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US 2004O229038A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0229038A1 Cooper et al. (43) Pub. Date: Nov. 18, 2004

(54) NANOPARTICULATE (22) Filed: Feb. 24, 2004 FORMULATIONS Related U.S. Application Data (75) Inventors: Eugene R. Cooper, Berwyn, PA (US); Tuula Ryde, Malvern, PA (US); John (60) Provisional application No. 60/450,705, filed on Mar. Pruitt, Collegeville, PA (US); Laura 3, 2003. Kline, Harleysville, PA (US (US) Publication Classification Correspondence Address: FOLEY AND LARDNER (51) Int. Cl...... B32B 25/00 SUTE 500 (52) U.S. Cl...... 428/402.21; 428/402; 428/402.22 3000 KSTREET NW (57) ABSTRACT WASHINGTON, DC 20007 (US) The present invention is directed- 0 to nanoparticulate compo (73) Assignee: Elan Pharma International Ltd. Sitions comprising meloxicam. The meloxicam particles of the composition have an effective average particle size of (21) Appl. No.: 10/784,900 less than about 2000 nm.

3,500

2. 5 O O -0-NanoCrystal6) Colloidal Dispersion - NanoCrystalE) Lyophilized Wafer -- Mobic Tablet 2. OO O

1 5 O O

1 OO O

O 5 10 15 2O 25 30 35 40 45 Time Post-Dosing (hrs) Patent Application Publication Nov. 18, 2004 US 2004/0229038A1 FIGURE 1

3.500

2. 5 OO -0-NanoCrystal(8) Colloidal Dispersion --NanoCrystal(8) Lyophilized Wafer -A-Mobico8 Tablet

1.500

O.OOO -- O 5 1O 15 20 25 30 35 40 45 Time Post-Dosing (hrs) US 2004/0229038A1 Nov. 18, 2004

NANOPARTICULATE MELOXCAM ing Charged Phospholipids to Reduce Aggregation; U.S. FORMULATIONS Pat. No. 5,472,683 for “Nanoparticulate Diagnostic Mixed Carbamic Anhydrides as X-Ray Contrast Agents for Blood FIELD OF THE INVENTION Pool and Lymphatic System Imaging; U.S. Pat. No. 5,500, 0001. The present invention relates to nanoparticulate 204 for “Nanoparticulate Diagnostic Dimers as X-Ray Con compositions comprising meloxicam and at least one Surface trast Agents for Blood Pool and Lymphatic System Imag stabilizer adsorbed to or associated with the Surface of the ing.” U.S. Pat. No. 5,518,738 for “Nanoparticulate NSAID drug. The nanoparticulate meloxicam particles have an Formulations;” U.S. Pat. No. 5,521,218 for “Nanoparticu effective average particle size of less than about 2000 nm. late Iododipamide Derivatives for Use as X-Ray Contrast Agents; U.S. Pat. No. 5,525,328 for “Nanoparticulate Diag BACKGROUND OF THE INVENTION nostic Diatrizoxy Ester X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging; U.S. Pat. No. 5,543, 0002 A. Background Regarding Nanoparticulate Active 133 for “Process of Preparing X-Ray Contrast Compositions Agent Compositions Containing Nanoparticles;” U.S. Pat. No. 5,552,160 for 0.003 Nanoparticulate active agent compositions, first “Surface Modified NSAID Nanoparticles;” U.S. Pat. No. described in U.S. Pat. No. 5,145,684 (“the 684 patent”), are 5,560,931 for “Formulations of Compounds as Nanoparticu particles consisting of a poorly Soluble therapeutic or diag late Dispersions in Digestible Oils or Fatty Acids; U.S. Pat. nostic agent having adsorbed onto the Surface thereof a No. 5,565,188 for “Polyalkylene Block Copolymers as non-crosslinked surface stabilizer. The 684 patent does not Surface Modifiers for Nanoparticles;” U.S. Pat. No. 5,569, describe nanoparticulate compositions of meloxicam. 448 for “Sulfated Non-ionic Block Copolymer Surfactant as Stabilizer Coatings for Nanoparticle Compositions; U.S. 0004 Methods of making nanoparticulate active agent Pat. No. 5,571,536 for “Formulations of Compounds as compositions are described, for example, in U.S. Pat. Nos. Nanoparticulate Dispersions in Digestible Oils or Fatty 5,518,187 and 5,862.999, both for “Method of Grinding Pharmaceutical Substances; U.S. Pat. No. 5,718,388, for Acids;” U.S. Pat. No. 5,573,749 for “Nanoparticulate Diag “Continuous Method of Grinding Pharmaceutical Sub nostic Mixed Carboxylic Anydrides as X-Ray Contrast stances;” and U.S. Pat. No. 5,510,118 for “Process of Agents for Blood Pool and Lymphatic System Imaging,” Preparing Therapeutic Compositions Containing Nanopar U.S. Pat. No. 5,573,750 for “Diagnostic Imaging X-Ray Contrast Agents;” U.S. Pat. No. 5,573,783 for “Redispers ticles.” ible Nanoparticulate Film Matrices With Protective Over 0005 Nanoparticulate active agent compositions are also coats;” U.S. Pat. No. 5,580,579 for “Site-specific Adhesion described, for example, in U.S. Pat. No. 5,298,262 for “Use Within the GI Tract Using Nanoparticles Stabilized by High of Ionic Cloud Point Modifiers to Prevent Particle Aggre Molecular Weight, Linear Poly( Oxide) Polymers;” gation During Sterilization; U.S. Pat. No. 5,302,401 for U.S. Pat. No. 5,585,108 for “Formulations of Oral Gas “Method to Reduce Particle Size Growth During Lyophiliza trointestinal Therapeutic Agents in Combination with Phar tion;” U.S. Pat. No. 5,318,767 for “X-Ray Contrast Com maceutically Acceptable Clays; U.S. Pat. No. 5,587,143 for positions Useful in Medical Imaging; U.S. Pat. No. 5,326, “Butylene Oxide-Ethylene Oxide Block Copolymers Sur 552 for “Novel Formulation For Nanoparticulate X-Ray factants as Stabilizer Coatings for Nanoparticulate Compo Blood Pool Contrast Agents Using High Molecular Weight sitions;” U.S. Pat. No. 5,591,456 for “Milled with Non-ionic Surfactants; U.S. Pat. No. 5,328,404 for Hydroxypropyl Cellulose as Dispersion Stabilizer; U.S. “Method of X-Ray Imaging Using Iodinated Aromatic Pro Pat. No. 5,593,657 for “Novel Salt Formulations panedioates;” U.S. Pat. No. 5,336,507 for “Use of Charged Stabilized by Non-ionic and Anionic Stabilizers; U.S. Pat. Phospholipids to Reduce Nanoparticle Aggregation; U.S. No. 5,622,938 for “Sugar Based Surfactant for Nanocrys Pat. No. 5,340,564 for “Formulations Comprising Olin 10-G tals;” U.S. Pat. No. 5,628,981 for “Improved Formulations to Prevent Particle Aggregation and Increase Stability; U.S. of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents Pat. No. 5,346,702 for “Use of Non-Ionic Cloud Point and Oral Gastrointestinal Therapeutic Agents; U.S. Pat. No. Modifiers to Minimize Nanoparticulate Aggregation During 5,643,552 for “Nanoparticulate Diagnostic Mixed Carbonic Sterilization;” U.S. Pat. No. 5,349,957 for “Preparation and Anhydrides as X-Ray Contrast Agents for Blood Pool and Magnetic Properties of Very Small Magnetic-Dextran Par Lymphatic System Imaging; U.S. Pat. No. 5,718,388 for ticles; U.S. Pat. No. 5,352,459 for “Use of Purified Surface “Continuous Method of Grinding Pharmaceutical Sub Modifiers to Prevent Particle Aggregation During Steriliza stances;” U.S. Pat. No. 5,718,919 for “Nanoparticles Con tion; U.S. Pat. No. 5,399,363 and U.S. Pat. No. 5,494,683, taining the R(-)Enantiomer of .” U.S. Pat. No. both for “Surface Modified Anticancer Nanoparticles; U.S. 5,747,001 for “Aerosols Containing Beclomethasone Nano Pat. No. 5,401,492 for “Water Insoluble Non-Magnetic particle Dispersions;” U.S. Pat. No. 5,834,025 for “Reduc Manganese Particles as Magnetic Resonance Enhancement tion of Intravenously Administered Nanoparticulate Formu Agents;" U.S. Pat. No. 5,429,824 for “Use of Tyloxapol as lation Induced Adverse Physiological Reactions; U.S. Pat. a Nanoparticulate Stabilizer;” U.S. Pat. No. 5,447,710 for No. 6,045,829 “Nanocrystalline Formulations of Human “Method for Making Nanoparticulate X-Ray Blood Pool Immunodeficiency Virus (HIV) Protease Inhibitors. Using Contrast Agents. Using High Molecular Weight Non-ionic Cellulosic Surface Stabilizers; U.S. Pat. No. 6,068,858 for Surfactants;” U.S. Pat. No. 5,451,393 for “X-Ray Contrast “Methods of Making Nanocrystalline Formulations of Compositions Useful in Medical Imaging; U.S. Pat. No. Human Immunodeficiency Virus (HIV) Protease Inhibitors 5,466,440 for “Formulations of Oral Gastrointestinal Diag Using Cellulosic Surface Stabilizers;” U.S. Pat. No. 6,153, nostic X-Ray Contrast Agents in Combination with Phar 225 for “Injectable Formulations of Nanoparticulate maceutically Acceptable Clays;” U.S. Pat. No. 5,470,583 for Naproxen;” U.S. Pat. No. 6,165,506 for “New Solid Dose “Method of Preparing Nanoparticle Compositions Contain Form of Nanoparticulate Naproxen; U.S. Pat. No. 6,221, US 2004/0229038A1 Nov. 18, 2004

400 for “Methods of Treating Mammals Using Nanocrys talline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors;” U.S. Pat. No. 6,264,922 for “Nebulized Aerosols Containing Nanoparticle Dispersions;” U.S. Pat. No. 6,267,989 for “Methods for Preventing Crystal Growth and Particle Aggregation in Nanoparticle Compo sitions.” U.S. Pat. No. 6,270.806 for “Use of PEG-Deriva N s1 N tized Lipids as Surface Stabilizers for Nanoparticulate Com MV positions;” U.S. Pat. No. 6,316,029 for “Rapidly O O Disintegrating Solid Oral Dosage Form,” U.S. Pat. No. 6,375,986 for “Solid Dose Nanoparticulate Compositions Comprising a Synergistic Combination of a Polymeric Sur 0011 Meloxicam has an empirical formula of face Stabilizer and Dioctyl Sodium Sulfosuccinate,” U.S. Pat. No. 6,428,814 for “Bioadhesive Nanoparticulate Com CHNOS and a molecular weight of 351.41. See The positions Having Cationic Surface Stabilizers; U.S. Pat. Physicians' Desk Reference, 56" Ed., pp. 1054 (2002); and No. 6,431,478 for “Small Scale Mill; U.S. Pat. No. 6,432, The , 13" Ed., pp. 1040-1041 (Merck & Co. 381 for “Methods for Targeting Drug Delivery to the Upper 2001). Meloxicam is practically insoluble in water with and/or Lower Gastrointestinal Tract, U.S. Pat. No. 6,582, higher Solubility observed in Strong acids and bases. It is 285 for “Apparatus for Sanitary Wet Milling," U.S. Pat. No. very slightly soluble in . The Physicians' Desk 6,592,903 for “Nanoparticulate Dispersions Comprising a Reference, 56" Ed., pp. 1054. Synergistic Combination of a Polymeric Surface Stabilizer 0012 4-hydroxy-2H-1,2-benzothiazine-3-carboxamide and Dioctyl Sodium Sulfosuccinate,” and U.S. Pat. No. 6,656,504 for “Nanoparticulate Compositions Comprising 1,1-dioxides and Salts thereof, as well as methods of pre Amorphous Cyclosporine and Methods of Making and paring these compounds, pharmaceutical compositions con Using Such Compositions,” all of which are specifically taining them as active ingredients, and methods of using incorporated by reference. them as antiphlogistics, are discussed in U.S. Pat. No. 4,233,299. See also German Patent No. 2,756,113. The 0006. In addition, U.S. Patent Application No. pharmacology of meloxicam in horses is discussed in Lees 20020012675 A1, published on Jan. 31, 2002, for “Con et al., Brit. Vet. J, 147: 97 (1991); veterinary trials in dogs trolled Release Nanoparticulate Compositions,” and WO are discussed in Henderson et al., Prakt. Tierarzt., 75:179 02/098565 for “System and Method for Milling Materials,” (1994); the physiochemical properties of meloxicam are describe nanoparticulate active agent compositions, and are discussed in Tsai et al., Helv. Chim. Acta, 76:842 (1993); the Specifically incorporated by reference. None of these refer pharmacology, mechanism of action, and clinical efficacy ences describe nanoparticulate compositions of meloxicam. are discussed in Brit. J. Rheumatol., 35(Suppl. 1): 1-77 0007 U.S. Patent Application No. 20020028238, pub (1996); and clinical trials of gastrointestinal tolerability in lished on Mar. 7, 2002, for “Use of a Composition arthritis is discussed in Hawkey et al., Brit. J. Rheumatol., for Fast Pain Relief.” U.S. Patent Application No. 37:937 (1998), and Dequeker et al., Brit. J Rheumatol, 20020006951, published on Jan. 17, 2002, for “Solid State 37:946 (1998). Form of Celecoxib Having Enhanced Bioavailability;” and 0013 Meloxicam exhibits anti-inflammatory, , U.S. Patent Application No. 20020019431, published on and antifebrile activities. Like other NSAIDs, the primary Feb. 14, 2002, for “Porous Celecoxib Matrices and Methods mechanism of action of meloxicam is via inhibition of the of Manufacture Thereof.” describe nanoparticulate cele (COX) system resulting in coxib compositions. decreased Synthesis. See The Physicians 0008 Amorphous small particle compositions are Desk Reference, 56" Ed., pp. 1054 (2002). The COX described, for example, in U.S. Pat. No. 4,783,484 for enzyme System is comprised of at least two isoforms of “Particulate Composition and Use Thereof as Antimicrobial COX. COX-1 is constituatively expressed in the gastrointes Agent;” U.S. Pat. No. 4,826,689 for “Method for Making tinal tract and the kidneys and is involved in the production Uniformly Sized Particles from Water-Insoluble Organic of required for gastric mucosal production Compounds;" U.S. Pat. No. 4,997,454 for “Method for and proper renal blood flow. See Vane et al., Proc. Natl. Making Uniformly-Sized Particles From Insoluble Com Acad. Sci. USA, 91:2046-2050 (1994); Oulette et al., Proc. pounds;” U.S. Pat. No. 5,741,522 for “Ultrasmall, Non Natl. Acad. Sci., 98:14583-14588 (2001); and Seibert et al., aggregated Porous Particles of Uniform Size for Entrapping Proc. Natl. Acad. Sci., 91:12013-12017 (1994). In contrast, Gas Bubbles Within and Methods;” and U.S. Pat. No. COX-2 is not present in healthy tissue and its expression is 5,776,496, for “Ultrasmall Porous Particles for Enhancing induced in certain inflammatory States. Id. Ultrasound Back Scatter.” 0014. The pathological production of prostaglandins by 0009 B. Background Regarding Meloxicam COX-2 is implicated in a number of human disease States, including rheumatoid arthritis, osteoarthritis, pyrexia, 0.010 Meloxicam, also known as 4-hydroxy-2-methyl-N- asthma, bone resorption, cardiovascular diseases, nephro (5-methyl-2-thiazolyl)-2-H-1,2-benzothiazine-3-carboxam toxicity, atherOSclerosis, and hypotension. Id. Elevated lev ide 1,1-dioxide, is a member of the enolic acid group of els of prostaglandins enhance or prolong pro-inflammatory nonsteroidal anti-inflammatory drugs (NSAIDs). Meloxi Signals which cause the pain, Stiffness, and inflammation cam is an derivative with the following chemical associated with these conditions. See Smith et al., Proc. Structure: Natl. Acad. Sci., 95:13313-13318 (1998). US 2004/0229038A1 Nov. 18, 2004

0.015 Meloxicam is Superior to traditional non-selective 0019 NSAIDs, like meloxicam, are useful in pain man NSAIDs because it selectively inhibits COX-2, thus causing agement because NSAIDS provide an analgesic effect with fewer gastrointestinal problems. Such as bleeding, heartburn, out the Sedation and addictive properties of narcotic anal reflux, diarrhea, nausea, and abdominal pain. Meloxicam gesics. Furthermore, the long to of meloxicam makes it preferentially inhibits COX-2 with a COX-2/COX-1 inhi useful for long-lasting relief which is not provided by bition ratio of 0.09. It is desirable to selectively inhibit COX-2 and the pathological production of prostaglandins narcotic . However, due to their typically long for which that enzyme is responsible because the therapeutic onset of action, conventional NSAIDs, including conven analgesic/anti-inflammatory properties of NSAIDS occur by tional meloxicam, are frequently inappropriate for manage inhibition of inducible COX-2 at the site of inflammation. ment of acute pain. Conversely, the majority of adverse drug reactions to NSAIDS, including gastrointestinal ulcers and renal failure, 0020. Because meloxicam is practically insoluble in result from inhibition of the consitutative COX-1 . water, attaining Sufficient bioavailability of this drug is This is because as a result of Such COX-1 inhibition, problematic. Prior art methods of increasing the bioavail prostaglandins necessary for gastric mucosal production and ability of meloxicam include increasing its Solubility by renal blood circulation are not produced. See Vane et al., forming a cyclodextrin complex of the drug (see U.S. Pat. Proc. Natl. Acad. Sci. USA, 91:2046 (1994); Oulette et al., No. 6,284.269) or by forming a salt of meloxicam with an Proc. Natl. Acad. Sci., 98:14583 (2001); and Seibert et al., inorganic or organic base (U.S. Pat. Applin. Pub. No. US Proc. Natl. Acad. Sci., 91:12013 (1994). Compounds that selectively inhibit the biosynthesis of prostaglandins by 2002/0035107 A1). inhibiting the activity of the inducible enzyme, COX-2, 0021 Published U.S. Patent Application No. exert anti-inflammatory effects without the adverse side 20020035264, for “Ophthalmic Formulation of a Selective effects associated with COX-1 inhibition. Cyclooxygenase-2 Inhibitory Drug, describes pharmaceu 0016 Some of the trade names under which meloxicam tical compositions Suitable for topical administration to an has or is marketed include MOBIC(R), MOBEC(Rg), MOBI eye which contain a selective COX-2 inhibitory drug, or COXCR, MOVALISCR), and MOVATEC(R). Meloxicam has nanoparticles of a drug of low water Solubility, in a concen been shown to be useful in the Symptomatic treatment of tration effective for treatment and/or prophylaxis of a dis painful osteoarthritis (arthrosis, degenerative joint disease), order in the eye, and one or more ophthalmically acceptable Symptomatic treatment of rheumatoid arthritis, Symptomatic excipients that reduce rate of removal from the eye Such that treatment of ankylosing spondylitis, and Symptomatic treat the composition has an effective residence time of about 2 to ment of the Signs and Symptoms of Osteoarthritis, including about 24 hours. Examples of Such ophthalmically acceptable pain, Stiffness, and inflammation. excipients given in the published application include croSS 0.017. The form of meloxicam currently marketed in the linked carboxyl-containing polymers which form in Situ United States is MOBIC(R) (Boehringer Ingelheim Pharma gellable aqueous Solution, Suspension or Solution/Suspen ceuticals, Inc., Ridgefield, Conn.), provided in 7.5 and 15 Sion. Such excipients, which are described in U.S. Pat. No. mg tablets. The bioavailability of a single 30 mg oral dose 5,192,535, can be undesirable. Moreover, this disclosure, is 89% as compared to a 30 mg intravenous bolus injection. whis is limited to ocular formulations, does not address a The of a Single intravenous dose of need for oral fast onset meloxicam formulations for treating meloxicam is dose-proportional in the range of 5 to 60 mg. migraine. See The Physicians' Desk Reference, 56" Ed., pp. 1054 (2002). After administration of multiple oral doses of 0022) Published U.S. Patent Application No. meloxicam, the pharmacokinetics is dose-proportional in the 20020077328, for “Selective Cyclooxygenase-2 Inhibitors range of 7.5 to 15 mg. The rate or extent of absorption is not and Vasomodulator Compounds for Generalized Pain and affected by multiple dose administration. Under fasted Headache Pain,” refers to a therapeutic combination useful Steady State conditions, the mean C is achieved within in the treatment, amelioration, prevention, or delay of pain four to five hours, with a Second meloxicam concentration comprising a high energy form of a Selective cyclooxyge peak occurring at approximately twelve to fourteen hours nase-2 inhibitor, a vasomodulator, and a pharmaceutically post-dose, which Suggests gastrointestinal recirculation. acceptable excipient, carrier, or diluent. The cyclooxyge Under Steady State fed conditions in healthy adult males, the nase-2 inhibitor and vasomodulator are each being present in 7.5 mg tablets have a mean C of 1.05 ug/mL, a T of an amount effective to contribute to the treatment, preven 4.9 hrs, and a tie of 20.1 hours. Under steady state fed tion, ameloriation or delay of pain. Disclosed vasomodula conditions in elderly males and females, the 15 mg tablets tors include vasoconstrictors, vasodilators, bronchodilation have a C of 2.3 and 3.2 g/mL, respectively, a T of 5 agents, and bronchoconstriction agents, Such as rennin and 6 hrs,respectively, and a to of 21 and 24 hrs, respec angiotensin System antagonists, nitrovasodilators, direct tively. See The Physicians' Desk Reference, 56" Ed., pp. vasodilators, channel blocking drugs, phosphodi 1054 (2002). esterase inhibitors, Sympathomimetics, Sympatholytics, and Synthase inhibitors. Such additional pharmaceu 0.018. Although meloxicam has been tested and approved tical agents can be undesirable, as they can cause unwanted by the FDA only for relief of the signs and symptoms of Side-effects. Osteoarthritis, it may be useful in relieving the Signs and Symptoms of rheumatoid arthritis, lower back pain, and 0023 There is a need in the art to provide a readily acute pain, e.g. treatment of post Surgical pain, treatment of bioavailable form of meloxicam while avoiding the prior art pain resulting from battle field wounds, and migraine head methods of using Solubilizing agents, as well as avoiding the aches. Meloxicam may be especially effective for treatment prior art COX-2 inhibitor formulations having undesirable of all types of pain associated with inflammation. qualities. The present invention Satisfies this need. US 2004/0229038A1 Nov. 18, 2004

0024. There is a need in the art for nanoparticulate pyrexia, asthma, bone resorption, cardiovascular diseases, meloxicam formulations which overcome these and other nephrotoxicity, atherosclerosis, hypotension, arthrosis, problems associated with prior conventional meloxicam ankylosing spondylitis, joint Stiffness, lower back pain, pain formulations. The present invention Satisfies these needs. asSociated with inflammation, inflammatory-related disor ders, cancer, kidney disease, Alzheimer's disease, familial SUMMARY OF THE INVENTION adenomatous polyposis, fever, acute mastitis, diarrhea, 0.025 The present invention relates to compositions com colonic adenomas, and tumors. prising nanoparticulate meloxicam. The compositions com 0031. The compositions of the invention are useful in prise nanoparticulate meloxicam and at least one Surface treating indications where anti-inflammatory agents, anti stabilizer adsorbed on or associated with the Surface of the angiogenesis agents, antitumorigenic agents, immunoSup meloxicam particles. The nanoparticulate meloxicam par pressive agents, NSAIDs, COX-2 inhibitors, analgesic ticles, which have an effective average particle size of leSS agents, anti-thrombotic agents, narcotics, or antifebrile than about 2000 nm, Surprisingly exhibit Superior T agents are typically used. profiles as compared to conventional prior meloxicam for mulations. 0032 Such methods comprise administering to a subject 0026. The present invention also relates to compositions a therapeutically effective amount of a nanoparticulate of nanoparticulate meloxicam in combination with one or meloxicam composition according to the invention. Alter more other conventional or nanoparticulate active agents. If natively, Such methods comprise administering to a Subject Such other active agents are in a nanoparticulate form, then a therapeutically effective amount of a nanoparticulate Such other active agents will have one or more Surface meloxicam composition in combination with one or more Stabilizers adsorbed on or associated with to the Surface of non-meloxicam active agents. Such non-meloxicam active the active agent. The phrase “conventional active agents or agents can be either conventional or nanoparticulate. drugs,” as used in this application, refers to non-nanopar 0033. Both the foregoing general description and the ticulate active agents or drugs. Non-nanoparticulate active following detailed description are exemplary and explana agents have an effective average particle size of greater than tory and are intended to provide further explanation of the about 2 microns. invention as claimed. Other objects, advantages, and novel 0027. Another aspect of the invention is directed to features will be readily apparent to those skilled in the art pharmaceutical compositions comprising a nanoparticulate from the following detailed description of the invention. meloxicam composition of the invention. The pharmaceu tical compositions preferably comprise nanoparticulate BRIEF DESCRIPTION OF THE FIGURE meloxicam, at least one Surface Stabilizer, and a pharma ceutically acceptable carrier, as well as any desired excipi 0034 FIG. 1: Shows the plasma concentration over time ents. Alternatively, Such pharmaceutical compositions can of meloxicam following administration of three different additionally comprise one or more non-meloxicam conven meloxicam formulations: a liquid dispersion of nanoparticu tional or nanoparticulate active agents. late meloxicam, a lyophilized wafer of nanoparticulate 0028. The nanoparticulate meloxicam formulations of the meloxicam, and a tablet of conventional non-nanoparticulate invention may require Smaller doses as compared to prior meloxicam, MOBIC(R) (Boehringer Ingelheim Pharmaceu conventional meloxicam formulations. In addition, the ticals, Inc.). nanoparticulate meloxicam formulations of the invention may exhibit increased bioavailability, and Superior C. DETAILED DESCRIPTION OF THE profiles as compared to conventional prior meloxicam for INVENTION mulations. 0035. The present invention is directed to compositions 0029. This invention further discloses a method of mak comprising nanoparticulate meloxicam. The compositions ing a nanoparticulate meloxicam composition according to comprise nanoparticulate meloxicam and at least one Surface the invention. Such a method comprises contacting meloxi stabilizer adsorbed on or associated with the Surface of the cam and at least one Surface Stabilizer for a time and under drug. The nanoparticulate meloxicam particles, which have conditions Sufficient to provide a nanoparticulate meloxicam an effective average particle Size of less than about 2000 nm, composition. The one or more Surface Stabilizers can be Surprisingly exhibit Superior T. profiles as compared to contacted with meloxicam either before, during, or after size conventional prior meloxicam formulations. reduction of the meloxicam. Alternatively, one or more 0036 AS taught in the 684 patent, not every combination non-meloxicam active agents can be reduced in size at the of Surface Stabilizer and active agent will result in a stable Same time as meloxicam, to produce a nanoparticulate nanoparticulate composition. It was Surprisingly discovered meloxican and nanoparticulate non-meloxicam active agent that Stable nanoparticulate meloxicam formulations can be composition. A non-meloxicam active agent, which is either made. AS described in more detail below, preferred Surface conventional or nanoparticulate sized, can also be added to stabilizers include polyvinylpyrrolidone (e.g., Kollidon(R) 12 the nanoparticulate meloxicam composition after Size reduc PF, Kollidon(R) 17 PF), docusate sodium, block polymers of tion. polyethylene glycol and polypropylene glycol, poloxamers 0030 The present invention is directed to methods of (e.g., Pluronics F68(R) and F1086), which are block copoly using the compositions of the invention in the treatment of, mers of ethylene oxide and propylene oxide), polyethylene for example, pain, Such as post-Surgical pain, pain associated sorbitan monooleate (Polysorbate 80), sodium Deoxycho with battlefield wounds, and migraine headaches. The com late, lecithin, lysozyme, and mixtures thereof. Docusate positions of the invention can also be used in methods of Sodium is particularly useful as a Surface Stabilizer in treating the Signs and Symptoms of, for example, arthritis, combination with one or more other Surface Stabilizers. US 2004/0229038A1 Nov. 18, 2004

0037 AS described in Example 3 below, many of these using Such combination compositions are also encompassed Surface Stabilizers are particularly Suited for injectable nano by the invention. For example, additional analgesic drugs particulate meloxicam formulations. This is significant, and can be used in combination with nanoparticulate meloxicam, Surprising, as for injectable formulations it is critical that Such as one or more COX-2 inhibitors, NSAIDs, or narcot very small meloxicam particles be obtained. Moreover, the ics. Other exemplary types of active agents which can be composition must be stable, with very little or no particle used in combination with nanoparticulate meloxicam are Size growth observed, as injectable formulations having described below. If the non-meloxicam active agent is in large particles can cause embolism. nanoparticulate form, then Such a non-meloxicam active 0.038 Nanoparticulate meloxicam formulations suitable agent also has one or more Surface Stabilizers adsorbed on or parenteral injection (e.g., intravenous, intramuscular, or Sub asSociated with the Surface of the active agent. The Surface cutaneous) for the treatment of acute pain are highly Supe Stabilizer(s) adsorbed on or associated with the Surface of rior to conventional meloxicam formulations because they the non-meloxicam active agent can be the same as or have much faster onset of action due to the nanoparticulate different from the surface stabilizer(s) adsorbed on or asso Size of the active agent. ciated with the Surface of the nanoparticulate meloxicam. 0039. In addition to exhibiting dramatically Superior 0046. In general, Such non-meloxicam active agents do T profiles, the nanoparticulate meloxicam formulations not include vasomodulators, Such as those described in U.S. preferably also exhibit improved pharmacokinetic profiles Published Patent Application No. 20020077328. as compared to conventional meloxicam formulations, 0047. In yet another embodiment of the invention, a first resulting in faster onset of action and Smaller effective doses meloxicam formulation providing the pharmacokinetic pro as compared to prior conventional meloxicam formulations. file required herein is co-administered with at least one other meloxicam formulation that generates a different pharma 0040 Conventional formulations of meloxicam are inap cokinetic profile, Specifically one exhibiting slower absorp propriate for management of acute pain due to delayed onset tion into the bloodstream and therefore a longer T, and of action, as Such meloxicam formulations have a T of typically a lower C. For example, the Second meloxicam 4-6 hours, which is more than five times as long as most formulation can have a conventional particle size, which narcotic analgesic drugs. See The Physician 's Desk Refer produces a longer Ta, and typically a lower C. Alter ence, 56" Ed., pp. 446 and 1054. Unlike conventional natively, a Second, third, or fourth meloxicam formulation meloxicam formulations, nanoparticulate meloxicam formu can differ from the first, and from each other, in the effective lations, which exhibit faster onset of action, are useful in average particle sizes of each composition. The different treating acute pain where fast pain relief is required. particle sizes produce different T. The combination of 0041 Additionally, any drug, including meloxicam, can fast pain relief provided by the first formulation and longer have adverse Side effects. Thus, lower doses of meloxicam lasting pain relief provided by the Second (or third, fourth, which can achieve the same or better therapeutic effects as etc.) formulation can reduce the dose frequency required. those observed with larger doses of conventional meloxicam 0048 Preferably where co-administration of a “fast-act are desired. ing formulation and a “longer-lasting formulation is 0.042 Nanoparticulate formulations of meloxicam also desired, the two formulations are combined within a Single provide a longer duration of pain relief as compared to composition, for example a dual-release composition. traditional narcotic analgesic drugs. While traditional nar 0049. A. Compositions cotics provide fast onset of action, the duration of pain relief is short. Nanoparticulate meloxicam formulations combine 0050. The invention provides compositions comprising the fast onset of traditional narcotics with the duration of nanoparticulate meloxicam particles and at least one Surface pain relief of conventional NSAIDs. The long half-life of Stabilizer. The Surface Stabilizers are adsorbed on or asso meloxicam, approximately 20 hours as compared to 2-3 ciated with the Surface of the meloxicam particles. Surface hours for most narcotics, confers a long duration of action Stabilizers useful herein physically adhere on the Surface of and thus requires leSS frequent dosing. the nanoparticulate meloxicam but do not chemically react with the meloxicam particles or itself. Individual molecules 0043. Additionally, nanoparticulate meloxicam formula of the Surface Stabilizer are essentially free of intermolecular tions do not possess the Sedative and addictive properties of croSS-linkages. narcotic analgesics. Meloxicam does not cause drowsineSS and is not addictive, making it a preferred analgesic when 0051. The invention also provides compositions of nano ambulation is important or when treatment is protracted and particulate meloxicam in combination with one or more chemical dependency could result from continued use of conventional or nanoparticulate non-meloxicam drugs. narcotic analgesics. 0052 The present invention includes nanoparticulate 0044 Nanoparticulate formulations can be prepared for meloxicam compositions together with one or more non oral administration for treatment of, for example, migraine toxic physiologically acceptable carriers, adjuvants, or headaches. The use of oral nanoparticulate formulations also vehicles, collectively referred to as carriers. The composi provide much faster onset of action as compared to conven tions can be formulated for parenteral injection (e.g., intra venous, intramuscular, or Subcutaneous), oral (in Solid, tional orally dosed meloxicam formulations. liquid, or aerosol form), vaginal, nasal, rectal, ocular, local 0.045. In addition, the invention encompasses composi (powders, ointments or drops), buccal, intracisternal, intra tions comprising nanoparticulate meloxicam, one or more peritoneal, or topical administration, and the like. Such Surface Stabilizers, and one or more non-meloxicam active compositions can also comprise one or more conventional or agents, either conventional or nanoparticulate. Methods of nanoparticulate non-meloxicam drugs. US 2004/0229038A1 Nov. 18, 2004

0053. The present invention provides compositions of 0061 Nanoparticulate meloxicam compositions are con meloxicam with a desirable pharmacokinetic profile when templated to be useful in treatment and/or prevention of a administered to mammalian Subjects. Preferably, the T of wide range of conditions and disorders mediated by COX-2, a 7.5 mg orally administered dose of nanoparticulate including but not limited to, disorders characterized by meloxicam, when assayed in the plasma of a mammalian inflammation, pain, and/or fever. Such compositions are Subject following administration of an initial dose, is leSS especially useful as anti-inflammatory agents, Such as in than about 5 hours, less than about 4 hours, less than about treatment of arthritis, with the additional benefit of having 3 hours, less than about 2 hours, less than about 1 hour, leSS Significantly leSS harmful side effects than compositions of conventional NSAIDs that lack selectivity for COX-2 over than less than about 50 minutes, less than about 45 minutes, COX-1. In particular, Such compositions have reduced less than about 40 minutes, less than about 35 minutes, less potential for gastrointestinal toxicity and gastrointestinal than about 30 minutes, less than about 20 minutes, less than irritation including upper gastrointestinal ulceration and about 15 minutes, less than about 10 minutes, or less than bleeding, reduced potential for renal Side effects Such as about 5 minutes. reduction in renal function leading to fluid retention and 0054) In addition, preferably the C of a 7.5 mg orally exacerbation of hypertension, reduced effect on bleeding administered dose of nanoparticulate meloxicam, when times including inhibition of platelet function, and possibly assayed in the plasma of a mammalian Subject following a lessened ability to induce asthma attacks in administration of an initial dose, is greater than about 1 Sensitive asthmatic Subjects, by comparison with composi tug/mL, greater than about 3 ug/mL, greater than about 5 tions of conventional NSAIDs. tug/mL, greater than about 10 ug/mL, or greater than about 0062) Thus, nanoparticulate meloxicam compositions of 15 lug/mL. the invention are particularly useful as an alternative to conventional NSAIDs where Such NSAIDs are contraindi 0.055 The desirable pharmacokinetic profile, as used cated, for example in patients with peptic ulcers, gastritis, herein, is the pharmacokinetic profile measured after the regional enteritis, ulcerative colitis, diverticulitis, or with a initial dose of meloxicam. The compositions can be formu recurrent history of gastrointestinal lesions, gastrointestinal lated in any way as described below. bleeding, coagulation disorders including anemia Such as 0056. A preferred nanoparticulate meloxicam formula hypoprothrombinemia, hemophilia, or other bleeding prob tion of the invention exhibits in comparative pharmacoki lems, kidney disease, or in patients prior to Surgery or netic testing with a standard commercial formulation of patients taking anticoagulants. meloxicam, such as MOBICCR) from Boehringer Ingelheim Pharmaceuticals, Inc., a T not greater than about 90%, 0063. Because of the rapid onset of therapeutic effect not greater than about 80%, not greater than about 70%, not observed with the compositions of the invention, these greater than about 60%, not greater than about 50%, not compositions have particular advantages over prior conven greater than about 30%, not greater than about 25%, not tional formulations for treatment of acute COX-2 mediated greater than about 20%, not greater than about 15%, or not disorders, especially for relief of pain, for example in greater than about 10% of the T exhibited by a standard headache, including Sinus headache and migraine. commercial meloxicam formulation, e.g., MOBIC(R) tablets. 0064 Meloxicam is also useful in treating and/or pre venting, for example, arthritic disorders, gastrointestinal 0057. In addition, a preferred nanoparticulate meloxicam conditions, inflammatory conditions, pulmonary inflamma formulation of the invention exhibits in comparative phar tion, opthalmic diseases, central nervous Systems disorders, macokinetic testing with a Standard commercial formulation pain, inflammation-related cardiovascular disorders, angio of meloxicam, such as MOBIC(R) from Boehringer Ingel genesis-related disorders, benign and malignant tumors, heim Pharmaceuticals, Inc., a C, which is greater than adenomatous polyps, disorders of the female reproductive about 20%, greater than about 40%, greater than about 60%, System Such as endometriosis, osteoporosis, dySmenorrhea, greater than about 80%, greater than about 100%, greater premature labor, asthma, eosinophil-related disorders, pyr than about 140%, greater than about 180%, greater than exia, bone resorption, nephrotoxicity, hypotension, arthro about 200%, greater than about 240%, greater than about sis, joint Stiffness, kidney disease, liver disease including 280%, greater than about 300%, greater than about 340%, hepatitis, acute mastitis, diarrhea, colonic adenomas, bron greater than about 380%, or greater than about 400% of the chitis, allergic neuritis, cytomegalovirus infectivity, apopto C exhibited by a Standard commercial meloxicam for sis including HIV-induced apoptosis, lumbago; skin-related mulation, e.g., MOBIC(R) capsules. conditions Such as psoriasis, eczema, acne, burns, dermati 0.058 Any nanoparticulate meloxicam formulation giv tis, and ultraViolet radiation damage including Sunburn; ing the desired pharmacokinetic profile is Suitable for allergic rhinitis, respiratory distreSS Syndrome, and endot administration according to the present methods. OXin Shock Syndrome. Nanoparticulate meloxicam is also useful as an immunosuppressive agent. 0059) 1. Meloxicam Particles 0065 Exemplary forms of arthritic disorders which can 0060 AS used herein the term meloxicam, which is the be treated include, but are not limited to, Osteoarthritis, active ingredient in the composition, is used to mean meloxi rheumatoid arthritis, spondyloarthropathies, gouty arthritis, cam (4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2-H-1, juvenile arthritis, gout, ankylosing spondylitis, Systemic 2-benzothiazine-3-carboxamide 1,1-dioxide) or any Salt lupus erythematosus, bursitis, tendinitis, myofascial pain, thereof. Meloxicam can be present in a crystalline phase, an carpal tunnel Syndrome, fibromyalgia Syndrome, infectious amorphous phase, a Semi-crystalline phase, a Semi-amor arthritis, psoriatic arthritis, reiter's Syndrome, and Sclero phous phase, or a mixture thereof. derma US 2004/0229038A1 Nov. 18, 2004

0.066 Exemplary gastrointestinal conditions or ulcerative cardiac transplant atherosclerosis, myocardial infarction, diseases which can be treated include, but are not limited to, embolism, Stroke, thrombosis including venous thrombosis, inflammatory bowel disease, Crohn's disease, gastritis, irri angina including unstable angina, coronary plaque inflam table bowel Syndrome, ulcerative colitis, gastric ulcer, mation, bacterial-induced inflammation including Chlamy pathological but non-malignant conditions Such as heman dia-induced inflammation, Viral induced inflammation, and giomas, including infantile hemaginomas, angiofibroma of inflammation associated with Surgical procedures Such as the nasopharynx, and avascular necrosis of bone. vascular grafting including coronary artery bypass Surgery, 0067 Exemplary inflammation conditions which can be revascularization procedures including angioplasty, Stent treated include, but are not limited to, migraine headaches, placement, endarterectomy, or other invasive procedures periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin’s involving arteries, veins, and capillaries. Exemplary angio disease, Sclerodoma, rheumatic fever, type I diabetes, neu genesis-related disorders include, but are not limited to, romuscular junction disease including myasthenia gravis, inhibition of tumor angiogenesis. Such compositions are white matter disease including multiple Sclerosis, Sarcoido useful in treatment of neoplasia, including metastasis, sis, nephrotic Syndrome, Behcet's Syndrome, polymyositis, benign and malignant tumors, and neoplasia including can cer, Such as colorectal cancer, brain cancer, bone cancer, gingivitis, nephritis, hyperSensitivity, Swelling occurring epithelial cell-derived neoplasia (epithelial carcinoma) Such after injury including brain edema, myocardial ischemia, as basal cell carcinoma, adenocarcinoma, gastrointestinal post-operative inflammation including that following oph cancer Such as lip cancer, mouth cancer, esophageal cancer, thalmic Surgery Such as cataract Surgery or refractive Sur Small bowel cancer, Stomach cancer, colon cancer, liver gery, and the like. cancer, bladder cancer, pancreas cancer, ovary cancer, cer 0068 Exemplary pulmonary inflammation conditions Vical cancer, lung cancer, breast cancer, skin cancer Such as which can be treated include, but are not limited to, inflam Squamous cell and basal cell cancers, prostate cancer, renal mation associated with Viral infections and cystic fibrosis, cell carcinoma, and other known cancers that effect epithe and in bone resorption Such as that associated with lial cells throughout the body. Neoplasias for which com Osteoporosis. positions of the invention are contemplated to be particularly 0069 Exemplary opthalmic diseases or conditions which useful are gastrointestinal cancer, Barrett's esophagus, liver can be treated include, but are not limited to, retinitis, cancer, bladder cancer, pancreatic cancer, ovarian cancer, conjunctivitis, retinopathies, uveitis, ocular photophobia, prostate cancer, cerVical cancer, lung cancer, breast cancer acute injury to the eye tissue, corneal graft rejection, ocular and skin cancer. The nanoparticulate meloxicam composi neovascularization, retinal neovascularization including tions of the invention can also be used to treat fibrosis that neovascularization following injury or infection, diabetic occurs with radiation therapy. retinopathy, macular degeneration, retrolental fibroplasia, 0074 The compositions of the invention can be used to glaucoma, and neovascular glaucoma. treat Subjects having adenomatous polyps, including those 0070) Exemplary central nervous system disorders which with familial adenomatous polyposis (FAP). Additionally, can be treated include, but are not limited to, cortical Such compositions can be used to prevent polyps from dementias including Alzheimer's disease, neurodegenera forming in patients at risk of FAP. tion, and central nervous System damage resulting from 0075 Because the meloxicam compositions of the inven Stroke, ischemia, and trauma. The term “treatment' in the tion inhibit -induced Smooth muscle contraction present context includes partial or total inhibition of demen by inhibiting Synthesis of contractile , the com tias, including Alzheimer's disease, vascular dementia, positions can be used in the treatment of dysmenorrhea, multi-infarct dementia, pre-Senile dementia, alcoholic premature labor, asthma, and eosinophil-related disorders. dementia, and Senile dementia. 0076. The compositions of the invention are also useful 0071 Exemplary pain conditions which can be treated in treating indications where anti-inflammatory agents, anti include, but are not limited to, postoperative pain, pain angiogenesis agents, antitumorigenic agents, immunoSup resulting from battle field wounds, dental pain, muscular pressive agents, NSAIDs, COX-2 inhibitors, analgesic pain, pain resulting from cancer, headaches, including Sinus agents, anti-thrombotic agents, narcotics, or antifebrile headache and migraine, menstrual cramps, and pain associ agents are typically used. ated with inflammation. 0.072 The compositions of the invention are useful for 0.077 2. Non-Meloxicam Active Agents relief of pain, fever, and inflammation in a variety of 0078. The nanoparticulate meloxicam compositions of conditions including rheumatic fever, influenza, and other the invention can additionally comprise one or more non Viral infections including common cold, low back, and neck meloxicam active agents, in either a conventional or nano pain, dySmenorrhea, headache, toothache, Sprains and particulate form. The non-meloxicam active agents can be Strains, myositis, neuralgia, Synovitis, arthritis, including present in a crystalline phase, an amorphous phase, a Semi rheumatoid arthritis, degenerative joint diseases (osteoar crystalline phase, a Semi-amorphous phase, or a mixture thritis), gout, ankylosing spondylitis, bursitis, burns, and thereof. trauma following Surgical and dental procedures. 0079 If the non-meloxicam active agent is in a nanopar 0.073 Exemplary inflammation-related cardiovascular ticulate form, then it will have one or more Surface Stabi disorders which can be treated or prevented using the lizers adsorbed on or associated with the Surface of the compositions of the invention include, but are not limited to, active agent. In addition, if the active agent is in a nano vascular diseases, coronary artery disease, aneurysm, Vas particulate form it is preferably poorly Soluble, and is cular rejection, arteriosclerosis, atherOSclerosis including dispersible in at least one liquid dispersion medium. By US 2004/0229038A1 Nov. 18, 2004

“poorly Soluble' it is meant that the active agent has a Stituents of fruits, evening primrose oil, flax Seeds, solubility in a liquid dispersion medium of less than about 10 fish and marine animal oils, and probiotics. Nutra mg/mL, and preferably less than about 1 mg/mL. Useful ceuticals and dietary Supplements also include bio liquid dispersion mediums include, but are not limited to, engineered foods genetically engineered to have a water, aqueous Salt Solutions, Safflower oil, and Solvents desired property, also known as “pharmafoods.” Such as , t-butanol, hexane, and glycol. 0084 Nanoparticulate meloxican compositions useful in 0080 Such active agents can be, for example, an active, methods of the present invention can be used in combination therapeutic, or diagnostic agent. A therapeutic agent can be therapies with and other analgesics, including nar a pharmaceutical agent, including biologicS Such as proteins, cotic analgesics, Mu antagonists, Kappa receptor peptides, and nucleotides, or a diagnostic agent, Such as a antagonists, non-narcotic (i.e., non-addictive) analgesics, contrast agent, including X-ray contrast agents. The active monoamine uptake inhibitors, adenosine regulating agents, agent can be Selected from a variety of known classes of derivatives, Substance Pantagonists, neuroki drugs, including, for example, proteins, peptides, nucle nin-1 receptor antagonists and blockers, otides, anti-obesity drugs, nutraceuticals, dietary Supple among others. ments, carotenoids, corticosteroids, elastase inhibitors, anti fungals, oncology therapies, anti-emetics, analgesics, 0085 Preferred combination therapies comprise a com cardiovascular agents, anti-inflammatory agents, Such as position useful in methods of the invention with one or more NSAIDs and COX-2 inhibitors, anthelmintics, anti-arrhyth compounds Selected from , , e-aceta mic agents, antibiotics (including penicillins), anticoagul midocaproic acid, acetaminophen, acetaminoSalol, acetanil lants, antidepressants, antidiabetic agents, antiepileptics, ide, acetylsalicylic acid (aspirin), S-adenosylmethionine, antihistamines, antihypertensive agents, antimuscarinic , , allylprodine, , , agents, antimycobacterial agents, antineoplastic agents, alphaprodine, aluminum bis(acetylsalicylate), , immunosuppressants, antithyroid agents, antiviral agents, aminochlorthenoxazin, 3-amino-4-hydroxybutyric acid, anxiolytics, Sedatives (hypnotics and neuroleptics), astrin 2-amino-4-picoline, aminopropylon, aminopyrine, amix gents, beta-adrenoceptor blocking agents, blood products etrine, ammonium Salicylate, , amtolimetin and Substitutes, cardiac inotropic agents, contrast media, guacil, anilleridine, antipyrine, antipyrine Salicylate, antrafe corticosteroids, cough Suppressants (expectorants and nine, apaZone, , benorylate, , benz mucolytics), diagnostic agents, diagnostic imaging agents, piperylon, , , bermoprofen, diuretics, dopaminergics (antiparkinsonian agents), haemo , '-bisabolol, , p-bromoacetanilide, Statics, immunological agents, lipid regulating agents, 5-bromoSalicylic acid acetate, bromosaligenin, , muscle relaxants, parasympathomimetics, parathyroid cal bucloxic acid, bucolome, , bumadizon, buprenor citonin and biphosphonates, prostaglandins, radio-pharma phine, butacetin, butibufen, butophanol, calcium acetylsali ceuticals, Sex hormones (including Steroids), anti-allergic cylate, , carbiphene, , carSalam, agents, Stimulants and anoretics, Sympathomimetics, thyroid , chlorthenoxazin, choline Salicylate, cin agents, vasodilators, and Xanthines. chophen, cinmetacin, , clidanac, clometacin, clonitaZene, , clopirac, , , codeine 0081. A description of these classes of active agents and methyl , codeine phosphate, codeine Sulfate, cro a listing of Species within each class can be found in propamide, crotethamide, , , dex Martindale's The Extra Pharmacopoeia, 31 Edition (The tromoramide, , diampromide, Sodium, Pharmaceutical Press, London, 1996), specifically incorpo , , , , rated by reference. The active agents are commercially dihydrocodeinone enol acetate, , dihy available and/or can be prepared by techniques known in the droxyaluminum acetylsalicylate, , dimephep art. tanol, , dioxaphetyl butyrate, dipi 0082) Exemplary nutraceuticals and dietary supplements panone, diprocetyl, dipyrone, ditaZol, , are disclosed, for example, in Roberts et al., Nutraceuticals. emorfaZone, enfenamic acid, , , eter The Complete Encyclopedia of Supplements, Herbs, Vita Salate, , , ethoxazene, ethylmeth mins, and Healing Foods (American Nutraceutical ASSocia ylthiambutene, , , , eto tion, 2001), which is specifically incorporated by reference. nitaZene, , , , , A nutraceutical or dietary Supplement, also known fendosal, , , , fepradinol, fepra Zone, , , , fluo 0083) as phytochemicals or functional foods, is gen resone, , flu., , fosfosal, gen erally any one of a class of dietary Supplements, tisic acid, , glucame tacin, glycol Salicylate, Vitamins, minerals, herbs, or healing foods that have guaiaZulene, , , hydroxypethi medical or pharmaceutical effects on the body. dine, ibufenac, ibuprofen, , Salicylate, Exemplary nutraceuticals or dietary Supplements indomethacin, , isofeZolac, isoladol, isometha include, but are not limited to, lutein, folic acid, fatty done, isonixin, isoxepac, , , ketopro acids (e.g., DHA and ARA), fruit and vegetable fen, , p-lactophenetide, , , extracts, Vitamin and mineral Supplements, phos , , lomoxicam, , lysine acetyl phatidylserine, lipoic acid, melatonin, / Salicylate, acetylsalicylate, , chondroitin, Aloe Vera, Guggul, , amino , meperidine, , meSalamine, acids (e.g., iso-leucine, leucine, lysine, methionine, , hydrochloride, methotrimeprazine, phenylanine, threonine, tryptophan, and valine), metiaZinic acid, metofoline, , , mof green tea, lycopene, whole foods, food additives, eZolac, , , morphine hydrochloride, mor herbs, phytonutrients, antioxidants, con phine Sulfate, morpholine Salicylate, myrophine, nabume US 2004/0229038A1 Nov. 18, 2004 tone, , 1-naphthyl Salicylate, naproxen, narceline, celecoxib, (Vioxx(R), meloxicam (MOBIC(R), co , , , , nime marketed by Abbott Laboratories, Chicago, Ill., and Boe Sulide, 5'-nitro-2'-propoxyacetanilide, norlevorphanol, hiringer Ingelheim Pharmaceuticals, Inc.), (G.D. , normorphine, , olSalazine, Searle & Co.), (G.D. Searle & Co.), MK-966 , , Oxametacine, , , (Merck, in Phase III studies), (MK-663; Merck, , , papaveretum, paranyline, in Phase II studies), SC-236 (chemical name of 4-5-(4- parSalmide, , perisoxal, , phenadox chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benze one, , hydrochloride, pheno coll, , phenopyrazone, phenyl acetylsalicy nesulfonamide; G.D. Searle & Co., Skokie, Ill.); NS-398 late, , phenyl Salicylate, phenyramidol, (N-(2-cyclohexyloxy-4-nitrophenyl)methane Sulfonamide; , , pipebuZone, , piprofen, Taisho Pharmaceutical Co., Ltd., Japan); SC-58125 (methyl piraZolac, , , , proglu meta sulfone spiro(2.4)hept-5-ene I; Pharmacia/Searle & Co.); cin, , promedol, , , pro SC-57666 (Pharmacia/Searle & Co.); SC-58635 (celex poxyphene, , produaZone, protizinic acid, coxib; Pharmacia/Searle & Co.); SC-558 (Pharmacia/Searle ramifenaZone, , metilsulfate, Salac & Co.); SC-560 (Pharmacia/Searle & Co.); etodolac (Lod etamide, , , Salicylamide O-, ine(R), Wyeth-Ayerst Laboratories, Inc.); DFU (5,5-dimethyl Salicylsulfuric acid, Salsalte, Salverine, Simetride, Sodium 3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl 2(5H)-fura Salicylate, , SulfaSalazine, , Superoxide none); MK-476, L-745337, L-761066, L-761000, dismutase, , , talniflumate, , L-748780, and L-748731 (all Merck & Co.); DUP-697 , terofenamate, , thiazolinobutaZone, (5-Bromo-2-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl; , tiaramide, , tinoridine, tolfenamic DuPont Merck Pharmaceutical Co.); PGV 20229 (1-(7-tert.- acid, , , tropesin, , Xenbucin, Ximo butyl-2,3-dihydro-3,3-dimethylbenzo(b)furan-5-yl)-4-cy profen, , and . See The Merck Index, clopropylbutan-1-one) (Procter & Gamble Pharmaceuti 12th Edition (1996), Therapeutic Category and Biological cals); T-614 (3-formylamino-7-methylsulfonylamino-6- Activity Index, lists therein headed “Analgesic”, “Anti phenoxy-4H-1-benzopyran-4-one; Toyama Corp., Japan); inflammatory”, and “Antipyretic'). BF 389 (Biofor, USA); PD 136005, PD 142893, and PD 0.086 Particularly preferred combination therapies com 145065 (all Parke-Davis/Warner-Lambert Co.); flurbiprofen prise use of a nanoparticulate meloxicam composition of the (Ansaid(R); Pharmacia & Upjohn); (NIM-03, invention with an compound, more particularly MeSulid(R); Hisamitsu, Japan), (Relafen(R); where the opioid compound is codeine, meperidine, mor SmithKline Beecham, plc); flosulide (CGP28238; Novartis/ phine, or a derivative thereof. Ciba Geigy); piroxicam (Feldene(R); Pfizer); dicofenac 0087. The compound to be administered in combination (Voltaren(R) and Cataflam(R), Novartis); COX-189 (Novartis); with a nanoparticulate meloxicam composition of the inven D 1367 (Celltech Chiroscience, plc); R 805 (4 nitro 2 tion can be formulated Separately from Said composition or phenoxymethane sulfonanilide); R 807 (3 benzoyldifluo co-formulated with Said composition. Where a meloxicam romethane sulfonanilide, diflumidone); JTE-522 (Japan composition is co-formulated with a Second drug, for , Japan); FK-3311 (4'-Acetyl-2'-(2,4-difluorophe example an opioid drug, the Second drug can be formulated noxy)methanesulfonanilide; Fujisawa, Japan); FK 867 in immediate-release, rapid-onset, Sustained-release, or (Fujisawa, Japan); FR 115068 (Fujisawa, Japan); GR dual-release form. 253035 (Glaxo Wellcome); RWJ 63556 (Johnson & 0088. In an embodiment of the invention, particularly Johnson); RWJ 20485 (Johnson & Johnson); ZK 38997 where the COX-2 mediated condition is headache or (Schering); S 2474 (E)-(5)-(3,5-di-tert-butyl-4-hydroxy migraine, the nanoparticulate meloxicam composition is benzylidene)-2-ethyl-1,2-isothiazolidine-1,1-dioxide administered in combination therapy with a vasomodulator, indomethacin; Shionogi & Co., Ltd., Japan); CL 1004 preferably a Xanthine derivative having vasomodulatory (Parke-Davis); RS57067 (Hoffmann La Roche); RS 104894 effect, more preferably an alkylxanthine compound. (Hoffmann La Roche); SC 41930 (Monsanto); SB 205312 (SmithKline Beecham); SKB 209670 (SmithKline Bee 0089 Combination therapies wherein an alkylxanthine cham, plc); and Ono 1078 (Ono Pharmaceutical Co., Japan). compound is co-administered with a nanoparticulate meloxicam composition as provided herein are embraced by 0091) 3. Surface Stabilizers the present embodiment of the invention whether or not the alkylxanthine is a vasomodulator and whether or not the 0092. The choice of one or more surface stabilizers for therapeutic effectiveness of the combination is to any degree meloxicam is non-trivial and required extensive experimen attributable to a vasomodulatory effect. The term “alkylx tation to realize a desirable formulation. Accordingly, the anthine' herein embraces Xanthine derivatives having one or present invention is directed to the Surprising discovery that more C-4 alkyl Substituents, preferably methyl, and phar nanoparticulate meloxicam compositions can be made. maceutically acceptable Salts of Such Xanthine derivatives. Dimethylxanthines and trimethylxanthines, including caf 0093 Combinations of more than one surface stabilizer can be used in the invention. Useful Surface stabilizers feine, theobromine, and theophylline, are especially pre which can be employed in the invention include, but are not ferred. Most preferably, the alkylxanthine compound is limited to, known organic and inorganic pharmaceutical caffeine. excipients. Such excipients include various polymers, low 0090 Exemplary COX-2 inhibitors which can be formu molecular weight oligomers, natural products, and Surfac lated in combination with the nanoparticulate meloxicam tants. Preferred Surface Stabilizers include nonionic, cat composition of the invention include, but are not limited to, ionic, and ionic Surfactants. US 2004/0229038A1 Nov. 18, 2004

0094) Representative examples of surface stabilizers monium bromide, coconut trimethyl ammonium chloride or include hydroxypropyl methylcellulose, hydroxypropylcel bromide, coconut methyl dihydroxyethyl ammonium chlo lulose, polyvinylpyrrollidone, Sodium lauryl Sulfate, dioctyl ride or bromide, decyl triethyl ammonium chloride, decyl SulfoSuccinate, gelatin, casein, lecithin (phosphatides), dex dimethyl hydroxyethyl ammonium chloride or bromide, tran, gum acacia, , tragacanth, Stearic acid, C-dimethyl hydroxyethyl ammonium chloride or bro benzalkonium chloride, calcium Stearate, glycerol mide, coconut dimethyl hydroxyethyl ammonium chloride monoStearate, cetoStearyl , cetomacrogol emulsify or bromide, myristyl trimethyl ammonium methyl Sulphate, ing wax, Sorbitan esters, polyoxyethylene alkyl ethers (e.g., lauryl dimethyl benzyl ammonium chloride or bromide, lauryl dimethyl (ethenoxy) ammonium chloride or bro macrogol etherS Such as cetomacrogol 1000), polyoxyeth mide, N-alkyl (Cs)dimethylbenzyl ammonium chloride, ylene castor oil derivatives, polyoxyethylene Sorbitan fatty N-alkyl (Cs)dimethyl-benzyl ammonium chloride, acid esters (e.g., the commercially available Tweens(R) Such N-tetradecylidmethylbenzyl ammonium chloride monohy as e.g., Tween 2008) and Tween 808) (ICI Speciality Chemi drate, dimethyl didecyl ammonium chloride, N-alkyl and cals)); polyethylene glycols (e.g., CarbowaXS 3550(R) and (C2) dimethyl 1-napthylmethyl ammonium chloride, tri 934' (Union Carbide)), polyoxyethylene stearates, colloidal methylammonium halide, alkyl-trimethylammonium Salts Silicon dioxide, phosphates, carboxymethylcellulose cal and dialkyl-dimethylammonium Salts, lauryl trimethyl cium, carboxymethylcellulose Sodium, methylcellulose, ammonium chloride, ethoxylated alkyamidoalkyldialkylam hydroxyethylcellulose, hydroxypropylmethylcellulose monium Salt and/or an ethoxylated trialkyl ammonium Salt, phthalate, noncrystalline cellulose, magnesium aluminium dialkylbenzene dialkylammonium chloride, N-didecyldim silicate, triethanolamine, polyvinyl alcohol (PVA), 4-(1,1,3, ethyl ammonium chloride, N-tetradecyldimethylbenzyl 3-tetramethylbutyl)- polymer with ethylene oxide and ammonium, chloride monohydrate, N-alkyl(C) dim (also known as tyloxapol, Superione, and ethyl 1-naphthylmethyl ammonium chloride and dode triton), poloxamers (e.g., Pluronics F68(R) and F1086, which cyldimethylbenzyl ammonium chloride, dialkyl are block copolymers of ethylene oxide and propylene alkyl ammonium chloride, lauryl trimethyl ammonium oxide); poloxamines (e.g., Tetronic 9080E, also known as chloride, alkylbenzyl methyl ammonium chloride, alkyl Poloxamine 9080E), which is a tetrafunctional block copoly benzyl dimethyl ammonium bromide, C2, Cs, C7 trim mer derived from Sequential addition of propylene oxide and ethyl ammonium , dodecylbenzyl triethyl ammo ethylene oxide to ethylenediamine (BASF Wyandotte Cor nium chloride, poly-diallyldimethylammonium chloride (DADMAC), dimethyl ammonium chlorides, alkyldimethy poration, Parsippany, N.J.)); Tetronic 1508(R) (T-1508, a lammonium halogenides, tricetyl methyl ammonium chlo poloxamine) (BASF Wyandotte Corporation), Tritons ride, decyltrimethylammonium bromide, dodecyltriethylam X-2008, which is an alkyl aryl polyether sulfonate (Rohm monium bromide, tetradecyltrimethylammonium bromide, and Haas); Crodestas F-110(R), which is a mixture of methyl trioctylammonium chloride (ALIQUAT 336 TM), Stearate and Sucrose distearate (Croda Inc.), p-isononylphe POLYQUAT 10TM (polyguatemium 10; Buckman Labora noxypoly-(glycidol), also known as Olin-10G(R) or Surfac tories, TN), tetrabutylammonium bromide, benzyl trimethy tant 10-G(R) (Olin Chemicals, Stamford, Conn.); Crodestas lammonium bromide, choline esters (Such as choline esters SL-40B (Croda, Inc.); and SA90HCO, which is of fatty acids), benzalkonium chloride, Stearalkonium chlo CHCHC(O)N(CH)-CH(CHOH)(CHOH) (East ride compounds (Such as Stearyltrimonium chloride and man Kodak Co.); decanoyl-N-methylglucamide; n-decyl Di-stearyldimonium chloride), cetyl pyridinium bromide or B-D-glucopyranoside; n-decyl B-D-maltopyranoside; chloride, halide Salts of quaternized polyoxyethylalky n-dodecyl B-D-glucopyranoside; n-dodecyl B-D-maltoside; lamines, MIRAPOLTM (quaternized ammonium salt poly heptanoyl-N-methylglucamide; n-heptyl-B-D-glucopyrano mers) and ALKAQUATTM (benzalkonium chloride) (Alkaril Side; n-heptyl B-D-thioglucoside; n-hexyl B-D-glucopyrano Chemical Company), alkyl pyridinium Salts; amines, Such as Side; nonanoyl-N-methylglucamide; n-noyl B-D-glucopyra alkylamines, dialkylamines, alkanolamines, polyethylenep noside; octanoyl-N-methylglucamide; n-octyl-f-D- olyamines, N,N-dialkylaminoalkyl acrylates, and Vinyl pyri glucopyranoside; octyl B-D-thioglucopyranoside, PEG dine, amine Salts, Such as lauryl amine acetate, Stearylamine phospholipid, PEG-cholesterol, PEG-cholesterol derivative, acetate, alkylpyridinium Salt, and alkylimidazolium Salt, and PEG-vitamin A, PEG-vitamin E, lysozyme, random copoly amine oxides, imide azolinium Salts, protonated quaternary acrylamides, methylated quaternary polymers, Such as poly mers of vinyl pyrrollidone and Vinyl acetate, and the like. diallyl dimethylammonium chloride and poly-N-methyl 0.095 Examples of useful cationic surface stabilizers vinyl pyridinium chloride; and cationic guar. include, but are not limited to, polymers, biopolymers, 0097 Such exemplary cationic surface stabilizers and polysaccharides, cellulosics, alginates, phospholipids, and other useful cationic Surface Stabilizers are described in J. nonpolymeric compounds, Such as Zwitterionic Stabilizers, CroSS and E. Singer, Cationic Surfactants. Analytical and poly-n-methylpyridinium, anthryul pyridinium chloride, Biological Evaluation (Marcel Dekker, 1994); P and D. cationic phospholipids, chitosan, polylysine, polyvinylimi Rubingh (Editor), Cationic Surfactants. Physical Chemistry dazole, polybrene, polymethylmethacrylate trimethylammo (Marcel Dekker, 1991); and J. Richmond, Cationic Surfac niumbromide bromide (PMMTMABr), hexyldesyltrimethy tants. Organic Chemistry, (Marcel Dekker, 1990). lammonium bromide (HDMAB), and polyvinylpyrrollidone 2-dimethylaminoethyl methacrylate dimethyl sulfate. 0098. Nonpolymeric surface stabilizers are any nonpoly meric compound, Such benzalkonium chloride, a carbonium 0.096 Other useful cationic stabilizers include, but are not compound, a phosphonium compound, an OXonium com limited to, cationic lipids, Sulfonium, phosphonium, and pound, a halonium compound, a cationic organometallic quarternary ammonium compounds, Such as Stearyltrim compound, a quarternary phosphorous compound, a pyri ethylammonium chloride, benzyl-di(2-chloroethyl)ethylam dinium compound, an anilinium compound, an ammonium US 2004/0229038A1 Nov. 18, 2004 compound, a hydroxylammonium compound, a primary 0113. The surface stabilizers are commercially available ammonium compound, a Secondary ammonium compound, and/or can be prepared by techniques known in the art. a tertiary ammonium compound, and quarternary ammo nium compounds of the formula NRRRR''. For com 0114. 4. Other Pharmaceutical Excipients pounds of the formula NR. R.R.R.'": 0115 Pharmaceutical compositions according to the invention may also comprise one or more binding agents, 0099 (i) none of R-R are CH; filling agents, lubricating agents, Suspending agents, Sweet eners, flavoring agents, preservatives, buffers, wetting 0100 (ii) one of R-R is CH; agents, disintegrants, effervescent agents, and other excipi 0101 (iii) three of R-R are CH; ents. Such excipients are known in the art. 0102) (iv) all of R-R are CH; 0116 Examples of filling agents are lactose monohy drate, lactose anhydrous, and various Starches, examples of 0103 (v) two of R-R are CH, one of R-R is binding agents are various celluloses and croSS-linked poly CHCH, and one of R-R is an alkyl chain of Vinylpyrrolidone, microcrystalline cellulose, Such as Seven carbon atoms or less, Avice1(R) PH101 and Avicel(R) PH102, microcrystalline cel 0104 (vi) two of R-R are CH, one of R-R is lulose, and silicified microcrystalline cellulose (ProSolv CHCH, and one of R-R is an alkyl chain of SMCCTM). nineteen carbon atoms or more, 0117 Suitable lubricants, including agents that act on the 0105 (vii) two of R-R are CH and one of R-R flowability of a powder to be compressed, are colloidal is the group CH3(CH2), where n>1; Silicon dioxide, Such as AeroSilf) 200, talc, Stearic acid, magnesium Stearate, calcium Stearate, and Silica gel. 0106 (viii) two of R-R are CH, one of R-R is 0118. Examples of Sweeteners are any natural or artificial CHCH, and one of R-R comprises at least one Sweetener, Such as Sucrose, Xylitol, Sodium Saccharin, cycla heteroatom; mate, aspartame, and acSulfame. Examples of flavoring 0107 (ix) two of R-R are CH, one of R-R is agents are Magnasweet(R) (trademark of MAFCO), bubble CHCH, and one of R-R comprises at least one gum flavor, mint flavor, and fruit flavors, and the like. halogen; 0119) Examples of preservatives are potassium Sorbate, 0108 (x) two of R-R are CH, one of R-R is methylparaben, propylparaben, benzoic acid and its Salts, CHCH, and one of R-R comprises at least one other esters of parahydroxybenzoic acid Such as butylpara cyclic fragment; ben, Such as ethyl or benzyl alcohol, phenolic compounds Such as phenol, or quarternary compounds Such 0109 (xi) two of R-R are CH and one of R-R is a phenyl ring; or as benzalkonium chloride. 0120 Suitable diluents include pharmaceutically accept 0110 (xii) two of R-R are CH and two of R-R able inert fillers, Such as microcrystalline cellulose, lactose, are purely aliphatic fragments. dibasic calcium phosphate, Saccharides, and/or mixtures of 0111 Such compounds include, but are not limited to, any of the foregoing. Examples of diluents include micro behenalkonium chloride, benzethonium chloride, cetylpyri crystalline cellulose, such as Avice1(R) PH101 and Avicel(R) dinium chloride, behentrimonium chloride, lauralkonium PH102; lactose Such as lactose monohydrate, lactose anhy chloride, cetalkonium chloride, cetrimonium bromide, cet drous, and Pharmatose(RDCL21; dibasic calcium phosphate rimonium chloride, cethylamine hydrofluoride, chlorallyl Such as Emcompress(E); mannitol, Starch, Sorbitol; Sucrose; methenamine chloride (Quaternium-15), distearyldimonium and . chloride (Quaternium-5), dodecyl dimethyl ethylbenzyl 0121 Suitable disintegrants include lightly crosslinked ammonium chloride(Quaternium-14), Quaternium-22, polyvinyl pyrrollidone, corn Starch, potato Starch, maize Quaternium-26, Quaternium-18 hectorite, dimethylaminoet Starch, and modified Starches, croScarmelloSe Sodium, croSS hylchloride hydrochloride, cysteine hydrochloride, dietha poVidone, Sodium Starch glycolate, and mixtures thereof. nolammonium POE (10) oletyl ether phosphate, diethano lammonium POE (3)oleyl ether phosphate, tallow alkonium 0.122 Examples of effervescent agents are effervescent chloride, dimethyl dioctadecylammoniumbentonite, Stear couples Such as an organic acid and a carbonate or bicar alkonium chloride, domiphen bromide, denatonium ben bonate. Suitable organic acids include, for example, citric, Zoate, myristalkonium chloride, laurtrimonium chloride, tartaric, malic, fumaric, adipic, Succinic, and alginic acids ethylenediamine dihydrochloride, guanidine hydrochloride, and anhydrides and acid Salts. Suitable carbonates and pyridoxine HCl, iofetamine hydrochloride, meglumine bicarbonates include, for example, Sodium carbonate, hydrochloride, methylbenzethonium chloride, myrtrimo Sodium bicarbonate, potassium carbonate, potassium bicar nium bromide, oleyltrimonium chloride, polyguaternium-1, bonate, magnesium carbonate, Sodium carbonate, procainehydrochloride, cocobetaine, Stearalkonium bento L-lysine carbonate, and arginine carbonate. Alternatively, nite, Stearalkoniumhectonite, Stearyl trihydroxyethyl propy only the Sodium bicarbonate component of the effervescent lenediamine dihydrofluoride, tallowtrimonium chloride, and couple may be present. hexadecyltrimethyl ammonium bromide. 0112 Most of these surface stabilizers are known phar 0123 5. Nanoparticulate Meloxicam and Active Agent maceutical excipients and are described in detail in the Particle Size Handbook of Pharmaceutical Excipients, published jointly 0.124. The compositions of the invention comprise by the American Pharmaceutical Association and The Phar meloxicam nanoparticles which have an effective average maceutical Society of Great Britain (The Pharmaceutical particle size of less than about 2000 nm (i.e., 2 microns), less Press, 2000), specifically incorporated by reference. than about 1500 nm, less than about 1000 nm, less than US 2004/0229038A1 Nov. 18, 2004

about 900 nm, less than about 800 nm, less than about 700 Pharmaceutical Agents with Crystal Growth Modifiers;” nm, less than about 600 nm, less than about 500 nm, less U.S. Pat. No. 5,560,932 for “Microprecipitation of Nano than about 400 nm, less than about 300 nm, less than about particulate Pharmaceutical Agents; U.S. Pat. No. 5,543,133 250 nm, less than about 200 nm, less than about 150 nm, less for “Process of Preparing X-Ray Contrast Compositions than about 100 nm, less than about 75 nm, or less than about Containing Nanoparticles;” U.S. Pat. No. 5,534.270 for 50 nm, as measured by light-Scattering methods, microS “Method of Preparing Stable Drug Nanoparticles; U.S. Pat. copy, or other appropriate methods. No. 5,510,118 for “Process of Preparing Therapeutic Com 0.125 If the composition additionally comprises one or positions Containing Nanoparticles;” and U.S. Pat. No. more non-meloxicam nanoparticulate active agents, then 5,470,583 for “Method of Preparing Nanoparticle Compo Such active agents have an effective average particle size of Sitions Containing Charged Phospholipids to Reduce Aggre less than about 2000 nm (i.e., 2 microns), less than about gation,” all of which are specifically incorporated by refer 1500 nm, less than about 1000 nm, less than about 900 nm, CCC. less than about 800 nm, less than about 700 nm, less than 0133) One or more non-meloxicam active agents can also about 600 nm, less than about 500 nm, less than about 400 be reduced in size at the same time as meloxicam, to produce nm, less than about 300 nm, less than about 250 nm, less a nanoparticulate meloxican and nanoparticulate non than about 200 nm, less than about 150 nm, less than about meloxicam active agent composition. A non-meloxicam 100 nm, less than about 75 nm, or less than about 50 nm, as active agent, which is either conventional or nanoparticulate measured by light-Scattering methods, microScopy, or other sized, can also be added to the nanoparticulate meloxicam appropriate methods. composition after Size reduction. 0.126 By “an effective average particle size of less than about 2000 nm it is meant that at least 50% of the 0.134. In yet another embodiment of the invention, nano meloxicam or nanoparticulate active agent particles have a particulate meloxicam compositions of the invention can be particle size of less than about 2000 nm when measured by made in which the formulation comprises multiple nanopar the above-noted techniques. Preferably, at least 70%, 90%, ticulate meloxicam compositions, each of which has a or 95% of the meloxicam particles have a particle size of less different effective average particle size. Such a composition than the desired particle size, e.g., 2000 nm, 1500 nm, 1000 can be made by preparing the individual nanoparticulate nm, etc. meloxicam formulations using, for example, milling, pre 0127 6. Concentration of Nanoparticulate Meloxicam, cipitation, or homogenization techniques, followed by com Surface Stabilizers, and Optional One or More Active bining the different compositions to prepare a Single dosage Agents form. 0128. The relative amounts of meloxicam and one or 0.135 1. Milling to Obtain Nanoparticulate Meloxicam more Surface Stabilizers can vary widely. The optimal Dispersions amount of the individual components can depend, for 0.136 Milling meloxicam to obtain a nanoparticulate dis example, upon the particular active agent Selected, the persion comprises dispersing meloxicam particles in a liquid hydrophilic lipophilic balance (HLB), , and the dispersion medium in which meloxicam is poorly Soluble, Surface tension of water Solutions of the Stabilizer, etc. followed by applying mechanical means in the presence of 0129. The concentration of meloxicam can vary from rigid grinding media to reduce the particle Size of meloxi about 99.5% to about 0.001%, from about 95% to about cam to the desired effective average particle size. The 0.1%, and from about 90% to about 0.5%, by weight, based dispersion medium can be, for example, water, Safflower oil, on the total combined weight of the meloxicam and at least ethanol, t-butanol, glycerin, polyethylene glycol (PEG), one Surface Stabilizer, not including other excipients. hexane, or glycol. 0130. The concentration of the at least one surface sta 0.137 The meloxicam particles can be reduced in size in bilizer can vary from about 0.01% to about 99.5%, from the presence of at least one Surface Stabilizer. Alternatively, about 0.1% to about 95%, and from about 0.5% to about the meloxicam particles can be contacted with one or more 90%, by weight, based on the total combined dry weight of Surface Stabilizers after attrition. Other compounds, Such as the meloxicam and at least one Surface Stabilizer, not includ a diluent, can be added to the meloxicam/Surface Stabilizer ing other excipients. composition during the size reduction process. Dispersions can be manufactured continuously or in a batch mode. The 0131 B. Methods of Making Nanoparticulate Formula resultant nanoparticulate meloxicam dispersion can be uti tions lized in Solid or liquid dosage formulations, Such as liquid 0132) The nanoparticulate meloxicam compositions can dispersions, gels, aerosols, ointments, creams, controlled be made using, for example, milling, homogenization, or release formulations, fast melt formulations, lyophilized precipitation techniques. Exemplary methods of making formulations, tablets, capsules, delayed release formula nanoparticulate compositions are described in the 684 tions, extended release formulations, pulsatile release for patent. Methods of making nanoparticulate compositions are mulations, mixed immediate release and controlled release also described in U.S. Pat. No. 5,518,187 for “Method of formulations, etc. Grinding Pharmaceutical Substances; U.S. Pat. No. 5,718, 0.138 2. Precipitation to Obtain Nanoparticulate Meloxi 388 for “Continuous Method of Grinding Pharmaceutical cam Compositions Substances; U.S. Pat. No. 5,862.999 for “Method of Grind ing Pharmaceutical Substances;” U.S. Pat. No. 5,665,331 for 0.139. Another method of forming the desired nanopar “Co-Microprecipitation of Nanoparticulate Pharmaceutical ticulate meloxicam composition is by microprecipitation. Agents with Crystal Growth Modifiers; U.S. Pat. No. This is a method of preparing Stable dispersions of poorly 5,662,883 for “Co-Microprecipitation of Nanoparticulate Soluble active agents in the presence of one or more Surface US 2004/0229038A1 Nov. 18, 2004

Stabilizers and one or more colloid Stability enhancing 0145 Compositions suitable for parenteral injection may Surface active agents free of any trace toxic Solvents or comprise physiologically acceptable Sterile aqueous or non Solubilized heavy metal impurities. Such a method com aqueous Solutions, dispersions, Suspensions or emulsions, prises, for example: (1) dissolving meloxicam in a Suitable and Sterile powders for reconstitution into Sterile injectable Solvent; (2) adding the formulation from Step (1) to a Solutions or dispersions. Examples of Suitable aqueous and Solution comprising at least one Surface Stabilizer; and (3) nonaqueous carriers, diluents, Solvents, or vehicles includ precipitating the formulation from Step (2) using an appro ing water, ethanol, polyols (propyleneglycol, polyethylene priate non-solvent. The method can be followed by removal glycol, glycerol, and the like), Suitable mixtures thereof, of any formed Salt, if present, by dialysis or diafiltration and vegetable oils (Such as ) and injectable organic concentration of the dispersion by conventional means. The esterS Such as ethyl oleate. Proper fluidity can be maintained, resultant nanoparticulate meloxicam dispersion can be uti for example, by the use of a coating Such as lecithin, by the lized in Solid or liquid dosage formulations, Such as liquid maintenance of the required particle size in the case of dispersions, gels, aerosols, ointments, creams, controlled dispersions, and by the use of Surfactants. release formulations, fast melt formulations, lyophilized formulations, tablets, capsules, delayed release formula 0146 The nanoparticulate compositions may also contain tions, extended release formulations, pulsatile release for adjuvants Such as preserving, wetting, emulsifying, and mulations, mixed immediate release and controlled release dispensing agents. Prevention of the growth of microorgan formulations, etc. isms can be ensured by various antibacterial and antifungal agents, Such as parabens, chlorobutanol, phenol, Sorbic acid, 0140. 3. Homogenization to Obtain Meloxicam Nanopar and the like. It may also be desirable to include isotonic ticulate Compositions agents, Such as Sugars, Sodium chloride, and the like. Pro longed absorption of the injectable pharmaceutical form can 0141 Exemplary homogenization methods of preparing be brought about by the use of agents delaying absorption, active agent nanoparticulate compositions are described in Such as aluminum monoStearate and gelatin. U.S. Pat. No. 5,510,118, for “Process of Preparing Thera peutic Compositions Containing Nanoparticles.” Such a 0147 Solid dosage forms for oral administration include, method comprises dispersing meloxicain particles in a liquid but are not limited to, capsules, tablets, pills, powders, and dispersion medium, followed by Subjecting the dispersion to granules. In Such Solid dosage forms, the active agent is homogenization to reduce the particle size of the meloxicam admixed with at least one of the following: (a) one or more to the desired effective average particle size. The meloxicam inert excipients (or carriers), Such as Sodium citrate or particles can be reduced in size in the presence of at least one dicalcium phosphate; (b) fillers or extenders, Such as Surface Stabilizer. Alternatively, the meloxicam particles can Starches, lactose, Sucrose, glucose, mannitol, and Silicic be contacted with one or more Surface Stabilizers either acid; (c) binders, Such as carboxymethylcellulose, alignates, before or after attrition. Other compounds, Such as a diluent, can be added to the meloxicam/Surface Stabilizer composi gelatin, polyvinylpyrrolidone, Sucrose, and acacia; (d) tion either before, during, or after the Size reduction process. humectants, Such as glycerol; (e) disintegrating agents, Such Dispersions can be manufactured continuously or in a batch as agar-agar, calcium carbonate, potato or tapioca Starch, mode. The resultant nanoparticulate meloxicam dispersion alginic acid, certain complex Silicates, and Sodium carbon can be utilized in Solid or liquid dosage formulations, Such ate, (f) Solution retarders, Such as paraffin, (g) absorption as liquid dispersions, gels, aerosols, ointments, creams, accelerators, Such as quaternary ammonium compounds, (h) controlled release formulations, fast melt formulations, lyo wetting agents, Such as cetyl alcohol and glycerol philized formulations, tablets, capsules, delayed release for monostearate; (ii) adsorbents, Such as kaolin and bentonite; mulations, extended release formulations, pulsatile release and () lubricants, Such as talc, calcium Stearate, magnesium formulations, mixed immediate release and controlled Stearate, Solid polyethylene glycols, Sodium lauryl Sulfate, or mixtures thereof. For capsules, tablets, and pills, the dosage release formulations, etc. forms may also comprise buffering agents. 0142. C. Methods of Using Meloxicam Formulations of the Current Invention 0.148. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, Solutions, 0143. The meloxicam compositions of the present inven Suspensions, Syrups, and elixirs. In addition to the active tion can be administered to a Subject via any conventional agent, the liquid dosage forms may comprise inert diluents means including, but not limited to, orally, rectally, ocularly, commonly used in the art, Such as water or other Solvents, parenterally (e.g., intravenous, intramuscular, or Subcutane Solubilizing agents, and emulsifiers. Exemplary emulsifiers ous), intracisternally, pulmonary, intravaginally, intraperito are ethyl alcohol, , ethyl carbonate, ethyl neally, locally (e.g., powders, ointments or drops), or as a acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, buccal or nasal Spray. AS used herein, the term “Subject' is 1,3-butyleneglycol, dimethylformamide, oils, Such as cot used to mean an animal, preferably a mammal, including a tonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, human or non-human. The terms patient and Subject may be and Sesame oil, glycerol, tetrahydrofurfuryl alcohol, poly used interchangeably. ethyleneglycols, fatty acid esters of Sorbitan, or mixtures of 0144. The present invention provides a method of rapidly these Substances, and the like. increasing the plasma levels of meloxicam in a Subject. Such 0149 Besides such inert diluents, the composition can a method comprises administering to a Subject an effective also include adjuvants, Such as wetting agents, emulsifying amount of a composition comprising nanoparticulate and Suspending agents, Sweetening, flavoring, and perfum meloxicam. ing agents. US 2004/0229038A1 Nov. 18, 2004

0150 Ocular dosage forms of the nanoparticulate O157 The compositions of the invention are also useful meloxicam of the invention preferably do not include croSS in treating indications where anti-inflammatory agents, anti linked carboxyl-containing polymers, used as excipients, as angiogenesis agents, antitumorigenic agents, immunoSup described in U.S. Pat. No. 5,192,535. Such excipients can be pressive agents, NSAIDs, COX-2 inhibitors, analgesic undesirable. agents, anti-thrombotic agents, narcotics, or antifebrile agents are typically used. 0151. One of ordinary skill will appreciate that effective 0158 More detailed descriptions of the arthritis disease amounts of meloxicam can be determined empirically and conditions Osteoarthritis and rheumatoid arthritis are given can be employed in pure form or, where Such forms exist, in below. pharmaceutically acceptable Salt, ester, or prodrug form. Actual dosage levels of meloxicam in the nanoparticulate 0159) 3. Arthritis compositions of the invention may be varied to obtain an 0160 Although the term “arthritis' literally means joint amount of meloxicam that is effective to obtain a desired inflammation, arthritis refers to a group of more than 100 therapeutic response for a particular composition and rheumatic diseases and conditions that can cause pain, method of administration. The Selected dosage level there Stiffness, and Swelling in the joints. Certain conditions may fore depends upon the desired therapeutic effect, the route of affect other parts of the body, Such as the muscles, bones, administration, the potency of the administered meloxicam, and Some internal organs, and can result in debilitating, and the desired duration of treatment, and other factors. Sometimes life-threatening, complications. If left undiag nosed and untreated, arthritis can cause irreversible damage 0152 Dosage unit compositions may contain Such to the joints. amounts of Such Submultiples thereof as may be used to make up the daily dose. It will be understood, however, that 0.161 Arthritis already affects more than 42 million the Specific dose level for any particular patient will depend Americans in its chronic form, including 300,000 children. upon a variety of factors: the type and degree of the cellular By 2020, the Center for Disease Control estimates that 60 or physiological response to be achieved; activity of the million people will be affected, and that more than 11 Specific agent or composition employed; the Specific agents million will be disabled. See http://www.fda.gov/fdac/fea or composition employed; the age, body weight, general tures/2000/300 arth.html. The two most common forms of health, Sex, and diet of the patient; the time of administra the disease, osteoarthritis and rheumatoid arthritis, have the tion, route of administration, and rate of of the greatest public health implications, according to the Arthritis agent; the duration of the treatment; drugs used in combi Foundation. Id. Other common forms arthritis and related nation or coincidental with the Specific agent; and like conditions include juvenile arthritis, gout, ankylosing factors well known in the medical arts. spondylitis, Systemic lupus erythematosus, bursitis, tendini tis and myofascial pain, carpal tunnel Syndrome, fibromy 0153 1. Use of Additional Active Agents algia Syndrome, infectious arthritis, psoriatic arthritis, reit er's Syndrome, and Scleroderma. 0154) The methods of the invention also encompass administering a nanoparticulate meloxicam composition of 0162 Osteoarthritis, previously known as “degenerative the invention in combination with one or more non-meloxi joint disease, results from wear and tear on the joints, like cam active agents, in either a conventional or nanoparticu the knees, hips and fingers, or from an injury. The preSSure late form. In general, Such additional active agents do not of gravity causes physical damage to the joints and Sur include vasomodulators, Such as those described in U.S. rounding tissues, leading to pain, tenderness, Swelling, and Published Application No. 2002007328. decreased function. Initially, osteoarthritis is non-inflamma tory and its onset is Subtle and gradual, usually involving O155 2. Treatment Applications one or only a few joints. Pain is the earliest Symptom, usually made worse by repetitive use. Risk factors for 0156 The compositions of the invention are useful in Osteoarthritis include aging, joint trauma, obesity, repetitive treating and/or preventing, for example, conditions in which joint use, and diabetes. NSAIDS are contraindicated, arthritic disorders, gastrointes tinal conditions, inflammatory conditions, pulmonary 0163 Many people may have only mild discomfort with inflammation, opthalmic diseases, central nervous Systems Osteoarthritis. But as cartilage covering the ends of bones in disorders, pain, fever, inflammation-related cardiovascular the joints wears away, considerable pain, inflammation, and disorders, angiogenesis-related disorders, benign and malig loSS of movement can result. Osteoarthritis affects all parts nant tumors, adenomatous polyps, fibrosis which occurs of a joint, causing pain and Stiffness, especially after physi with radiation treatment, disorders of the female reproduc cal activity. tive System Such as endometriosis, osteoporosis, dysmenor 0164. Osteoarthritis affects more than 20 million people, rhea, premature labor, asthma, eosinophil-related disorders, and the risk of getting it increases with age. It is the most pyrexia, bone resorption, nephrotoxicity, hypotension, common joint disease. About one-third of people over age arthrosis, joint Stiffness, kidney disease, liver disease includ 35 show Some Signs of Osteoarthritis when they have X-rayS. ing hepatitis, acute mastitis, diarrhea, colonic adenomas, The joints most often affected are the knee, hip, and hand. bronchitis, allergic neuritis, cytomegalovirus infectivity, In people over age 55, Osteoarthritis of the hip is more apoptosis including HIV-induced apoptosis, lumbago, Skin common in men and Osteoarthritis of the fingerS is more related conditions Such as pSoriasis, eczema, acne, burns, common in Women. Osteoarthritis of the knees causes dermatitis, and ultraViolet radiation damage including Sun problems for both men and women. In the United States, burn, allergic rhinitis, respiratory distreSS Syndrome, and about 100,000 people can’t walk from their beds to their endotoxin shock Syndrome. Nanoparticulate meloxicam is bathrooms without help because of osteoarthritis of the knee also useful as an immunosuppressive agent. or hip. US 2004/0229038A1 Nov. 18, 2004

0.165 Rheumatoid arthritis is an autoimmune disease that occurs when the body's own immune System mistakenly TABLE 1-continued attacks the Synovium (cell lining inside the joint). This chronic, potentially disabling disease causes pain, Stiffness, Percent of Total (Per Swelling, and loSS of function in the joints. Rheumatoid Ingredient Description Tablet) arthritis affects about one in every 100 people. It affects Sodium Starch Glycorlate (Explotab (R) 5.3 Women three times more often than men. The people most Croscarmellose Sodium USP (Ac-Di-Sol (R) 4.0 likely to develop rheumatoid arthritis are those between the Magnesium Stearate NF 0.5 ages of 35 and 50. Totals 1OO.O 0166 Rheumatoid arthritis affects the joint membranes, cartilage, and bones the way Osteoarthritis does. But unlike Osteoarthritis, rheumatoid arthritis can also affect the whole body, with loSS of appetite, a general feeling of being unwell, 0173 The tablets are expected to show excellent redis and other Symptoms. The exact cause of rheumatoid arthritis persion in water as well as in Simulated biological fluids. is unknown, although it may be triggered by the immune This is significant as redispersion in Simulated biological System (the body's defenses) turning against the body. fluids is predictive of redispersion under in Vivo conditions. 0167 The following examples are given to illustrate the present invention. It should be understood, however, that the EXAMPLE 3 invention is not to be limited to the Specific conditions or 0.174. The purpose of this example was to prepare nano details described in these examples. Throughout the Speci fication, any and all references to a publicly available particulate dispersions of meloxicam Stabilized with various document, including a U.S. patent, are specifically incorpo Surface modifiers intended for injectable administration. rated by reference. 0.175 Aqueous dispersions of 5 wt. % meloxicam (Unichem Laboratories, Ltd.) and 1 wt.% stabilizer (see EXAMPLE 1. Table 2, below) were charged into a NanoMill?F) milling 0168 The purpose of this example is describe how a System (Elan Drug Delivery, Inc., King of Prussia, Pa.; See nanoparticle dispersion of meloxicam could be prepared. e.g., U.S. Pat. No. 6,431,478 for “Small Scale Mill”) 0169. A desired quantity of meloxicam and at least one equipped with a 10 cc batch chamber. surface stabilizer can be milled in the presence of suitable rigid grinding media for a Suitable period of time in, for 0176) The following NanoMillE) milling system param example, a DYNO(E)-Mill KDL (Willy A. Bachofen AG, eters were used for all of the formulations: mill speed=5500 Maschinenfabrik, Basel, Switzerland), a roller mill (U.S. rpm; total milling time=1 hour, polymeric milling media Stoneware), or a NanoMill(R) (Elan Drug Delivery Inc.) (see type=polyMilTM-200 (The Dow Chemical Co.); and a media e.g., WO 00/72973 for “Small-Scale Mill and Method load Sufficient to process. Thereof). 0177 Particle size analysis of the resultant milled dis 0170 The mean particle size of the resultant composi persions was performed using a Horiba LA-910 particle size tions, as measured using, for example, a Horiba LA-910 analyzer ((Horiba Instruments, Irvine, Calif.). The results Laser Scattering Particle Size Distribution Analyzer (Horiba are shown below in Table 2. In the table below, the value for Instruments, Irvine, Calif.) is expected to be less than 2 D50 is the particle size below which 50% of the active agent microns. The dispersion is expected to exhibit excellent particles fall. Similarly, D90 is the particle size below which Stability over an extended period of time over a range of 90% of the active agent particles fall. temperatures. TABLE 2 EXAMPLE 2 Stabilizer Mean D50 D90 Optical 0171 The purpose of this example is to describe how a Stabilizer Manufacturer (nm) (nm) (nm) Microscopy Solid dose form of nanoparticulate meloxicam could be prepared. Pluronic (E) F68 BASF 133 110 226 Stable (poloxamer 188) 0172 The nanoparticulate dispersion of Example 1 can Pluronic (E) F108 BASF 129 108 219 Stable (poloxamer 388) be spray dried, lyophilized, or Spray granulated to form a Kollidon (E) 12 PF BASF 98 90 125 Stable powder. The resulting powder or granules of nanoparticulate Kodon (R) 17 PF BASF 98 95 135 Stable meloxicam can then be mixed with the Suitable excipients, Polysorbate 80 Spectrum 227 227 322 Stable such as the ingredients listed in Table 1, followed by Sodium Prodotti 119 101 198 Stable tableting. Deoxycholate Chimici Lecithin Penta 190 169 271 Mild aggregation TABLE 1. at initial Lysozyme Fordras 95 89 117 Moderate Percent of Total (Per aggregation Ingredient Description Tablet) at initial; Stable at 24 Nanoparticulate Meloxicam Spray Dried Powder 50.2 hours Pregelatinized Starch NF (Colorcon (R) Starch 2O.O 1500) *All formulations were taken at initial time except for Lethicin and Microcrystalline Cellulose NF (Avicel(R) PH101) 2O.O Lysozyme, wherein the initial particle size was measured at 24 hr. US 2004/0229038A1 Nov. 18, 2004

0.178 The results demonstrate that meloxicam can be 0190. A wafer tray was then filled by adding 2 grams of formulated into Stable nanoparticulate compositions Suitable the diluted dispersion to each 2.5 cc well and the wafer tray for IV administration with each of the Surface stabilizers was then placed in a lyophilizer for 48 hours to produce the shown in Table 2, as all of the formulations have a particle final lyophilized wafer dosage form. Size Suitable for injectable compositions. Nanoparticulate compositions shown in Table 2 had mean particles sizes 0191 The meloxicam particle size in the lyophilized ranging from 95 to 227 nm, with D50 and D90 sizes ranging waferS appears Stable. After 2.5 months the reconstituted from 89 nm to 227 nm and 117 nm to 322 nm, respectively. mean particle size of the meloxicam particles was 111 nm. 0192) Formulation #3 (Tablet) EXAMPLE 4 0193) MOBIC(R) Tablets (Boehringer Ingelheim), 7.5 mg. 0179 The purpose of this example was to test in vivo the nanoparticulate meloxicam compositions of the invention. 0194) Dog Study Protocol 0180 Four male and four female Beagle dogs were fasted 0.195. In Phase 1, each dog received a single oral gavage overnight. In addition, each dog was fasted for four (4) hours dose of 7.5 mg meloxicam (0.75 ml of a 10 mg/ml Formu post dose. Each dog received three different meloxicam lation #1), followed by an approximately 10 mL tap water formualtions, which are described in more detail below. flush of the gavage tube. Formulation #1 was a liquid dispersion of nanoparticulate meloxicam particles; Formulation #2 was a lyophilized table 0196. In Phase 2, after a 7-day washout period, the same of nanoparticulate meloxicam particles, and Formulation #3 eight dogs received a 7.5 mg dose of meloxicam as a Single was a MOBIC(R) 7.5 mg Tablet (Boehringer Ingelheim lyophilized wafer (Formulation #2). Pharmaceuticals, Inc.). 0197). In Phase 3, after a 7-day washout period, the same 8 dogs received a single 7.5 mg tablet of MOBIC(R) (lot # 0181 Summary of Formulations Used in the Protocol 251586N) (Formulation #3). 0182 Formulation # 1. (Liquid Dispersion) 0198 Results 0183 8.0 g meloxicam (Unichem Laboratories, Ltd.) was added to a Solution containing 1.6 g F127 NF Lutrol.E) 0199 Blood samples were collected and processed to (BASF) and 70.4 g water. Lutrol(R) F127, also known as plasma at the conclusion of each phase as follows: Blood Poloxamer 407, is a block polymer consisting of 73% of Samples (approximately 1 mL) were drawn at specified time polyethylene glycol and 27% polypropylene glycol. This points into tubes containing potassium EDTA (blood col lected predose and at 0.167, 0.333,0.5,0.75, 1, 1.5, 2, 2.5, mixture was then milled in a DYNO(E)-Mill KDL (Willy A. 3, 4, 6, 8, 12, 16, 24, and 48 hours postdose). The samples Bachofen AG, Maschinenfabrik, Basel, Switzerland) at 4200 were placed on wet ice following collection. Plasma was RPM with PolyMill®-500 polymeric media for 160 min Separated and Stored frozen in tubes containing potassium utes. The mean (weight average) final meloxicam particle EDTA at approximately -20° C. until shipped to the Spon size was 111 nm, as measured on a Horiba LB-910 particle Sor-designated laboratory. The Ca, T, and AUC for the size analyzer (Horiba Instruments, Irvine, Calif.). three different formulations is shown below in Table 3. 018.4 5 grams of the meloxicam dispersion was then added to 45 grams of water to give a final concentration of TABLE 4 1% meloxicam. Formulation Cmax (ug/mL) Tmax (hours) AUC 0185. Formulation # 2 (Lyophilzed Wafers) 1 (liquid dispersion) 3.499 0.750 118.225 0186. A “fast melt” lyophilized dosage form was pre 2 (lyophilized wafer) 3.42O 1.292 106.642 pared from a nanoparticulate dispersion of meloxicam to See 3 (MOBIC (R) 2.768 3.375 99.870 how the lyophilization and reconstitution proceSS affected the pharmacokinetic data. 0200 Both the liquid dispersion of nanoparticulate 0187 8.0 g meloxicam (Unichem Laboratories, Ltd.) was meloxicam (Formulation #1) and the lyophilized wafer of added to a Solution containing 2.4 g polyvinylpyrrollidone nanoparticulate meloxicam (Formulation #2) showed a (PVP) Plasdoneg K29/32 (ISP Technologies), 1.6 g docusate faster onset time and a larger C than the commercial Sodium (Cytec), and 68 g water. This mixture was then MOBIC(R) tablet. In addition, the smaller particle sizes of the milled in a DYNO-Mill KDL (Willy A. Bachofen AG, nanoparticulate meloxicam formulations resulted in faster Maschinenfabrik, Basel, Switzerland) at 4200 RPM with dissolution, thereby producting a much shorter T(0.75 PolyMill(R)-500 polymeric media for 150 minutes. and 1.3 hours, respectively, for Formulations #1 and #2, as compared to 3.4 hours for Formulation #3). See FIG. 1. 0188 The mean particle size of the meloxicam dispersion following milling was 101 nm, as measured on a Horiba 0201 It will be apparent to those skilled in the art that LA-910 particle size analyzer. various modifications and variations can be made in the methods and compositions of the present invention without 0189 1.5 grams of the dispersion was then added to 4.0 departing from the Spirit or Scope of the invention. Thus, it grams Mannitol USP/NF (Specturm), 1.2 grams Pullulan is intended that the present invention cover the modifications (Hayashibara), 0.8 grams Glycerol USP (Spectrum), and and variations of this invention provided they come within 32.5 grams of water. the Scope of the appended claims and their equivalents. US 2004/0229038A1 Nov. 18, 2004

We claim: polyoxyethylene castor oil derivatives, polyoxyethylene Sor 1. A Stable meloxicam nanoparticulate composition com bitan fatty acid esters, polyethylene glycols, dodecyl trim prising: ethyl ammonium bromide, polyoxyethylene Stearates, col loidal Silicon dioxide, phosphates, Sodium dodecylsulfate, (a) particles of meloxicam or a Salt thereof, and carboxymethylcellulose calcium, hydroxypropyl celluloses, (b) at least one Surface Stabilizer, hydroxypropyl methylcellulose, carboxyymethylcellulose wherein the meloxicam particles have an effective aver Sodium, methylcellulose, hydroxyethylcellulose, hydrox age particle size of less than about 2000 nm. ypropylmethyl-cellulose phthalate, noncrystalline cellulose, 2. The composition of claim 1, wherein the meloxicam is magnesium aluminum Silicate, triethanolamine, polyvinyl Selected from the group consisting of a crystalline phase, an alcohol, polyvinylpyrrolidone, 4-(1,1,3,3-tetramethylbutyl)- amorphous phase, a Semi-crystalline phase, a Semi-amor phenol polymer with ethylene oxide and formaldehyde, phous phase, and mixtures thereof. poloxamers, poloxamines, a charged phospholipid, dioctyl 3. The composition of claim 1, wherein the effective SulfoSuccinate, dialkylesters of Sodium SulfoSuccinic acid, average particle Size of the nanoparticulate meloxicam par Sodium lauryl Sulfate, alkyl aryl polyether Sulfonates, mix ticles is Selected from the group consisting of less than about tures of Sucrose Stearate and Sucrose distearate, 1500 nm, less than about 1000 nm, less than about 900 nm, C.H.CHC(O)N(CH)-CH(CHOH)(CHOH), less than about 800 nm, less than about 700 nm, less than p-isononylphenoxypoly-(glycidol), decanoyl-N-methylglu about 600 nm, less than about 500 nm, less than about 400 camide; n-decyl B-D-glucopyranoside; n-decyl B-D-malto nm, less than about 300 nm, less than about 250 nm, less pyranoside; n-dodecyl B-D-glucopyranoside; n-dodecyl than about 200 nm, less than about 100 nm, less than about B-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-3- 75 nm, and less than about 50 nm. D-glucopyranoside; n-heptyl B-D-thioglucoside; n-hexyl 4. The composition of claim 1, wherein the composition B-D-glucopyranoside; nonanoyl-N-methylglucamide, is formulated for administration Selected from the group n-noyl B-D-glucopyranoside; octanoyl-N-methylglucamide; consisting of oral, pulmonary, rectal, opthalmic, colonic, n-octyl-B-D-glucopyranoside, octyl B-D-thioglucopyrano parenteral, intracisternal, intravaginal, intraperitoneal, local, side; lysozyme, PEG-phospholipid, PEG-cholesterol, PEG buccal, nasal, and topical administration. cholesterol derivative, PEG-vitamin A, PEG-vitamin E, and 5. The composition of claim 1, wherein the composition random copolymers of Vinyl acetate and Vinyl pyrrolidone. is formulated into a dosage form Selected from the group 12. The composition of claim 10, wherein at least one consisting of liquid dispersions, gels, aeroSols, ointments, cationic Surface stabilizer is selected from the group con creams, controlled release formulations, fast melt formula Sisting of a polymer, a biopolymer, a polysaccharide, a tions, lyophilized formulations, tablets, capsules, delayed cellulosic, an alginate, a nonpolymeric compound, and a release formulations, extended release formulations, pulsa phospholipid. tile release formulations, and mixed immediate release and 13. The composition of claim 10, wherein the surface controlled release formulations. Stabilizer is Selected from the group consisting of cationic 6. The composition of claim 1, wherein the composition lipids, polymethylmethacrylate trimethylammonium bro further comprises one or more pharmaceutically acceptable mide, Sulfonium compounds, polyvinylpyrrollidone-2-dim excipients, carriers, or a combination thereof. ethylaminoethyl methacrylate dimethyl Sulfate, hexadecyl 7. The composition of claim 1, wherein the meloxicam is trimethyl ammonium bromide, phosphonium compounds, present in an amount Selected from the group consisting of quartemary ammonium compounds, benzyl-di(2-chloroeth from about 99.5% to about 0.001%, from about 95% to yl)ethylammonium bromide, coconut trimethyl ammonium about 0.1%, and from about 90% to about 0.5%, by weight, chloride, coconut trimethyl ammonium bromide, coconut based on the total combined weight of the meloxicam and at methyl dihydroxyethyl ammonium chloride, coconut methyl least one Surface Stabilizer, not including other excipients. dihydroxyethyl ammonium bromide, decyl triethyl ammo 8. The composition of claim 1, wherein the at least one nium chloride, decyl dimethyl hydroxyethyl ammonium Surface Stabilizer is present in an amount Selected from the chloride, decyl dimethyl hydroxyethyl ammonium chloride group consisting of from about 0.01% to about 99.5% by bromide, C-15dimethyl hydroxyethyl ammonium chlo weight, from about 0.1% to about 95% by weight, and from ride, C2-sdimethyl hydroxyethyl ammonium chloride bro about 0.5% to about 90% by weight, based on the total mide, coconut dimethyl hydroxyethyl ammonium chloride, combined dry weight of meloxicam and at least one Surface coconut dimethyl hydroxyethyl ammonium bromide, myri Stabilizer, not including other excipients. Styl trimethyl ammonium methyl Sulphate, lauryl dimethyl 9. The composition of claim 1, comprising at least one benzyl ammonium chloride, lauryl dimethylbenzyl ammo primary Surface Stabilizer and at least one Secondary Surface nium bromide, lauryl dimethyl (ethenoxy) ammonium stabilizer. chloride, lauryl dimethyl (ethenoxy) ammonium bromide, 10. The composition of claim 1, wherein the surface N-alkyl (Cs)dimethylbenzyl ammonium chloride, Stabilizer is Selected from the group consisting of an anionic N-alkyl (Cs)dimethyl-benzyl ammonium chloride, Surface Stabilizer, a cationic Surface Stabilizer, and an ionic N-tetradecylidmethylbenzyl ammonium chloride monohy Surface Stabilizer. drate, dimethyl didecyl ammonium chloride, N-alkyl and 11. The composition of claim 10, wherein at least one (C) dimethyl 1-napthylmethyl ammonium chloride, tri Surface Stabilizer is Selected from the group consisting of methylammonium halide, alkyl-trimethylammonium Salts, cetyl pyridinium chloride, gelatin, casein, phosphatides, dialkyl-dimethylammonium Salts, lauryl trimethyl ammo dextran, glycerol, gum acacia, cholesterol, tragacanth, nium chloride, ethoxylated alkyamidoalkyldialkylammo Stearic acid, benzalkonium chloride, calcium Stearate, glyc nium Salt, an ethoxylated trialkyl ammonium Salt, dialkyl erol monoStearate, cetostearyl alcohol, cetomacrogol emul benzene dialkylammonium chloride, N-didecyldimethyl Sifying wax, Sorbitan esters, polyoxyethylene alkyl ethers, ammonium chloride, N-tetradecyldimethylbenzyl ammo US 2004/0229038A1 Nov. 18, 2004 nium, chloride monohydrate, N-alkyl(C-1) dimethyl 19. The composition of claim 1, additionally comprising 1-naphthylmethyl ammonium chloride, dodecyldimethyl at least one additional nanoparticulate meloxicam composi benzyl ammonium chloride, dialkyl benzenealkyl ammo tion, having an effective average particle size of less than nium chloride, lauryl trimethyl ammonium chloride, alkyl about 2 microns, wherein Said additional nanoparticulate benzyl methyl ammonium chloride, alkylbenzyl dimethyl meloxicam composition has an effective average particle ammonium bromide, C2 trimethyl ammonium bromides, Size which is different than particle size of the nanoparticu Cs trimethyl ammonium bromides, C7 trimethyl ammo late meloxicam composition of claim 1. nium bromides, dodecylbenzyl triethyl ammonium chloride, 20. The composition of claim 1, additionally comprising poly-diallyldimethylammonium chloride (DADMAC), dim at least one non-meloxicam active agent Selected from the ethyl ammonium chlorides, alkyldimethylammonium halo group consisting of proteins, peptides, nucleotides, anti genides, tricetyl methyl ammonium chloride, decyltrimethy obesity drugs, nutraceuticals, dietary Supplements, caro lammonium bromide, dodecyltriethylammonium bromide, tenoids, corticosteroids, elastase inhibitors, anti-fungals, tetradecyltrimethylammonium bromide, methyl trioctylam alkylxanthine, oncology therapies, anti-emetics, analgesics, opioids, antipyretics, cardiovascular agents, anti-inflamma monium chloride, POLYOUAT 10TM, tetrabutylammonium tory agents, anthelmintics, anti-arrhythmic agents, antibiot bromide, benzyl trimethylammonium bromide, choline ics, anticoagulants, antidepressants, antidiabetic agents, esters, benzalkonium chloride, Stearalkonium chloride com antiepileptics, antihistamines, antihypertensive agents, anti pounds, cetyl pyridinium bromide, cetyl pyridinium chlo muscarinic agents, antimycobacterial agents, antineoplastic ride, halide Salts of quaternized polyoxyethylalkylamines, agents, immunosuppressants, antithyroid agents, antiviral MIRAPOLTM, ALKAQUATTM, alkyl pyridinium salts; agents, anxiolytics, Sedatives, astringents, beta-adrenoceptor amines, amine Salts, amine oxides, imide azolinium Salts, blocking agents, blood products, blood Substitutes, cardiac protonated quaternary acrylamides, methylated quaternary inotropic agents, contrast media, corticosteroids, cough Sup polymers, and cationic guar. preSSants, diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics, haemoStatics, immunological 14. The composition of claim 1, wherein the T of the agents, lipid regulating agents, muscle relaxants, parasym composition, when assayed in the plasma of the mammalian pathomimetics, parathyroid calcitonin and biphosphonates, Subject, is Selected from the group consisting of less than prostaglandins, radio-pharmaceuticals, SeX hormones, anti about 5 hours, less than about 4 hours, less than about 3 allergic agents, Stimulants, anoretics, Sympathomimetics, hours, less than about 2 hours, less than about 1 hour, leSS thyroid agents, Mu receptor antagonists, Kappa receptor than less than about 50 minutes, less than about 45 minutes, antagonists, non-narcotic analgesics, monoamine uptake less than about 40 minutes, less than about 35 minutes, less inhibitors, adenosine regulating agents, cannabinoid deriva than about 30 minutes, less than about 20 minutes, less than tives, antagonists, neurokinin-1 receptor about 15 minutes, less than about 10 minutes, and less than antagonists, and Sodium channel blockers. about 5 minutes. 21. The composition of claim 20, wherein Said nutraceu 15. The composition of claim 1, wherein in comparative tical is Selected from the group consisting of lutein, folic pharmacokinetic testing with a Standard non-nanoparticulate acid, fatty acids, fruit extracts, vegetable extracts, Vitamin commercial formulation of meloxicam, the composition of Supplements, mineral Supplements, phosphatidylserine, claim 1 exhibits a T. Selected from the group consisting of lipoic acid, melatonin, glucosamine/chondroitin, Aloe Vera, less than about 90%, less than about 80%, less than about Guggul, glutamine, amino acids, green tea, lycopene, whole 70%, less than about 50%, less than about 30%, less than foods, food additives, herbs, phytonutrients, antioxidants, about 25%, less than about 20%, less than about 15%, and flavonoid constituents of fruits, evening primrose oil, flax less than about 10% of the T exhibited by the standard Seeds, fish oils, marine animal oils, and probiotics. commercial meloxicam formulation. 22. The composition of claim 20, wherein said anti inflammatory agent is a COX-2 inhibitor selected from the 16. The composition of claim 1, wherein the C of the group consisting of celecoxib, rofecoxib, Valdecoxib, pare composition, when assayed in the plasma of the mammalian coxib, MK-966, etoricoxib, 4-5-(4-chlorophenyl)-3-(trif Subject, is Selected from the group consisting of greater than luoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide, N-(2- about 1 lug/mL, greater than about 3 ug/mL, greater than cyclohexyloxy-4-nitrophenyl)methane Sulfonamide, methyl about 5 lug/mL, greater than about 10 ug/mL, and greater sulfone spiro(2.4)hept-5-ene I, SC-57666, celexcoxib, than about 15 lug/mL. SC-558, SC-560, etodolac, 5,5-dimethyl-3-(3-fluorophe 17. The composition of claim 1, wherein in comparative nyl)-4-(4-methylsulfonyl)phenyl 2(5H)-furanone, MK-476, pharmacokinetic testing with a Standard non-nanoparticulate L-745337, L-761066, L-761000, L-748780, L-748731, commercial formulation of meloxicam, the composition of 5-Bromo-2-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl, claim 1 exhibits a C. Selected from the group consisting 1-(7-tert-butyl-2,3-dihydro-3,3-dimethylbenzo(b)furan-5- of greater than about 20%, greater than about 40%, greater yl)-4-cyclopropylbutan-1-one, 3-formylamino-7-methylsul than about 60%, greater than about 80%, greater than about fonylamino-6-phenoxy-4H-1-benzopyran-4-one, BF 389, PD 136005, PD 142893, PD 145065, flurbiprofen, nime 100%, greater than about 140%, greater than about 180%, Sulide, nabumetone, floSulide, piroXicam, dicofenac, COX greater than about 200%, greater than about 240%, greater 189, D 1367, 4 nitro 2 phenoxymethane Sulfonanilide, (3 than about 280%, greater than about 300%, greater than benzoyldifluoromethane Sulfonanilide, diflumidone), JTE about 340%, greater than about 380%, and greater than 522, 4'-Acetyl-2'-(2,4-difluorophenoxy)methanesulfo about 400% of the C exhibited by a standard commercial nanilide, FK 867, FR 115068, GR 253035, RWJ 63556, meloxicam formulation. RWJ 20485, ZK 38997, (E)-(5)-(3,5-di-tert-butyl-4-hy 18. The composition of claim 1, additionally comprising droxybenzylidene)-2-ethyl-1,2-isothiazolidine-1,1-dioxide a meloxicam composition having an effective average par indomethacin, CL 1004, RS 57067, RS 104894, SC 41930, ticle size which is greater than about 2 microns. SB 205312, SKB 2.09670, and Ono 1078. US 2004/0229038A1 Nov. 18, 2004

23. The composition of claim 20, wherein said non Salicylsulfuric acid, Salsalte, Salverine, Simetride, Sodium meloxicam active agent is Selected from the group consist Salicylate, Sufentanil, SulfaSalazine, Sulindac, Superoxide ing of aceclofenac, acemetacin, e-acetamidocaproic acid, dismutase, Suprofen, SuxibuZone, talniflumate, tenidap, acetaminophen, acetaminoSalol, , acetylsalicylic tenoxicam, terofenamate, tetrandrine, thiazolinobutaZone, acid, S-adenosylmethionine, alclofenac, alfentanil, allylpro tiaprofenic acid, tiaramide, tilidine, tinoridine, tolfenamic dine, alminoprofen, aloxiprin, alphaprodine, aluminum acid, tolmetin, tramadol, tropesin, Viminol, Xenbucin, Ximo bis(acetylsalicylate), amfenac, aminochlorthenoxazin, profen, Zaltoprofen, and Zomepirac. 3-amino-4-hydroxybutyric acid, 2 -amino-4-picoline, ami 24. The composition of any of claims 20, 21, 22, or 23, nopropylon, aminopyrine, amiXetrine, ammonium Salicy wherein at least one the non-meloxicam active agents has an late, ampiroXicam, amtolimetin guacil, anilleridine, antipy effective average particle size of less than about 2 microns. rine, antipyrine Salicylate, , apaZone, bendazac, 25. The composition of any of 20, 21, 22, or 23, wherein benorylate, benoxaprofen, benzpiperylon, benzydamine, at least one the non-meloxicam active agents is a conven benzylmorphine, bermoprofen, bezitramide, '-bisabolol, tional particle sized active agent. bromfenac, p-bromoacetanilide, 5-bromosalicylic acid 26. A method of making a nanoparticulate composition acetate, bromosaligenin, bucetin, bucloxic acid, bucolome, comprising contacting meloxicam particles with at least one bufeXamac, bumadizon, , butacetin, buti Surface Stabilizer for a time and under conditions Sufficient bufen, butophanol, calcium acetylsalicylate, carbamazepine, to provide a nanoparticulate meloxicam composition having carbiphene, carprofen, carSalam, chlorobutanol, chlorth an effective average particle size of less than about 2000 nm. enoxazin, choline Salicylate, cinchophen, cinmetacin, cira 27. The method of claim 26, wherein said contacting madol, clidanac, clometacin, clonitaZene, clonixin, clopirac, comprises grinding. clove, codeine, codeine methyl bromide, codeine phosphate, 28. The method of claim 27, wherein said grinding codeine Sulfate, cropropamide, crotethamide, desomor comprises wet grinding. phine, deXOXadrol, , dezocine, diampro 29. The method of claim 26, wherein said contacting mide, diclofenac Sodium, difenamizole, difenpiramide, comprises homogenizing. diflunisal, dihydrocodeine, dihydrocodeinone enol acetate, 30. The method of claim 26, wherein said contacting dihydromorphine, dihydroxyaluminum acetylsalicylate, comprises: dimenoxadol, , dimethylthiambutene, diox aphetylbutyrate, , diprocetyl, dipyrone, ditazol, (a) dissolving the meloxicam particles in a Solvent; droXicam, emorfaZone, enfenamic acid, epirizole, eptaZO cine, etersalate, ethenZamide, ethoheptazine, ethoxazene, (b) adding the resulting meloxicam Solution to a Solution , ethylmorphine, etodolac, etofe comprising at least one Surface Stabilizer; and namate, etonitaZene, eugenol, felbinac, fenbufen, fenclozic (c) precipitating the Solubilized meloxicam having at least acid, fendosal, fenoprofen, fentanyl, fentiazac, fepradinol, one Surface Stabilizer associated with the Surface , floctafenine, flufenamic acid, flunoxaprofen, thereof by the addition thereto of a non-solvent. fluoresone, flupirtine, flu.proquaZone, flurbiprofen, fosfosal, 31. The method of claim 26, wherein the meloxicam is gentisic acid, glafenine, glucame tacin, glycol Salicylate, Selected from the group consisting of a crystalline phase, an guaiaZulene, hydrocodone, hydromorphone, hydroxypethi amorphous phase, a Semi-crystalline phase, a Semi-amor dine, ibufenac, ibuprofen, ibuproxam, , phous phase, and mixtures thereof. indomethacin, indoprofen, isofeZolac, isoladol, isometha done, isonixin, isoxepac, isoxicam, ketobemidone, ketopro 32. The method of claim 26, wherein the effective average fen, ketorolac, p-lactophenetide, lefetamine, levorphanol, particle Size of the nanoparticulate meloxicam particles is lofentanil, lonazolac, lomoxicam, loxoprofen, lysine acetyl selected from the group consisting of less than about 1500 Salicylate, magnesium acetylsalicylate, meclofenamic acid, nm, less than about 1000 nm, less than about 900 nm, less mefenamic acid, meperidine, meptazinol, meSalamine, than about 800 mm, less than about 700 nm, less than about metazocine, methadone hydrochloride, methotrimeprazine, 600 nm, less than about 500 nm, less than about 400 nm, less metiazinic acid, metofoline, metopon, mofebutaZone, mof than about 300 nm, less than about 250 rim, less than about eZolac, moraZone, morphine, morphine hydrochloride, mor 200 nm, less than about 100 nm, less than about 75 nm, and phine Sulfate, morpholine Salicylate, myrophine, nabume less than about 50 nm. tone, nalbuphine, 1-naphthyl Salicylate, naproxen, narceline, 33. The method of claim 26, wherein the composition is nefopam, nicomorphine, nifenaZone, niflumic acid, nime formulated for an administration form selected from the Sulide, 5'-nitro-2'-propoxyacetanilide, norlevorphanol, group consisting of oral, pulmonary, rectal, opthalmic, normethadone, normorphine, norpipanone, olSalazine, colonic, parenteral, intracisternal, intravaginal, intraperito opium, oxaceprol, Oxametacine, Oxaprozin, Oxycodone, neal, local, buccal, nasal, and topical administration. Oxymorphone, oxyphenbutaZone, papaveretum, paranyline, 34. The method of claim 26, wherein the composition is parSalmide, pentazocine, perisoxal, phenacetin, phenadox formulated into a dosage form Selected from the group one, phenazocine, phenazopyridine hydrochloride, pheno consisting of liquid dispersions, gels, aeroSols, ointments, coll, phenoperidine, phenopyrazone, phenyl acetylsalicy creams, controlled release formulations, fast melt formula late, phenylbutaZone, phenyl Salicylate, phenyramidol, tions, lyophilized formulations, tablets, capsules, delayed piketoprofen, piminodine, pipebuZone, piperylone, piprofen, release formulations, extended release formulations, pulsa piraZolac, piritramide, piroXicam, pranoprofen, proglu meta tile release formulations, and mixed immediate release and cin, proheptazine, promedol, propacetamol, propiram, pro controlled release formulations. poxyphene, propyphenaZone, produaZone, protizinic acid, 35. The method of claim 26, wherein the composition ramifenaZone, remifentanil, rimazolium metilsulfate, Salac further comprises one or more pharmaceutically acceptable etamide, Salicin, Salicylamide, Salicylamide O-acetic acid, excipients, carriers, or a combination thereof. US 2004/0229038A1 Nov. 18, 2004

36. The method of claim 26, wherein the meloxicam is ammonium compounds, benzyl-di(2-chloroethyl)ethylam present in an amount Selected from the group consisting of monium bromide, coconut trimethyl ammonium chloride, from about 99% to about 0.001%, from about 95% to about coconut trimethyl ammonium bromide, coconut methyl 0.5%, and from about 90% to about 0.5%, by weight, based dihydroxyethyl ammonium chloride, coconut methyl dihy on the total combined weight of the meloxicam and at least droxyethyl ammonium bromide, decyl triethyl ammonium one Surface Stabilizer, not including other excipients. chloride, decyl dimethyl hydroxyethyl ammonium chloride, 37. The method of claim 26, wherein at least one Surface decyl dimethyl hydroxyethyl ammonium chloride bromide, Stabilizer is present in an amount Selected from the group C-dimethyl hydroxyethyl ammonium chloride, C2 consisting of from about 0.01% to about 99.5% by weight, 15 dimethyl hydroxyethyl ammonium chloride bromide, from about 0.1% to about 95% by weight, and from about coconut dimethyl hydroxyethyl ammonium chloride, coco 0.5% to about 90% by weight, based on the total combined nut dimethyl hydroxyethyl ammonium bromide, myristyl dry weight of the meloxicam and at least one Surface trimethyl ammonium methyl Sulphate, lauryl dimethylben Stabilizer, not including other excipients. Zyl ammonium chloride, lauryl dimethylbenzyl ammonium 38. The method of claim 26, comprising at least one bromide, lauryl dimethyl (ethenoxy) ammonium chloride, primary Surface Stabilizer and at least one Secondary Surface lauryl dimethyl (ethenoxy) ammonium bromide, N-alkyl stabilizer. (Cs)dimethylbenzyl ammonium chloride, N-alkyl (C- 39. The method of claim 26, wherein the Surface stabilizer 1s)dimethyl-benzyl ammonium chloride, N-tetradecylidm is Selected from the group consisting of an anionic Surface ethylbenzyl ammonium chloride monohydrate, dimethyl Stabilizer, a cationic Surface Stabilizer, and an ionic Surface didecyl ammonium chloride, N-alkyl and (C) dimethyl stabilizer. 1-napthylmethyl ammonium chloride, trimethylammonium 40. The method of claim 39, wherein at least one Surface halide, alkyl-trimethylammonium Salts, dialkyl-dimethy Stabilizer is Selected from the group consisting of cetyl lammonium Salts, lauryl trimethyl ammonium chloride, pyridinium chloride, gelatin, casein, phosphatides, dextran, ethoxylated alkyamidoalkyldialkylammonium Salt, an glycerol, gum acacia, cholesterol, tragacanth, Stearic acid, ethoxylated trialkyl ammonium Salt, dialkylbenzene dialky benzalkonium chloride, calcium Stearate, glycerol lammonium chloride, N-didecyldimethyl ammonium chlo monoStearate, cetoStearyl alcohol, cetomacrogol emulsify ride, N-tetradecyldimethylbenzyl ammonium, chloride ing wax, Sorbitan esters, polyoxyethylene alkyl ethers, poly monohydrate, N-alkyl(C-1) dimethyl 1-naphthylmethyl oxyethylene castor oil derivatives, polyoxyethylene Sorbitan ammonium chloride, dodecyldimethylbenzyl ammonium fatty acid esters, polyethylene glycols, dodecyl trimethyl chloride, dialkyl benzenealkyl ammonium chloride, lauryl ammonium bromide, polyoxyethylene Stearates, colloidal trimethyl ammonium chloride, alkylbenzyl methyl ammo Silicon dioxide, phosphates, Sodium dodecylsulfate, car nium chloride, alkylbenzyl dimethyl ammonium bromide, boxymethylcellulose calcium, hydroxypropyl celluloses, C2 trimethyl ammonium bromides, Cs trimethyl ammo hydroxypropyl methylcellulose, carboxymethylcellulose nium bromides, C, trimethyl ammonium bromides, dode Sodium, methylcellulose, hydroxyethylcellulose, hydrox cylbenzyl triethyl ammonium chloride, poly-diallyldimethy ypropylmethyl-cellulose phthalate, noncrystalline cellulose, lammonium chloride (DADMAC), dimethyl ammonium magnesium aluminum Silicate, triethanolamine, polyvinyl chlorides, alkyldimethylammonium halogenides, tricetyl alcohol, polyvinylpyrrolidone, 4-(1,1,3,3-tetramethylbutyl)- methyl ammonium chloride, decyltrimethylammonium bro phenol polymer with ethylene oxide and formaldehyde, mide, dodecyltriethylammonium bromide, tetradecyltrim poloxamers, poloxamines, a charged phospholipid, dioctyl ethylammonium bromide, methyl trioctylammonium chlo SulfoSuccinate, dialkylesters of Sodium SulfoSuccinic acid, ride, POLYQUAT 10TM, tetrabutylammonium bromide, Sodium lauryl Sulfate, alkyl aryl polyether Sulfonates, mix benzyl trimethylammonium bromide, choline esters, benza tures of Sucrose Stearate and Sucrose distearate, Ikonium chloride, Stearalkonium chloride compounds, cetyl CHCHC(O)N(CH)-CH(CHOH)(CHOH), pyridinium bromide, cetyl pyridinium chloride, halide Salts p-isononylphenoxypoly-(glycidol), decanoyl-N-methylglu of quaternized polyoxyethylalkylamines, MIRAPOLTM, camide; n-decyl B-D-glucopyranoside; n-decyl B-D-malto ALKAQUATTM, alkylpyridinium salts; amines, amine salts, pyranoside; n-dodecyl B-D-glucopyranoside; n-dodecyl amine oxides, imide azolinium Salts, protonated quaternary B-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-3- acrylamides, methylated quaternary polymers, and cationic D-glucopyranoside; n-heptyl B-D-thioglucoside; n-hexyl guar. B-D-glucopyranoside; nonanoyl-N-methylglucamide, 43. The method of claim 26, wherein after preparation of n-noyl B-D-glucopyranoside; octanoyl-N-methylglucamide; a first nanoparticulate meloxicam composition, a Second n-octyl-B-D-glucopyranoside, octyl B-D-thioglucopyrano meloxicam composition having an effective average particle side; lysozyme, PEG-phospholipid, PEG-cholesterol, PEG Size of greater than about 2 microns is combined with the cholesterol derivative, PEG-vitamin A, PEG-vitamin E, and first nanoparticulate meloxicam composition. random copolymers of Vinyl acetate and vinyl pyrrolidone. 44. The method of claim 26, wherein either prior to or 41. The method of claim 39, wherein at least one cationic Subsequent to preparation of the nanoparticulate meloxicam Surface Stabilizer is Selected from the group consisting of a composition, at least one non-meloxicam active agent is polymer, a biopolymer, a polysaccharide, a cellulosic, an added to the meloxicam composition, wherein Said non alginate, a nonpolymeric compound, and a phospholipid. meloxicam active agent is Selected from the group consist 42. The method of claim 39, wherein the Surface stabilizer ing of proteins, peptides, nucleotides, anti-obesity drugs, is Selected from the group consisting of cationic lipids, nutraceuticals, dietary Supplements, carotenoids, corticos polymethylmethacrylate trimethylammonium bromide, Sul teroids, elastase inhibitors, anti-fungals, alkylxanthine, fonium compounds, polyvinylpyrrollidone-2-dimethylami Oncology therapies, anti-emetics, analgesics, opioids, anti noethyl methacrylate dimethyl sulfate, hexadecyltrimethyl pyretics, cardiovascular agents, anti-inflammatory agents, ammonium bromide, phosphonium compounds, quarternary anthelmintics, anti-arrhythmic agents, antibiotics, antico US 2004/0229038A1 Nov. 18, 2004 agulants, antidepressants, antidiabetic agents, antiepileptics, p-bromoacetanilide, 5-bromosalicylic acid acetate, bromo antihistamines, antihypertensive agents, antimuscarinic Saligenin, bucetin, bucloxic acid, bucolome, bufeXamac, agents, antimycobacterial agents, antineoplastic agents, bumadizon, buprenorphine, butacetin, butibufen, butopha immunosuppressants, antithyroid agents, antiviral agents, nol, calcium acetylsalicylate, carbamazepine, carbiphene, anxiolytics, Sedatives, astringents, beta-adrenoceptor block carprofen, carSalam, chlorobutanol, chlorthenoxazin, cho ing agents, blood products, blood Substitutes, cardiac ino line Salicylate, cinchophen, cinmetacin, ciramadol, clidanac, tropic agents, contrast media, corticosteroids, cough Sup clometacin, clonitaZene, clonixin, clopirac, clove, codeine, preSSants, diagnostic agents, diagnostic imaging agents, codeine methyl bromide, codeine phosphate, codeine Sul diuretics, dopaminergics, haemoStatics, immunological fate, cropropamide, crotethamide, desomorphine, deXOXa agents, lipid regulating agents, muscle relaxants, parasym drol, dextromoramide, dezocine, diampromide, diclofenac pathomimetics, parathyroid calcitonin and biphosphonates, Sodium, difenamizole, difenpiramide, diflunisal, dihydroco prostaglandins, radio-pharmaceuticals, SeX hormones, anti deine, dihydrocodeinone enol acetate, dihydromorphine, allergic agents, Stimulants, anoretics, Sympathomimetics, dihydroxyaluminum acetylsalicylate, dimenoxadol, dime thyroid agents, Mu receptor antagonists, Kappa receptor pheptanol, dimethylthiambutene, dioxaphetylbutyrate, dipi antagonists, non-narcotic analgesics, monoamine uptake panone, diprocetyl, dipyrone, ditazol, droxicam, emorfa inhibitors, adenosine regulating agents, cannabinoid deriva Zone, enfenamic acid, epirizole, eptazocine, eterSalate, tives, Substance P antagonists, neurokinin-1 receptor ethenZamide, ethoheptazine, ethoxazene, ethylmethylthiam antagonists, and Sodium channel blockers. , ethylmorphine, etodolac, etofenamate, etonitaZene, 45. The method of claim 44, wherein said nutraceutical is eugenol, felbinac, fenbufen, fenclozic acid, fendosal, feno Selected from the group consisting of lutein, folic acid, fatty profen, fentanyl, fentiazac, fepradinol, feprazone, floctafe acids, fruit extracts, vegetable extracts, Vitamin Supple nine, flufenamic acid, flunoxaprofen, fluoresone, flupirtine, ments, mineral Supplements, phosphatidylserine, lipoic acid, flu.proquaZone, flurbiprofen, fosfosal, gentisic acid, glafe melatonin, glucosamine/chondroitin, Aloe Vera, Guggul, nine, glucame tacin, glycol Salicylate, guaiaZulene, hydroc glutamine, amino acids, green tea, lycopene, whole foods, odone, hydromorphone, hydroxypethidine, ibufenac, ibu food additives, herbs, phytonutrients, antioxidants, fla profen, ibuproxam, imidazole Salicylate, indomethacin, vonoid constituents of fruits, evening primrose oil, flax indoprofen, isofeZolac, isoladol, , isonixin, Seeds, fish oils, marine animal oils, and probiotics. isoxepac, isoxicam, ketobemidone, , ketorolac, 46. The method of claim 44, wherein said anti-inflamma p-lactophenetide, lefetamine, levorphanol, lofentanil, lona tory agent is a COX-2 inhibitor Selected from the group Zolac, lomoxicam, loxoprofen, lysine acetylsalicylate, mag consisting of celecoxib, rofecoxib, Valdecoxib, parecoxib, nesium acetylsalicylate, meclofenamic acid, mefenamic MK-966, etoricoxib, 4-5-(4-chlorophenyl)-3-(trifluorom acid, meperidine, meptazinol, meSalamine, metazocine, ethyl)-1H-pyrazol-1-yl) benzenesulfonamide, N-(2-cyclo methadone hydrochloride, methotrimeprazine, metiazinic hexyloxy-4-nitrophenyl)methane Sulfonamide, methyl Sul acid, metofoline, metopon, mofebutaZone, , mora fone spiro(2.4)hept-5-ene I, SC-57666, celexcoxib, SC-558, Zone, morphine, morphine hydrochloride, morphine Sulfate, SC-560, etodolac, 5,5-dimethyl-3-(3-fluorophenyl)-4-(4- morpholine Salicylate, myrophine, nabumetone, nalbuphine, methylsulfonyl)phenyl 2(5H)-furanone, MK-476, 1-naphthyl Salicylate, naproxen, narceline, nefopam, nico L-745337, L-761066, L-761000, L-748780, L-748731, morphine, nifenaZone, niflumic acid, nimeSulide, 5'-nitro 5-Bromo-2-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl, 2'-propoxyacetanilide, norlevorphanol, normethadone, nor 1-(7-tert-butyl-2,3-dihydro-3,3-dimethylbenzo(b)furan-5- morphine, norpipanone, olSalazine, opium, oxaceprol, yl)-4-cyclopropylbutan-1-one, 3-formylamino-7-methylsul Oxametacine, Oxaprozin, oxycodone, oxymorphone, fonylamino-6-phenoxy-4H-1-benzopyran-4-one, BF 389, OxyphenbutaZone, papaveretum, paranyline, parSalmide, PD 136005, PD 142893, PD 145065, flurbiprofen, nime pentazocine, perisoxal, phenacetin, , phenaZO Sulide, nabumetone, floSulide, piroXicam, dicofenac, COX cine, phenazopyridine hydrochloride, phenocol, phenope 189, D 1367, 4 nitro 2 phenoxymethane sulfonanilide, (3 ridine, phenopyrazone, phenyl acetylsalicylate, phenylbuta benzoyldifluoromethane Sulfonanilide, diflumidone), JTE Zone, phenyl Salicylate, phenyramidol, piketoprofen, 522, 4'-Acetyl-2'-(2,4-difluorophenoxy)methanesulfo piminodine, pipebu Zone, piperylone, piprofen, piraZolac, nanilide, FK 867, FR 115068, GR 253035, RWJ 63556, piritramide, pirOXicam, pranoprofen, , pro RWJ 20485, ZK 38997, (E)-(5)-(3,5-di-tert-butyl-4-hy heptazine, promedol, propacetamol, propiram, pro droxybenzylidene)-2-ethyl-1,2-isothiazolidine-1,1-dioxide poxyphene, propyphenaZone, proguaZone, protizinic acid, indomethacin, CL 1004, RS 57067, RS 104894, SC 41930, ramifenaZone, remifentanil, rimazolium metilsulfate, Salac SB 205312, SKB 2.09670, and Ono 1078. etamide, Salicin, Salicylamide, Salicylamide O-acetic acid, 47. The method of claim 44, wherein said non-meloxicam Salicylsulfuric acid, Salsalte, Salverine, Simetride, Sodium active agent is Selected from the group consisting of ace Salicylate, Sufentanil, SulfaSalazine, Sulindac, Superoxide clofenac, acemetacin, e-acetamidocaproic acid, acetami dismutase, Suprofen, SuxibuZone, talniflumate, tenidap, nophen, acetaminoSalol, acetanilide, acetylsalicylic acid, tenoxicam, terofenamate, tetrandrine, thiazolinobutaZone, S-adenosylmethionine, alclofenac, alfentanil, allylprodine, tiaprofenic acid, tiaramide, tilidine, tinoridine, tolfenamic alminoprofen, aloxiprin, alphaprodine, aluminum bis(ace acid, tolmetin, tramadol, tropesin, Viminol, Xenbucin, Ximo tylsalicylate), amfenac, aminochlorthenoxazin, 3-amino-4- profen, Zaltoprofen, and Zomepirac. hydroxybutyric acid, 2 -amino-4-picoline, aminopropylon, 48. The method of any of claims 44, 45,46, or 47, wherein aminopyrine, amiXetrine, ammonium Salicylate, ampiroxi at least one non-meloxicam active agent has an effective cam, amtolimetin guacil, anilleridine, antipyrine, antipyrine average particle size of less than about 2 microns. Salicylate, antrafenine, apaZone, bendaZac, benorylate, 49. The method of any of claims 44, 45,46, or 47, wherein benoxaprofen, benzpiperylon, benzydamine, benzylmor at least one non-meloxicam active agent has an effective phine, bermoprofen, bezitramide, '-bisabolol, bromfenac, average particle size of greater than about 2 microns. US 2004/0229038A1 Nov. 18, 2004 22

50. A method of treating a subject in need with a nano ethyl ammonium bromide, polyoxyethylene Stearates, col particulate meloxicam formulation comprising administer loidal Silicon dioxide, phosphates, Sodium dodecylsulfate, ing to the Subject an effective amount of a nanoparticulate carboxymethylcellulose calcium, hydroxypropyl celluloses, composition comprising meloxicam particles and at least hydroxypropyl methylcellulose, carboxymethylcellulose one Surface Stabilizer, wherein the meloxicam particles have Sodium, methylcellulose, hydroxyethylcellulose, hydrox an effective average particle size of less than about 2000 nm. ypropylmethyl-cellulose phthalate, noncrystalline cellulose, 51. The method of claim 50, wherein the meloxicam is magnesium aluminum Silicate, triethanolamine, polyvinyl Selected from the group consisting of a crystalline phase, an alcohol, polyvinylpyrrolidone, 4-(1,1,3,3-tetramethylbutyl)- amorphous phase, a Semi-crystalline phase, a Semi-amor phenol polymer with ethylene oxide and formaldehyde, phous phase, and mixtures thereof. poloxamers, poloxamines, a charged phospholipid, dioctyl 52. The method of claim 50, wherein the effective average SulfoSuccinate, dialkylesters of Sodium SulfoSuccinic acid, particle Size of the nanoparticulate meloxicam particles is Sodium lauryl Sulfate, alkyl aryl polyether Sulfonates, mix selected from the group consisting of less than about 1500 tures of Sucrose Stearate and Sucrose distearate, nm, less than about 1000 nm, less than about 900 nm, less CHCHC(O)N(CH)-CH(CHOH)(CHOH), than about 800 nm, less than about 700 nm, less than about p-isononylphenoxypoly-(glycidol), decanoyl-N-methylglu 600 nm, less than about 500 nm, less than about 400 nm, less camide; n-decyl B-D-glucopyranoside; n-decyl B-D-malto than about 300 nm, less than about 250 nm, less than about pyranoside; n-dodecyl B-D-glucopyranoside; n-dodecyl 200 nm, less than about 100 nm, less than about 75 nm, and B-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-3- less than about 50 nm. D-glucopyranoside; n-heptyl B-D-thioglucoside; n-hexyl 53. The method of claim 50, wherein the composition is B-D-glucopyranoside; nonanoyl-N-methylglucamide, formulated for an administration form selected from the n-noyl B-D-glucopyranoside; octanoyl-N-methylglucamide; group consisting of oral, pulmonary, rectal, opthalmic, n-octyl-B-D-glucopyranoside, octyl B-D-thioglucopyrano colonic, parenteral, intracistemal, intravaginal, intraperito side; lysozyme, PEG-phospholipid, PEG-cholesterol, PEG neal, local, buccal, nasal, and topical administration. cholesterol derivative, PEG-vitamin A, PEG-vitamin E, and 54. The method of claim 50, wherein the composition is random copolymers of Vinyl acetate and Vinyl pyrrolidone. a dosage form Selected from the group consisting of liquid 61. The method of claim 59, wherein at least one cationic dispersions, gels, aerosols, ointments, creams, controlled Surface Stabilizer is Selected from the group consisting of a release formulations, fast melt formulations, lyophilized polymer, a biopolymer, a polysaccharide, a cellulosic, an formulations, tablets, capsules, delayed release formula alginate, a nonpolymeric compound, and a phospholipid. tions, extended release formulations, pulsatile release for 62. The method of claim 59, wherein the Surface stabilizer mulations, and mixed immediate release and controlled is Selected from the group consisting of benzalkonium release formulations. chloride, polymethylmethacrylate trimethylammonium bro 55. The method of claim 50, wherein the composition mide, polyvinylpyrrollidone-2-dimethylaminoethyl meth further comprises one or more pharmaceutically acceptable acrylate dimethyl Sulfate, hexadecyltrimethyl ammonium excipients, carriers, or a combination thereof. bromide, cationic lipids, Sulfonium compounds, phospho 56. The method of claim 50, wherein the meloxicam is nium compounds, quarternary ammonium compounds, ben present in an amount Selected from the group consisting of Zyl-di(2-chloroethyl)ethylammonium bromide, coconut tri from about 99% to about 0.001%, from about 95% to about methyl ammonium chloride, coconut trimethyl ammonium 0.5%, and from about 90% to about 0.5%, by weight, based bromide, coconut methyl dihydroxyethyl ammonium chlo on the total combined weight of the meloxicam and at least ride, coconut methyl dihydroxyethyl ammonium bromide, one Surface Stabilizer, not including other excipients. decyl triethyl ammonium chloride, decyl dimethyl hydroxy 57. The method of claim 50, wherein at least one Surface ethyl ammonium chloride, decyl dimethyl hydroxyethyl Stabilizer is present in an amount Selected from the group ammonium chloride bromide, C-dimethyl hydroxyethyl consisting of from about 0.01% to about 99.5% by weight, ammonium chloride, C-dimethyl hydroxyethyl ammo from about 0.1% to about 95% by weight, and from about nium chloride bromide, coconut dimethyl hydroxyethyl 0.5% to about 90% by weight, based on the total combined ammonium chloride, coconut dimethyl hydroxyethyl ammo dry weight of meloxicam and at least one Surface Stabilizer, nium bromide, myristyl trimethyl ammonium methyl Sul not including other excipients. phate, lauryl dimethyl benzyl ammonium chloride, lauryl 58. The method of claim 50, comprising at least one dimethyl benzyl ammonium bromide, lauryl dimethyl primary Surface Stabilizer and at least one Secondary Surface (ethenoxy) ammonium chloride, lauryl dimethyl stabilizer. (ethenoXY), ammonium bromide, N-alkyl (C1-)dimeth 59. The method of claim 50, wherein the Surface stabilizer ylbenzyl ammonium chloride, N-alkyl (Cs)dimethyl is Selected from the group consisting of an anionic Surface benzyl ammonium chloride, N-tetradecylidmethylbenzyl Stabilizer, a cationic Surface Stabilizer, and an ionic Surface ammonium chloride monohydrate, dimethyl didecyl ammo stabilizer. nium chloride, N-alkyl and (C2) dimethyl 1-napthylm 60. The method of claim 59, wherein the at least one ethyl ammonium chloride, trimethylammonium halide, Surface Stabilizer is Selected from the group consisting of alkyl-trimethylammonium Salts, dialkyl-dimethylammo cetyl pyridinium chloride, gelatin, casein, phosphatides, nium Salts, lauryl trimethyl ammonium chloride, ethoxy dextran, glycerol, gum acacia, cholesterol, tragacanth, lated alkyamidoalkyldialkylammonium Salt, an ethoxylated Stearic acid, benzalkonium chloride, calcium Stearate, glyc trialkyl ammonium Salt, dialkylbenzene dialkylammonium erol monoStearate, cetostearyl alcohol, cetomacrogol emul chloride, N-didecyldimethyl ammonium chloride, N-tet Sifying wax, Sorbitan esters, polyoxyethylene alkyl ethers, radecyldimethylbenzyl ammonium, chloride monohydrate, polyoxyethylene castor oil derivatives, polyoxyethylene Sor N-alkyl(C2) dimethyl 1-naphthylmethyl ammonium bitan fatty acid esters, polyethylene glycols, dodecyl trim chloride, dodecyldimethylbenzyl ammonium chloride, US 2004/0229038A1 Nov. 18, 2004 23 dialkyl benzenealkyl ammonium chloride, lauryl trimethyl 68. The method of claim 50, wherein said composition ammonium chloride, alkylbenzyl methyl ammonium chlo additionally comprising at least one non-meloxicam active ride, alkylbenzyl dimethyl ammonium bromide, C2 trim agent Selected from the group consisting of proteins, pep ethyl ammonium bromides, Cs trimethyl ammonium bro tides, nucleotides, anti-obesity drugs, nutraceuticals, dietary mides, C, trimethyl ammonium bromides, dodecylbenzyl Supplements, carotenoids, corticosteroids, elastase inhibi triethyl ammonium chloride, poly-diallyldimethylammo tors, anti-fungals, alkylxanthine, oncology therapies, anti nium chloride (DADMAC), dimethyl ammonium chlorides, emetics, analgesics, opioids, antipyretics, cardiovascular alkyldimethylammonium halogenides, tricetyl methyl agents, anti-inflammatory agents, anthelmintics, anti-ar rhythmic agents, antibiotics, anticoagulants, antidepres ammonium chloride, decyltrimethylammonium bromide, Sants, antidiabetic agents, antiepileptics, antihistamines, dodecyltriethylammonium bromide, tetradecyltrimethylam antihypertensive agents, antimuscarinic agents, antimyco monium bromide, methyl trioctylammonium chloride, bacterial agents, antineoplastic agents, immunosuppres POLYOUAT 10TM, tetrabutylammonium bromide, benzyl Sants, antithyroid agents, antiviral agents, anxiolytics, Seda trimethylammonium bromide, choline esters, benzalko tives, astringents, beta-adrenoceptor blocking agents, blood nium chloride, Stearalkonium chloride compounds, cetyl products, blood Substitutes, cardiac inotropic agents, con pyridinium bromide, cetyl pyridinium chloride, halide Salts trast media, corticosteroids, cough Suppressants, diagnostic of quaternized polyoxyethylalkylamines, MIRAPOLTM, agents, diagnostic imaging agents, diuretics, dopaminergics, ALKAQUATTM, alkyl pyridinium salts; amines, amine salts, haemostatics, immunological agents, lipid regulating agents, amine oxides, imide azolinium Salts, protonated quaternary muscle relaxants, parasympathomimetics, parathyroid cal acrylamides, methylated quaternary polymers, and cationic citonin and biphosphonates, prostaglandins, radio-pharma guar. ceuticals, SeX hormones, anti-allergic agents, Stimulants, 63. The method of claim 50, wherein the T of the anoretics, Sympathomimetics, thyroid agents, Mu receptor nanoparticulate composition, when assayed in the plasma of antagonists, Kappa receptor antagonists, non-narcotic anal the mammalian Subject, is Selected from the group consist gesics, monoamine uptake inhibitors, adenosine regulating ing of less than about 5 hours, less than about 4 hours, leSS agents, cannabinoid derivatives, Substance Pantagonists, than about 3 hours, less than 2 hours, less than about 1 hour, neurokinin-1 receptor antagonists, and Sodium channel less than less than about 50 minutes, less than about 45 blockers. minutes, less than about 40 minutes, less than about 35 69. The method of claim 68, wherein said nutraceutical is minutes, less than about 30 minutes, less than about 20 Selected from the group consisting of lutein, folic acid, fatty acids, fruit extracts, vegetable extracts, Vitamin Supple minutes, less than about 15 minutes, less than about 10 ments, mineral Supplements, phosphatidylserine, lipoic acid, minutes, and less than about 5 minutes. melatonin, glucosamine/chondroitin, Aloe Vera, Guggul, 64. The method of claim 50, wherein the C. of the glutamine, amino acids, green tea, lycopene, whole foods, nanoparticulate composition, when assayed in the plasma of food additives, herbs, phytonutrients, antioxidants, fla the mammalian Subject, is Selected from the group consist vonoid constituents of fruits, evening primrose oil, flax ing of greater than about 1 lug/mL, greater than about 3 Seeds, fish oils, marine animal oils, and probiotics. tug/mL, greater than about 5 lug/mL, greater than about 10 70. The method of claim 68, wherein said anti-inflamma tug/mL, and greater than about 15 lug/mL. tory agent is a COX-2 inhibitor selected from the group 65. The method of claim 50, wherein the method is used consisting of celecoxib, rofecoxib, Valdecoxib, parecoxib, to treat a condition Selected from the group consisting of MK-966, etoricoxib, 4-5-(4-chlorophenyl)-3-(trifluorom conditions in which NSAIDs are contraindicated, arthritic ethyl)-1H-pyrazol-1-yl) benzenesulfonamide, N-(2-cyclo disorders, gastrointestinal conditions, inflammatory condi hexyloxy-4-nitrophenyl)methane Sulfonamide, methyl Sul tions, pulmonary inflammation, opthalmic diseases, central fone spiro(2.4)hept-5-ene I, SC-57666, celexcoxib, SC-558, nervous Systems disorders, pain, fever, inflammation-related SC-560, etodolac, 5,5-dimethyl-3-(3-fluorophenyl)-4-(4- cardiovascular disorders, angiogenesis-related disorders, methylsulfonyl)phenyl 2(5H)-furanone, MK-476, benign tumors, malignant tumors, adenomatous polyps, L-745337, L-761066, L-761000, L-748780, L-748731, endometriosis, osteoporosis, dysmenorrhea, premature 5-Bromo-2-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl, labor, asthma, fibrosis which occurs with radiation treat 1-(7-tert-butyl-2,3-dihydro-3,3-dimethylbenzo(b)furan-5- ment, eosinophil-related disorders, pyrexia, bone resorption, yl)-4 -cyclopropylbutan-1-one, 3-formylamino-7-methyl nephrotoxicity, hypotension, arthrosis, joint Stiffness, kidney Sulfonylamino-6-phenoxy-4H-1-benzopyran-4-one, BF disease, liver disease, acute mastitis, diarrhea, colonic 389, PD 136005, PD 142893, PD 145065, flurbiprofen, adenomas, bronchitis, allergic neuritis, cytomegalovirus nimeSulide, nabumetone, floSulide, piroXicam, dicofenac, infectivity, apoptosis, lumbago, pSoriasis, eczema, acne, COX-189, D 1367, 4 nitro 2 phenoxymethane sulfonanilide, burns, dermatitis, ultraViolet radiation damage, allergic (3 benzoyldifluoromethane Sulfonanilide, diflumidone), rhinitis, respiratory distress Syndrome, and endotoxin shock JTE-522, 4'-Acetyl-2'-(2,4-difluorophenoxy)methanesulfo Syndrome. nanilide, FK 867, FR 115068, GR 253035, RWJ 63556, 66. The method of claim 50, wherein the method is used RWJ 20485, ZK 38997, (E)-(5)-(3,5-di-tert-butyl-4-hy to treat an indication in which anti-inflammatory agents, droxybenzylidene)-2-ethyl-1,2-isothiazolidine-1,1-dioxide anti-angiogenesis agents, antitumorigenic agents, immuno indomethacin, CL 1004, RS 57067, RS 104894, SC 41930, Suppressive agents, NSAIDS, COX-2 inhibitors, analgesic SB 205312, SKB 2.09670, and Ono 1078. agents, anti-thrombotic agents, narcotics, or antifebrile 71. The method of claim 68, wherein said non-meloxicam agents are typically used. active agent is Selected from the group consisting of ace 67. The method of claim 50, wherein said subject is a clofenac, acemetacin, e-acetamidocaproic acid, acetami human. nophen, acetaminoSalol, acetanilide, acetylsalicylic acid, US 2004/0229038A1 Nov. 18, 2004 24

S-adenosylmethionine, alclofenac, alfentanil, allylprodine, nesium acetylsalicylate, meclofenamic acid, mefenamic alminoprofen, aloxiprin, alphaprodine, aluminum bis(ace acid, meperidine, meptazinol, meSalamine, metazocine, tylsalicylate), amfenac, aminochlorthenoxazin, 3-amino-4- methadone hydrochloride, methotrimeprazine, metiazinic hydroxybutyric acid, 2-amino-4-picoline, aminopropylon, acid; metofoline, metopon, mofebutaZone, mofeZolac, mora aminopyrine, amiXetrine, ammonium Salicylate, ampiroxi Zone, morphine, morphine hydrochloride, morphine Sulfate, cam, amtolimetin guacil, anilleridine, antipyrine, antipyrine morpholine Salicylate, myrophine, nabumetone, nalbuphine, Salicylate, antrafenine, apaZone, bendaZac, benorylate, 1-naphthyl Salicylate, naproxen, narceline, nefopam, nico benoxaprofen, benzpiperylon, benzydamine, benzylmor morphine, nifenaZone, niflumic acid, nimeSulide, 5'-nitro phine, bermoprofen, beZitramide, '-bisabolol, bromfenac, 2'-propoxyacetanilide, norlevorphanol, normethadone, nor p-bromoacetanilide, 5-bromosalicylic acid acetate, bromo morphine, norpipanone, olSalazine, opium, oxaceprol, Saligenin, bucetin, bucloxic acid, bucolome, bufeXamac, Oxametacine, Oxaprozin, oxycodone, oxymorphone, bumadizon, buprenorphine, butacetin, butibufen, butopha OxyphenbutaZone, papaveretum, paranyline, parSalmide, nol, calcium acetylsalicylate, carbamazepine, carbiphene, pentazocine, perisoxal, phenacetin, phenadoxone, phenaZO carprofen, carSalam, chlorobutanol, chlorthenoxazin, cho cine, phenazopyridine hydrochloride, phenocol, phenope line Salicylate, cinchophen, cinmetacin, ciramadol, clidanac, ridine, phenopyrazone, phenyl acetylsalicylate, phenylbuta clometacin, clonitaZene, clonixin, clopirac, clove, codeine, Zone, phenyl Salicylate, phenyramidol, piketoprofen, codeine methyl bromide, codeine phosphate, codeine Sul piminodine, pipebu Zone, piperylone, piprofen, piraZolac, fate, cropropamide, crotethamide, desomorphine, deXOXa piritramide, pirOXicam, pranoprofen, proglumetacin, pro drol, dextromoramide, dezocine, diampromide, diclofenac heptazine, promedol, propacetamol, propiram, pro Sodium, difenamizole, difenpiramide, diflunisal, dihydroco poxyphene, propyphenaZone, proguaZone, protizinic acid, deine, dihydrocodeinone enol acetate, dihydromorphine, ramifenaZone, remifentanil, rimazolium metilsulfate, Salac dihydroxyaluminum acetylsalicylate, dimenoxadol, dime etamide, Salicin, Salicylamide, Salicylamide O-acetic acid, pheptanol, dimethylthiambutene, dioxaphetylbutyrate, dipi Salicylsulfuric acid, Salsalte, Salverine, Simetride, Sodium panone, diprocetyl, dipyrone, ditazol, droxicam, emorfa Salicylate, Sufentanil, SulfaSalazine, Sulindac, Superoxide Zone, enfenamic acid, epirizole, eptazocine, eterSalate, dismutase, Suprofen, SuxibuZone, talniflumate, tenidap, ethenZamide, ethoheptazine, ethoxazene, ethylmethylthiam tenoxicam, terofenamate, tetrandrine, thiazolinobutaZone, butene, ethylmorphine, etodolac, etofenamate, etonitaZene, tiaprofenic acid, tiaramide, tilidine, tinoridine, tolfenamic eugenol, felbinac, fenbufen, fenclozic acid, fendosal, feno acid, tolmetin, tramadol, tropesin, Viminol, Xenbucin, Ximo profen, fentanyl, fentiaZac, fepradinol, feprazone, floctafe profen, Zaltoprofen, and Zomepirac. nine, flufenamic acid, flunoxaprofen, fluoresone, flupirtine, 72. The method of any of claims 68, 69,70, or 71, wherein flu.proquaZone, flurbiprofen, fosfosal, gentisic acid, glafe at least one non-meloxicam active agent has an effective nine, glucame tacin, glycol Salicylate, guaiaZulene, hydroc average particle size of less than about 2 microns. odone, hydromorphone, hydroxypethidine, ibufenac, ibu 73. The method of any of claims 68, 69,70, or 71, wherein profen, ibuproxam, imidazole Salicylate, indomethacin, at least one non-meloxicam active agent has composition of indoprofen, isofeZolac, isoladol, isomethadone, isonixin, any of claims 18, 19, or 20, wherein at least one of said at isoxepac, isoxicam, ketobemidone, ketoprofen, ketorolac, least one active agent is a conventional sized active agent. p-lactophenetide, lefetamine, levorphanol, lofentanil, lona Zolac, lomoxicam, loxoprofen, lysine acetylsalicylate, mag