2000 nm, and ethyl ammonium bromide, polyoxyethylene Stearates, col (b) at least one Surface Stabilizer. loidal Silicon dioxide, phosphates, Sodium dodecylsulfate, 64. The method of claim 63, wherein the nimeSulide or a carboxymethylcellulose calcium, hydroxypropyl celluloses, Salt thereof is Selected from the group consisting of a hypromellose, carboxymethylcellulose Sodium, methylcel crystalline phase, an amorphous phase, a Semi-crystalline lulose, hydroxyethylcellulose, hypromellose phthalate, non phase, a Semi-amorphous phase, and mixtures thereof. crystalline cellulose, magnesium aluminum Silicate, trietha 65. The method of claim 63, wherein the effective average nolamine, polyvinyl alcohol, polyvinylpyrrolidone, 4-(1,1, particle size of the nimeSulide particles is Selected from the 3,3-tetramethylbutyl)-phenol polymer with ethylene oxide group consisting of less than about 1900 nm, less than about and formaldehyde, poloxamers, poloxamines, a charged 1800 nm, less than about 1700 nm, less than about 1600 nm, phospholipid, dioctylsulfoSuccinate, dialkylesters of Sodium less than about 1500 nm, less than about 1400 nm, less than SulfoSuccinic acid, Sodium lauryl Sulfate, alkyl aryl poly about 1300 nm, less than about 1200 nm, less than about ether Sulfonates, mixtures of Sucrose Stearate and Sucrose 1100 nm, less than about 1000 nm, less than about 900 nm, distearate, p-isononylphenoxypoly-(glycidol), decanoyl-N- less than about 800 nm, less than about 700 nm, less than methylglucamide; n-decyl B-D-glucopyranoside; n-decyl about 600 nm, less than about 500 nm, less than about 400 B-D-maltopyranoside; n-dodecyl B-D-glucopyranoside; nm, less than about 300 run, less than about 250 mm, less n-dodecyl 3-D-maltoside; heptanoyl-N-methylglucamide; than about 200 nm, less than about 100 nm, less than about n-heptyl-B-D-glucopyranoside; n-heptyl B-D-thioglucoside; 75 nm, and less than about 50 nm. n-hexyl B-D-glucopyranoside; nonanoyl-N-methylglucam 66. The method of claim 63, wherein the composition is ide; n-noyl B-D-glucopyranoSide; octanoyl-N-methylgluca formulated for administration Selected from the group con mide; n-octyl-B-D-glucopyranoside; octyl B-D-thioglucopy Sisting of oral, pulmonary, rectal, opthalmic, colonic, ranoside; lysozyme, PEG-phospholipid, PEG-cholesterol, parenteral, intracisternal, intravaginal, intraperitoneal, local, PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin buccal, nasal, and topical administration. E, and random copolymers of vinyl acetate and vinyl pyr 67. The method of claim 63, wherein the composition is rolidone. a dosage form Selected from the group consisting of liquid 74. The method of claim 72, wherein the at least one dispersions, oral Suspensions, gels, aerosols, ointments, cationic Surface Stabilizer is Selected from the group con creams, controlled release formulations, fast melt formula Sisting of a polymer, a biopolymer, a polysaccharide, a tions, lyophilized formulations, tablets, capsules, delayed cellulosic, an alginate, a nonpolymeric compound, and a release formulations, extended release formulations, pulsa phospholipid. tile release formulations, and mixed immediate release and 75. The method of claim 72, wherein the Surface stabilizer controlled release formulations. is Selected from the group consisting of benzalkonium 68. The method of claim 63, wherein the composition chloride, polymethylmethacrylate trimethylammonium bro further comprises one or more pharmaceutically acceptable mide, polyvinylpyrrollidone-2-dimethylaminoethyl meth excipients, carriers, or a combination thereof. acrylate dimethyl Sulfate, hexadecyltrimethyl ammonium 69. The method of claim 63, wherein the nimeSulide or a bromide, cationic lipids, Sulfonium compounds, phospho Salt thereof is present in an amount Selected from the group nium compounds, quarternary ammonium compounds, ben consisting of from about 99.5% to about 0.001%, from about Zyl-di(2-chloroethyl)ethylammonium bromide, coconut tri 95% to about 0.1%, and from about 90% to about 0.5%, by methyl ammonium chloride, coconut trimethyl ammonium weight, based on the total combined dry weight of the bromide, coconut methyl dihydroxyethyl ammonium chlo nimeSulide or a Salt thereof and at least one Surface Stabi ride, coconut methyl dihydroxyethyl ammonium bromide, lizer, not including other excipients. decyl triethyl ammonium chloride, decyl dimethyl hydroxy 70. The method of claim 63, wherein the at least one ethyl ammonium chloride, decyl dimethyl hydroxyethyl Surface Stabilizer is present in an amount Selected from the ammonium chloride bromide, C-dimethyl hydroxyethyl group consisting of from about 0.5% to about 99.999% by ammonium chloride, C2-sdimethyl hydroxyethyl ammo weight, from about 5.0% to about 99.9% by weight, and nium chloride bromide, coconut dimethyl hydroxyethyl from about 10% to about 99.5% by weight, based on the ammonium chloride, coconut dimethyl hydroxyethyl ammo total combined dry weight of the nimeSulide or a salt thereof nium bromide, myristyl trimethyl ammonium methyl Sul and at least one Surface Stabilizer, not including other phate, lauryl dimethyl benzyl ammonium chloride, lauryl excipients. dimethyl benzyl ammonium bromide, lauryl dimethyl 71. The method of claim 63, comprising at two surface (ethenoxy), ammonium chloride, lauryl dimethyl stabilizers. (ethenoxy), ammonium bromide, N-alkyl (C2s)dimethyl 72. The method of claim 63, wherein the Surface stabilizer benzyl ammonium chloride, N-alkyl (Cs)dimethyl-ben is Selected from the group consisting of an anionic Surface Zyl ammonium chloride, N-tetradecylidmethylbenzyl Stabilizer, a cationic Surface Stabilizer, a Zwitterionic Surface ammonium chloride monohydrate, dimethyl didecyl ammo Stabilizer, and an ionic Surface Stabilizer. nium chloride, N-alkyl and (C2) dimethyl 1-napthylm 73. The method of claim 72, wherein the at least one ethyl ammonium chloride, trimethylammonium halide, Surface Stabilizer is Selected from the group consisting of alkyl-trimethylammonium Salts, dialkyl-dimethylammo cetyl pyridinium chloride, gelatin, casein, phosphatides, nium Salts, lauryl trimethyl ammonium chloride, ethoxy US 2004/O156872 A1 Aug. 12, 2004 25 lated alkyamidoalkyldialkylammonium Salt, an ethoxylated greater than about 80%, not greater than about 70%, not trialkyl ammonium Salt, dialkylbenzene dialkylammonium greater than about 60%, not greater than about 50%, not chloride, N-didecyldimethyl ammonium chloride, N-tet greater than about 30%, not greater than about 25%, not radecyldimethylbenzyl ammonium, chloride monohydrate, greater than about 20%, not greater than about 15%, and not N-alkyl(C2) dimethyl 1-naphthylmethyl ammonium greater than about 10% of the T, exhibited by a non chloride, dodecyldimethylbenzyl ammonium chloride, nanoparticulate formulation of nimeSulide, administered at dialkyl benzenealkyl ammonium chloride, lauryl trimethyl the same dosage. ammonium chloride, alkylbenzyl methyl ammonium chlo 85. The method of claim 63, wherein the Cmax of the ride, alkylbenzyl dimethyl ammonium bromide, C trim nimeSulide, when assayed in the plasma of a mammalian ethyl ammonium bromides, Cs trimethyl ammonium bro Subject following administration, is greater than the Cmax mides, C, trimethyl ammonium bromides, dodecylbenzyl for a conventional, non-nanoparticulate form of nimeSulide, triethyl ammonium chloride, poly-diallyldimethylammo administered at the same dosage. nium chloride (DADMAC), dimethyl ammonium chlorides, 86. The method of claim 85, wherein the C is selected alkyldimethylammonium halogenides, tricetyl methyl from the group consisting of at least about 10%, at least ammonium chloride, decyltrimethylammonium bromide, about 20%, at least about 30%, at least about 40%, at least dodecyltriethylammonium bromide, tetradecyltrimethylam about 50%, at least about 60%, at least about 70%, at least monium bromide, methyl trioctylammonium chloride, about 80%, at least about 90%, and at least about 100% POLYOUAT 10TM, tetrabutylammonium bromide, benzyl greater than the C exhibited by a non-nanoparticulate trimethylammonium bromide, choline esters, benzalkonium formulation of nimeSulide, administered at the same dosage. chloride, Stearalkonium chloride compounds, cetyl pyri 87. The method of claim 63, wherein the AUC of the dinium bromide, cetyl pyridinium chloride, halide Salts of nimeSulide, when assayed in the plasma of a mammalian quaternized polyoxyethylalkylamines, MIRAPOLTM, Subject following administration, is greater than the AUC for ALKAQUATTM, alkyl pyridinium salts; amines, amine salts, a conventional, non-nanoparticulate form of nimeSulide, amine oxides, imide azolinium Salts, protonated quaternary administered at the same dosage. acrylamides, methylated quaternary polymers, and cationic 88. The method of claim 87, wherein the AUC is selected guar. from the group consisting of at least about 10%, at least 76. The method of claim 63, utilizing as a surface stabi about 20%, at least about 30%, at least about 40%, at least lizer a random copolymer of vinyl acetate and Vinyl pyr about 50%, at least about 60%, at least about 70%, at least rolidone, hydroxypropylmethyl cellulose, or tyloxapol. about 80%, at least about 90%, and at least about 100% 77. The method of any of claims 72,74, or 75, wherein the greater than the AUC exhibited by a non-nanoparticulate composition is bioadhesive. formulation of nimeSulide, administered at the same dosage. 78. The method of claim 63, wherein administration of the 89. The method of claim 63, additionally comprising nimeSulide composition does not produce Significantly dif administering one or more non-nimeSulide active agents. ferent absorption levels when administered under fed as 90. The method of claim 63, additionally comprising compared to fasting conditions, when administered to a administering one or more non-nimeSulide active agents human. effective for treating fever, inflammation or pain. 79. The method of claim 78, wherein the difference in 91. The method of claim 89, wherein said non-nimeSulide absorption of the nimeSulide composition of the invention, active agent is Selected from the group consisting of an when administered in the fed verSuS the fasted State, is analgesic, an anti-inflammatory, an antipyretic, and a vaso Selected from the group consisting of less than about 100%, modulator. less than about 90%, less than about 80%, less than about 92. The method of claim 89, wherein said non-nimeSulide 70%, less than about 60%, less than about 50%, less than active agent is Selected from the group consisting of nutra about 40%, less than about 30%, less than about 25%, less ceuticals, proteins, peptides, nucleotides, amino acids, anti than about 20%, less than about 15%, less than about 10%, obesity drugs, central nervous System Stimulants, caro less than about 5%, and less than about 3%. tenoids, corticosteroids, elastase inhibitors, anti-fungals, 80. The method of claim 63, wherein administration of the oncology therapies, anti-emetics, analgesics, cardiovascular composition to a Subject in a fasted State is bioeduivalent to agents, anti-inflammatory agents, NSAIDS, non-nimeSulide administration of the composition to a Subject in a fed State, COX-2 inhibitors, anthelmintics, anti-arrhythmic agents, when administered to a human. antibiotics, anticoagulants, antidepressants, antidiabetic 81. The method of claim 80, wherein “bioeduivalency” is agents, antiepileptics, antihistamines, antihypertensive established by a 90% Confidence Interval of between 0.80 agents, antimuscarinic agents, antimycobacterial agents, and 1.25 for both C, and AUC, when administered to a antineoplastic agents, immunosuppressants, antithyroid human. agents, antiviral agents, anxiolytics, Sedatives, astringents, 82. The method of claim 80, wherein “bioeduivalency” is alpha-adrenergic receptor blocking agents, beta-adrenocep established by a 90% Confidence Interval of between 0.80 tor blocking agents, blood products and Substitutes, cardiac and 1.25 for AUC and a 90% Confidence Interval of between inotropic agents, contrast media, corticosteroids, cough Sup 0.70 to 1.43 for Cmax, when administered to a human. preSSants, diagnostic agents, diagnostic imaging agents, 83. The method of claim 63, wherein the T of the diuretics, dopaminergics, haemoStatics, immunological nimeSulide, when assayed in the plasma of a mammalian agents, lipid regulating agents, muscle relaxants, parasym Subject following administration, is less than the T for a Pathomimetics, parathyroid calcitonin and biphosphonates, conventional, non-nanoparticulate form of nimeSulide, prostaglandins, radio-pharmaceuticals, SeX hormones, anti administered at the same dosage. allergic agents, Stimulants and anoretics, SymPathomimet 84. The method of claim 83, wherein the T is Selected ics, thyroid agents, vasodilators, vasomodulators, and Xan from the group consisting of not greater than about 90%, not thines. US 2004/O156872 A1 Aug. 12, 2004 26

93. The method of claim 63, wherein the subject is a tis, bronchitis nephrotoxicity, mastitis, asthma, cancer, human. trauma, Surgery, migraine headaches, kidney disease, Alzhe 94. The method of claim 63, wherein the method is used imer's disease, familial adenomatous polyposis, diarrhea, to treat a condition Selected from the group consisting of colonic adenomas bone resorption, and related conditions. rheumatic and joint diseases, arthritis, rheumatoid arthritis, 95. The method of claim 63, wherein the method is used Osteoarthritis, periarthritis, tendonitis, burSitis, ankylosing to treat a condition where anti-inflammatory agents, anti spondylitis, joint Stiffness, lower back pain, gynecological angiogenesis agents, antitumorigenic agents, immunoSup conditions, menstrual migraine attack, dySmenorrhoea, pel pressive agents, NSAIDs, COX-2 inhibitors, analgesic Vic inflammatory disease, urological conditions, urethritis, agents, anti-thrombotic agents, narcotics, or antifebrile prostatitis, and Vesiculitis pyrexia, cardiovascular diseases, agents are typically used. atherosclerosis, hypotension, thrombophlebitis, arthrosis, inflammatory conditions, otitis, rhinitis, Sinusitis, pharyngi k k k k k