JP2007522079A - Nimesulide composition - Google Patents

Abstract

The present invention provides nanoparticulate nimesulide compositions. The composition preferably comprises nimesulide and at least one surface stabilizer adsorbed or attached to the surface of the nimesulide particles. Preferably, the nanoparticulate nimesulide particles have an effective average particle size of less than about 2000 nm. The present invention also provides methods for making and using nanoparticulate nimesulide compositions.

Description

FIELD OF THE INVENTION The present invention relates to a nanoparticle composition comprising nimesulide. The nimesulide particles of these compositions preferably have an effective average particle size of less than about 2000 nm.

Background of the Invention
I. Background Regarding Nanoparticulate Active Agent Compositions Nanoparticulate active agent compositions were first described in US Pat. No. 5,145,684 (“the '684 patent”) and comprise particles of sparingly soluble therapeutic or diagnostic agents, Has a non-crosslinked surface stabilizer adsorbed or attached to the surface. Such compositions have excellent bioavailability that can be influenced by factors such as drug dosage form and dissolution rate. Low bioavailability is a serious problem encountered in the development of pharmaceutical compositions, particularly those that contain active ingredients that are sparingly soluble in water. By reducing the particle size of the active agent, the surface area of the composition is increased, generally resulting in increased bioavailability. The '684 patent does not teach a nanoparticulate composition of nimesulide.

  Methods for producing nanoparticulate active agent compositions include, for example, U.S. Patent Nos. 5,518,187 and 5,862,999, both for `` Method of Grinding Pharmaceutical Substances '', U.S. Pat.No. 5,718,388 for `` Continuous Method of Grinding Pharmaceutical Substances '', And US Pat. No. 5,510,118 for “Process of Preparing Therapeutic Compositions Containing Nanoparticles”.

  Nanoparticle activator compositions include, for example, U.S. Pat.No. 5,298,262 for `` Use of Ionic Cloud Point Modifiers to Prevent Particle Aggregation During Sterilization '', U.S. Pat.No. 5,302,401 for `` Method to Reduce Particle Size Growth During Lyophilization '', US Patent No. 5,318,767 for `` X-Ray Contrast Compositions Useful in Medical Imaging '', US Patent No. 5,326,552 for `` Novel Formulation For Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants '', `` Method U.S. Patent No. 5,328,404 for `` of X-Ray Imaging Using Iodinated Aromatic Propanedioates '', U.S. Pat.No. 5,336,507 for `` Use of Charged Phospholipids to Reduce Nanoparticle Aggregation '', `` Formulations Comprising Olin 10-G to Prevent Particle Aggregation and Increase Stability U.S. Patent No. 5,340,564, "Use of Non-Ionic Cloud Point Modifiers to Minimize Nanopart" U.S. Patent No. 5,346,702 for `` Iculate Aggregation During Sterilization '', U.S. Patent No. 5,349,957 for `` Preparation and Magnetic Properties of Very Small Magnetic-Dextran Particles '', U.S.A. for `` Use of Purified Surface Modifiers to Prevent Particle Aggregation During Sterilization '' No. 5,352,459, U.S. Pat.Nos. 5,399,363 and 5,494,683 for `` Surface Modified Anticancer Nanoparticles '', U.S. Pat.No. 5,401,492 for `` Water Insoluble Non-Magnetic Manganese Particles as Magnetic Resonance Enhancement Agents '', `` Use of Tyloxapol US Patent No. 5,429,824 for `` as a Nanoparticulate Stabilizer '', US Patent No. 5,447,710 for `` Method for Making Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants '', `` X-Ray Contrast Compositions Useful in U.S. Pat.No. 5,451,393 for `` Medical Imaging '', `` Formulatio ns of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents in Combination with Pharmaceutically Acceptable Clays '' U.S. Patent No. 5,466,440, `` Method of Preparing Nanoparticle Compositions Containing Charged Phospholipids to Reduce Aggregation '' U.S. Pat.No. 5,470,583, `` Nanoparticulate Diagnostic Mixed '' US Patent No. 5,472,683 for `` Carbamic Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging '', US Patent No. 5,500,204 for `` Nanoparticulate Diagnostic Dimers as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging '', US Patent No. 5,518,738 for `` Nanoparticulate NSAID Formulations '', US Patent No. 5,521,218 for `` Nanoparticulate Indodipamide Derivatives for Use as X-Ray Contrast Agents '', `` Nanoparticulate Diagnostic Diatrizoxy Ester X-Ray Contrast Agents for Blood Pool and Lymphatic System '' US Patent No. 5,525,32 for "Imaging" No. 8, U.S. Pat.No. 5,543,133 on `` Process of Preparing X-Ray Contrast Compositions Containing Nanoparticles '', U.S. Pat.No. 5,552,160 on `` Surface Modified NSAID Nanoparticles '', `` Formulations of Compounds as Nanoparticulate Dispersions in Digestible Oils or Fatty Acids U.S. Pat.No. 5,560,931, `` Polyalkylene Block Copolymers as Surface Modifiers for Nanoparticles '', U.S. Pat.No. 5,565,188, `` Sulfated Non-ionic Block Copolymer Surfactant as Stabilizer Coatings for Nanoparticle Compositions '', U.S. Pat.No. 5,569,448, U.S. Patent No. 5,571,536 for `` Formulations of Compounds as Nanoparticulate Dispersions in Digestible Oils or Fatty Acids '', U.S. Patent No. 5,573,749 for `` Nanoparticulate Diagnostic Mixed Carboxylic Anydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging '', About Diagnostic Imaging X-Ray Contrast Agents U.S. Pat.No. 5,573,750, U.S. Pat.No. 5,573,783 on `` Redispersible Nanoparticulate Film Matrices With Protective Overcoats '', `` Site-specific Adhesion Within the GI Tract Using Nanoparticles Stabilized by High Molecular Weight, Linear Poly (ethylene Oxide) Polymers '' U.S. Pat.No. 5,580,579, U.S. Pat.No. 5,585,108 on `` Formulations of Oral Gastrointestinal Therapeutic Agents in Combination with Pharmaceutically Acceptable Clays '', U.S. Pat.No. 5,587,143 , `` Milled Naproxen with Hydroxypropyl Cellulose as Dispersion Stabilizer '', U.S. Patent No. 5,591,456, `` Novel Barium Salt Formulations Stabilized by Non-ionic and Anionic Stabilizers '' U.S. Patent No. 5,593,657, `` Sugar Based Surfactant for Nanocrystals '' U.S. Pat.No. 5,622,938 , U.S. Patent No. 5,628,981 for `` Improved Formulations of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents and Oral Gastrointestinal Therapeutic Agents '', U.S.A. No. 5,643,552, U.S. Pat.No. 5,718,388 for `` Continuous Method of Grinding Pharmaceutical Substances '', U.S. Pat.No. 5,718,919 for `` Nanoparticles Containing the R (-) Enantiomer of Ibuprofen '', `` Aerosols Containing Beclomethasone Nanoparticle Dispersions '' U.S. Pat.No. 5,747,001, U.S. Pat. No. 829, U.S. Pat.No. 6,068,858 on Methods of Making Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic Surface Stabilizers, U.S. Pat.No. 6,153,225 on Injectable Formulations of Nanoparticulate Naproxen, New Solid Dose U.S. Patent No. 6,165,506 for `` Form of Nanoparticulate Naproxen '', U.S. Patent No. 6,221,400 for `` Methods of Treating Mammals Using Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors '', U.S. Patent for `` Nebulized Aerosols Containing Nanoparticle Dispersions '' No. 6,264,922, U.S. Pat.No. 6,267,989 on `` Methods for Preventing Crystal Growth and Particle Aggregation in Nanoparticle Compositions '', U.S. Pat.No. 6,270,806 on `` Use of PEG-Derivatized Lipids as Surface Stabilizers for Nanoparticulate Compositions '', `` Rapidly Disintegrating '' Solid Oral Dosage F U.S. Patent No. 6,316,029 for `` Orm '', U.S. Patent No. 6,375,986 for `` Solid Dose Nanoparticulate Compositions Comprising a Synergistic Combination of a Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate '', U.S. Patent for `` Bioadhesive Nanoparticulate Compositions Having Cationic Surface Stabilizers '' No. 6,428,814, U.S. Pat.No. 6,431,478 for `` Small Scale Mill '', and U.S. Pat.No. 6,432,381 for `` Methods for Targeting Drug Delivery to the Upper and / or Lower Gastrointestinal Tract '', all of which Specifically incorporated by reference. In addition, US Patent Application No. 20020012675 A1 published on January 31, 2002 for "Controlled Release Nanoparticulate Compositions" and WO 02/098565 for "System and Method for Milling Materials" The composition is described and specifically incorporated by reference. None of these references describe nanoparticulate nimesulide compositions.

  Amorphous small particle compositions include, for example, U.S. Pat.No. 4,783,484 for `` Particulate Composition and Use Thereof as Antimicrobial Agent '', U.S. Pat.No. 4,826,689 for `` Method for Making Uniformly Sized Particles from Water-Insoluble Organic Compounds '', U.S. Pat.No. 4,997,454 on `` Method for Making Uniformly-Sized Particles From Insoluble Compounds '', U.S. Pat.No. 5,741,522 on `` Ultrasmall, Non-aggregated Porous Particles of Uniform Size for Entrapping Gas Bubbles Within and Methods '', and `` Ultrasmall U.S. Pat. No. 5,776,496 for Porous Particles for Enhancing Ultrasound Back Scatter.

を有する非ステロイド系抗炎症薬（NSAID）である。ニメスリドは308.31 g/molの分子量を有し、事実上水に不溶であり、約4時間の半減期を有する。ニメスリドはシクロオキシゲナーゼ-2（COX-2）を選択的に阻害することにより機能する。 II. Background on Nimesulide
Nimesulide, also known as N- (4-nitro-2-phenoxy-phenyl) -methanesulfonamide, has the following structure:

It is a non-steroidal anti-inflammatory drug (NSAID). Nimesulide has a molecular weight of 308.31 g / mol, is virtually insoluble in water, and has a half-life of about 4 hours. Nimesulide functions by selectively inhibiting cyclooxygenase-2 (COX-2).

  The therapeutic concentration of nimesulide elicits several effects, including: (a) inhibition of prostaglandin synthesis, (b) inhibition of toxic oxygen metabolite formation, (c) inhibition of cytokine release, (d) inhibition of histamine release, and (e) inhibition of cartilage degeneration. Consistent with these actions, nimesulide effectively treats a wide range of disorders because it exerts anti-inflammatory, analgesic and antipyretic activities.

  One disadvantage of nimesulide is that it can be difficult to administer because it is almost insoluble in water. Several methods have been reported in the art that allow more biomedical use of nimesulide. US Pat. No. 5,756,546 to Pirotte et al. Discloses a water-soluble salt formed from equimolar amounts of nimesulide and L-lysine, but this salt is in excess from a 1: 1 molar ratio depending on any variation. Of L-lysine or insoluble nimesulide. US Pat. No. 5,744,165 to Geczy et al. Relates to alkali and alkaline earth salts of nimesulide that are soluble in water when mixed with cyclodextrins to form inclusion complexes. However, this type of composition can deliver unwanted amounts of cyclodextrin and sodium ions to the patient. Giorgetti US Pat. No. 6,194,462 discloses a soluble formulation of nimesulide achieved by dissolving the drug in a mixture of water at basic pH and one or more alcohols such as ethanol. In contrast, U.S. Pat.No. 6,288,121 to Bader et al. Discloses a liquid crystalline form of nimesulide emulsion for controlled release of the drug, while Giorgetti U.S. Pat.No. 5,998,480 discloses nimesulide, phospholipids and organic acids or It relates to bioavailable formulations of inorganic acids.

  Nimesulide is Ainex (R), Aulin (R), Donulide (R), Edrigyl (R), Eskaflam (R), Fansidol (R), Flogovital (R), Guaxan (R) , Heugan (R), Mesulid (R), Nemil (R), Nexen (R), Nide (R), Nidol (R), Nimed (R), Nimedex (R), Nisulid (Trademark), Plarium (R), Scaflam (R), Scaflan (R), and Slidene (R) are traded under a number of trade names.

  There is a need in the art for a nimesulide composition that can reduce dosing frequency, improve clinical efficacy, and potentially reduce side effects. The present invention fulfills these needs.

SUMMARY OF THE INVENTION The present invention provides a nanoparticulate nimesulide composition. The composition preferably comprises nimesulide and at least one surface stabilizer adsorbed or attached to the surface of the nimesulide particles. Preferably, the nanoparticulate nimesulide particles have an effective average particle size of less than about 2000 nm.

  The present invention also provides a pharmaceutical composition comprising nanoparticulate nimesulide. The pharmaceutical composition preferably comprises nimesulide, at least one surface stabilizer, and at least one pharmaceutically acceptable carrier, and any desirable excipients known to those skilled in the art. The composition can be formulated into any desired dosage form.

In other aspects, the present invention provides nanoparticles with improved pharmacokinetic profiles and AUC parameters, such as improved T _max , C _max , compared to conventional solubilized microcrystalline or non-nanoparticulate nimesulide formulations Nimesulide composition.

In still other aspects, the invention provides a pharmacokinetic profile that is substantially unaffected by the eating or fasting status of a subject taking the composition, preferably C _max and the US Food and Drug Administration and / or Includes nimesulide compositions having a profile defined by the AUC guidelines granted by the corresponding European Supervisory Authority (EMEA).

  Other aspects of the present invention include, but are not limited to, nanoparticulate nimesulide compositions preferably having one or more of the following properties compared to conventional non-nanoparticulate formulations of nimesulide: (1) Small dosage form size; (2) small dose of drug required to achieve the same pharmacological effect; (3) increased bioavailability; (4) increased dissolution rate of nanoparticulate nimesulide composition; and (5) living body Adhesive nimesulide composition.

  The present invention further discloses a method of producing a nanoparticulate nimesulide composition. The method includes contacting nimesulide and at least one surface stabilizer for a time and under conditions sufficient to provide a nanoparticulate nimesulide composition. One or more surface stabilizers may contact the nimesulide before, preferably during or after the nimesulide grinding.

  The present invention provides nanoparticulate nimesulide compositions for treating a wide range of conditions and disorders mediated by COX-2, including but not limited to disorders characterized by inflammation, pain, and / or heat. The method used is also included. Therefore, anti-inflammatory agents, anti-angiogenic agents, antitumor agents, immunosuppressive agents, NSAIDs, COX-2 inhibitors, analgesics, antithrombotic agents, anesthetics or antipyretic agents are usually used in the composition of the present invention. Useful for cases indications.

  The method includes administering to the subject a therapeutically effective amount of a nanoparticulate nimesulide pharmaceutical composition of the invention. In addition, the subject can be administered a therapeutic amount of a pharmaceutical composition comprising both nanoparticulate and non-nanoparticulate nimesulide. Alternatively, the method comprises administering to the subject a therapeutically effective amount of a nanoparticulate nimesulide composition in combination with one or more non-nimesulide active agents.

  Both the foregoing summary and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the claimed invention. Other objects, advantages, and novel features will be readily apparent to those skilled in the art from the following detailed description of the invention.

Detailed Description of the Invention The present invention relates to nanoparticulate nimesulide compositions. The composition preferably includes nimesulide and at least one surface stabilizer adsorbed or associated with the surface of the nimesulide particles. The nanoparticulate nimesulide particles preferably have an effective average particle size of less than about 2000 nm.

  The invention also relates to pharmaceutical compositions comprising a nanoparticulate nimesulide active agent. The pharmaceutical composition preferably comprises nimesulide, at least one surface stabilizer, and at least one pharmaceutically acceptable carrier. Non-toxic physiologically acceptable carriers, adjuvants, and vehicles are collectively referred to herein as carriers.

  The pharmaceutical composition can be administered intravenously, intramuscularly, or subcutaneously; orally administered in solid, liquid, or aerosol dosage forms; or vagina, nasal, rectal, eye, topical (powder, ointment or infusion), buccal, intracapsular Can be formulated for parenteral injection, including intraperitoneal or topical administration.

  Although any pharmaceutically acceptable dosage form can be used, a solid dosage form is preferred. Typical solid dosage forms include, but are not limited to, tablets, capsules, sachets, electuary, powders, pills, or granules. Solid dosage forms can be, for example, fast melting dosage forms, controlled release dosage forms, lyophilized dosage forms, delayed release dosage forms, sustained release dosage forms, pulsed release dosage forms, mixed immediate release and controlled release dosage forms, or It can be a combination of these. A solid dose tablet formulation is preferred.

I. As taught in the technical problem “684” overcome by the inventors, not all combinations of surface stabilizers and active agents result in stable nanoparticle compositions. Therefore, the discovery that a stable nanoparticulate nimesulide formulation can be produced was surprising.

  In general, the dissolution rate of particulate drugs increases with increasing surface area, eg, decreasing particle size. Therefore, methods for producing fine-grained drugs have been studied and efforts have been made to control the size and size range of drug particles in pharmaceutical compositions. A nanoparticulate active agent formulation suitable for administration as a drug requires formulation of the active ingredient into a colloidal dispersion that exhibits an acceptable nanoparticle size range and stability to maintain the size range without agglomeration. Therefore, increasing the surface area simply by reducing the particle size does not guarantee success. Further challenges include shaping a redispersible solid dosage form into a nanoparticulate dosage form upon administration to a patient in order to retain the advantages of nanoparticulate nimesulide over conventional particulate or solubilized nimesulide dosage forms. .

II. Summary of Benefits of Nanoparticulate Nimesulide Formulations Compared to conventional non-nanoparticulate or soluble formulations of nimesulide, the benefits of nanoparticulate nimesulide formulation are (1) faster onset of action; (2) potential dosing frequency (3) smaller tablet (or other solid dosage form) diameter or liquid dose volume; (4) small dose of drug required to achieve the same pharmacological effect; (5) increased bioavailability; 6) increased dissolution rate; (7) high redispersibility of nanoparticulate nimesulide particles present in the composition of the invention after administration; (8) higher dose loading, such as oral, intravenous, subcutaneous, Or improved performance characteristics for intramuscular injection; (9) improved pharmacokinetic profiles, such as improved T _max , C _max , and AUC profiles; (10) in fed state versus fasted state Substantially similar or biologically when administered Nanoparticulate nimesulide compositions of equal pharmacokinetic profile; (11) bioadhesive nimesulide compositions; (12) low viscosity liquid nanoparticulate nimesulide dosage forms can be produced; (13) liquid nanoparticulate nimesulide with low viscosity In the composition, subject compliance is improved by recognition of lighter formulations that are easier to ingest and digest; (14) In liquid nanoparticulate nimesulide compositions with low viscosity, cups or syringes can be used, which facilitates dispersion (15) the nanoparticulate nimesulide composition can be sterile filtered; (16) the nanoparticulate nimesulide composition can be used in combination with other active agents; (17) the nanoparticulate nimesulide composition is suitable for parenteral administration And (18) that the nanoparticulate nimesulide composition does not require an organic solvent or pH extreme, but is not limited thereto.

  Furthermore, nanoparticulate nimesulide formulations do not have the sedative and addictive properties of narcotic analgesics. Nimesulide is drowsy and not addictive, so it is a preferred analgesic when mobility is important or when treatment is prolonged, and drug addiction can result from long-term use of narcotic analgesics.

III. Definitions The present invention is described herein using several definitions, as set forth below and throughout the specification.

  “About” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which the term is used. Where there is a use of a term that is not clear to the skilled person in the context in which it is used, “about” means up to plus or minus 10% of the specific term.

  By “conventional” or “non-nanoparticulate active agent” is meant an active agent that is solubilized or has an effective average particle size greater than about 2 microns. “Effective average particle size greater than about 2 microns” means that at least 50% of the particles of the composition have a size greater than about 2 microns.

  “Pharmaceutically acceptable” as used herein refers to the right medical judgment, according to a reasonable effect / risk ratio, without excessive toxicity, irritation, allergic response, or other problems or complications. Within the scope of the present invention refers to compounds, materials, compositions, and / or dosage forms suitable for use in contact with human and animal tissues.

  As used herein, “pharmaceutically acceptable salt” refers to a derivative in which the parent compound is modified by making acid or basic salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts are derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid; acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid , Butyric acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamonic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, Including salts prepared from organic acids such as methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and isethionic acid.

  As used herein, a “poorly water-soluble drug” refers to a solubility of less than about 30 mg / ml, preferably less than about 20 mg / ml, preferably less than about 10 mg / ml, or preferably less than about 1 mg / ml. Means a drug having Such drugs tend to be cleared from the gastrointestinal tract before being absorbed into the blood circulation. Furthermore, poorly water-soluble drugs tend to be unsafe for intravenous administration techniques and are used primarily in combination with highly water-soluble drug substances.

  As used herein with respect to stable nimesulide particles, “stable” includes, but is not limited to, one or more of the following parameters. (1) Nimesulide particles do not agglomerate or agglomerate due to attractive force between particles, or do not significantly increase the particle size with time by other methods; (2) Physics of Nimesulide particles such as change from amorphous phase to crystalline phase (3) Nimesulide particles are chemically stable; and / or (4) Nimesulide is not subjected to the heating step above the melting point of Nimesulide in the preparation of the nanoparticles of the present invention.

  A “therapeutically effective amount” as used herein with respect to a drug dose provides a specific pharmacological response to a drug administered to a significant number of subjects in need of such treatment. Means dose. A “therapeutically effective amount” administered to a particular subject in an individual case is not necessarily described herein, even if such a dose is considered a “therapeutically effective amount” by those skilled in the art. Does not effectively treat certain diseases. Throughout this specification, drug dose relates to the drug concentration measured in each case as an oral dose or measured in the blood.

IV. Preferred Features of Nanoparticulate Nimesulide Composition
A. rapid expression especially important for activity, conventional nimesulide formulation has a T _max of 4-6 hours, because the T _max is longer than five times the majority of narcotic analgesics, conventional The Nimesulide formulation is unsuitable for treating acute pain due to its delayed onset of action. ^{The Physician's Desk Reference, 56 th} Ed., See pp. 446 and 1054. Unlike conventional nimesulide formulations, nanoparticulate nimesulide formulations show a more rapid onset of action and are useful for treating acute pain when rapid analgesia is required.

B. Increased bioavailability and decreased dose Compared to conventional nimesulide formulations, the nanoparticulate nimesulide compositions of the present invention show increased bioavailability, require lower doses, and have longer plasma concentrations It preferably exhibits a half-life.

  As another advantage, Nimesulide nanoparticulate formulations also provide longer-term analgesia compared to traditional anesthetic analgesics. Traditional anesthesia provides rapid onset of action, but the period of analgesia is short. The nanoparticulate nimesulide formulation combines the rapid onset of traditional anesthesia with the analgesic period of conventional NSAIDs. The long half-life of nimesulide, about 20 hours compared to 2-3 hours for most anesthesia, gives long-term effects and does not require frequent dosing.

  Enhanced bioavailability allows the use of low doses and also results in a reduction in toxicity associated with nimesulide. In this regard, low dose nanoparticulate nimesulide may achieve the same or improved therapeutic effect as conventional high dose nimesulide. Such low doses can be realized thanks to the high bioavailability of nanoparticulate drug formulations compared to conventional drug formulations. Nimesulide, like other drugs, can have side effects. Therefore, side effects can be reduced by administering a smaller dose.

  Enhanced bioavailability may also allow the use of smaller dosage forms. This is meaningful for certain patient populations, such as the elderly, the young and infants.

C. Improved Pharmacokinetic Profile The nanoparticulate nimesulide composition of the present invention preferably also exhibits a desirable pharmacokinetic profile when administered to a mammalian subject. Desirable pharmacokinetic profiles are (1) when assaying plasma of a mammalian subject after administration, the T _{max of} nimesulide is preferably less than the T _max of a conventional nimesulide non-nanoparticle dosage form administered at the same dose (2) when assaying the plasma of a mammalian subject after administration, the C _{max of} nimesulide is preferably greater than the C _max of a conventional nimesulide non-nanoparticle dosage form administered at the same dose; and / or (3) When the plasma of a mammalian subject is assayed after administration, preferably the Niuclide AUC preferably exceeds the AUC of the conventional Nimesulide non-nanoparticle dosage form administered at the same dose, It is not limited to these.

  The desired pharmacokinetic profile used herein is the pharmacokinetic profile measured after the initial administration of nimesulide. The dose can be formulated in any manner known to those of skill in the art as described below.

A preferred nanoparticulate nimesulide composition is about 90% or less, about 80% or less of the T _max exhibited by a non-nanoparticulate formulation of nimesulide in a comparative pharmacokinetic study with a non-nanoparticulate formulation of nimesulide administered at the same dose, _Tmax of about 70% or less, about 60% or less, about 50% or less, about 30% or less, about 25% or less, about 20% or less, about 15% or less, or about 10% or less.

A preferred nanoparticulate nimesulide composition is at least about 10%, at least about 20% above the C _max exhibited by the non-nanoparticulate formulation of nimesulide in a comparative pharmacokinetic study with a non-nanoparticulate formulation of nimesulide administered at the same dose, A C _max that is at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 100% greater.

  A preferred nanoparticulate nimesulide composition is at least about 10%, at least about 20%, at least about at least about 10% more than the AUC exhibited by a non-nanoparticulate formulation of nimesulide in a comparative pharmacokinetic study with a non-nanoparticulate formulation of nimesulide administered at the same dose. AUC that is about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 100% greater.

  Any formulation that provides the desired pharmacokinetic profile in accordance with the present invention is suitable for administration. Typical dosage form types that impart such a profile are liquid dispersions, gels, aerosols, ointments, creams and solid dosage forms.

D. The pharmacokinetic profile is not affected by the eating or fasting state of the subject taking the composition. Certain drugs are administered in the fasted state compared to those administered immediately after the standard test meal. Have been shown to have significantly lower plasma concentrations. This significant difference is undesirable.

  The nanoparticulate nimesulide formulation of the present invention preferably mitigates this problem. That is, it is preferred that the difference in absorption concentration when administered under a fed state compared to a fasted state, or more preferably not significantly different.

  Accordingly, the present invention encompasses nimesulide compositions having a pharmacokinetic profile that is substantially unaffected by the fed or fasted state of the subject taking the composition. This means that there is no substantial difference in the amount of drug absorbed or the rate of drug absorption when the nanoparticulate nimesulide composition is administered in a fed state versus a fasted state.

The invention also encompasses a nimesulide composition wherein administration to a fasted subject is biologically equivalent to administration to a fed subject. “Bioequivalence” is the 90% confidence interval (CI) from 0.80 to 1.25 for both C _max and AUC under US Food and Drug Administration regulatory guidance, or 0.80 to 1.25 for AUC under European EMEA regulatory guidance. Preferably, it is established by 90% CI up to 90% CI for C _max from 0.70 to 1.43 (T _max is not relevant for determination of _{bioequivalence} under USFDA and EMEA regulatory guidelines).

  Advantages of dosage forms that substantially eliminate the effects of food include increased convenience, and patient compliance is increased because the patient does not have to commit to taking a dose with or without food. This is significant because the patient's low compliance can negate his intention to administer the drug.

  The difference in absorption of the nimesulide composition of the invention is less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 60% when administered in a fed state versus a fasted state, Preferably less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, or less than about 3% .

E. Rapid dissolution profile The nanoparticulate nimesulide composition of the present invention preferably has a rapid dissolution profile. Rapid dissolution of the administered active agent is desirable because faster dissolution generally leads to faster onset of action and increased bioavailability. In order to maximize the dissolution profile and bioavailability of Nimesulide, it is useful to increase the dissolution of the drug so that levels close to 100% can be reached.

  The nimesulide composition of the present invention preferably has a dissolution profile in which at least about 20% of the composition dissolves within 5 minutes. In other embodiments, at least about 30% or about 40% of the nimesulide composition dissolves within about 5 minutes. In still other embodiments, it is preferred that at least about 40%, about 50%, about 60%, about 70%, or about 80% of the nimesulide composition dissolve within about 10 minutes. Finally, in other embodiments, it is preferred that at least about 70%, about 80%, about 90%, or about 100% of the nimesulide composition dissolve within about 20 minutes.

  Dissolution is preferably measured in a discernable solvent. Such dissolution solvents produce two different dissolution curves for two products with different dissolution profiles in gastric juice. That is, the dissolution medium predicts in vivo dissolution of the composition. A typical dissolving solvent is an aqueous solvent containing 0.025 M surfactant sodium lauryl sulfate. The amount of dissolution can be measured spectrophotometrically. The rotating blade method (European Pharmacopoeia) can be used to measure dissolution.

F. Redispersion of Nanoparticulate Nimesulide Dosage Form into Nanoparticle Size The nanoparticulate nimesulide composition of the present invention may be redispersed such that the effective average particle size of the redispersed nimesulide particles is less than about 2 microns. preferable. This is very important because if the nanoparticulate nimesulide composition is not substantially redispersed to the nanoparticle size upon administration, this dosage form may lose the advantages of the nanoparticulate formulation.

  This is because nanoparticulate active agent compositions benefit from the small particle size of the active agent. If the active agent is not redispersed to a small particle size upon administration, the extremely high surface free energy and thermodynamic driving force of the nanoparticle system that achieves a general reduction of free energy will result in “lumps” or agglomerated active agent particles. It is formed. With the formation of such agglomerated particles, the bioavailability of this dosage form can be well below that observed with liquid dispersion dosage forms of nanoparticulate active agents.

  Furthermore, the nanoparticulate nimesulide composition of the present invention preferably exhibits dramatic redispersion upon administration to a mammal such as a human or animal. This can be demonstrated by reconstitution / redispersion in a biorelevant aqueous solvent such that the effective average particle size of the redispersed nimesulide particles is less than about 2 microns. Biorelevant aqueous solvents include any aqueous solvent that exhibits typical ionic strength and pH. Desirable pH and ionic strength are representative of physiological conditions found in the human body. Such biorelevant aqueous solvent can be, for example, an aqueous electrolyte solution or solution of any salt, acid, base, or combination thereof.

  Biorelevant pH is well known in the art. For example, in the stomach, the pH varies from a little less than 2 (but usually greater than 1) to 4 or 5. In the small intestine, the pH can vary from 4 to 6, and in the colon from 6 to 8. Biologically related ionic strength is also well known in the art. Fasted state gastric fluid has an ionic strength of about 0.1 M, while fasted state intestinal fluid has an ionic strength of about 0.14. See, for example, Lindahl et al., “Characterization of Fluids from the Stomach and Proximal Jejunum in Men and Women”, Pharm. Res., 14 (4): 497-502 (1997).

  It is believed that the pH and ionic strength of the test solution is more important than the specific chemical content. Accordingly, suitable pH and ionic strength values are many such as strong acids, strong bases, salts, one or more conjugated acid base pairs, monobasic and polybasic electrolytes (eg, weak acids and salts corresponding to the acids). It can obtain by the combination of these.

  Exemplary electrolyte solutions can be, but are not limited to, HCl solutions in the concentration range of about 0.001 to about 0.1 M, NaCl solutions in the concentration range of about 0.001 to about 0.1 M, and combinations thereof. For example, the electrolyte solution is about 0.1 M or less HCl, about 0.01 M or less HCl, about 0.001 M or less HCl, about 0.1 M or less NaCl, about 0.01 M or less NaCl, about 0.001 M or less NaCl, and However, it is not limited to these. Of these electrolyte solutions, 0.01 M HCl and / or 0.1 M NaCl are most typical of the fasted human physiological state due to pH and ionic strength conditions of the proximal gastrointestinal tract.

  The electrolyte concentrations of 0.001 M HCl, 0.01 M HCl, and 0.1 M HCl correspond to pH 3, pH 2, and pH 1, respectively. Thus, 0.01 M HCl solution mimics the normal acidic state found in the stomach. A 0.1 M NaCl solution provides a good approximation of the ionic strength conditions found in the body, including gastrointestinal fluids, but concentrations higher than 0.1 M should be used to mimic feeding conditions in the human GI tract You can also.

  Typical solutions of salts, acids, bases or combinations thereof that exhibit the desired pH and ionic strength are phosphate / phosphate + chloride sodium, potassium and calcium salts, acetic acid / acetate + chloride Including sodium, potassium and calcium salts, carbonate / bicarbonate + chloride sodium, potassium and calcium salts, and citric acid / citrate + chloride sodium, potassium and calcium salts. It is not limited.

  In other embodiments of the invention, redispersed nimesulide particles (redispersed in aqueous, biologically relevant, or any other suitable solvent) are measured by light scattering, microscopy, or other suitable methods. Then, less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, about 1000 nm Less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, about 150 nm Having an effective average particle size of less than, less than about 100 nm, less than about 75 nm, or less than about 50 nm.

  By “effective average particle size less than about 2000 nm”, at least 50% of the nimesulide particles have a particle size less than the effective weight average, ie less than about 2000 nm, 1900 nm, 1800 nm, etc., as measured by the above technique. Is meant. Preferably, at least about 70%, about 90%, about 95%, or about 99% of the nimesulide particles have a particle size below the effective average, i.e., less than about 2000 nm, 1900 nm, 1800 nm, 1700 nm, and the like.

  Redispersibility can be tested using any suitable means known in the art. See, for example, the Example section of US Pat. No. 6,375,986 for “Solid Dose Nanoparticulate Compositions Comprising a Synergistic Combination of a Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate”.

G. Bioadhesive Nanoparticulate Nimesulide Composition The nanoparticulate nimesulide composition of the present invention may exhibit bioadhesive properties. Such compositions include one or more cationic surface stabilizers, which are described in more detail below.

  The term “bioadhesion” refers to any attractive interaction between two biological surfaces or between a biological surface and a synthetic surface. In the case of a bioadhesive nanoparticulate nimesulide composition, the term “bioadhesion” refers to the adhesion between the nanoparticulate nimesulide composition and a biomatrix (eg, gastrointestinal mucin, lung tissue, nasal mucosa, etc.). See, for example, US Pat. No. 6,428,814 for “Bioadhesive Nanoparticulate Compositions Having Cationic Surface Stabilizers”. This is specifically incorporated by reference. Nimesulide bioadhesive formulations exhibit bioadhesion to exceptional biomatrix.

  The bioadhesive nimesulide composition is useful in any situation where it is desirable to apply the composition to a biological surface. The bioadhesive nimesulide composition coats the target surface of a continuous and uniform film, which is invisible to the human eye.

  Bioadhesion delays the transport of the nimesulide composition, and some nimesulide particles necessarily adhere to tissues other than mucosal cells. This increases dose absorption and bioavailability by providing long-term exposure to nimesulide.

H. Low Viscosity Liquid Nanoparticulate Nimesulide Composition Liquid dosage forms of conventional microcrystalline or non-nanoparticulate or solubilized nimesulide compositions are relatively viscous and are highly viscous substances that will not be well accepted by the patient population. It can be expected to be. This is significant because liquid dosage forms can be particularly useful for patient populations such as the elderly and infants.

  The liquid dosage form of the nanoparticulate nimesulide composition of the present invention provides significant advantages over the liquid dosage forms of conventional microcrystalline or solubilized nimesulide compositions. The low viscosity and smooth texture of the liquid dosage form of the nanoparticulate nimesulide composition of the present invention provides advantages for both preparation and use. These benefits include, for example: (1) subject compliance improved by perception of easier to take, lighter formulations; (2) easier dispensing compared to high viscosity formulations; (3) lower dose volume and hence test Includes the possibility of formulating high concentrations of nimesulide that result in a smaller body intake volume; and (4) general formulation concerns that are easier to deal with.

  The viscosity of the liquid dosage form of the nanoparticulate nimesulide of the present invention is less than about 1/200, less than about 1/175, about 1 of the topical liquid dosage form of the non-nanoparticulate nimesulide composition at approximately the same concentration per ml of nimesulide. Preferably less than / 150, less than about 1/125, less than about 1/100, less than about 1/75, less than about 1/50, or less than about 1/25.

  Typically, the viscosity of the liquid nanoparticulate nimesulide dosage forms of the present invention is from about 2000 mPa s to about 1 mPa s, from about 1900 mPa · s to about 1 when measured at 20 ° C. with a shear rate of 0.1 (1 / s). mPa ・ s, about 1800 mPa ・ s to about 1 mPa ・ s, about 1700 mPa ・ s to about 1 mPa ・ s, about 1600 mPa ・ s to about 1 mPa ・ s, about 1500 mPa ・ s About 1 mPa ・ s, about 1400 mPa ・ s to about 1 mPa ・ s, about 1300 mPa ・ s to about 1 mPa ・ s, about 1200 mPa ・ s to about 1 mPa ・ s, about 1100 mPa ・ s s to about 1 mPas, about 1000 mPas to about 1 mPas, about 900 mPas to about 1 mPas, about 800 mPas to about 1 mPas, about 700 mPa ・ s to about 1 mPa ・ s, about 600 mPa ・ s to about 1 mPa ・ s, about 500 mPa ・ s to about 1 mPa ・ s, about 400 mPa ・ s to about 1 mPa ・ s, About 300 mPa · s to about 1 mPa · s, about 200 mPa · s to about 1 mPa · s, about 175 mPa · s to about 1 mPa · s, about 150 mPa · s to about 1 mPa · s Until, 125 mPa · s to 1 mPa · s, 100 mPa · s to 1 mPa · s, 75 mPa · s to 1 mPa · s, 50 mPa · s to 1 mPa · s From about 25 mPa · s to about 1 mPa · s, from about 15 mPa · s to about 1 mPa · s, from about 10 mPa · s to about 1 mPa · s, or from about 5 mPa · s to about 1 mPa · s・ Up to s.

  Viscosity depends on concentration and temperature. Usually, a high concentration results in a high viscosity, while a high temperature results in a low viscosity. The viscosity as defined above refers to a measurement performed at about 20 ° C. (the viscosity of water at 20 ° C. is 1 mPa s). The present invention encompasses equivalent viscosities measured at different temperatures.

  The liquid formulation of the present invention can be formulated in any volume dose, but is preferably in a volume that is less than or equal to the liquid dosage form of the non-nanoparticle or solubilized nimesulide composition.

I. Sterile Filtered Nanoparticulate Nimesulide Composition The nanoparticulate nimesulide composition of the present invention can be sterile filtered. This eliminates the need for heat sterilization that can harm or degrade Nimesulide and lead to crystal growth and particle aggregation.

  Sterile filtration can be difficult because the particle size of the composition needs to be small. Since a 0.2 micron filter is basically sufficient to remove all bacteria, filtration with a membrane filter pore size below about 0.2 microns (200 nm) is an effective method for sterilizing homogeneous solutions . Sterile filtration is usually not used to sterilize such nimesulide suspensions because micron-sized nimesulide particles are too large to pass through the membrane pores.

  Sterile nanoparticulate nimesulide formulations are particularly useful for treating immunocompromised patients, infants or juveniles, and the elderly. This is because these patient groups are most susceptible to infections caused by non-sterile liquid dosage forms.

  The nanoparticulate nimesulide composition of the present invention formulated in a liquid dosage form is suitable for parenteral administration because it can be sterile filtered and can have an effective average particle size of very small nimesulide.

J. Combined Pharmacokinetic Profile Composition In one embodiment of the invention, the first nimesulide formulation providing the pharmacokinetic profile described above is at least one other nimesulide formulation that produces a different pharmacokinetic profile, particularly a slower blood flow. _Are therefore co-administered with formulations that exhibit longer T _max and typically lower C _max . For example, the second nimesulide formulation may have a conventional particle size that results in a longer T _max and typically a lower C _max . Alternatively, the second, third, or fourth nimesulide formulations can have different effective average particle sizes for each composition than the first and can differ from each other. The difference in particle size results in different T _max values. The combination of rapid analgesia provided by the first formulation and long-lasting analgesia provided by the second (or third, fourth, etc.) formulation may reduce the required dosing frequency.

  Where the second nimesulide composition has a nanoparticle size, the nimesulide particles of the second composition preferably have at least one surface stabilizer associated with the surface of the drug particles. The one or more surface stabilizers may be the same as or different from the surface stabilizer present in the first nimesulide composition.

  Preferably, where co-administration of a “fast acting” formulation and a “long lasting” formulation is desired, the two formulations are mixed within a single composition, eg, a dual release composition.

K. Combination Active Agent Compositions The present invention includes nanoparticulate nimesulide compositions of the present invention formulated or co-administered with one or more non-nimesulide active agents. A method of using such a combination composition is also encompassed by the present invention. The non-nimesulide active agent can be present in a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase, or a mixture thereof.

  The compound administered in combination with the nanoparticulate nimesulide composition of the invention can be formulated separately from the nanoparticulate nimesulide composition or can be coformulated with the nanoparticulate nimesulide composition. When the nanoparticulate nimesulide composition is co-formulated with a second active agent, the second active agent is formulated in any suitable manner, such as immediate release, rapid onset, sustained release, or dual release. Can be done.

  Such non-nimesulide active agents can be, for example, therapeutic agents. The therapeutic agent can be a pharmaceutical agent that includes diagnostic agents such as biological agents such as proteins, peptides, and nucleotides, or contrast agents including x-ray contrast agents. Active agents include, for example, amino acids, proteins, peptides, nucleotides, anti-obesity drugs, central nervous system stimulants, carotenoids, corticosteroids, elastase inhibitors, antifungal agents, cancer therapy, antiemetics, analgesics, cardiovascular action Drugs (cardiovascular agents), anti-inflammatory agents, NSAID and COX-2 inhibitors, anthelmintics, antiarrhythmic agents, antibiotics (including penicillin), anticoagulants, antidepressants, antidiabetics, antiepileptics , Antihistamine, antihypertensive, antimuscarinic, antimycobacterial, antineoplastic, immunosuppressive, antithyroid, antiviral, anxiolytic, sedative (sleeping and neuroleptic), astringent , Α-adrenergic receptor blockers, β-adrenergic receptor blockers, blood products and blood substitutes, cardiotonic agents, contrast agents, corticosteroids, antitussives (descending and mucolytic agents), diagnostic agents, diagnostic imaging Agents, diuretics, dopaminergic agents (anti-parkinsonian agents), hemostatic agents, immune agents, lipid regulators, muscle relaxants, parasympathomimetic agents, parathyroid calcitonin and biphosphonates, prostaglandins, radiopharmaceuticals, Various known types of drugs, including sex hormones (including steroids), antiallergic agents, stimulants and appetite suppressants, sympathomimetics, thyroid agents, vasodilators, vasomodulators, and xanthines Can be selected.

  Examples of representative active agents useful in the present invention include acyclovir, alprazolam, altretamine, amiloride, amiodarone, benztropine, mesylate, bupropion, cabergoline, candesartan, cerivastatin, chlorpromazine, ciprofl Loxacin, cisapride, clarithromycin, clonidine, clopidogrel, cyclobenzaprine, cyproheptadine, delavirdine, desmopressin, diltiazem, dipyridamole, dolasetron, enalapril maleate, enalapril, famotidine, felodipine, furazolidone, lipizide g , Irbesartan, ketoconazole, lansoprazole, loratadine, loxapine, mebe Dasol, mercaptopurine, milrinone lactate, minocycline, mitoxantrone, nelfinavir mesylate, nimodipine, norfloxacin, olanzapine, omeprazole, penciclovir, pimozide, tacolimus, quazepam, raloxifene, rifabutin, rifabutin, rifabutin, rifabutin , Rizatriptan, saquinavir, sertraline, sildenafil, acetylsulfisoxazole, temazepam, thiabendazole, thioguanine, trandolapril, triamterene, trimethrexate, troglitazone, trovafloxacin, verapamil Vinblastine sulfate, mycophenolate, atovaquone, atovaquone, proguanil, ceftazidi , Cefuroxime, etoposide, terbinafine, thalidomide, fluconazole, amsacrine, dacarbazine, teniposide, and including acetyl salicylate, and the like.

A description of these classes of active agents and a listing of the species within each class can be found in Martindale's The Extra Pharmacopoeia, 31 ^st Edition (The Pharmaceutical Press, London, 1996), specifically incorporated by reference. Active agents are commercially available and / or can be prepared by techniques known in the art.

  Typical dietary supplements or dietary supplements include lutein, folic acid, fatty acids (eg, DHA and ARA), fruit and vegetable extracts, vitamin and mineral supplements, phosphatidylserine, lipoic acid, melatonin, glucosamine / chondroitin , Aloe, guggul, glutamine, amino acids (eg, arginine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine), green tea, lycopene, natural foods, food additives, medicinal herbs, Includes, but is not limited to, phytonutrients, antioxidants, fruit flavonoid components, evening primrose oil, flaxseed, fish and marine oils, and probiotics. Nutritional supplements and dietary supplements also include bio-engineered foods, also known as “pharmafoods”, that have been genetically engineered to have the desired properties.

  Typical nutritional supplements and dietary supplements are disclosed, for example, in Roberts et al., Nutraceuticals: The Complete Encyclopedia of Supplements, Herbs, Vitamins, and Healing Foods (American Nutraceutical Association, 2001), which is specifically by reference. Be incorporated. Nutritional supplements and supplements are also disclosed in Physician's Desk Reference for Nutritional Supplements, 1st Ed. (2001) and The Physicians' Desk Reference for Herbal Medicines, 1st Ed. (2001), both of which are incorporated by reference It is done. Nutritional supplements or dietary supplements, also known as phytochemicals or functional foods, generally are either dietary supplements, vitamins, minerals, herbs, or a class of healing foods that have a medical or pharmaceutical effect on the body. It is.

Preferred combination therapies include aceclofenac, acemethacin, e-acetamidocaproic acid, acetaminophen, acetaminosalol, acetanilide, acetylsalicylic acid (aspirin), S-adenosylmethionine, alclofenac, alfentanil ( alfentanil), allylprozin, aluminoprofen, aloxipurine, alphaprozin, bis (acetylsalicylic acid) aluminum, ampenac, aminochlorthenoxazin, 3-amino-4-hydroxybutyric acid, 2-amino-4 -Picoline, aminopropyrone, aminopyrine, amixetrine, ammonium salicylate, ampiroxicam, amtolmetin guacil, anilellidine, antipyrine, salicy Antipyrine acid, antrafenine, apazone, bendazac, benorylate, benoxaprofen, benzpiperylon, benzidamine, benzylmorphine, bermoprofen, vegetramide ( bezitramide), α-bisabolol, bromfenac, p-bromoacetanilide, 5-bromosalicylate acetate, bromosaligenin, bucetin, bucloxic acid, bucolome, bufexamac ), Bumadizon, buprenorphine, butacetin, butibufen, butophanol, calcium acetylsalicylate, carbamazepine, carbiphene, carprofen, carsa Ram (carsalam), chlorobutanol, chlorthenoxazin, choline salicylate, cinchofene, cinmetacin, ciramadol, clidanac, clometacin, clonitazene, clonixin, Clopirac, clove, codeine, codeine methyl bromide, codeine phosphate, codeine sulfate, cropropamide, crotethamide, desomorphine, dextran Dexoxadrol, dextromoramide, dezocine, diampromide, diclofenac sodium, difenamizole, difenpiramide, diflunisal, dihydroco Diyne, dihydrocodeinone enol acetate, dihydromorphine, dihydroxyaluminum acetylsalicylate, dimenoxadol, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipiphanone, diprocetyl (Diprocetyl), dipyrone, ditazol, droxicam, emorfazone, enfenamic acid, epilysole, eptazocine, etersalate, etenzazide, etoheptazine, ethoxazene, ethyl Methylmethylthiambutene, ethylmorphine, etodolac, etofenamate, etonitazene, eugenol, fe Binac (felbinac), fenbufen, fenclozic acid, fendosal, fenoprofen, fentanyl, fenthiazaku, fepradinol (fepradinol), feprazone, fructophenine, flufenamic acid, flunoxaprofen, Fluoresone, flupirtine, fluproquazone, flurbiprofen, fosfosal, gentisic acid, grafenine, glucametacin, salicylic acid glycol, guaiazulene, hydrocodone, hydromorphone, hydroxypethidine hydroxypethidine), ibufenac, ibuprofen, ibuproxam, imidazolic salicylate, indomethacin, indoprofen, Sofezolac, isoladol, isomethadone, isonixin, isoxepac, isoxicam, ketobemidone, ketoprofen, ketorolac, p-lactophenetide, lefetamine, lefetamine, lefetamine Fentanyl, lonazolac, lomoxicam, loxoprofen, lysine acetylsalicylate, magnesium acetylsalicylate, meclofenamic acid, mefenamic acid, meperidine, meptazinol, mesalamine, metazocine (metazocine) Methadone hydrochloride, methotrimeprazine, methiazine acid, metofolin, methopone, mofebutazone, mofezolac, morazon (m orazone), morphine, morphine hydrochloride, morphine sulfate, morpholine salicylate, myrophine, nabumetone, nalbuphine, 1-naphthyl salicylate, naproxen, narcein, nefopam, nicomorphine, nifenazone, niflumic acid, nimes '-Nitro-2'-propoxyacetanilide, norlevorphanol, normethadone, normorphine, norpipanone, olsalazine, opium, oxaceprol, oxametacine, oxaprozin, oxycodone, oxymorphone, oxyphenbuta Zon, papaveretam, paranyline, parsalmide, pentazocine, perisoxal, phenacetin, phenadoxone, phenazosin, phenazopyridine hydrochloride Phenocoll, phenoperidine, phenopyrazone, phenyl acetylsalicylate, phenylbutazone, phenyl salicylate, phenylamidol, piketoprofen, pimidine, pipebuzone, piperylone, piperfen , Pyrazolac, pyritramide, piroxicam, pranoprofen, proglumetacin, proheptazine, promedol, propacetamol, propiram, propoxifen, propifenazone (Propyphenazone), proquazone, protidic acid, ramifenazone, remifentanil, rimazolium metilsulfate , Salacecetamide, salicin, salicylamide, salicylamide o-acetic acid, salicyl sulfate, salsalte, salverine, cimetrid, sodium salicylate, sufentanil, sulfasalazine, sulindac, superoxide dismutase, suprofen, suxibzon suxibuzone, talniflumate, tenidap, tenoxicam, terofenamate, tetrandrine, thiazolinobutazone, thiaprofenic acid, tiaramide, tilidine , Tinolidine, tolfenamic acid, tolmetine, tramadol, tropesin, viminol, xenbucin, ximoprofen, zaltoprofen (zal) toprofen), and one or more compounds selected from Zomepirac, together with compositions useful in the methods of the invention. ^{The Merck Index, 12 th Edition (} 1996), Therapeutic Category and Biological Activity Index, "analgesic" in its "anti-inflammatory agent", and see a list of the heading "antipyretic".

  In a particularly preferred embodiment of the invention, the nanoparticulate nimesulide composition is used in combination with at least one analgesic. Useful analgesics include, for example, NSAIDs and non-nimesulide COX-2 inhibitors.

  Particularly preferred combination treatments include the use of opioid compounds, more specifically opioid compounds that are codeine, meperidine, morphine, or derivatives thereof, and the nanoparticulate nimesulide composition of the present invention.

  In an embodiment of the present invention, particularly when the condition mediated by COX-2 is headache or migraine, the nanoparticulate nimesulide composition is a vascular regulator, preferably a xanthine derivative having a vascular regulatory effect, more preferably an alkylxanthine compound. And in combination therapy.

Combination therapies in which the alkylxanthine compound is co-administered with the nanoparticulate nimesulide composition provided herein, whether or not the alkylxanthine is a vascular regulator, and to what extent is the therapeutic effectiveness of the combination It is encompassed by this aspect of the invention, whether or not due to a vascular regulatory effect. As used herein, the term “alkylxanthine” encompasses xanthine derivatives having one or more C _1-4 alkyl substituents, preferably methyl, and pharmaceutically acceptable salts of such xanthine derivatives. . Dimethylxanthine and trimethylxanthine, including caffeine, theobromine, and theophylline, are particularly preferred. Most preferably, the alkylxanthine compound is caffeine.

  Exemplary NSAIDs that can be formulated in combination with the nanoparticulate nimesulide compositions of the present invention include, but are not limited to, suitable non-acidic and acidic compounds. Suitable non-acidic compounds include, for example, nabumetone, tiaramid, proquazone, bufexamac, flumizole, epirazole, tinolidine, thymegadine, and dapsone.

  Exemplary acidic NSAID compounds that can be formulated in combination with the nanoparticulate nimesulide compositions of the present invention include, but are not limited to, carboxylic acids and enolic acids. Suitable carboxylic acid NSAIDs include, for example, (1) salicylic acid and its esters such as aspirin, diflunisal, benolylate, and phosphosar; (2) acetic acid including phenylacetic acid such as diclofenac, alclofenac, and fenclofenac; 3) Carbocyclic and heterocyclic acetic acids such as etodolac, indomethacin, sulindac, tolmetine, fentiazak, and tilomisole; (4) carprofen, fenbufen, flurbiprofen, ketoprofen, oxaprozin, suprofen, thiaprofenic acid, Propionic acids such as ibuprofen, naproxen, fenoprofen, indoprofen, pyrprofen; and (5) phenas such as flufenam, mefenam, meclofenam, and niflume. Including the acid. Suitable enolic acid NSAIDs that can be formulated in combination with the nanoparticulate nimesulide compositions of the present invention include (1) pyrazolones such as oxyphenbutazone, phenylbutazone, apazone, and feprazone; and (2) piroxicam, sudoxicam ( sudoxicam), isoxicam, and oxicam such as tenoxicam, but are not limited thereto.

  Exemplary COX-2 inhibitors that can be formulated in combination with the nanoparticulate nimesulide compositions of the present invention include celecoxib (SC-58635, CELEBREX®, Pharmacia / Searle & Co.), rofecoxib (MK-966). , L-748731, VIOXX®, Merck & Co.), meloxicam (MOBIC®, Abbott Laboratories, co-marketed by Chicago, Illinois, and Boehringer Ingelheim Pharmaceuticals), valdecoxib (BEXTRA®) ), GD Searle & Co.), parecoxib (GD Searle & Co.), etoricoxib (MK-663; Merck), SC-236 (4- [5- (4-chlorophenyl) -3- Chemical name of (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide; GD Searle & Co., Skokie, IL); NS-398 (N- (2-cyclohexyloxy-4-nitrophenyl) Methanesulfonamide; Taisho Pharm aceutical Co., Ltd., Japan); SC-58125 (methylsulfone spiro (2.4) hept-5-ene I; Pharmacia / Searle &Co.); SC-57666 (Pharmacia / Searle &Co.); SC-558 (Pharmacia / Searle &Co.); SC-560 (Pharmacia / Searle &Co.); Etodolac (Lodine®, Wyeth-Ayerst Laboratories, Inc.); DFU (5,5-dimethyl-3- (3 -Fluorophenyl) -4- (4-methylsulfonyl) phenyl 2 (5H) -furanone); monteleukast (MK-476), L-745337 (5- (methanesulfonamide-6- (2, 4-difluorothio-phenyl) -1-indanone), L-761066, L-761000, L-748780 (all Merck &Co.); DUP-697 (5-bromo-2- (4-fluorophenyl) -3 -(4- (methylsulfonyl) phenyl; DuPont Merck Pharmaceutical Co.); PGV 20229 (1- (7-tert.-butyl-2,3-dihydro-3,3-dimethylbenzo (b) furan-5-yl ) -4-Cyclopropylbutan-1-one; Procter & Gamble Pharmaceuticals); iguratimod (T-614; 3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one; Toyama Corp., Japan); BF 389 (Biofor, United States); CL 1004 (PD 136095); PD 136005, PD 142893, PD 138387, and PD 145065 (all Parke-Davis / Warner-Lambert Co.); flurbiprofen (ANSAID®; Pharmacia & Upjohn) Nabumetone (FELAFEN®; SmithKline Beecham, plc); flosulide (CGP 28238; Novartis / Ciba Geigy); piroxicam (FELDANE®; Pfizer); diclofenac (VOLTAREN® and CATAFLAM) Registered trademark), Novartis); lumiracoxib (COX-189; Novartis); D 1367 (Celltech Chiroscience, plc); R 807 (3 benzoyldifluoromethanesulfonanilide, diflumidone); JTE-522 (Japan Tobacco) FK-3311 (4'-acetyl-2 '-(2,4-difluorophenoxy) methanesulfonanilide), FK 867, FR 140423, and FR 115068 (all Fujisawa, Japan), GR 253035 (Glaxo Wellcome) ); RWJ 63556 (Johnson &Johnson); RWJ 20485 (Johnson &Johnson); ZK 38997 (Schering); S 2474 ((E)-(5)-(3,5-di-tert-butyl-4-hydroxybenzylidene) ) -2-ethyl-1,2-isothiazolidine-1,1-dioxide indomethacin; Shionogi & Co., Ltd., Japan); Zomepirac analogs such as RS 57067 and RS 104897 (Hoffmann La Roche); RS 104894 (Hoffmann La Roche); SC 41930 (Monsanto); pranlukast (SB 205312, Ono-1078, ONON®, ULTAIR®; SmithKline Beecham); SB 209670 (SmithKline Beecham); Including, but not limited to APHS (Heptynyl sulfide).

L. Widespread advantages of the nanoparticulate nimesulide composition of the present invention The nanoparticulate nimesulide composition preferably exhibits an increased dissolution rate compared to the microcrystalline or non-nanoparticulate form of nimesulide. Also, the nanoparticulate nimesulide composition preferably exhibits improved performance characteristics for oral, intravenous, subcutaneous, or intramuscular injection, such as higher dose loading and smaller tablet or liquid dose volumes. Furthermore, the nanoparticulate nimesulide composition of the present invention does not require organic solvents or extreme pH.

V. Compositions The present invention includes nanoparticulate active agent compositions comprising nimesulide. The composition preferably comprises nimesulide and at least one surface stabilizer adsorbed or attached to the surface of nimesulide. The nanoparticulate nimesulide particles preferably have an effective average particle size of less than about 2000 nm. In other aspects, the present invention provides novel combinations of nimesulide and other active agents.

  The present invention also provides nanoparticulate nimesulide compositions with one or more non-toxic physiologically acceptable carriers, adjuvants, or vehicles, collectively referred to as carriers. The composition can be oral, vaginal, rectal, nasal, ocular, parenteral injection (eg, intravenous, intramuscular, or subcutaneous), topical (eg, powder, ointment or infusion form), buccal, intracapsular, abdominal cavity It can be formulated for various routes of administration including, but not limited to, internal or local administration and the like.

を有する、N-（4-ニトロ-2-フェノキシ-フェニル）-メタンスルホンアミド、またはその類似体もしくは塩を意味する。ニメスリドは、結晶相、不定形相、半結晶相、半不定形相、またはその混合物であり得る。 A. Nimesulide Particles As used herein, “nimesulide” refers to the following structure:

Means N- (4-nitro-2-phenoxy-phenyl) -methanesulfonamide, or an analog or salt thereof. Nimesulide can be a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase, or a mixture thereof.

  Nanoparticulate nimesulide compositions are used to treat and / or prevent a wide range of conditions and disorders mediated by COX-2, including but not limited to disorders characterized by inflammation, pain, and / or heat. It is intended to be useful. Such compositions have the added benefit of significantly fewer harmful side effects than conventional NSAID compositions that lack selectivity for COX-2 over COX-1, such as for the treatment of arthritis. It is particularly useful as an inflammatory agent. In particular, such compositions have lower gastrointestinal toxicity and the possibility of gastrointestinal irritation including ulceration and bleeding of the upper gastrointestinal tract compared to conventional NSAID compositions, resulting in renal function leading to fluid retention and hypertension Renal side effects, such as a decrease in blood pressure, are less likely, have less effect on bleeding time, including inhibition of platelet function, and are probably less capable of inducing asthma attacks in aspirin-sensitive asthmatic subjects.

  Thus, patients with a history of recurrent NSAIDs such as peptic ulcer, gastritis, localized enteritis, ulcerative colitis, diverticulitis, or gastrointestinal lesions; gastrointestinal bleeding; hypoprothrombinemia, hemophilia, or others Coagulation disorders including anemia, such as bleeding problems; kidney disease; or if contraindicated in patients prior to surgery or taking anticoagulants, the nanoparticulate nimesulide composition of the present invention is an alternative to conventional NSAIDs It is particularly useful.

  Because of the rapid onset of therapeutic effects observed with the compositions of the present invention, these compositions treat acute COX-2 mediated disorders, particularly headaches including sinus headaches and migraines It has particular advantages over conventional formulations for reducing pain.

  Nimesulide can be used, for example, for joint disorders, gastrointestinal conditions, inflammatory conditions, lung inflammation, opthalmic disease, central nervous system disorders, pain, inflammation-related cardiovascular disorders, angiogenesis-related disorders, benign and malignant Tumor, adenomatous polyp, endometriosis, osteoporosis, dysmenorrhea, female reproductive system disorders such as preterm birth, asthma, eosinophil related disorders, fever, bone resorption, nephrotoxicity, hypotension, joints Disease, joint stiffness, kidney disease, liver disease including hepatitis, acute mastitis, diarrhea, colon adenoma, bronchitis, allergic neuritis, cytomegalovirus infection, apoptosis including HIV-induced apoptosis, low back pain, psoriasis, eczema, Skin-related conditions such as acne, burns, dermatitis, and UV damage including sunburn; treat and / or treat allergic rhinitis, respiratory distress syndrome, and endotoxic shock syndrome Is also useful for prevention. Nanoparticulate nimesulide is also useful as an immunosuppressant.

  Typical types of joint disorders that can be treated are osteoarthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, juvenile arthritis, gout, ankylosing spondylitis, systemic lupus erythematosus, bursitis, tendon Including, but not limited to, inflammation, fascial pain, carpal tunnel syndrome, fibromyalgia syndrome, infectious arthritis, psoriatic arthritis, Reiter's syndrome, and scleroderma.

  Typical gastrointestinal conditions or ulcer diseases that can be treated include inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, gastric ulcers, hemangiomas including infantile hemangioma, and other pathological but non-malignant Conditions include, but are not limited to, nasopharyngeal angiofibromas, and ischemic necrosis of bone.

  Typical inflammatory conditions that can be treated include migraine, nodular periarteritis, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, myasthenia gravis Joint disease, white matter disease including multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, nephritis, hypersensitivity, swelling after injury including brain edema, myocardial ischemia, cataract surgery or Including, but not limited to, postoperative inflammation including ophthalmic surgery such as refractive surgery.

  Exemplary pulmonary inflammatory conditions that can be treated include, but are not limited to, inflammation associated with viral infection and cystic fibrosis, and inflammation of bone resorption such as that associated with osteoporosis.

  Typical ocular diseases or conditions that can be treated include retinitis, conjunctivitis, retinopathy, uveitis, eye phobia, acute damage to ocular tissue, corneal transplant rejection, ocular neovascularization, damage or infection Retinal neovascularization, including later neovascularization, including but not limited to diabetic retinopathy, muscle degeneration, post-lens fibroproliferation, glaucoma and neovascular glaucoma.

  Typical central nervous system disorders that can be treated include, but are not limited to, cortical dementias including Alzheimer's disease, neurodegeneration, and central nervous system damage resulting from stroke, ischemia, and trauma. The term “treatment” in this context refers to partial or complete dementia, including Alzheimer's disease, vascular dementia, multiple cerebral infarction dementia, presenile dementia, alcoholic dementia, and senile dementia. Inhibition

  Typical pain conditions that can be treated include postoperative pain, pain due to battlefield wounds, toothache, myalgia, pain due to cancer, headache including sinus headache and migraine, menstrual pain, and inflammation Including but not limited to pain associated with.

  Exemplary inflammation-related cardiovascular disorders that can be treated or prevented using the compositions of the present invention include vascular disease, coronary artery disease, aneurysm, vascular rejection, arteriosclerosis, heart transplant atherosclerosis Atherosclerosis, myocardial infarction, embolism, stroke, thrombosis including thrombophlebitis, angina including unstable angina, coronary plaque inflammation, bacterial-induced inflammation including chlamydia-induced inflammation, virus-induced Inflammation and surgical procedures such as vascular grafts, including coronary artery bypass surgery, revascularization including vasculature, stenting, endarterectomy, or other invasive procedures involving arteries, veins, and capillaries Including but not limited to associated inflammation.

  Exemplary angiogenesis-related disorders for which the compositions of the invention are useful include, but are not limited to, inhibition of tumor angiogenesis. Such compositions include neoplasia, including metastasis, benign and malignant tumors, and neoplasia from epithelial cells such as colorectal cancer, brain tumor, osteosarcoma, basal cell carcinoma (epithelial cancer), glandular Cancer, gastrointestinal cancer such as lip cancer, oral cancer, esophageal cancer, small intestine cancer, gastric cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, squamous cell and basal cell cancer It is also useful for treating neoplasia, including cancers such as skin cancer, testicular cancer, renal cell cancer, and other known cancers that affect systemic epithelial cells. Neoplastic formations for which the compositions of the invention are intended to be particularly useful are gastrointestinal cancer, Barrett's esophagus, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, testicular cancer, cervical cancer, lung cancer, breast cancer and skin cancer . The nanoparticulate nimesulide composition of the present invention can also be used to treat fibrosis caused by radiation therapy.

  The compositions of the invention can be used to treat subjects with adenomatous polyps, including subjects with familial adenomatous polyposis (FAP). Further, such compositions can be used to prevent polyp formation in patients at risk for FAP.

  The nimesulide composition of the present invention inhibits prostanoid-induced smooth muscle contraction by inhibiting the synthesis of contractile prostanoids, thus treating dysmenorrhea, premature birth, asthma and eosinophil related disorders Can be used.

  The composition of the present invention has indications that anti-inflammatory agents, anti-angiogenic agents, anti-tumor agents, immunosuppressive agents, NSAIDs, COX-2 inhibitors, analgesics, antithrombotic agents, anesthesia, or antipyretic agents are commonly used. It is also useful when treating.

B. Surface Stabilizers Particularly useful surface stabilizers herein are physically attached to or associated with the surface of the nanoparticulate nimesulide particles, but do not chemically react with the nimesulide particles or themselves. It is preferred that the individual molecules of the surface stabilizer are basically not intermolecularly crosslinked.

  A combination of more than one surface stabilizer can be used in the present invention. Useful surface stabilizers include, but are not limited to, known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products, and surfactants. Preferred surface stabilizers include nonionic, ionic, anionic, cationic, and zwitterionic surfactants.

Representative examples of surface stabilizers are hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, sodium lauryl sulfate, dioctylsulfosuccinate, gelatin, casein, lecithin (phosphatide), dextran, gum arabic, cholesterol, tragacanth, stearic acid, Benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (eg, macrogol esters such as cetomacrogol 1000), Polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (eg, Tween 20® and Tween 80 (registered) Standard) (commercially available Tween®) such as ICI Specialty Chemicals), polyethylene glycol (eg Carbowax 3550® and 934® (Union Carbide)) polyoxyethylene stearate, colloidal silicon dioxide , Phosphate, carboxymethylcellulose calcium, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose phthalate, amorphous cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), 4- (1,1,3,3-tetramethylbutyl) -phenolic polymer of ethylene oxide and formaldehyde (also known as tyloxapol, superione, and triton), poloxa -(Eg Pluronic F68® and F108®, which are block copolymers of ethylene oxide and propylene oxide); Poloxamine (eg Tetronic 908®, also known as Poloxamine 908®) This is a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Wyandotte Corporation, Parsippany, NJ); Tetronic 1508® (T-1508) (BASF Wyandotte Corporation) ), An alkylaryl polyether sulfonate (Dow Chemical) Triton X-200®; a mixture of sucrose stearate and sucrose distearate, Crodestas F-110® (Croda Inc.); Olin- lOG (R) or Surfactant 10-G (R) (Olin P-isononylphenoxypoly- (glycidol), also known as Chemicals, Stamford, Connecticut); Crodetas SL-40® (Croda, Inc.); and C ₁₈ H ₃₇ CH ₂ C (O) N SA9OHCO (Eastman Kodak Co.) which is (CH ₃ ) —CH ₂ (CHOH) ₄ (CH ₂ OH) ₂ ; decanoyl-N-methylglucamide; n-decyl β-D-glucopyranoside; n-decyl β-D N-dodecyl β-D-glucopyranoside; n-dodecyl β-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-β-D-glucopyranoside; n-heptyl β-D-thioglucoside; n -Hexyl β-D-glucopyranoside; nonanoyl-N-methylglucamide; n-noyl β-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-β-D-glucopyranoside; octyl β-D-thioglucopyranoside Phospholipids derivatized with PEG, derivatized with PEG Cholesterol, cholesterol derivatives derivatized with PEG, vitamin A derivatized with PEG, vitamin E derivatized with PEG, lysozyme, random copolymer of vinylpyrrolidone and vinyl acetate, pyrrolidone and vinyl acetate in a 60:40 ratio Including Plasdone® S630.

  Additional examples of useful surface stabilizers include non-polymeric compounds such as polymers, biopolymers, polysaccharides, cellulosic materials, alginate, phospholipids, and zwitterionic stabilizers, poly-n-methylpyridinium, anthryl chloride ) Pyridinium, cationic phospholipid, chitosan, polylysine, polyvinyl imidazole, polybrene, polymethyl methacrylate, trimethylammonium bromide bromide (PMMTMABr), hexadecyltrimethylammonium bromide (HDMAB), and polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate Including but not limited to dimethyl sulfate.

Other useful cationic stabilizers include cationic lipids, sulfonium, phosphonium, and quaternary ammonium compounds such as stearyltrimethylammonium chloride, benzyl-di (2-chloroethyl) ethylammonium bromide, coconut trimethylammonium chloride. Or bromide, coconut methyldihydroxyethylammonium chloride or bromide, decyltriethylammonium chloride, decyldimethylhydroxyethylammonium chloride or bromide, C _12-15 dimethylhydroxyethylammonium chloride or bromide, coconut dimethylhydroxyethylammonium chloride or bromide, myristyl Trimethyl ammonium methyl sulfate, lauryl dimethyl benzyl ammonium Nium chloride or bromide, lauryl dimethyl (ethenoxy) ₄ ammonium chloride or bromide, N-alkyl (C _12-18 ) dimethylbenzyl ammonium chloride, N-alkyl (C _14-18 ) dimethyl-benzyl ammonium chloride, N-tetradecylide Methylbenzylammonium chloride monohydrate, dimethyldidecylammonium chloride, N-alkyl and (C _12-14 ) dimethyl 1-naphthylmethylammonium chloride, trimethylammonium halide, alkyl-trimethylammonium and dialkyl-dimethylammonium salts, lauryl Trimethylammonium chloride, ethoxylated alkyl (alky) amidoalkyldialkylammonium salt and / or ethoxylated trialkylammonium salt, dialkylbenzene di Le Kill ammonium chloride, N- didecyl dimethyl ammonium chloride, N- tetradecyl dimethyl benzyl ammonium chloride monohydrate, N- alkyl (C _12-14) dimethyl 1-naphthylmethyl ammonium chloride and dodecyl dimethyl benzyl ammonium chloride, dialkyl benzenes alkyl ammonium chloride, lauryl trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium _{bromide, C 12, C 15, C} 17 trimethyl ammonium bromide, dodecyl benzyl triethyl ammonium chloride, poly - diallyldimethylammonium chloride (DADMAC), dimethyl Ammonium chloride, alkyldimethylammonium halide, tricetylmethylammonium chloride Lido, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyltrioctylammonium chloride (ALIQUAT 336 ™), POLYQUAT 10 ™, tetrabutylammonium bromide, benzyltrimethylammonium bromide, choline ester ( Fatty acid choline esters), benzalkonium chloride, stearalkonium chloride compounds (such as stearyltrimonium chloride and Di-stearyldimonium chloride), cetylpyridinium bromide or chloride, quaternized polyoxyethylalkylamines Halide salts, MIRAPOL ™ and ALKAQUAT ™ (Alkaril Chemical Company), alkylpyridinium salts; alkylamines, dia Amines such as kill amines, alkanolamines, polyethylene polyamines, N, N-dialkylaminoalkyl acrylates, and vinylpyridines, amine salts such as laurylamine acetate, stearylamine acetate, alkylpyridinium salts, and alkylimidazolium salts, and amine oxides; Imidoazolinium salts; protonated quaternary acrylamides; methylated quaternary polymers such as poly [diallyldimethylammonium chloride] and poly- [N-methylvinylpyridinium chloride]; and cationic guar Including, but not limited to.

  Such typical cationic surface stabilizers and other useful cationic surface stabilizers are described by J. Cross and E. Singer, Cationic Surfactants: Analytical and Biological Evaluation (Marcel Dekker, 1994); P. and D. Rubingh (Editor), Cationic Surfactants: Physical Chemistry (Marcel Dekker, 1991); and J. Richmond, Cationic Surfactants: Organic Chemistry, (Marcel Dekker, 1990).

Non-polymerizable surface stabilizers include benzalkonium chloride, carbonium compounds, phosphonium compounds, oxonium compounds, halonium compounds, cationic organometallic compounds, quaternary phosphorus compounds, pyridinium compounds, anilinium compounds, ammonium compounds, Includes non-polymerizable compounds such as hydroxyammonium compounds, primary ammonium compounds, secondary ammonium compounds, tertiary ammonium compounds, and quaternary ammonium compounds of the formula NR ₁ R ₂ R ₃ R ₄ ⁽⁺⁾ . For compounds of formula NR ₁ R ₂ R ₃ R ₄ ⁽⁺⁾
(I) none of R _{1 to} R ₄ is CH ₃ ;
(Ii) one of R _{1 to} R ₄ is CH ₃ ;
(Iii) three of R _{1 to} R ₄ are CH ₃ ;
(Iv) R _{1 to} R ₄ are all CH ₃ ;
(V) Two of R _{1 to} R ₄ are CH ₃ , one of R _{1 to} R ₄ is C ₆ H ₅ CH ₂ , and one of R _{1 to} R ₄ is an alkyl chain having 7 or less carbon atoms. is there;
(Vi) Two of R _{1 to} R ₄ are CH ₃ , one of R _{1 to} R ₄ is C ₆ H ₅ CH ₂ , and one of R _{1 to} R ₄ is an alkyl chain having 19 or more carbon atoms. is there;
(Vii) two of R _{1 to} R ₄ are CH ₃ , one of R _{1 to} R ₄ is a C ₆ H ₅ (CH ₂ ) _n group, and n>1;
(Viii) two of R _{1 to} R ₄ are CH ₃ , one of R _{1 to} R ₄ is C ₆ H ₅ CH ₂ , and one of R _{1 to} R ₄ contains at least one heteroatom;
(Ix) two of R _{1 to} R ₄ are CH ₃ , one of R _{1 to} R ₄ is C ₆ H ₅ CH ₂ , and one of R _{1 to} R ₄ contains at least one halogen;
(X) two of R _{1 to} R ₄ are CH ₃ , one of R _{1 to} R ₄ is C ₆ H ₅ CH ₂ , and one of R _{1 to} R ₄ includes at least one cyclic fragment;
(Xi) two of R _{1 to} R ₄ are CH ₃ and one of R _{1 to} R ₄ is a phenyl ring; or (xii) two of R _{1 to} R ₄ are CH ₃ and R _{1 to} R 4 Two of the _four are purely aliphatic fragments.

  Such compounds include behenalkonium chloride, benzethonium chloride, cetylpyridinium chloride, behentrimonium chloride, lauralkonium chloride, cetalkonium chloride, cetrimonium bromide, cetrimonium chloride, cetylamine Hydrofluoride, Chloroallylmethenamine chloride (Quotanium-15), Distearyldimonium chloride (Quotanium-5), Dodecyldimethylethylbenzylammonium chloride (Quotanium-14), Quotanium-22, Quotanium-26, Quotanium-18hect Hectorite, dimethylaminoethyl chloride / hydrochloride, cysteine hydrochloride, diethanolammonium POE (10) olethyl ether phosphate, di Ethanolammonium POE (3) oleyl ether phosphate, tallow alkonium chloride, dimethyl dioctadecyl ammonium bentonite, stearalkonium chloride, domifene bromide, denatonium benzoate, myristalkonium chloride, laurtrimonium (laurtrimonium) ) Chloride, ethylenediamine dihydrochloride, guanidine hydrochloride, pyridoxine HCl, iofetamine hydrochloride, meglumine hydrochloride, methylbenzethonium chloride, myrtrimonium bromide, oleyltrimonium chloride, polyquaternium-1, procaine hydrochloride, Cocobetaine, stearalkonium bentonite, stearalkonium hectorite Stearalkoniumhectonite), stearyl trihydroxyethyl propylenediamine dihydro fluoride, tallow trimonium chloride, and including hexadecyl trimethyl ammonium bromide, and the like.

  Most of these surface stabilizers are known pharmaceutical excipients and are described in detail in the Handbook of Pharmaceutical Excipients (The Pharmaceutical Press, 2000), co-published by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain. Yes. These are specifically incorporated herein by reference.

  Particularly preferred surface stabilizers include, but are not limited to, copovidone such as Plasdone® S-630 (ISP) and Kollidon® VA 64 (BASF). These are random copolymers of vinylpyrrolidone and vinyl acetate in a 60:40 ratio, hydroxypropyl methylcellulose, or tyloxapol.

  Each of these surface stabilizers is commercially available and / or can be prepared by techniques known in the art.

C. Other Pharmaceutical Excipients The pharmaceutical composition of the present invention may comprise one or more binders, fillers, lubricants, suspending agents, sweeteners, depending on the desired route of administration and dosage form. Perfumes, preservatives, buffering agents, wetting agents, disintegrating agents, blowing agents, and other excipients may also be included. Such excipients are well known in the art.

  Examples of fillers are lactose monohydrate, anhydrous lactose, and various starches; examples of binders are various celluloses and cross-linked polyvinyl pyrrolidone, such as Avicel® PH101 and Avicel® PH102 Of microcrystalline cellulose, microcrystalline cellulose, and silicified microcrystalline cellulose (ProSolv SMCC ™).

  Suitable lubricants include agents that affect the fluidity of the powder to be compressed, and are colloidal silicon dioxide such as Aerosil® 200, talc, stearyl acid, magnesium stearate, calcium stearate, and silica gel. .

  Examples of sweeteners are any natural or artificial sweetener such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acsulfame. Examples of flavors are Magnasweet® (trademark of MAFCO), bubble gum flavor, and fruit flavors.

  Examples of preservatives are potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol, and chloride. Quaternary compounds such as benzalkonium.

  Suitable diluents include pharmaceutically acceptable inert fillers such as microcrystalline cellulose, lactose, dicalcium phosphate, saccharides, and / or mixtures of any of these. Examples of diluents are microcrystalline celluloses such as Avicel® PH101 and Avicel® PH102; lactose monohydrate, anhydrous lactose, and lactose such as Pharmatose® DCL21; Emcompress® Diphosphate calcium; mannitol; starch; sorbitol; sucrose; and glucose.

  Suitable disintegrants include slightly cross-linked polyvinyl pyrrolidone, corn starch, starch starch, corn starch, and modified starch, croscarmellose sodium, cro-povidone, sodium starch glycolate, and mixtures thereof Including.

  Examples of blowing agents are organic acids and firing couples such as carbonates or bicarbonates. Suitable organic acids include, for example, citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, and alginic acid and anhydrides and acid salts. Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate, and arginine carbonate. Alternatively, only a foamed couple of sodium bicarbonate element may be present.

D. Nanoparticulate Nimesulide Particle Size Compositions of the present invention comprise nimesulide nanoparticles having an effective average particle size of less than about 2000 nm (ie, 2 microns). In preferred embodiments of the invention, the nimesulide nanoparticles are less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, as measured by light scattering, microscopy, or other suitable methods. Less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, Effective average particle size of less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm, or less than about 50 nm Have

  “Effective average particle size of less than about 2000 nm” means that at least 50% of the nimesulide particles are less than the effective weight average as measured by the above technique, ie, about 2000 nm, about 1900 nm, about 1800 nm. It means having a particle size of less than. Preferably, at least about 70%, at least about 90%, at least about 95%, or at least about 99% of nimesulide particles are less than the effective average, ie less than about 2000 nm, about 1900 nm, about 1800 nm, etc. Has a diameter.

  In the present invention, the D50 value of the nanoparticulate nimesulide composition is a value indicating that 50% by weight of the nimesulide particles are smaller than this particle size. Similarly, D90 is a value indicating that 90% by weight of the nimesulide particles are smaller than this particle size.

  If the composition of the present invention also includes microparticulate nimesulide or non-nimesulide active agents, the particles of such compounds have an effective average particle size of greater than about 2 microns. This means that at least 50% of the particles have a diameter greater than about 2 microns. In other embodiments of the invention, at least about 70%, at least about 90%, at least about 95%, or at least about 99% of the particles of Nimesulide microparticles or non-Nimesulide microparticles are greater than about 2 microns. Has a diameter.

E. Concentrations of nanoparticulate nimesulide and surface stabilizer The relative amounts of at least one nimesulide and one or more surface stabilizers can vary widely. The optimal amount of individual components depends on, for example, the physical and chemical properties of the selected surface stabilizer, such as hydrophilic / lipophilic balance (HLB), melting point, and surface tension of the aqueous solution of the stabilizer. To do.

  Preferably, the concentration of nimesulide is from about 99.5% to about 0.001%, from about 95% to about 0.1%, based on the combined weight of nimesulide and at least one surface stabilizer without other excipients. It can vary up to wt%, or from about 90 wt% to about 0.5 wt%. Higher concentrations of the active ingredient are generally preferred from a dose and cost efficiency standpoint.

  Preferably, the concentration of surface stabilizer is from about 0.5% to about 99.999%, about 5.0% by weight, based on the total dry weight of nimesulide and at least one surface stabilizer without other excipients. To about 99.9% by weight, or from about 10% to about 99.5% by weight.

VI. Methods of Producing Nanoparticulate Nimesulide Compositions Nanoparticulate nimesulide compositions can be produced using any suitable method known in the art, such as, for example, grinding, homogenization, or sedimentation techniques. A typical method for producing nanoparticle compositions is described in the “684” patent. Methods for producing nanoparticle compositions include US Pat.No. 5,518,187 for `` Method of Grinding Pharmaceutical Substances '', US Pat.No. 5,718,388 for `` Continuous Method of Grinding Pharmaceutical Substances '', US for `` Method of Grinding Pharmaceutical Substances '' Patent No. 5,862,999, U.S. Pat.No. 5,665,331 on `` Co-Microprecipitation of Nanoparticulate Pharmaceutical Agents with Crystal Growth Modifiers '', U.S. Pat.No. 5,662,883 on `` Co-Microprecipitation of Nanoparticulate Pharmaceutical Agents with Crystal Growth Modifiers '', `` Microprecipitation of U.S. Patent No. 5,560,932 for `` Nanoparticulate Pharmaceutical Agents '', U.S. Pat.No. 5,543,133 for `` Process of Preparing X-Ray Contrast Compositions Containing Nanoparticles '', U.S. Patent No. 5,534,270 for `` Method of Preparing Stable Drug Nanoparticles '', `` Process of Preparing Therapeutic Compositio U.S. Pat. No. 5,510,118 for “Ns Containing Nanoparticles” and U.S. Pat. No. 5,470,583 for “Method of Preparing Nanoparticle Compositions Containing Charged Phospholipids to Reduce Aggregation”. All of these are specifically incorporated herein by reference.

  The resulting nanoparticulate nimesulide composition or dispersion can be a solid, semi-solid, or liquid dosage formulation such as a liquid dispersion, gel, aerosol, ointment, cream, controlled release formulation, fast melting formulation, lyophilized formulation, It can be used in tablets, capsules, delayed release preparations, sustained release preparations, pulse release preparations, immediate release / controlled release mixed preparations, and the like. A solid dosage form of the novel nimesulide formulation dispersion of the present invention can be prepared as described in US Pat. No. 6,375,986.

A. Grinding to obtain a nanoparticulate nimesulide dispersion The grinding of nimesulide to obtain a nanoparticulate nimesulide dispersion is a process of dispersing nimesulide particles in a liquid dispersion medium in which nimesulide is sparingly soluble, followed by the presence of the grinding medium. Applying mechanical means below to reduce the particle size of nimesulide to the desired effective average particle size. The dispersion medium can be, for example, water, safflower oil, ethanol, t-butanol, glycerin, polyethylene glycol (PEG), hexane, or glycol. Water is a preferred dispersion medium.

  Nimesulide particles can be reduced in size, preferably in the presence of at least one surface stabilizer. Alternatively, the nimesulide particles can contact one or more surface stabilizers after abrasion. Other compounds, such as a diluent, can be added to the nimesulide / surface stabilizer composition during the particle size reduction process. Dispersions can be made continuously or in a batch mode.

B. Sedimentation to obtain a nanoparticulate nimesulide composition Another method of shaping nanoparticulate nimesulide compositions is microprecipitation. It is sparingly soluble in the presence of any trace toxic solvent or one or more surface stabilizers free of solubilized heavy metal impurities and one or more surface active agents that enhance colloidal stability. Preparing a stable dispersion of the active agent. Such methods include, for example, (1) dissolving nimesulide in a suitable solvent; (2) adding the formulation obtained from step (1) to a solution containing at least one surface stabilizer; and (3) Precipitating the formulation obtained from step (2) using a suitable solvent-free. The method can subsequently remove any formed salt, if present, by dialysis or diafiltration and concentration of the dispersion by conventional means.

C. Homogenization to Obtain Nimesulide Nanoparticle Compositions A typical homogenization method for preparing active agent nanoparticle compositions is described in US Pat. No. 5,510,118 for “Process of Preparing Therapeutic Compositions Containing Nanoparticles”. ing. Such a method includes a step of dispersing nimesulide particles in a liquid dispersion medium in which nimesulide is hardly soluble, and subsequently subjecting the dispersion to homogenization to reduce the particle size of nimesulide to a desired effective average particle size. including. Nimesulide particles can be reduced in size in the presence of at least one surface stabilizer. Alternatively, the nimesulide particles can be contacted with one or more surface stabilizers either before or after abrasion. Other compounds, such as a diluent, can be added to the nimesulide / surface stabilizer composition either before, during, or after the particle size reduction process. Dispersions can be made continuously or in a batch mode.

VII. Method using the Nimesulide Formulation of the Present Invention The nimesulide composition of the present invention is preferably oral, vaginal, rectal, ophthalmic, parenteral (eg, intravenous, intramuscular, or subcutaneous), sac, lung, intravaginal, abdominal cavity. The subject can be administered to the subject via any conventional means including, but not limited to, internal, topical, topical (eg, powder, ointment, or infusion), or as a buccal or nasal spray. As used herein, the term “subject” is used to mean an animal, preferably a mammal, including a human or non-human. The terms patient and subject may be used interchangeably.

  The present invention provides a method of sustaining a subject's nimesulide plasma concentration while achieving a desired therapeutic effect.

  In one aspect, the compositions of the invention are administered to treat conditions characterized by pain, inflammation, or heat. Many such states are shown above.

  Compositions suitable for parenteral injection are for reconstitution into physiologically acceptable aqueous or non-aqueous sterile solutions, dispersions, suspensions or emulsions, and injectable sterile solutions or dispersions. Sterile powder may be included. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or media include water, ethanol, polyols (polypropylene glycol, polyethylene-glycol, glycerol, etc.), suitable mixtures thereof, vegetable oils (such as olive oil) and olein Contains injectable organic esters such as ethyl acid. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.

  Nanoparticulate nimesulide compositions can also include adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial growth can also be ensured by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid. It may also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of injectable pharmaceutical dosage forms can be brought about by the use of agents which delay absorption such as aluminum monostearate and gelatin.

  Solid dosage forms for oral administration are preferred and include, but are not limited to, capsules, tablets, pills, powders, caplets, and granules. In such solid dosage forms, the active agent (ie, the composition of the present invention) is mixed with at least one of the following: (A) one or more inert excipients (or carriers) such as sodium citrate or dicalcium phosphate; (b) fillers or bulking such as starch, lactose, sucrose, glucose, mannitol, and silicic acid. Agents; (c) binders such as carboxymethylcellulose, alignate, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (d) humectants such as glycerol; (e) agar, calcium carbonate, starch starch or tapioca starch, alginic acid , Certain complex silicates, and disintegrants such as sodium carbonate; (f) dissolution retardants such as paraffin; (g) absorption enhancers such as quaternary ammonium compounds; (h) cetyl alcohol and monostearic acid Humectants such as glycerol; (i) kaolin and bentonite What adsorbent; (j) talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or lubricants such as mixtures thereof. For capsules, tablets, and pills, the dosage forms may also contain buffering agents.

  Liquid dosage forms for oral administration include pharmaceutically acceptable dispersions, emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active agent, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers. Typical emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, cottonseed oil, peanut oil, corn germ oil, olive oil, castor Oils, and oils such as sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, fatty acid esters of sorbitan, or mixtures of these substances.

  In addition to such inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

  An effective amount of the nimesulide composition of the present invention can be determined experimentally. The composition can be used in a pure dosage form or, if such a dosage form is present, in a pharmaceutically acceptable salt, ester, or prodrug dosage form. The actual dose level of nimesulide in the nanoparticle compositions of the present invention can be varied to obtain an effective amount of nimesulide so as to obtain the desired therapeutic response for the particular composition, method of administration and condition being treated. . Thus, the selected dosage level will vary depending on the desired therapeutic effect, the route of administration, the efficacy of the administered nimesulide, the desired duration of treatment, and other factors.

  Dosage unit compositions may contain such sub-multiple amounts as may be used to make up the daily dose. However, it is understood that the specific dose level for any particular patient will depend on various factors. The type and degree of cellular or physiological response to be achieved; the activity of the specific agent or composition used; the specific agent or composition used; the age, weight, general health, gender of the patient And diet; administration time, route of administration, and drug excretion rate; duration of treatment; drugs used in combination with or simultaneously with specific agents; and similar factors well known in the medical field.

A. Therapeutic Applications Nanoparticulate nimesulide compositions treat and / or treat a wide range of conditions and disorders mediated by COX-2, including but not limited to disorders characterized by inflammation, pain, and / or heat. Useful for prevention. Such a composition is particularly useful as an anti-inflammatory agent, such as for the treatment of arthritis, and has the added benefit of significantly fewer adverse side effects than conventional NSAID compositions that lack selectivity for COX-2 over COX-1. There are advantages. Specifically, such compositions reduce gastrointestinal toxicity and gastrointestinal inflammation, including ulceration and bleeding of the upper gastrointestinal tract, and exacerbation of fluid retention and hypertension compared to conventional NSAID compositions Reduce the potential for side effects of the kidneys, such as reduced renal function, and have less effect on bleeding time, including inhibition of platelet function, and perhaps the ability of aspirin-sensitive asthmatic subjects to induce asthma attacks.

  Thus, NSAIDs such as those with a history of peptic ulcer, gastritis, localized enteritis, ulcerative colitis, diverticulitis, or gastrointestinal lesions; gastrointestinal bleeding; hypoprothrombinemia, hemophilia Or if it is contraindicated in patients prior to surgery or taking anticoagulants, the nanoparticulate nimesulide composition of the present invention is a conventional NSAID It is particularly useful as an alternative.

  Because of the rapid onset of therapeutic effects observed with the compositions of the present invention, these compositions treat acute COX-2 mediated disorders, particularly headaches including sinus headaches and migraines It has particular advantages over conventional formulations for reducing pain.

  Nimesulide can be used for example in joint disorders, gastrointestinal conditions, inflammatory conditions, lung inflammation, eye diseases, central nervous system disorders, pain, inflammation-related cardiovascular disorders, angiogenesis-related disorders, benign and malignant tumors, adenomas Sexual polyps, endometriosis, osteoporosis, dysmenorrhea, female reproductive system disorders such as premature birth, asthma, eosinophil related disorders, fever, bone resorption, nephrotoxicity, hypotension, arthropathy, joints Stiffness, kidney disease, liver disease including hepatitis, acute mastitis, diarrhea, colon adenoma, bronchitis, allergic neuritis, cytomegalovirus infection, apoptosis including HIV-induced apoptosis, low back pain, psoriasis, eczema, acne, burns Skin-related conditions such as UV damage, including dermatitis, and sunburn; treat and / or prevent allergic rhinitis, respiratory distress syndrome, and endotoxic shock syndrome Also useful. Nanoparticulate nimesulide is also useful as an immunosuppressant.

  Typical forms of joint disorders that can be treated are osteoarthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, juvenile arthritis, gout, ankylosing spondylitis, systemic lupus erythematosus, bursitis, tendon Including, but not limited to, inflammation, fascial pain, carpal tunnel syndrome, fibromyalgia syndrome, infectious arthritis, psoriatic arthritis, Reiter's syndrome, and scleroderma.

  Typical gastrointestinal conditions or ulcer diseases that can be treated include inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, gastric ulcers, hemangiomas including infantile hemangioma, and other pathological but non-malignant Conditions include, but are not limited to, nasopharyngeal angiofibromas, and ischemic necrosis of bone.

  Typical inflammatory conditions that can be treated include migraine, nodular periarteritis, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, myasthenia gravis Joint disease, white matter disease including multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, nephritis, hypersensitivity, swelling after injury including brain edema, myocardial ischemia, cataract surgery or Including, but not limited to, postoperative inflammation including ophthalmic surgery such as refractive surgery.

  Exemplary pulmonary inflammatory conditions that can be treated include, but are not limited to, inflammation associated with viral infection and cystic fibrosis, and inflammation of bone resorption such as that associated with osteoporosis.

  Typical ocular diseases or conditions that can be treated include retinitis, conjunctivitis, retinopathy, uveitis, eye phobia, acute damage to ocular tissue, corneal transplant rejection, ocular neovascularization, damage or infection Retinal neovascularization, including later neovascularization, including but not limited to diabetic retinopathy, muscle degeneration, post-lens fibroproliferation, glaucoma and neovascular glaucoma.

  Typical central nervous system disorders that can be treated include, but are not limited to, cortical dementias including Alzheimer's disease, neurodegeneration, and central nervous system damage resulting from stroke, ischemia, and trauma. The term “treatment” in this context refers to partial or complete dementia, including Alzheimer's disease, vascular dementia, multiple cerebral infarction dementia, presenile dementia, alcoholic dementia, and senile dementia. Inhibition

  Typical pain conditions that can be treated include postoperative pain, pain due to battlefield wounds, toothache, myalgia, pain due to cancer, headache including sinus headache and migraine, menstrual pain, and inflammation Including but not limited to pain associated with.

  Exemplary inflammation-related cardiovascular disorders that can be treated or prevented using the compositions of the present invention include vascular disease, coronary artery disease, aneurysm, vascular rejection, arteriosclerosis, heart transplant atherosclerosis Atherosclerosis, myocardial infarction, embolism, stroke, thrombosis including thrombophlebitis, angina including unstable angina, coronary plaque inflammation, bacterial-induced inflammation including chlamydia-induced inflammation, virus-induced Inflammation and surgical procedures such as vascular grafts, including coronary artery bypass surgery, revascularization including vasculature, stenting, endarterectomy, or other invasive procedures involving arteries, veins, and capillaries Including but not limited to associated inflammation.

  Exemplary angiogenesis-related disorders for which the compositions of the invention are useful include, but are not limited to, inhibition of tumor angiogenesis. Such compositions include neoplasia, including metastasis, benign and malignant tumors, and neoplasia from epithelial cells such as colorectal cancer, brain tumor, osteosarcoma, basal cell carcinoma (epithelial cancer), glandular Cancer, gastrointestinal cancer such as lip cancer, oral cancer, esophageal cancer, small intestine cancer, gastric cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, squamous cell and basal cell cancer It is also useful for treating neoplasia, including cancers such as skin cancer, testicular cancer, renal cell cancer, and other known cancers that affect systemic epithelial cells. Neoplastic formations for which the compositions of the invention are intended to be particularly useful are gastrointestinal cancer, Barrett's esophagus, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, testicular cancer, cervical cancer, lung cancer, breast cancer and skin cancer . The nanoparticulate nimesulide composition of the present invention can also be used to treat fibrosis caused by radiation therapy.

  The compositions of the invention can be used to treat subjects with adenomatous polyps, including subjects with familial adenomatous polyposis (FAP). Further, such compositions can be used to prevent polyp formation in patients at risk for FAP.

  The nimesulide composition of the present invention inhibits prostanoid-induced smooth muscle contraction by inhibiting the synthesis of contractile prostanoids, thus treating dysmenorrhea, premature birth, asthma and eosinophil related disorders Can be used.

  The composition of the present invention has indications that anti-inflammatory agents, anti-angiogenic agents, anti-tumor agents, immunosuppressive agents, NSAIDs, COX-2 inhibitors, analgesics, antithrombotic agents, anesthesia, or antipyretic agents are commonly used. It is also useful when treating.

  The following examples are provided to illustrate the invention. However, it should be understood that the invention is not to be limited to the specific conditions or details described in these examples. Throughout this specification, any and all references to publicly available documents, including US patents, are hereby incorporated by reference.

Example 1
The purpose of this example was to prepare a nanoparticulate composition of Nimesulide (Sigma, St. Louis, MO), a COX-2 inhibitor.

  An aqueous solution of 1% (w / w) Plasdone® S-630 (International Specialty Products, Wayne, NJ), a random copolymer of vinyl acetate and vinyl pyrrolidone, was added to 0.89 g Plasdone in 79.9 g deionized water. It was prepared by dissolving (registered trademark) S-630. The surface stabilizer solution was mixed with 4.25 g of Nimesulide (5% w / w) and PolyMill ™ -200 Polystyrene Milling Media (Dow Chemical, Midland, MI) and DYNO®-Mill Type KDL media mill. A 150 cc batch chamber (Willy Bachofen AG, Basel, Switzerland) was filled. The mill was operated at 4200 rpm for 1 hour with cold water (10 ° C.) recirculated through the mill chamber.

  According to the above process, 150 nm average particle size, 124 nm D50, 256 nm D90, and 293 nm D95 as measured using a Horiba LA-910 Laser Scattering Particle Size Distribution Analyzer (Horiba Instruments, Irvine, Calif.) A colloidal dispersion of Nimesulide with

Example 2
The purpose of this example was to prepare a nanoparticulate composition of nimesulide.

  Aqueous solutions of 1% (w / w) Plasdone® S-630 (International Specialty Products, Wayne, NJ) and 0.2% (w / w) sodium docusate (DOSS; Cytec Industries Inc., West Patterson, NJ) Was prepared by dissolving 0.85 g Plasdone® S-630 and 0.17 g DOSS in 79.73 g deionized water. The surface stabilizer solution was mixed with 4.25 g of Nimesulide (5% w / w) and PolyMill ™ -200 Polystyrene Milling Media (Dow Chemical, Midland, MI) and DYNO®-Mill Type KDL media mill. A 150 cc batch chamber (Willy Bachofen AG, Basel, Switzerland) was filled. The mill was operated at 4200 rpm for 2 hours while cold water (10 ° C.) was recirculated through the mill chamber.

  By the above process, an average particle size of 131 nm, a D50 of 111 nm, a D90 of 216 nm, and a D95 of 253 nm as measured using a Horiba LA-910 Laser Scattering Particle Size Distribution Analyzer (Horiba Instruments, Irvine, Calif.) A colloidal dispersion of Nimesulide with

Example 3
The purpose of this example was to prepare a nanoparticulate composition of nimesulide.

  An aqueous solution of 1% (w / w) Plasdone® S-630 (International Specialty Products, Wayne, NJ) and 0.05% (w / w) sodium lauryl sulfate (SLS) was dissolved in 79.9 g of deionized water at 0.85 Prepared by dissolving g Plasdone® S-630 and 0.04 g SLS. The surface stabilizer solution was mixed with 4.25 g of Nimesulide (5% w / w) and PolyMill ™ -200 Polystyrene Milling Media (Dow Chemical, Midland, MI) and DYNO®-Mill Type KDL media mill. A 150 cc batch chamber (Willy Bachofen AG, Basel, Switzerland) was filled. The mill was operated at 4200 rpm for 2 hours while cold water (10 ° C.) was recirculated through the mill chamber.

  According to the above process, an average particle size of 116 nm, a D50 of 104 nm, a D90 of 175 nm, and a D95 of 212 nm as measured using a Horiba LA-910 Laser Scattering Particle Size Distribution Analyzer (Horiba Instruments, Irvine, Calif.) A colloidal dispersion of Nimesulide with

Example 4
The purpose of this example was to prepare a nanoparticulate composition of nimesulide.

  An aqueous solution of 2% (w / w) hydroxypropyl methylcellulose (HPMC, ShinEtsu) was prepared by dissolving 1.7 g HPMC in 74.8 g deionized water. The surface stabilizer solution was mixed with 8.5 g Nimesulide (10% w / w) and PolyMill ™ -200 Polystyrene Milling Media (Dow Chemical, Midland, MI) and DYNO®-Mill Type KDL media mill A 150 cc batch chamber (Willy Bachofen AG, Basel, Switzerland) was filled. The mill was operated at 4200 rpm for 2 hours while cold water (10 ° C.) was recirculated through the mill chamber.

  By the above process, 110 nm average particle size, 103 nm D50, 157 nm D90, and 183 nm D95 as measured using a Horiba LA-910 Laser Scattering Particle Size Distribution Analyzer (Horiba Instruments, Irvine, Calif.) A colloidal dispersion of Nimesulide with

Example 5
The purpose of this example was to prepare a nanoparticulate composition of nimesulide.

  An aqueous solution of 2% (w / w) tyloxapol (Organichem Corp.) was prepared by dissolving 1.7 g of tyloxapol in 74.8 g of deionized water. The surface stabilizer solution was mixed with 8.5 g Nimesulide (10% w / w) and PolyMill ™ -200 Polystyrene Milling Media (Dow Chemical, Midland, MI) and DYNO®-Mill Type KDL media mill A 150 cc batch chamber (Willy Bachofen AG, Basel, Switzerland) was filled. The mill was operated at 4200 rpm for 2 hours while cold water (10 ° C.) was recirculated through the mill chamber.

  By the above process, an average particle size of 141 nm, a D50 of 127 nm, a D90 of 222 nm, and a D95 of 250 nm as measured using a Horiba LA-910 Laser Scattering Particle Size Distribution Analyzer (Horiba Instruments, Irvine, Calif.) A colloidal dispersion of Nimesulide with

  It will be apparent to those skilled in the art that various modifications and variations can be made in the methods and compositions of the present invention without departing from the spirit or scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention provided they come within the scope of the appended claims and their equivalents.

Claims (95)

(A) particles of nimesulide or a salt thereof, particles having an effective average particle size of less than about 2000 nm; and (b) a nimesulide composition comprising at least one surface stabilizer.   The composition of claim 1, wherein the nimesulide is selected from the group consisting of a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase, and mixtures thereof.   The effective average particle size of the Nimesulide particles is less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, about Less than 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, about 3. The composition of claim 1 or claim 2, selected from the group consisting of less than 200 nm, less than about 100 nm, less than about 75 nm, and less than about 50 nm.   2. Formulated for administration selected from the group consisting of oral, pulmonary, rectal, ocular, colon, parenteral, intracapsular, intravaginal, intraperitoneal, topical, buccal, nasal, and topical administration. The composition of any one of -3.   Liquid dispersions, oral suspensions, gels, aerosols, ointments, creams, controlled release formulations, fast melting formulations, lyophilized formulations, tablets, capsules, delayed release formulations, sustained release formulations, pulsed release formulations, and immediate release / control The composition according to any one of claims 1 to 4, which is formulated into a dosage form selected from the group consisting of a release mixed preparation.   6. The composition of any one of claims 1-5, further comprising one or more pharmaceutically acceptable excipients, carriers, or combinations thereof.   Nimesulide or a salt thereof, from about 99.5% by weight to about 0.001% by weight, from about 95% by weight, based on the total dry weight of nimesulide or a salt thereof and at least one surface stabilizer without other excipients 7. A composition according to any one of claims 1 to 6 present in an amount selected from the group consisting of up to about 0.1 wt% and from about 90 wt% to about 0.5 wt%.   At least one surface stabilizer is from about 0.5 wt% to about 99.999 wt%, about 5.0 wt%, based on the total dry weight of nimesulide or salt thereof and at least one surface stabilizer without other excipients 8. The composition of any one of claims 1-7, wherein the composition is present in an amount selected from the group consisting of from% to about 99.9% by weight, and from about 10% to about 99.5% by weight.   9. A composition according to any one of the preceding claims comprising two or more surface stabilizers.   The surface stabilizer is selected from the group consisting of an anionic surface stabilizer, a cationic surface stabilizer, a zwitterionic surface stabilizer, and an ionic surface stabilizer. The composition as described.   At least one surface stabilizer is cetylpyridinium chloride, gelatin, casein, phosphatide, dextran, glycerol, gum arabic, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, ceto Macrogol emulsifying wax, sorbitan ester, polyoxyethylene alkyl ether, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyethylene glycol, dodecyltrimethylammonium bromide, polyoxyethylene stearate, colloidal silicon dioxide, phosphate , Sodium dodecyl sulfate, carboxymethyl cellulose calcium, hydroxypropyl cellulose, hip 4- (1,1,3,3) of methylose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hypromellose phthalate, amorphous cellulose, aluminum magnesium silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, ethylene oxide and formaldehyde -Tetramethylbutyl) -phenol polymer, poloxamer; poloxamine, charged phospholipid, dioctyl sulfosuccinate, dialkyl ester of sodium sulfosuccinic acid, sodium lauryl sulfate, alkylaryl polyether sulfonate, mixture of sucrose stearate and sucrose distearate , P-isononylphenoxypoly- (glycidol), decanoyl-N-methylglucamide; n-decyl β-D-glucopyrano N-decyl β-D-maltopyranoside; n-dodecyl β-D-glucopyranoside; n-dodecyl β-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-β-D-glucopyranoside; n-heptyl β-D-thioglucoside; n-hexyl β-D-glucopyranoside; nonanoyl-N-methylglucamide; n-noyl β-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-β-D-glucopyranoside Octyl β-D-thioglucopyranoside; selected from the group consisting of lysozyme, PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivatives, PEG-vitamin A, and a random copolymer of vinyl acetate and vinylpyrrolidone. The composition according to any one of 1 to 10.   11. The composition of claim 10, wherein the at least one cationic surface stabilizer is selected from the group consisting of a polymer, biopolymer, polysaccharide, cellulosic material, alginate, non-polymeric compound, and phospholipid. Surface stabilizers are cationic lipids, polymethylmethacrylate / trimethylammonium bromide, sulfonium compounds, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate / dimethylsulfate, hexadecyltrimethylammonium bromide, phosphonium compounds, quaternary ammonium compounds, benzyl -Di (2-chloroethyl) ethylammonium bromide, coconut trimethylammonium chloride, coconut trimethylammonium bromide, coconut methyldihydroxyethylammonium chloride, coconut methyldihydroxyethylammonium bromide, decyltriethylammonium chloride, decyldimethylhydroxyethylammonium chloride , Decyldimethylhydroxyethylammoni Solid Lori Dobro bromide, C _12-15 dimethyl hydroxyethyl ammonium chloride, C _12-15 dimethyl hydroxyethyl ammonium chloride bromide, coconut dimethyl hydroxyethyl ammonium chloride, coconut dimethyl hydroxyethyl ammonium bromide, myristyl trimethyl ammonium methyl sulphate, lauryl dimethyl benzyl Ammonium chloride, lauryl dimethyl benzyl ammonium bromide, lauryl dimethyl (ethenoxy) ₄ ammonium chloride, lauryl dimethyl (ethenoxy) ₄ ammonium bromide, N-alkyl (C _12-18 ) dimethyl benzyl ammonium chloride, N-alkyl (C _14-18 ) Dimethyl-benzylammonium chloride, N-tetradecylide methylbenzylammonium chloride monohydrate Dimethyldidecylammonium chloride, N-alkyl and (C _12-14 ) dimethyl 1-naphthylmethylammonium chloride, trimethylammonium halide, alkyl-trimethylammonium salt, dialkyl-dimethylammonium salt, lauryltrimethylammonium chloride, ethoxylated alkyl Amidoalkyldialkylammonium salt, ethoxylated trialkylammonium salt, dialkylbenzenedialkylammonium chloride, N-didecyldimethylammonium chloride, N-tetradecyldimethylbenzylammonium chloride monohydrate, N-alkyl (C _12-14 ) dimethyl 1-naphthylmethylammonium chloride, dodecyldimethylbenzylammonium chloride, dialkylbenzene alkylammonium chloride, lauryl Trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium bromide, C ₁₂ trimethyl ammonium bromide, C ₁₅ trimethyl ammonium bromide, C ₁₇ trimethyl ammonium bromide, dodecyl benzyl triethyl ammonium chloride, poly - diallyl dimethyl ammonium chloride (DADMAC) , Dimethylammonium chloride, alkyldimethylammonium halide, tricetylmethylammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyltrioctylammonium chloride, POLYQUAT 10 ™, tetrabutylammonium bromide , Benzyltrimethyl Ammonium bromide, choline ester, benzalkonium chloride, stearalkonium chloride compound, cetylpyridinium bromide, cetylpyridinium chloride, halide salt of quaternized polyoxyethylalkylamine, MIRAPOL ™, ALKAQUAT ™, alkylpyridinium A salt; selected from the group consisting of amines, amine salts, amine oxides, imidoazolinium salts, protonated quaternary acrylamides, methylated quaternary polymers, and cationic guars. A composition according to claim 1.   The composition according to any one of claims 1 to 10, comprising a random copolymer of vinyl acetate and vinylpyrrolidone, hydroxypropylmethylcellulose, or tyloxapol as a surface stabilizer.   14. A composition according to any one of claims 10, 12, or 13, which is bioadhesive. The T _max of nimesulide is lower than the T _max of conventional non-nanoparticulate nimesulide administered at the same dose when assayed in plasma of a mammalian subject after administration. A composition according to item. T _max is about 90% or less, about 80% or less, about 70% or less, about 60% or less, about 50% or less, about 30% of T _max exhibited by a non-nanoparticle formulation of nimesulide administered at the same dose 17. The composition of claim 16, wherein the composition is selected from the group consisting of about 25% or less, about 20% or less, about 15% or less, and about 10% or less. The _Cmax of nimesulide exceeds the _Cmax of conventional non-nanoparticulate nimesulide administered at the same dose when assayed in plasma of a mammalian subject after administration. A composition according to item. C _max is at least about 10% greater, at least about 20% greater, at least about 30% greater, at least about 40% greater, at least about 50 greater than C _max exhibited by non-nanoparticulate formulations of nimesulide administered at the same dose 19. The composition of claim 18, selected from the group consisting of:% greater, at least about 60% greater, at least about 70% greater, at least about 80% greater, at least about 90% greater, and at least about 100% greater.   20. The AUC of nimesulide is greater than the AUC of conventional non-nanoparticulate nimesulide administered at the same dose when assayed in plasma of a mammalian subject after administration. Composition.   AUC is at least about 10% greater, at least about 20% greater, at least about 30% greater, at least about 40% greater, at least about 50% greater than AUC exhibited by a non-nanoparticulate formulation of nimesulide administered at the same dose 21. The composition of claim 20, wherein the composition is selected from the group consisting of: at least about 60% greater, at least about 70% greater, at least about 80% greater, at least about 90% greater, and at least about 100% greater.   22. A composition according to any one of claims 1-21, wherein the composition does not result in significantly different absorption levels when administered ingestion compared to a fasted state.   Less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 60% when the absorption difference of the nimesulide composition of the present invention is administered in the fed state relative to the fasted state Less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, and less than about 3%. 23. The composition of claim 22, wherein the composition is selected.   24. Any of claims 1-23, wherein administration of the composition to a fasted subject is bioequivalent to administration of the composition to a fed subject when administered to a human. A composition according to claim 1. 25. The composition of claim 24, wherein "bioequivalence" is established by a 90% confidence interval from 0.80 to 1.25 for both _Cmax and AUC when administered to a human. "Bioequivalence" is, in the case of administration to humans, is established by the 90% confidence interval 0.70 to 1.43 for the 90% confidence interval from 0.80 to 1.25, and C _max for AUC 25. The composition of claim 24.   27. The composition of any one of claims 1-26, further comprising at least one additional nimesulide composition having an effective average particle size that is different from the effective average particle size of the nimesulide composition of claim 1.   28. The composition of any one of claims 1-27, wherein the composition is redispersed upon administration such that the nimesulide particles have an effective average particle size of less than about 2000 nm.   Nimesulide particles less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, about Less than 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, about 30. The composition of claim 28, wherein the composition is redispersed upon administration to have an effective average particle size selected from the group consisting of less than 150 nm, less than about 100 nm, less than about 75 nm, and less than about 50 nm.   30. The composition of any one of claims 1-29, wherein the nimesulide particles are redispersed in a biorelevant medium such that the effective average particle size is less than about 2 microns.   Nimesulide particles less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, about Less than 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, about 32. The composition of claim 30, wherein the composition is redispersed in a biorelevant medium to have an effective average particle size selected from the group consisting of less than 150 nm, less than about 100 nm, less than about 75 nm, and less than about 50 nm. .   32. The composition of any one of claims 1-31, formulated into a liquid dosage form having a viscosity of less than about 2000 mPa · s when measured at 20 ° C. at a shear rate of 0.1 (1 / s). .   With a shear rate of 0.1 (1 / s), from about 2000 mPa · s to about 1 mPa · s, from about 1900 mPa · s to about 1 mPa · s, from about 1800 mPa · s to about 1 mPa · s, About 1700 mPa ・ s to about 1 mPa ・ s, about 1600 mPa ・ s to about 1 mPa ・ s, about 1500 mPa ・ s to about 1 mPa ・ s, about 1400 mPa ・ s to about 1 mPa ・ s From about 1300 mPa ・ s to about 1 mPa ・ s, from about 1200 mPa ・ s to about 1 mPa ・ s, from about 1100 mPa ・ s to about 1 mPa ・ s, from about 1000 mPa ・ s to about 1 mPa ・ s・ From about 900 mPa ・ s to about 1 mPa ・ s, from about 800 mPa ・ s to about 1 mPa ・ s, from about 700 mPa ・ s to about 1 mPa ・ s, from about 600 mPa ・ s Up to 1 mPa ・ s, about 500 mPa ・ s to about 1 mPa ・ s, about 400 mPa ・ s to about 1 mPa ・ s, about 300 mPa ・ s to about 1 mPa ・ s, about 200 mPa ・ s To about 1 mPa ・ s, about 175 mPa ・ s to about 1 mPa ・ s, about 150 mPa ・ s to about 1 mPa ・ s, about 125 mPa ・ s to about 1 mPa ・ s, about 100 mPa・ From s to about 1 mPa ・ s, about 75 mPa ・ s To about 1 mPa ・ s, about 50 mPa ・ s to about 1 mPa ・ s, about 25 mPa ・ s to about 1 mPa ・ s, about 15 mPa ・ s to about 1 mPa ・ s, about 10 mPa 35. The composition of claim 32, having a viscosity selected from the group consisting of: s to about 1 mPa · s, and about 5 mPa · s to about 1 mPa · s.   The viscosity of the dosage form is less than about 1/200, less than about 1/100, less than about 1/50, about 1/25 of the liquid dosage form of conventional non-nanoparticulate nimesulide at approximately the same concentration per ml of nimesulide. 35. The composition of claim 32, selected from the group consisting of less than and less than about 1/10.   The viscosity of the dosage form is less than about 5%, less than about 10%, less than about 15%, less than about 20%, about 25% of the liquid dosage form of conventional non-nanoparticulate nimesulide at approximately the same concentration per ml of nimesulide. %, Less than about 30%, less than about 35%, less than about 40%, less than about 45%, less than about 50%, less than about 55%, less than about 60%, less than about 65%, less than about 70%, about 75% 35. The composition of claim 32, wherein the composition is selected from the group consisting of less than%, less than about 80%, less than about 85%, and less than about 90%.   36. The composition of any one of claims 1-35, further comprising one or more non-nimesulide active agents.   40. The method of claim 36, wherein the non-nimesulide active agent is selected from the group consisting of analgesics, anti-inflammatory agents, antipyretic agents, and vascular regulators.   Non-nimesulide active agents are dietary supplements, proteins, peptides, nucleotides, amino acids, anti-obesity drugs, central nervous system stimulants, carotenoids, corticosteroids, elastase inhibitors, antifungal agents, cancer therapy, antiemetics, analgesics , Cardiovascular agonist, anti-inflammatory agent, NSAID, non-nimesulide COX-2 inhibitor, anthelmintic agent, antiarrhythmic agent, antibiotic agent, anticoagulant agent, antidepressant, antidiabetic agent, antiepileptic agent, antihistamine, Antihypertensive agent, antimuscarinic agent, antimycobacterial agent, antineoplastic agent, immunosuppressive agent, antithyroid agent, antiviral agent, anxiolytic agent, sedative agent, astringent agent, α-adrenergic receptor blocker, β -Adrenergic receptor blockers, blood products and blood substitutes, cardiotonic agents, contrast agents, corticosteroids, antitussives, diagnostic agents, diagnostic imaging agents, diuretics, dopaminergic agents, hemostatic agents, immunizing agents, lipid regulators, muscle relaxation Agents, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radiopharmaceuticals, sex hormones, antiallergic agents, stimulants and appetite suppressants, sympathomimetics, thyroid agents, vasodilators, vasomodulators 38. The composition of claim 36, wherein the composition is selected from the group consisting of: xanthine.   Nutritional supplements are lutein, folic acid, fatty acids, fruit extracts, vegetable extracts, vitamin supplements, mineral supplements, phosphatidylserine, lipoic acid, melatonin, glucosamine / chondroitin, aloe, guggle, glutamine, amino acids, green tea, lycopene 39, selected from the group consisting of: natural foods, food additives, herbs, phytonutrients, antioxidants, fruit flavonoid ingredients, evening primrose oil, flaxseed, fish oil, marine animal oil, and probiotics Composition.   Non-nimesulide activators include aceclofenac, acemetacin, e-acetamidocaproic acid, acetaminophen, acetaminosalol, acetanilide, acetylsalicylic acid, S-adenosylmethionine, alclofenac, alfentanil, allylprozin, aluminoprofen , Alloxypurine, alphaprozin, bis (acetylsalicylic acid) aluminum, ampenac, aminochlorocene oxazine, 3-amino-4-hydroxybutyric acid, 2-amino-4-picoline, aminopropyrone, aminopyrine, amixetrine, ammonium salicylate, Ampiroxicam, Amtormeching acyl, Anileridine, Antipyrine, Antipyrine salicylate, Anthrafenine, Apazone, Bendazac, Benolylate, Benoxaprofen, Benz Perillone, benzydamine, benzylmorphine, vermoprofen, vegitramide, α-bisabolol, bromfenac, p-bromoacetanilide, 5-bromosalicylic acid acetate, bromosaligenin, busetine, bucuroxy acid, bucolome, bufexamac, bumadizone, buprenorphine, Butacetin, Butibufen, Butofanol, Calcium acetylsalicylate, Carbamazepine, Carbifen, Carprofen, Calsalam, Chlorobutanol, Chlortenoxazine, Choline salicylate, Cincophen, Synmetacin, Silamadol, Cridanac, Clometacin, Clonitazen, Clonixine, Clopilac, Clove, Codeine, Odor Methylcodeine, codeine phosphate, codeine sulfate, clopropamide, crotetamide, desomorph , Dexoxadrol, dextromoramide, dezocine, diapromide, diclofenac sodium, diphenamizole, difenpyramide, diflunisal, dihydrocodeine, dihydrocodeinone enol acetate, dihydromorphine, acetylsalicylate dihydroxyaluminum, dimenoxazole, dimefeptanol, Dimethylthiabutene, Dioxafetil butyrate, Dipipanone, Diprocetyl, Dipyrone, Ditazole, Droxicam, Emorphazone, Enfenamic acid, Epilysole, Epazosin, Ethersalate, Etenzamid, Ethoheptadine, Ethoxazene, Ethylmethylthiambutene, Ethylmorphine, Etodolac, Etofenamate Ettonitazen, Eugenol, Felbinac, Fenbufen, Fen Crosinic acid, fendosar, fenoprofen, fentanyl, fenthiazaku, feprazinol, feprazone, fructaphenine, flufenamic acid, flunoxaprofen, fluoresson, flupirtine, fluproquazone, flurbiprofen, phosfosar, gentisic acid, grafenine, glucametacin, salicylic acid Glycol, guaiazulene, hydrocodone, hydromorphone, hydroxypethidine, ibufenac, ibuprofen, ibuproxam, imidazolic salicylate, indomethacin, indoprofen, isofezolak, isoladol, isomethadone, isonixin, isoxepac, isoxicam, ketobemidone, ketoprofen, ketorolac, fetalamine Levorfano , Lofentanyl, lonazolac, romoxicam, loxoprofen, lysine acetylsalicylate, magnesium acetylsalicylate, meclofenamic acid, mefenamic acid, meperidine, meptazinol, mesalamine, metazosin, methadone hydrochloride, methotrimiprazine, methiazine acid, metholine, methoprin, methoprin, mofebutazone Mofezolac, Morazone, Morphine, Morphine Hydrochloride, Morphine Hydrochloride, Morphine Sulfate, Morpholine Salicylate, Milohine, Nabumetone, Nalbuphine, 1-Naphthyl Salicylate, Naproxen, Narcein, Nefopam, Nicomorphine, Nifenazone, Niflumic Acid, Nimesulide, 5'-Nitro-2'-propoxy Acetanilide, norlevorphanol, normethadone, normorphine, norpipanone, olsalazine, opium, oxaseptro Oxametacin, oxaprozin, oxycodone, oxymorphone, oxyphenbutazone, papaveretam, paraniline, parsalmid, pentazocine, perisoxal, phenacetin, phenadoxone, phenazosin, phenazopyridine hydrochloride, phenocol, phenoperidine, phenopyrazone, phenyl acetylsalicylate, phenylbutazone, Phenyl salicylate, phenylamidol, piketoprofen, pimidine, pipebuzone, piperilone, piperfen, pyrazolac, pyritramide, piroxicam, pranoprofen, progouritacin, proheptadine, promedol, propacetamol, propiram, propoxyphene, propiphenazone, proquazone, protidine Acid, ramifenazone, remifentanil, methyl sulfate Rimazolium, salacetamide, salicin, salicylamide, salicylamide o-acetic acid, salicyl sulfate, salsarte, salverine, cimetride, sodium salicylate, sufentanil, sulfasalazine, sulindac, superoxide dismutase, suprofen, succibzone, talniflumate, tenidap, tenoxicam Claims selected from the group consisting of telofenamate, tetrandrine, thiazolinobtazone, thiaprofenic acid, thiaramide, thiridine, thynolysin, tolfenamic acid, tolmetine, tramadol, tropesin, biminol, xembucin, xymoprofen, zaltoprofen, and zomepirac. 36. The composition according to 36.   40. The composition of claim 38, wherein the vasomodulator is selected from the group consisting of caffeine, theobromine, and theophylline.   NSAID is nabumetone, tiaramid, proquazone, bufexamac, flumizole, epirazole, tinolidine, thymegadine, dapsone, aspirin, diflunisal, benolylate, phosphosar, diclofenac, alclofenac, fenclofenac, etodolac, indomethacin, sulindac , Fenthiazak, Tyromisole, Carprofen, Fenbufen, Flurbiprofen, Ketoprofen, Oxaprozin, Suprofen, Thiaprofenic acid, Ibuprofen, Naproxen, Fenoprofen, Indoprofen, Pyrprofen, Flufenam, Mefenam, Meclofenam, Niflum, Oxyphenbutazone, Phenylbutazone, apazone, feprazone, piroxicam, sudoxicam, a Kishikamu, and is selected from the group consisting of tenoxicam, claim 38 composition.   COX-2 inhibitors are celecoxib, rofecoxib, meloxicam, valdecoxib, parecoxib, etoroxib, SC-236, NS-398, SC-58125, SC-57666, SC-558, SC-560, etodolac, DFU, Monterey cast , L-745337, L-761066, L-761000, L-748780, DUP-697, PGV 20229, iguratimod, BF 389, CL 1004, PD 136005, PD 142893, PD 138387, PD 145065, flurbiprofen, nabumetone , Froslide, Piroxicam, Diclofenac, Lumiracoxib, D 1367, R 807, JTE-522, FK-3311, FK 867, FR 140423, FR 115068, GR 253035, RWJ 63556, RWJ 20485, ZK 38997, S 2474, Zomepirac analog 39. The composition of claim 38, wherein the composition is selected from the group consisting of: RS 104894, SC 41930, Pranlucast, SB 209670, and APHS.   44. The composition of any one of claims 1-43, which is sterile filtered.   Nimesulide comprising contacting nimesulide or a salt thereof with at least one surface stabilizer under a time and conditions sufficient to provide a nimesulide composition having an effective average particle size of less than about 2000 nm. A method for producing a composition.   46. The method of claim 45, wherein the contacting comprises a grinding step.   48. The method of claim 46, wherein the grinding comprises a wet grinding process.   46. The method of claim 45, wherein the contacting comprises a homogenization step. Contact,
(A) a step of dissolving nimesulide or a salt thereof in a solvent;
(B) adding the resulting nimesulide solution to a solution containing at least one surface stabilizer; and (c) precipitating solubilized nimesulide adsorbing at least one surface stabilizer on the surface by addition of a non-solvent. 46. The method of claim 45, comprising.   50. The method according to any one of claims 45 to 49, wherein the nimesulide or salt thereof is selected from the group consisting of a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase, and mixtures thereof.   The effective average particle size of Nimesulide particles is less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1000 nm, less than about 1400 nm, less than about 1300 nm, about <1200 nm, <1100 nm, <900 nm, <800 nm, <700 nm, <600 nm, <500 nm, <400 nm, <300 nm, <250 nm, <250 nm 51. The method of any one of claims 45-50, wherein the method is selected from the group consisting of less than 200 nm, less than about 100 nm, less than about 75 nm, and less than about 50 nm.   The composition is formulated for administration selected from the group consisting of oral, pulmonary, rectal, ocular, colon, parenteral, intracapsular, intravaginal, intraperitoneal, topical, buccal, nasal, and topical administration. 52. The method according to any one of claims 45 to 51.   53. The method of any one of claims 45 to 52, wherein the composition further comprises one or more pharmaceutically acceptable excipients, carriers, or combinations thereof.   Nimesulide or a salt thereof is from about 99.5% by weight to about 0.001% by weight, from about 95% to about 95% by weight, based on the combined weight of nimesulide or a salt thereof and at least one surface stabilizer without other excipients. 54. The method of any one of claims 45 to 53, wherein the method is present in an amount selected from the group consisting of up to 0.1 wt% and from about 90 wt% to about 0.5 wt%.   At least one surface stabilizer is from about 0.5 wt% to about 99.999 wt%, about 5.0 wt%, based on the total dry weight of nimesulide or salt thereof and at least one surface stabilizer without other excipients 55. The method according to any one of claims 45 to 54, wherein the method is present in an amount selected from the group consisting of from% to about 99.9% by weight and from about 10% to about 99.5% by weight.   56. A method according to any one of claims 45 to 55, comprising two surface stabilizers.   57. The surface stabilizer according to any one of claims 45 to 56, wherein the surface stabilizer is selected from the group consisting of an anionic surface stabilizer, a cationic surface stabilizer, a zwitterionic surface stabilizer, and an ionic surface stabilizer. The method described.   At least one surface stabilizer is cetylpyridinium chloride, gelatin, casein, phosphatide, dextran, glycerol, gum arabic, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, ceto Macrogol emulsifying wax, sorbitan ester, polyoxyethylene alkyl ether, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyethylene glycol, dodecyltrimethylammonium bromide, polyoxyethylene stearate, colloidal silicon dioxide, phosphate , Sodium dodecyl sulfate, carboxymethyl cellulose calcium, hydroxypropyl cellulose, hip 4- (1,1,3,3) of methylose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hypromellose phthalate, amorphous cellulose, aluminum magnesium silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, ethylene oxide and formaldehyde -Tetramethylbutyl) -phenol polymer, poloxamer; poloxamine, charged phospholipid, dioctyl sulfosuccinate, dialkyl ester of sodium sulfosuccinic acid, sodium lauryl sulfate, alkylaryl polyether sulfonate, mixture of sucrose stearate and sucrose distearate , P-isononylphenoxypoly- (glycidol), decanoyl-N-methylglucamide; n-decyl β-D-glucopyrano N-decyl β-D-maltopyranoside; n-dodecyl β-D-glucopyranoside; n-dodecyl β-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-β-D-glucopyranoside; n-heptyl β-D-thioglucoside; n-hexyl β-D-glucopyranoside; nonanoyl-N-methylglucamide; n-noyl β-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-β-D-glucopyranoside Octyl β-D-thioglucopyranoside; selected from the group consisting of lysozyme, PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivatives, PEG-vitamin A, PEG-vitamin E, and a random copolymer of vinyl acetate and vinylpyrrolidone 58. The method of claim 57, wherein:   58. The method of claim 57, wherein the at least one cationic surface stabilizer is selected from the group consisting of a polymer, biopolymer, polysaccharide, cellulosic material, alginate, non-polymeric compound, and phospholipid. Surface stabilizers are cationic lipids, polymethylmethacrylate / trimethylammonium bromide, sulfonium compounds, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate / dimethylsulfate, hexadecyltrimethylammonium bromide, phosphonium compounds, quaternary ammonium compounds, benzyl -Di (2-chloroethyl) ethylammonium bromide, coconut trimethylammonium chloride, coconut trimethylammonium bromide, coconut methyldihydroxyethylammonium chloride, coconut methyldihydroxyethylammonium bromide, decyltriethylammonium chloride, decyldimethylhydroxyethylammonium chloride , Decyldimethylhydroxyethylammoni Solid Lori Dobro bromide, C _12-15 dimethyl hydroxyethyl ammonium chloride, C _12-15 dimethyl hydroxyethyl ammonium chloride bromide, coconut dimethyl hydroxyethyl ammonium chloride, coconut dimethyl hydroxyethyl ammonium bromide, myristyl trimethyl ammonium methyl sulphate, lauryl dimethyl benzyl Ammonium chloride, lauryl dimethyl benzyl ammonium bromide, lauryl dimethyl (ethenoxy) ₄ ammonium chloride, lauryl dimethyl (ethenoxy) ₄ ammonium bromide, N-alkyl (C _12-18 ) dimethyl benzyl ammonium chloride, N-alkyl (C _14-18 ) Dimethyl-benzylammonium chloride, N-tetradecylide methylbenzylammonium chloride monohydrate Dimethyldidecylammonium chloride, N-alkyl and (C _12-14 ) dimethyl 1-naphthylmethylammonium chloride, trimethylammonium halide, alkyl-trimethylammonium salt, dialkyl-dimethylammonium salt, lauryltrimethylammonium chloride, ethoxylated alkyl Amidoalkyldialkylammonium salt, ethoxylated trialkylammonium salt, dialkylbenzenedialkylammonium chloride, N-didecyldimethylammonium chloride, N-tetradecyldimethylbenzylammonium chloride monohydrate, N-alkyl (C _12-14 ) dimethyl 1-naphthylmethylammonium chloride, dodecyldimethylbenzylammonium chloride, dialkylbenzene alkylammonium chloride, lauryl Trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium bromide, C ₁₂ trimethyl ammonium bromide, C ₁₅ trimethyl ammonium bromide, C ₁₇ trimethyl ammonium bromide, dodecyl benzyl triethyl ammonium chloride, poly - diallyl dimethyl ammonium chloride (DADMAC) , Dimethylammonium chloride, alkyldimethylammonium halide, tricetylmethylammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyltrioctylammonium chloride, POLYQUAT 10 ™, tetrabutylammonium bromide , Benzyltrimethyl Ammonium bromide, choline ester, benzalkonium chloride, stearalkonium chloride compound, cetylpyridinium bromide, cetylpyridinium chloride, halide salt of quaternized polyoxyethylalkylamine, MIRAPOL ™, ALKAQUAT ™, alkylpyridinium 58. The method of claim 57, selected from the group consisting of a salt; an amine, an amine salt, an amine oxide, an imidoazolinium salt, a protonated quaternary acrylamide, a methylated quaternary polymer, and a cationic guar.   58. The method according to any one of claims 45 to 57, wherein a random copolymer of vinyl acetate and vinyl pyrrolidone, hydroxypropyl methylcellulose, or tyloxapol is utilized as the surface stabilizer.   61. The method of any one of claims 57, 59, or 60, wherein the composition is bioadhesive. (A) particles of nimesulide or a salt thereof having an effective average particle size of less than about 2000 nm; and (b) administering to a subject in need an effective amount of a composition comprising at least one surface stabilizer. A method of treating the subject.   64. The method of claim 63, wherein the nimesulide or salt thereof is selected from the group consisting of a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase, and mixtures thereof.   The effective average particle size of the Nimesulide particles is less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, about Less than 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, about 65. The method of claim 63 or claim 64, wherein the method is selected from the group consisting of less than 200 nm, less than about 100 nm, less than about 75 nm, and less than about 50 nm.   The composition is formulated for administration selected from the group consisting of oral, pulmonary, rectal, ocular, colon, parenteral, intracapsular, intravaginal, intraperitoneal, topical, buccal, nasal, and topical administration. 66. A method according to any one of claims 63 to 65.   The composition comprises a liquid dispersion, an oral suspension, a gel, an aerosol, an ointment, a cream, a controlled release formulation, a rapid melt formulation, a lyophilized formulation, a tablet, a capsule, a delayed release formulation, a sustained release formulation, a pulsed release formulation, and 67. The method according to any one of claims 63 to 66, wherein the dosage form is selected from the group consisting of an immediate release / controlled release mixed preparation.   68. The method of any one of claims 63-67, wherein the composition further comprises one or more pharmaceutically acceptable excipients, carriers, or combinations thereof.   Nimesulide or a salt thereof is from about 99.5% by weight to about 0.001% by weight, from about 95% to about 95% by weight, based on the combined weight of nimesulide or a salt thereof and at least one surface stabilizer without other excipients. 69. The method of any one of claims 63 to 68, wherein the method is present in an amount selected from the group consisting of up to 0.1 wt%, and from about 90 wt% to about 0.5 wt%.   At least one surface stabilizer is from about 0.5 wt% to about 99.999 wt%, about 5.0 wt%, based on the total dry weight of nimesulide or salt thereof and at least one surface stabilizer without other excipients 70. The method of any one of claims 63-69, wherein the method is present in an amount selected from the group consisting of from about 10% to about 99.9% and from about 10% to about 99.5% by weight.   71. A method according to any one of claims 63 to 70, comprising two surface stabilizers.   72. The surface stabilizer is selected from the group consisting of an anionic surface stabilizer, a cationic surface stabilizer, a zwitterionic surface stabilizer, and an ionic surface stabilizer. The method described.   At least one surface stabilizer is cetylpyridinium chloride, gelatin, casein, phosphatide, dextran, glycerol, gum arabic, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, ceto Macrogol emulsifying wax, sorbitan ester, polyoxyethylene alkyl ether, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyethylene glycol, dodecyltrimethylammonium bromide, polyoxyethylene stearate, colloidal silicon dioxide, phosphate , Sodium dodecyl sulfate, carboxymethyl cellulose calcium, hydroxypropyl cellulose, hip 4- (1,1,3,3) of methylose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hypromellose phthalate, amorphous cellulose, aluminum magnesium silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, ethylene oxide and formaldehyde -Tetramethylbutyl) -phenol polymer, poloxamer; poloxamine, charged phospholipid, dioctyl sulfosuccinate, dialkyl ester of sodium sulfosuccinic acid, sodium lauryl sulfate, alkylaryl polyether sulfonate, mixture of sucrose stearate and sucrose distearate , P-isononylphenoxypoly- (glycidol), decanoyl-N-methylglucamide; n-decyl β-D-glucopyrano N-decyl β-D-maltopyranoside; n-dodecyl β-D-glucopyranoside; n-dodecyl β-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-β-D-glucopyranoside; n-heptyl β-D-thioglucoside; n-hexyl β-D-glucopyranoside; nonanoyl-N-methylglucamide; n-noyl β-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-β-D-glucopyranoside Octyl β-D-thioglucopyranoside; selected from the group consisting of lysozyme, PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivatives, PEG-vitamin A, PEG-vitamin E, and a random copolymer of vinyl acetate and vinylpyrrolidone 75. The method of claim 72, wherein:   73. The method of claim 72, wherein the at least one cationic surface stabilizer is selected from the group consisting of a polymer, a biopolymer, a polysaccharide, a cellulosic material, an alginate, a non-polymeric compound, and a phospholipid. Surface stabilizers include benzalkonium chloride, polymethylmethacrylate / trimethylammonium bromide, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate / dimethylsulfate, hexadecyltrimethylammonium bromide, cationic lipid, sulfonium compound, phosphonium compound, fourth Quaternary ammonium compounds, benzyl-di (2-chloroethyl) ethylammonium bromide, coconut trimethylammonium chloride, coconut trimethylammonium bromide, coconut methyldihydroxyethylammonium chloride, coconut methyldihydroxyethylammonium bromide, decyltriethylammonium chloride, decyl Dimethylhydroxyethylammonium chloride, decyl dimethyl ester B carboxyethyl ammonium chloride bromide, C _12-15 dimethyl hydroxyethyl ammonium chloride, C _12-15 dimethyl hydroxyethyl ammonium chloride bromide, coconut dimethyl hydroxyethyl ammonium chloride, coconut dimethyl hydroxyethyl ammonium bromide, myristyl trimethyl ammonium methyl sulphate, lauryl dimethyl benzyl ammonium chloride, lauryl dimethyl benzyl ammonium bromide, lauryl dimethyl (ethenoxy) ₄ ammonium chloride, lauryl dimethyl (ethenoxy) ₄ ammonium bromide, N- alkyl (C _12-18) dimethyl benzyl ammonium chloride, N- alkyl (C _{14- 18} ) Dimethyl-benzylammonium chloride, N-tetradecylide methylbenzylamine Monium chloride monohydrate, dimethyldidecylammonium chloride, N-alkyl and ( _C12-14 ) dimethyl 1-naphthylmethylammonium chloride, trimethylammonium halide, alkyl-trimethylammonium salt, dialkyl-dimethylammonium salt, lauryltrimethylammonium Chloride, ethoxylated alkylamidoalkyldialkylammonium salt, ethoxylated trialkylammonium salt, dialkylbenzenedialkylammonium chloride, N-didecyldimethylammonium chloride, N-tetradecyldimethylbenzylammonium chloride monohydrate, N-alkyl (C _12-14) dimethyl 1-naphthylmethyl ammonium chloride, dodecyl dimethyl benzyl ammonium chloride, dialkyl benzenealkyl en Moni Mukurorido, lauryl trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium bromide, C ₁₂ trimethyl ammonium bromide, C ₁₅ trimethyl ammonium bromide, C ₁₇ trimethyl ammonium bromide, dodecyl benzyl triethyl ammonium chloride, poly - diallyldimethylammonium chloride ( DADMAC), dimethylammonium chloride, alkyldimethylammonium halide, tricetylmethylammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyltrioctylammonium chloride, POLYQUAT 10 ™, tetrabutyl Ammonium bromi , Benzyltrimethylammonium bromide, choline ester, benzalkonium chloride, stearalkonium chloride compound, cetylpyridinium bromide, cetylpyridinium chloride, halide salt of quaternized polyoxyethylalkylamine, MIRAPOL ™, ALKAQUAT ™ 73. An alkylpyridinium salt; selected from the group consisting of amines, amine salts, amine oxides, imidoazolinium salts, protonated quaternary acrylamides, methylated quaternary polymers, and cationic guars. the method of.   73. The method according to any one of claims 63 to 72, wherein a random copolymer of vinyl acetate and vinyl pyrrolidone, hydroxypropyl methylcellulose, or tyloxapol is utilized as the surface stabilizer.   76. The method of any one of claims 72, 74, or 75, wherein the composition is bioadhesive.   78. The method of any one of claims 63-77, wherein administration of the nimesulide composition does not result in significantly different absorption levels when administered to a human when administered ingestion compared to a fasted state. .   Less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 60% when the absorption difference of the nimesulide composition of the invention is administered in a fed state relative to a fasted state, Selected from the group consisting of less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, and less than about 3% 79. The method of claim 78, wherein:   80. Any of claims 63-79, wherein administration of the composition to a fasted subject is biologically equivalent to administration of the composition to a fed subject when administered to a human. The method according to claim 1. 81. The method of claim 80, wherein "bioequivalence" is established by a 90% confidence interval from 0.80 to 1.25 for both _Cmax and AUC when administered to a human. "Bioequivalence" is, in the case of administration to humans, is established by the 90% confidence interval 0.70 to 1.43 for the 90% confidence interval from 0.80 to 1.25, and C _max for AUC 81. The method of claim 80. Nimesulide T _max is, when assayed in the plasma of a mammalian subject following administration, less than the T _max of nimesulide conventional non-nanoparticulate form, administered at the same dosage, one of claims 63 to 82 one The method described in the paragraph. T _max is about 90% or less, about 80% or less, about 70% or less, about 60% or less, about 50% or less, about 30% of T _max exhibited by a non-nanoparticle formulation of nimesulide administered at the same dose 84. The method of claim 83, wherein the method is selected from the group consisting of about 25% or less, about 20% or less, about 15% or less, and about 10% or less. C _max of nimesulide, when assayed in the plasma of a mammalian subject following administration, greater than the C _max of nimesulide conventional non-nanoparticulate form, administered at the same dosage, one of claims 63 to 84 one The method described in the paragraph. C _max is at least about 10% greater, at least about 20% greater, at least about 30% greater, at least about 40% greater, at least about 50 greater than C _max exhibited by non-nanoparticulate formulations of nimesulide administered at the same dose 86. The method of claim 85, selected from the group consisting of:% greater, at least about 60% greater, at least about 70% greater, at least about 80% greater, at least about 90% greater, and at least about 100% greater.   The AUC of nimesulide exceeds the AUC of conventional non-nanoparticulate nimesulide administered at the same dose when assayed in the plasma of a mammalian subject after administration, according to any of claims 63-86. the method of.   AUC is at least about 10% greater, at least about 20% greater, at least about 30% greater, at least about 40% greater, at least about 50% greater than AUC exhibited by a non-nanoparticulate formulation of nimesulide administered at the same dose 90. The method of claim 87, wherein the method is selected from the group consisting of: at least about 60% greater, at least about 70% greater, at least about 80% greater, at least about 90% greater, and at least about 100% greater.   90. The method of any one of claims 63-88, further comprising administering one or more non-nimesulide active agents.   90. The method of any one of claims 63-89, further comprising administering one or more non-nimesulide active agents effective to treat fever, inflammation, or pain.   90. The method of claim 89, wherein the non-nimesulide active agent is selected from the group consisting of analgesics, anti-inflammatory agents, antipyretic agents, and vascular regulators.   Non-nimesulide active agent is a dietary supplement, protein, peptide, nucleotide, amino acid, anti-obesity agent, central nervous system stimulant, carotenoid, corticosteroid, elastase inhibitor, antifungal agent, cancer therapy, antiemetic, analgesic , Cardiovascular agonist, anti-inflammatory agent, NSAID, non-nimesulide COX-2 inhibitor, anthelmintic agent, antiarrhythmic agent, antibiotic agent, anticoagulant agent, antidepressant, antidiabetic agent, antiepileptic agent, antihistamine, Antihypertensive agent, antimuscarinic agent, antimycobacterial agent, antineoplastic agent, immunosuppressive agent, antithyroid agent, antiviral agent, anxiolytic agent, sedative agent, astringent agent, α-adrenergic receptor blocker, β -Adrenergic receptor blockers, blood products and blood substitutes, cardiotonic agents, contrast agents, corticosteroids, antitussives, diagnostic agents, diagnostic imaging agents, diuretics, dopaminergic agents, hemostatic agents, immunizing agents, lipid regulators, muscle relaxation Agents, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radiopharmaceuticals, sex hormones, antiallergic agents, stimulants and appetite suppressants, sympathomimetics, thyroid agents, vasodilators, vasomodulators 90. The method of claim 89, wherein the method is selected from the group consisting of: xanthine.   93. The method according to any one of claims 63 to 92, wherein the subject is a human.   Rheumatoid arthritis, arthritis, rheumatoid arthritis, osteoarthritis, periarthritis, tendonitis, bursitis, ankylosing spondylitis, joint stiffness, low back pain, gynecological condition, menstrual migraine attack, dysmenorrhea Fever, cardiovascular disease, atherosclerosis, hypotension, thrombophlebitis, arthropathy, inflammatory condition, otitis, rhinitis, vice From rhinitis, sore throat, bronchitis, nephrotoxicity, mastitis, asthma, cancer, trauma, surgery, migraine, kidney disease, Alzheimer's disease, familial adenomatosis, diarrhea, colon adenoma, bone resorption, and related conditions 94. The method according to any one of claims 63 to 93, wherein the method is used to treat a condition selected from the group consisting of:   To treat conditions when anti-inflammatory agents, anti-angiogenic agents, antitumor agents, immunosuppressive agents, NSAIDs, COX-2 inhibitors, analgesics, antithrombotic agents, anesthetics, or antipyretics are commonly used 95. A method according to any one of claims 63 to 94, used.