US 20040141925A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0141925 A1 Bosch et al. (43) Pub. Date: Jul. 22, 2004

(54) NOVELTRIAMCINOLONE COMPOSITIONS Continuation-in-part of application No. 10/345,312, filed on Jan. 16, 2003, which is a continuation of (75) Inventors: H. William Bosch, Bryn Mawr, PA application No. 09/715,117, filed on Nov. 20, 2000, (US); Kevin D. Ostrander, Ringoes, now abandoned, and which is a continuation-in-part NJ (US); Eugene R. Cooper, Berwyn, of application No. 10/075,443, filed on Feb. 15, 2002, PA (US) now Pat. No. 6,592,903, which is a continuation of application No. 09/666,539, filed on Sep. 21, 2000, Correspondence Address: now Pat. No. 6,375,986. FOLEY AND LARDNER Continuation-in-part of application No. 10/357.514, SUTE 500 filed on Feb. 4, 2003. 3000 KSTREET NW Continuation-in-part of application No. 10/619,539. WASHINGTON, DC 20007 (US) (60) Provisional application No. 60/353,230, filed on Feb. (73) Assignee: Elan Pharma International Ltd. 4, 2002. Provisional application No. 60/396.530, filed on Jul. 16, 2002. (21) Appl. No.: 10/697,716 Publication Classification (22) Filed: Oct. 31, 2003 (51) Int. Cl." ...... A61L 9/04; A61K 9/14 Related U.S. Application Data (52) U.S. Cl...... 424/46; 424/489 (60) Continuation-in-part of application No. 09/190,138, filed on Nov. 12, 1998. (57) ABSTRACT Continuation-in-part of application No. 09/337,675, filed on Jun. 22, 1999. The invention is directed to nanoparticulate triamcinolone Continuation-in-part of application No. 10/004,808, and/or triamcinolone derivative compositions. The triamci filed on Dec. 7, 2001, which is a division of appli nolone or triamcinolone derivative particles of the compo cation No. 09/414,159, filed on Oct. 8, 1999, now Pat. Sition have an effective average particle Size of less than No. 6,428,814. about 2 microns. US 2004/014 1925 A1 Jul. 22, 2004

NOVELTRAMCINOLONE COMPOSITIONS Pat. No. 5,318,767 for “X-Ray Contrast Compositions Use ful in Medical Imaging.” U.S. Pat. No. 5,326,552 for “Novel CROSS-REFERENCE TO RELATED PATENT Formulation For Nanoparticulate X-Ray Blood Pool Con APPLICATIONS trast Agents Using High Molecular Weight Non-ionic Sur 0001. This application is a continuation in part of U.S. factants;” U.S. Pat. No. 5,328,404 for “Method of X-Ray patent application Ser. No. 10/004,808, filed on Dec. 7, 2001 Imaging Using Iodinated Aromatic Propanedioates, U.S. (pending), which is a divisional of U.S. patent application Pat. No. 5,336,507 for “Use of Charged Phospholipids to Ser. No. 09/414,159, filed on Oct. 8, 1999, now U.S. Pat. No. Reduce Nanoparticle Aggregation; U.S. Pat. No. 5,340,564 6,428,814. In addition, this application is a continuation-in for “Formulations Comprising Olin 10-G to Prevent Particle part of: (a) U.S. patent application Ser. No. 09/190,138, filed Aggregation and Increase Stability;” U.S. Pat. No. 5,346, on Nov. 12, 1998 (pending); (b) U.S. patent application Ser. 702 for “Use of Non-Ionic Cloud Point Modifiers to Mini No. 10/619,539, filed on Jul 16, 2003 (pending), which mize Nanoparticulate Aggregation During Sterilization; claims priority of U.S. patent application Ser. No. 60/396, U.S. Pat. No. 5,349,957 for “Preparation and Magnetic 530, filed on Jul. 16, 2002; (c) U.S. patent application Ser. Properties of Very Small Magnetic-Dextran Particles; U.S. No. 09/337,675, filed on Jun. 22, 1999 (pending); (d) U.S. Pat. No. 5,352.459 for “Use of Purified Surface Modifiers to patent application Ser. No. 10/357.514, filed on Feb. 4, 2003 Prevent Particle Aggregation During Sterilization; U.S. Pat. (pending), which claims priority of U.S. patent application Nos. 5,399,363 and 5,494,683, both for “Surface Modified Ser. No. 60/353,230, filed on Feb. 4, 2002; and (e) U.S. Anticancer Nanoparticles; U.S. Pat. No. 5,401,492 for patent application Ser. No. 10/345,312, filed on Jan. 16, “Water Insoluble Non-Magnetic Manganese Particles as 2003 (pending), which is a continuation of U.S. patent Magnetic Resonance Enhancement Agents; U.S. Pat. No. application Ser. No. 09/715,117, filed on Nov. 20, 2000 (now 5,429,824 for “Use of Tyloxapol as a Nanoparticulate Sta abandoned), and a continuation-in-part of U.S. patent appli bilizer;” U.S. Pat. No. 5,447,710 for “Method for Making cation Ser. No. 10/075,443, filed on Feb. 15, 2002, now U.S. Nanoparticulate X-Ray Blood Pool Contrast Agents. Using Pat. No. 6,592,903, which is a continuation of U.S. patent High Molecular Weight Non-ionic Surfactants; U.S. Pat. application Ser. No. 09/666,539, filed on Sep. 21, 2000, now No. 5,451,393 for “X-Ray Contrast Compositions Useful in U.S. Pat. No. 6,375,986. The prior disclosures are specifi Medical Imaging.” U.S. Pat. No. 5,466,440 for “Formula cally incorporated by reference. tions of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents in Combination with Pharmaceutically Acceptable FIELD OF THE INVENTION Clays;” U.S. Pat. No. 5,470,583 for “Method of Preparing Nanoparticle Compositions Containing Charged Phospho 0002 The present invention relates to novel composi lipids to Reduce Aggregation; U.S. Pat. No. 5,472,683 for tions of triamcinolone and triamcinolone derivatives, com “Nanoparticulate Diagnostic Mixed Carbamic Anhydrides prising particles of triamcinolone or derivatives thereof as X-Ray Contrast Agents for Blood Pool and Lymphatic having an effective average particle size of less than about System Imaging.” U.S. Pat. No. 5,500,204 for “Nanopar 2000 nm and at least one surface stabilizer that is preferably ticulate Diagnostic DimerS as X-Ray Contrast Agents for adsorbed to or associated with the Surface of the triamcino Blood Pool and Lymphatic System Imaging; U.S. Pat. No. lone particles. 5,518,738 for “Nanoparticulate NSAID Formulations;” U.S. Pat. No. 5,521,218 for “Nanoparticulate Iododipamide BACKGROUND OF THE INVENTION Derivatives for Use as X-Ray Contrast Agents; U.S. Pat. 0.003 I. Background Regarding Nanoparticulate Active No. 5,525,328 for “Nanoparticulate Diagnostic Diatrizoxy Agent Compositions Ester X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging.” U.S. Pat. No. 5,543,133 for “Process of 0004 Nanoparticulate active agent compositions, first Preparing X-Ray Contrast Compositions Containing Nano described in U.S. Pat. No. 5,145,684 (“the 684 patent”), are particles;” U.S. Pat. No. 5,552,160 for “Surface Modified particles consisting of a poorly Soluble therapeutic or diag NSAID Nanoparticles;” U.S. Pat. No. 5,560,931 for “For nostic agent having associated with the Surface thereof a mulations of Compounds as Nanoparticulate Dispersions in non-crosslinked surface stabilizer. The 684 patent does not Digestible Oils or Fatty Acids;” U.S. Pat. No. 5,565,188 for describe nanoparticulate triamcinolone or triamcinolone “Polyalkylene Block Copolymers as Surface Modifiers for derivative compositions. Nanoparticles;” U.S. Pat. No. 5,569,448 for “Sulfated Non ionic Block Copolymer Surfactant as Stabilizer Coatings for 0005 Methods of making nanoparticulate active agent Nanoparticle Compositions;” U.S. Pat. No. 5,571,536 for compositions are described, for example, in U.S. Pat. Nos. “Formulations of Compounds as Nanoparticulate Disper 5,518,187 and 5,862.999, both for “Method of Grinding sions in Digestible Oils or Fatty Acids; U.S. Pat. No. Pharmaceutical Substances; U.S. Pat. No. 5,718,388, for 5,573,749 for “Nanoparticulate Diagnostic Mixed Carboxy “Continuous Method of Grinding Pharmaceutical Sub lic Anydrides as X-Ray Contrast Agents for Blood Pool and stances;” and U.S. Pat. No. 5,510,118 for “Process of Lymphatic System Imaging.” U.S. Pat. No. 5,573,750 for Preparing Therapeutic Compositions Containing Nanopar “Diagnostic Imaging X-Ray Contrast Agents; U.S. Pat. No. ticles.” These patents do not describe methods of making 5,573,783 for “Redispersible Nanoparticulate Film Matrices nanoparticulate triamcinolone or triamcinolone derivatives. With Protective Overcoats; U.S. Pat. No. 5,580,579 for 0006 Nanoparticulate compositions are also described, “Site-specific Adhesion Within the GI Tract Using Nano for example, in U.S. Pat. No. 5,298,262 for “Use of Ionic particles Stabilized by High Molecular Weight, Linear Poly Cloud Point Modifiers to Prevent Particle Aggregation Dur (ethylene Oxide) Polymers;” U.S. Pat. No. 5,585,108 for ing Sterilization;” U.S. Pat. No. 5,302,401 for “Method to “Formulations of Oral Gastrointestinal Therapeutic Agents Reduce Particle Size Growth During Lyophilization; U.S. in Combination with Pharmaceutically Acceptable Clays;” US 2004/014 1925 A1 Jul. 22, 2004

U.S. Pat. No. 5,587,143 for “Butylene Oxide-Ethylene ences describe nanoparticulate compositions of triamcino Oxide Block Copolymers Surfactants as Stabilizer Coatings lone or triamcinolone derivatives. for Nanoparticulate Compositions; U.S. Pat. No. 5,591,456 for “Milled Naproxen with Hydroxypropyl Cellulose as 0007 Amorphous small particle compositions are Dispersion Stabilizer;” U.S. Pat. No. 5,593,657 for “Novel described, for example, in U.S. Pat. Nos. 4,783,484 for Barium Salt Formulations Stabilized by Non-ionic and “Particulate Composition and Use Thereof as Antimicrobial Anionic Stabilizers;” U.S. Pat. No. 5,622,938 for “Sugar Agent;” U.S. Pat. No. 4,826,689 for “Method for Making Based Surfactant for Nanocrystals;” U.S. Pat. No. 5,628,981 Uniformly Sized Particles from Water-Insoluble Organic for “Improved Formulations of Oral Gastrointestinal Diag Compounds;" U.S. Pat. No. 4,997,454 for “Method for nostic X-Ray Contrast Agents and Oral Gastrointestinal Making Uniformly-Sized Particles From Insoluble Com Therapeutic Agents;” U.S. Pat. No. 5,643,552 for “Nano pounds;” U.S. Pat. No. 5,741,522 for “Ultrasmall, Non particulate Diagnostic Mixed Carbonic Anhydrides as aggregated Porous Particles of Uniform Size for Entrapping X-Ray Contrast Agents for Blood Pool and Lymphatic Gas Bubbles Within and Methods;” and U.S. Pat. No. System Imaging; U.S. Pat. No. 5,718,388 for “Continuous 5,776,496, for “Ultrasmall Porous Particles for Enhancing Method of Grinding Pharmaceutical Substances; U.S. Pat. Ultrasound Back Scatter.” These references do not describe No. 5,718,919 for “Nanoparticles Containing the R(-) Enan nanoparticulate triamcinolone and triamcinolone deriva tiomer of Ibuprofen;” U.S. Pat. No. 5,747,001 for “Aerosols tives. Containing Beclomethasone Nanoparticle Dispersions,” 0008 II. Background Regarding Triamcinolone and Tri U.S. Pat. No. 5,834,025 for “Reduction of Intravenously amcinolone Derivatives Administered Nanoparticulate Formulation Induced Adverse Physiological Reactions;” U.S. Pat. No. 6,045,829 0009 Triamcinolone and derivatives thereof (“triamcino lone derivatives”) are corticosteroids of the glucocorticoid “Nanocrystalline Formulations of Human Immunodefi family. Glucocorticoids have anti-inflammatory properties ciency Virus (HIV) Protease Inhibitors. Using Cellulosic and are useful in the treatment of inflammation (Swelling, Surface Stabilizers; U.S. Pat. No. 6,068,858 for “Methods heat, redness, and pain). Glucocorticoids are used to treat of Making Nanocrystalline Formulations of Human Immu certain forms of arthritis, skin, blood, kidney, eye, thyroid, nodeficiency Virus (HIV) Protease Inhibitors. Using Cellu and intestinal disorders (e.g., colitis, irritable bowel disorder, losic Surface Stabilizers; U.S. Pat. No. 6,153,225 for and Crohn's disease), allergies, and asthma. Glucocorticoids “Injectable Formulations of Nanoparticulate Naproxen;” are also is administered with other drugs to prevent rejection U.S. Pat. No. 6,165,506 for “New Solid Dose Form of of transplanted organs and to treat certain types of cancer. Nanoparticulate Naproxen; U.S. Pat. No. 6,221,400 for “Methods of Treating Mammals. Using Nanocrystalline For 0010 Triamcinolone and triamcinolone derivatives, such mulations of Human Immunodeficiency Virus (HIV) Pro as triamcinolone acetonide, triamcinolone diacetate, triam tease Inhibitors; U.S. Pat. No. 6,264,922 for “Nebulized cinolone hexacetonide, and triamcinolone benetonide, are Aerosols Containing Nanoparticle Dispersions;” U.S. Pat. all derived from the naturally occurring parent compound No. 6,267,989 for “Methods for Preventing Crystal Growth prednisone. Predisone and prednisolone are members of the and Particle Aggregation in Nanoparticle Compositions,” glucocorticoid class of hormones. Naturally occurring cor ticosteroids have varying glucocorticoid and mineralocorti U.S. Pat. No. 6,270.806 for “Use of PEG-Derivatized Lipids coid activities. Synthetic corticosteroids are modifications of as Surface Stabilizers for Nanoparticulate Compositions;” the parent molecule typically having improved anti-inflam U.S. Pat. No. 6,316,029 for “Rapidly Disintegrating Solid matory activity and reduced mineralocorticoid activity. Oral Dosage Form.” U.S. Pat. No. 6,375,986 for “Solid Dose Additionally, the modifications to the parent corticosteroid Nanoparticulate Compositions Comprising a Synergistic alter the water solubility of the drug, which is thought to be Combination of a Polymeric Surface Stabilizer and Dioctyl asSociated with the duration of action. For example, triam Sodium Sulfosuccinate,” U.S. Pat. No. 6,428,814 for “Bio cinolone and triamcinolone acetonide are two-fold and adhesive nanoparticulate compositions having cationic Sur 8-fold more active, respectively, than prednisone in animal face stabilizers;” U.S. Pat. No. 6,431,478 for “Small Scale models of inflammation. See The Physicians' Desk Refer Mill;" U.S. Pat. No. 6,432,381 for “Methods for Targeting ence, 56th Ed., pp. 728 (Thompson PDR, Montvale N.J., Drug Delivery to the Upper and/or Lower Gastrointestinal Tract,” and U.S. Pat. No. 6,592,903 for “Nanoparticulate 2002). Dispersions Comprising a Synergistic Combination of a 0011. In general, corticosteroids with succinate and phos Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuc phate esters are water Soluble, have a short duration of cinate,” all of which are specifically incorporated by refer action, and are good for parenteral use. Corticosteroids with ence. In addition, U.S. patent application Ser. No. acetate and acetonide esters are more lipid-Soluble, have a 20020012675 A1, published on Jan. 31, 2002, for “Con longer duration of action, and are useful for in Situ admin trolled Release Nanoparticulate Compositions,” and WO istration (i.e., intra-artricular or intrabursal administaion). 02/098565 for “System and Method for Milling Materials,” Thus, Suitable applications and administrative routes are describe nanoparticulate active agent compositions, and are governed by the particular triamcinolone compound with its Specifically incorporated by reference. None of these refer inherent Solubility and pharmacokinetic properties. US 2004/014 1925 A1 Jul. 22, 2004

0012 A. Chemical Properties of Triamcinolone and Tri 0021 3. Triamcinolone Diacetate amcinolone Derivatives 0022 Triamcinolone diacetate, also known as 0013 1. Triamcinolone (11D,16D)-16.21-bis(acetyloxy)-9-fluoro-11,17 dihydrox 0014 Triamcinolone, also known as (11D,16D)-9-fluoro ypregna-1,4-diene-3,20-dione, has the following chemical 11,17,18,21-dihydroxy-pregna-1,4-diene-320-dione, has formula: the following chemical Structure:

0.015 Triamcinolone has an empirical formula of CH, FO and a molecular weight of 394.43. See The Merck Index, 13th Ed., pp. 1711-2 (Merck & Co. 2001). Triamci 0023 Triamcinolone diacetate has an empirical formula nolone is slightly Soluble in water, Very slightly Soluble in of CHFOs and a molecular weight of 478.51. See The chloroform and ether, 1 part into 40 parts soluble in alcohol, Physicians' Desk Reference at 1388 (Thompson P D R, and slightly soluble in methyl alcohol. Chem. Abstracts Montvale N.J., 2002) and The Merck Index at 1712. Triam Registration No. 124-94-7. cinolone diacetate is sparingly Soluble in water. The Merck Index at 1712. 0016 A comprehensive description of triamcinolone is disclosed in, e.g., Florey, Anal. Profiles Drug Subs. 1:367 0024. 4. Triamcinolone Hexacetonide 96, 423-442 (1972) and Sieh, Ibid. 11:593-614, 651-661 0025 Triamcinolone hexacetonide, also known as (11D, (1982). Methods of preparing triamcinolone are disclosed in, 16D)-21-(3.3dimethyl-1-oxobutoxy)-9-fluoro-11-hydroxy e.g., U.S. Pat. Nos. 2,789,118 and 3,021,347. 16,17-(1-methylethylidene)bis(oxy)-pregna-1,4-diene-3, 0017 2. Triamcinolone Acetonide 20-dione, has the following formula: 0018 Triamcinolone acetonide, also known as (11D, 160)-9-fluoro-11,21-dihydroxy-16,17-1- methyleth CHOCOCH2C(CH3)3. ylidenebis(oxy)-pregna-1,4-diene-3,20-dione, has the fol lowing chemical Structure:

0026 Triamcinolone hexacetonide has an empirical for mula of CHFNO, and a molecular weight of 532.64. See The Physician's Desk Reference at 1390 and The Merck Index at 1712. Triamcinolone hexacetonide has the follow 0.019 Triamcinolone acetonide has an empirical formula ing solubilities in g/100 ml solvent at 25 C.: >5 in chloro of CHFOs and a molecular weight of 434.5. See The form and dimethylacetamide, 0.77 in acetate, 0.59 in metha Physicians' Desk Reference, 56th Ed., pp. 728 (Thompson P nol, 0.5 in diethyl carbonate, 0.42 in glycerin, 0.13 in DR, Montvale N.J., 2002) and The Merck Index at 1712. propylene glycol, 0.03 in absolute alcohol, and 0.0002 Triamcinolone acetonide is sparingly Soluble in methane, 0.0004 in water. Id. acetone, and ethyl acetate. The Merck Index at 1712. 0027. A description of triamcinolone hexacetonide is 0020 Triamcinolone acetonide is described in, e.g., Flo provided in, e.g., Zbinovsky and Chrekian, Anal. Profiles rey, Anal. Profiles Drug Subs., 1:397 (1972) and Sieh, Ibid., Drug Subs., 6:579-95 (1977). Methods of preparing triam 11:615 (1982). Methods of preparing triamcinolone cinolone hexacetonide are disclosed in, e.g., U.S. Pat. No. acetonide are disclosed in, e.g., Fried et al., J. Am. Chem 3,457,348. The anti-inflammatory properties of triamcino Soc., 80:2238 (1958), Bernstein et al., Ibid., 81:1689 (1959), lone hexacetonide in rabbits are disclosed in Hunneyball, and U.S. Pat. Nos. 2,990,401 and 3,035,050. Clinical trials Agents Actions, 11:490 (1981) and early clinical studies are of triamcinolone acetonide in chronic asthma are disclosed disclosed in Bilka, Minnesota Med., 50:483 (1967) and in Bernstein et al., Chest, 81:20 (1982). Layman and Peterson, Id. at 669. US 2004/014 1925 A1 Jul. 22, 2004

0028) 5. Triamcinolone Benetonide pulmonary and nasal aerosol, aqueous nasal Spray, dental 0029 Triamcinolone benetonide, also known as (110, paste, injectable forms (intra-articular, intrabursal adminis 160)-21-3-(benzoylamino)-2-methyl-1-oxopropoxy-9- tration, intradermal, intramuscular), and topical formula fluoro-11-hydroxy-16,17-(1-methylethylidene)bis(oxy)- tions (aerosol spray, cream, ointment, and lotion). Triamci pregna-1,4-diene-3,20-dione, has the following chemical nolone and triamcinolone derivatives are also available Structure: mixed with other drugs, Such as anti-fungal agents. 0035. For example, triamcinolone is available under the

brand name KENALOG(R) (Bristol-Myers Squibb Pharma ceuticals Ltd., Hounslow, England) in topical formulations (e.g. aerosol, lotion, cream, ointment, and dental paste) indicated for the treatment of Skin irritation including irri tation caused by allergic reactions, psoriasis, eczema, and dermatitis. Triamcinolone is also available in injectable formulations marketed under the brand names KENA LOGGR), KENALOG-10(R), KENALOG-40(R), KENA JECTOR). 0036 Triamcinolone acetonide is currently marketed for oral/pulmonary inhalation under the brand name AZMA CORTE) (Aventis Pharmaceuticals, Inc., Bridgewater, N.J., USA). AZMACORTE) is indicated for the treatment of bronchial asthma and is Supplied as an inhalation aeroSol containing a 1% W/w microcrystalline Suspension of triam cinolone acetonide in the propellant dichlorodifluo romethane and dehydrated alcohol. See The Physician's Desk Reference at 728. 0037 Triamcinolone acetonide is also marketed under 0030 Triamcinolone benetonide has an empirical for the brand names NASACORTE) and NASACORTCE) AO mula of CHFNOs and a molecular weight of 623.71. See (Aventis Pharmaceuticals, Inc.) in the form of nasal inhal The Merck Index at 1712. Triamcinolone benetonide is ants for the treatment of the nasal Symptoms of Seasonal and Soluble in methanol, acetone, ethanol, dioxane, pyridine, perennial allergic rhinitis. See The Physician's Desk Refer DMF, and chloroform, but is insoluble in water. Id. ence at 750-3. When administered intranasally triamcino lone acetonide has a direct anti-inflammatory effect on the 0.031 Methods of preparing triamcinolone benetonide are nasal mucosa. NASACORTOR is provided as a 0.7% micro disclosed in, e.g., U.S. Pat. Nos. 3,749,712 and 3,035,050. crystalline Suspension of triamcinolone acetonide in dichlo Clinical Studies of triamcinolone benetonide are disclosed in rodifluoromethane and dehydrated alcohol. NASACORTOR Tazelaar, J. Int. Med. Res., 5:338 (1981). Down et al, Toxicol AQ is an aqueous, thixotropic Suspension of microcrystal Letters, 1:95 (1977), describes percutaneous absorption of line triamcinolone acetonide. The aqueous pharmaceutical triamcinolone benetonide in rats and rabbits. composition of NASACORTRAQ is disclosed in U.S. Pat. 0.032 B. Pharmaceutical Applications of Triamcinolone Nos. 5,976,573 and 6,143,329. and Triamcinolone Derivatives 0038 Triamcinolone acetonide is also available in cream, 0.033 Triamcinolone and triamcinolone derivatives are lotion, and ointment formulations indicated for the treatment indicated for the treatment of conditions where a powerful of itching, redness, dryneSS, crusting, Scaling, inflammation, Steroidal anti-inflammatory agent is required. Such condi and discomfort of various skin conditions. For example, tions include, but are not limited to, asthma, contact derma ARISTOCORTACE) is available as a 0.025%, 0.1% or 0.5% titis, atopic dermatitis, Seasonal or perennial allergic rhinitis, triamcinolone acetonide in AQUATAINR hydrophilic base oral inflammatory, lesions and ulcers, osteoarthritis, acute (Fujisawa Pharmaceutical Co., Ltd. Japan) or ointment nonspecific and posttraumatic osteoarthritis, rheumatoid (ARISTOCORTA(R) 0.1% ointment with propylene glycol). arthritis, burSitis, epicondylitis, keloids, and Skin disorders Additional products containing triamcinolone acetonide including psoriasis, eczema, and general dermatitis. Addi include nyStatin and triamcinolone acetonide cream and tional conditions where triamcinolone and triamcinolone ointment (Taro, Hawthorne, N.Y., USA), triamcinolone derivatives are useful include, but are not limited to, endo acetonide cream, lotion, and ointment (Watson Laboratories, crine disorders, lupus, acute rheumatic carditis, herpes Corona, Calif., USA), and triamcinolone acetonide dental Zoster ophthalmicus, intestinal disorders (e.g., irritable paste (Taro). bowel disorder, colitis, ulcerative colitis, gastroenteritis, and 0039 Triamcinolone diacetate is marketed under the Crohn's disease), hemolytic anemia, and neoplastic diseases brand names ARISTOCORTCE) and ARISTOCORTCE) Forte Such as leukemias and lymphoma. (Fujisawa Healthcare, Deerfield, Ill., USA). ARISTO 0034. Due to the broad range of uses, triamcinolone and CORTOR is available as a suspension of 25 mg/mL micron triamcinolone derivatives are currently available in a variety ized triamcinolone diacetate. ARISTOCORTE) is indicated of formulations Suitable for various administrative routes for intralesional injection only. The Physicians' Desk Ref including oral/pulmonary inhalation, nasal inhalation, topi erence at 1388. ARISTOCORTR Forte is supplied as a cal application, and injectable formulations. Triamcinolone Suspension of 40 mg/mL triamcinolone diacetate Suitable for and triamcinolone derivatives are formulated as an oral/ parenteral administration. ARISTOCORTF) Forte can be US 2004/014 1925 A1 Jul. 22, 2004

administered via intramuscular, intra-articular, or intra-Syn 0048 Higher doses of inhaled glucocorticoids are ovial routes but is not for intravenous administration. believed to decrease bone formation or increase bone reab Sorption, resulting in weak bones and increased instances of 0040 Triamcinolone hexacetonide is formulated for bone fractures. Corticosteroids, in general, are known to parenteral administration via intra-articular, intralesional or cause decreased resistance to localized infections and to Sublesional routes. Triamcinolone hexacetonide is marketed under the brand name ARISTOSPANE) and is available as an inhibit wound healing. aqueous Suspension of 5 mg/mL or 20 mg/mL micronized 0049 Systemic absorption of topical corticosteroids can triamcinolone hexacetonide. result in reversible hypothalamic-pituitary-adrenal (HPA) axis Suppression, Cushing's Syndrome-like Symptoms, and 0041 Triamcinolone benetonide is available as a topical hyperglycemia. Although complete recovery of HPA axis anti-inflammatory in a 0.075% cream. function is typically prompt upon discontinuing the drug, 0042. The pharmacokinetic properties of triamcinolone Signs and Symptoms of Steroid withdrawal can occur, requir acetonide are known. See The Physician's Desk Reference at ing Supplemental Systemic corticosteroids. 728, 750 and 752. Triamcinolone acetonide, administered 0050 Children are especially susceptible to systemic intravenously as the phosphate ester, has a plasma half-life toxicity caused by corticosteroids. In addition to the Symp (T) of 88 minutes. The plasma half-life of glucocorticoids toms experienced by adults, intracranial hypertension, retar generally does not correlate well with the biologic half-life. dation of growth and development, delayed weight gain, low 0043) Following a single oral dose of 800 mcg 'C- plasma cortisol levels, and absence of response to ACTH labeled triamcinolone acetonide, the maximum plasma con Stimulation has been reported in children receiving corti centration was achieved in 1.5 to 2 hours (T,). Plasma costeroids. Accordingly, administration of corticosteroids to protein binding of triamcinolone acetonide appears to be children should be limited. relatively low and consistent over a wide plasma concen 0051 Although topical (including inhaled) administra tration range. The overall mean percent fraction of triamci tion of corticosteroids, Such as triamcinolone and triamci nolone acetonide by plasma proteins was approximately nolone derivatives, minimizes the Side-effects as compared 68%. No triamcinolone acetonide was detected in the to Systemic administration, the active compounds are still plasma after 24 hours and greater than 90% of the oral absorbed into the circulation where they are Systemically 'C-radioactive dose was recovered within 5 days after active. administration in 5 out of the 6 test subjects. Of the recovered 'C-radioactivity, approximately 40% and 60% 0052 There is a need in the art for triamcinolone was found in the urine and feces, respectively. acetonide compositions which can decrease frequency of dosing, improve clinical efficacy, and potentially reduce Side 0044) Intranasal administration of 440 mcg/day dose of effects. The present invention Satisfies these needs. NASACORTR) resulted in a C of <1 ng/mL and a T. of 3.4 hours (ranging from 0.5 to 8.0 hours). The apparent SUMMARY OF THE INVENTION T was 4.0 hourst3 hours. 0053. The present invention relates to nanoparticulate compositions comprising triamcinolone, triamcinolone 0.045 Single dose intranasal administration of 220 mcg of derivatives, or a mixture thereof. The compositions com NASACORTR AQ Nasal Spray produced a C of prise triamcinolone and/or triamcinolone derivatives and at approximately 0.5 ng/mLit0.5 ng/mL and a T of approxi least one Surface Stabilizer, which is preferably adsorbed on mately 1.5 hours. The average T of triamcinolone or associated with the Surface of the triamcinolone or acetonide was 3.1 hours, the concentration was less than triamcinolone derivative particles. The nanoparticulate tri 0.06 ng/mL at 12 hours and below the assay detection limit amcinolone and triamcinolone derivative particles have an at 24 hours. The mean AUC values ranged from 1.4 ng-hr/ effective average particle size of less than about 2 microns. mL to 4.7 ng-hr/mL over the range of 110 mcg to 440 mcg. The C was linear over the range of 110 mcg or 220 mcg 0054 Another aspect of the invention is directed to when administered intranasally. Following multiple doses in pharmaceutical compositions comprising the nanoparticu pediatric patients receiving 440 mcg/day, plasma drug con late triamcinolone or triamcinolone derivative compositions centrations pharmacokinetic parameters were similar to of the invention. The pharmaceutical compositions prefer those values observed in adult patients. ably comprise triamcinolone and/or a triamcinolone deriva tive, at least one Surface Stabilizer, and at least one phar 0.046 C. Adverse Properties of Triamcinolone and Tri maceutically acceptable carrier, as well as any desired amcinolone Derivatives excipients. Advantages and properties of the compositions 0047 Corticosteroid administration can result in signifi of the invention are described herein. cant side effects. The most frequent side effects of inhaled 0055. The invention further discloses a method of making triamcinolone and triamcinolone derivates are mild cough nanoparticulate triamcinolone and triamcinolone derivative ing or wheezing and occasional oral candidiasis infection. compositions. Such a method comprises contacting triam Other nasopharyngeal side effects include dry mucous mem cinolone and/or a triamcinolone derivative and at least one branes, sinus congestion, throat discomfort, Sneezing, and Surface Stabilizer for a time and under conditions Sufficient epistaxis. Side effects apparent with topical administration to provide a nanoparticulate triamcinolone and/or triamci of triamcinolone and triamcinolone derivates to the skin are nolone derivative composition. The one or more Surface burning, itching, irritation, dryneSS, folliculitis, hypertricho Stabilizers can be contacted with triamcinolone and/or a sis, acne, hypopigmentation, perioral dermatitis, allergic triamcinolone derivative either before, preferably during, or contact dermatitis, maceration of the Skin, and Secondary after size reduction of the triamcinolone and/or triamcino infection. lone derivative. US 2004/014 1925 A1 Jul. 22, 2004

0056. The present invention is also directed to methods of nanoparticulate triamcinolone and triamcinolone derivative treatment using the nanoparticulate triamcinolone and tri compositions when administered in the fed versus the fasted amcinolone derivative compositions of the invention for State; (9) bioadhesive triamcinolone and triamcinolone treatment of conditions or disorders where a glucocorticoid derivative formulations, which can coat the gut, mucous composition is useful. Such conditions or disorders include, membranes, or the desired Site of application and be retained but are not limited to, arthritis, Skin disorders, blood disor for a period of time, thereby increasing the efficacy of the ders, kidney disorders, eye disorders, thyroid, intestinal drug as well as eliminating or decreasing the frequency of disorders, cancer, allergic reactions, asthma, contact derma dosing; (10) high redispersibility of the nanoparticulate titis, atopic dermatitis, Seasonal allergic rhinitis, perennial triamcinolone and triamcinolone derivative particles present allergic rhinitis, oral inflammatory, oral lesions, oral ulcers, in the compositions of the invention following administra Osteoarthritis, acute nonspecific osteoarthritis, posttraumatic tion; (11) the nanoparticulate triamcinolone and triamcino Osteoarthritis, rheumatoid arthritis, bursitis, epicondylitis, lone derivative compositions can be formulated in a dried pSoriasis, eczema, general dermatitis, endocrine disorders, form which readily redisperses; (12) low Viscosity liquid lupus, herpes Zoster ophthalmicus, ulcerative colitis, irri nanoparticulate triamcinolone and triamcinolone derivative table bowel disorder, Crohn's disease, gastroenteritis, dosage forms can be made; (13) liquid nanoparticulate hemolytic anemia, leukemia, and lymphoma. triamcinolone and triamcinolone derivative compositions having a low Viscosity result in better Subject compliance 0057. Both the foregoing general description and the due to the perception of a lighter formulation which is easier following detailed description are exemplary and explana to consume and digest, (14) liquid nanoparticulate triamci tory and are intended to provide further explanation of the nolone and triamcinolone derivative compositions having a invention as claimed. Other objects, advantages, and novel low Viscosity result in greater ease of dispensing because features will be readily apparent to those skilled in the art one can use a cup or a Syringe; (15) the nanoparticulate from the following detailed description of the invention. triamcinolone and triamcinolone derivative compositions can be used in conjunction with other active agents; (16) the DETAILED DESCRIPTION OF THE nanoparticulate triamcinolone and triamcinolone derivative INVENTION compositions can be sterile filtered; (17) the nanoparticulate 0.058. The present invention is directed to nanoparticulate triamcinolone and triamcinolone derivative compositions compositions comprising triamcinolone and/or at least one are Suitable for parenteral administration; and (18) the triamcinolone derivative. The compositions comprise triam nanoparticulate triamcinolone and triamcinolone derivative cinolone and/or a triamcinolone derivative and at least one compositions do not require organic Solvents or pH Surface Stabilizer that is preferably adsorbed on or associated eXtremeS. with the Surface of the drug. The nanoparticulate particles of 0062 Preferred dosage forms of the invention are aerosol triamcinolone and/or a triamcinolone derivative have an (pulmonary and nasal), liquid Suspension, and oral tablet effective average particle size of less than about 2 microns. formulations, although any pharmaceutically acceptable 0059 AS taught in the 684 patent, not every combination dosage form can be utilized. Other preferred dosage forms of Surface Stabilizer and active agent will result in a stable include topical cream, lotion and ointment formulations. nanoparticulate active agent composition. It was Surpris ingly discovered that Stable nanoparticulate formulations of 0063. The present invention is described herein using several definitions, as set forth below and throughout the triamcinolone and triamcinolone derivatives can be made. application. 0060. The current formulations of triamcinolone and tri amcinolone derivatives suffer from the following problems: 0064. As used herein, “about” will be understood by (1) the extremely poor solubility of the drugs results in low perSons of ordinary skill in the art and will vary to Some bioavailability; (2) for Some uses, dosing must be repeated extent on the context in which it is used. If there are uses of Several times each day; and (3) a wide variety of Side effects the term which are not clear to perSons of ordinary skill in are associated with the current dosage forms of the drug. the art given the context in which it is used, “about” will mean up to plus or minus 10% of the particular term. 0061 The present invention overcomes problems encountered with the prior art formulations of triamcinolone 0065 “Conventional” or “non-nanoparticulate active and triamcinolone derivatives. Specifically, the nanoparticu agent' shall mean an active agent which is Solubilized or late triamcinolone and triamcinolone derivative composi which has an effective average particle size of greater than tions of the invention may offer the following advantages as about 2 microns. Nanoparticulate active agents as defined compared to prior art compositions of conventional non herein have an effective average particle size of less than nanoparticulate triamcinolone and non-nanoparticulate tri about 2 microns. amcinolone derivatives: (1) faster onset of action; (2) a 0066 “Pharmaceutically acceptable” as used herein potential decrease in the frequency of dosing; (3) Smaller refers to those compounds, materials, compositions, and/or doses of triamcinolone and triamcinolone derivatives dosage forms which are, within the Scope of Sound medical required to obtain the same pharmacological effect; (4) judgment, Suitable for use in contact with the tissues of increased bioavailability; (5) an increased rate of dissolu human beings and animals without excessive toxicity, irri tion; (6) improved performance characteristics for oral, tation, allergic response, or other problem or complication, intravenous, Subcutaneous, or intramuscular injection, Such as higher dose loading and Smaller tablet or liquid dose commensurate with a reasonable benefit/risk ratio. Volumes; (7) improved pharmacokinetic profiles, such as 0067 “Pharmaceutically acceptable salts' as used herein improved T, C, and AUC profiles; (8) Substantially refers to derivatives wherein the parent compound is modi Similar or bioeduivalent pharmacokinetic profiles of the fied by making acid or base Salts thereof. Examples of US 2004/014 1925 A1 Jul. 22, 2004

pharmaceutically acceptable Salts include, but are not lim doses of triamcinolone and triamcinolone derivatives which ited to, mineral or organic acid Salts of basic residues Such can achieve the Same or better therapeutic effects as those as amines, alkali or organic Salts of acidic residues Such as observed with larger doses of non-nanoparticulate triamci carboxylic acids, and the like. The pharmaceutically accept nolone and triamcinolone derivative compositions are able Salts include the conventional non-toxic Salts or the desired. Such lower doses may be realized with the nano quaternary ammonium Salts of the parent compound formed, particulate triamcinolone and triamcinolone derivative com for example, from non-toxic inorganic or organic acids. For positions of the invention because the nanoparticulate tri example, Such conventional non-toxic Salts include those amcinolone and triamcinolone derivative compositions may derived from inorganic acids Such as hydrochloric, hydro exhibit greater bioavailability as compared to non-nanopar bromic, Sulfuric, Sulfamic, phosphoric, nitric, and the like; ticulate triamcinolone and triamcinolone derivative formu and the Salts prepared from organic acids Such as acetic, lations, which means that Smaller doses of triamcinolone propionic, Succinic, glycolic, Stearic, lactic, malic, tartaric, and triamcinolone derivative are likely required to obtain the citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylace desired therapeutic effect. tic, glutamic, benzoic, Salicylic, Sulfanilic, 2-acetoxyben 0075. In addition, conventional non-nanoparticulate tri Zoic, fumaric, toluenesulfonic, methaneSulfonic, ethane dis amcinolone and triamcinolone derivative compositions typi ulfonic, oxalic, isethionic, and the like. cally require multiple doses per day and often require 0068 “Poorly water soluble drugs” as used herein means multiple administrations per dose. those having a solubility of less than about 30 mg/ml, preferably less than about 20 mg/ml, preferably less than 0076 For adults, the typical recommended dosage of about 10 mg/ml, or preferably less than about 1 mg/ml. Such AZMACORT is 200 mcg3-4 times daily or 400 mcg twice drugs tend to be eliminated from the gastrointestinal tract daily. For children 6 to 12 years of age, the typical dosage is 100 to 200 mcg 3-4 times daily or 200-400 mcg twice before being absorbed into the circulation. daily. 0069. As used herein with reference to stable drug par ticles, stable includes, but is not limited to, one or more of 0077. The recommended dosage of NASACORTE) and the following parameters: (1) that the triamcinolone and NASACORTR AQ is two sprays/nostrile/day (220 mcg) triamcinolone derivative particles do not appreciably floc which can be increased for greater efficacy to four SprayS/ culate or agglomerate due to interparticle attractive forces, nostrile/day (440 mcg) depending on individual patient or otherwise Significantly increase in particle size over time; response. (2) that the physical Structure of the triamcinolone and 0078 Injectable conventional formulations can also triamcinolone derivative particles are not altered over time, require multiple administrations or doses per day. The Such as by conversion from an amorphous phase to crystal recommended parenteral dosage of KENALOGGR)-10 and 40 line phase; (3) that the triamcinolone and triamcinolone ranges from about /3 to 72 of the oral dose given every 12 derivative particles are chemically stable; and/or (4) where hours. the triamcinolone and triamcinolone derivative has not been Subject to a heating Step at or above the melting point of the 0079 For intrabursal administration, the manufacturer triamcinolone and triamcinolone derivative in the prepara recommends Single injections into Several joints for multiple tion of the nanoparticles of the invention. locus involvement, up to 60 mg. For intradermal adminis tration, the initial dose of a triamcinolone acetonide com 0070 Therapeutically effective amount as used herein position will vary depending upon the disease being treated with respect to a drug dosage, Shall mean that dosage that but should be limited to 1.0 mg (0.1 ml) per injection site provides the Specific pharmacological response for which because larger Volumes can produce cutaneous atrophy. The the drug is administered in a significant number of Subjects manufacturer recommends injection into multiple Sites in need of Such treatment. It is emphasized that therapeu (separated by one centimeter or more) to allow for admin tically effective amount, administered to a particular Subject istration of a Sufficient amount of drug without the compli in a particular instance will not always be effective in cations associated with large Volumes. treating the diseases described herein, even though Such dosage is deemed a therapeutically effective amount by 0080 For intra-articular or intra-bursal administration those skilled in the art. It is to be further understood that drug and for injection into tendon Sheaths, the initial recom dosages are, in particular instances, measured as oral dos mended dose varies from 2.5 to 5 mg triamcinolone for ages, or with reference to drug levels as measured in blood. Smaller joints and from 5 to 15 mg for larger joints. A Single local injection may Sufficient, but Several injections may be 0071 I. Preferred Characteristics of the Nanoparticulate required for adequate relief of Symptoms. Triamcinolone and Triamcinolone Derivative Compositions of the Invention 0081. The conventional topical formulations of triamci nolone and triamcinolone derivatives (e.g., lotions, creams, 0.072 A. Increased Bioavailability, Frequency of Dosing ointments, and dental paste) require two to four applications and Dosage Quantity daily. 0073. The nanoparticulate triamcinolone and triamcino 0082 In contrast, the triamcinolone and triamcinolone lone derivative compositions of the invention may prefer derivative compositions of the invention may be adminis ably exhibit increased bioavailability and require smaller tered less frequently and at lower doses in forms Such as doses as compared to prior non-nanoparticulate triamcino liquid dispersions, powders, Sprays, Solid re-dispersable lone acetonide compositions administered at the same dose. dosage forms, ointments, creams, etc. Exemplary types of 0.074 Any drug, including triamcinolone and triamcino formulations useful in the present invention include, but are lone derivatives, can have adverse Side effects. Thus, lower not limited to, liquid dispersions, Sachets, lozenges, oral US 2004/014 1925 A1 Jul. 22, 2004

Suspensions, gels, aerosols (pulmonary and nasal), oint pharmacokinetic testing with a non-nanoparticulate triam ments, creams, Solid dose forms, tablets, capsules, and cinolone or triamcinolone derivative composition, adminis powders etc. of nanoparticulate triamcinolone and triamci tered at the same dosage, a T not greater than about 90%, nolone derivatives. Lower dosages can be used because the not greater than about 80%, not greater than about 70%, not Small particle size of the particles ensure greater absorption, greater than about 60%, not greater than about 50%, not and in the case of bioadhesive nanoparticulate triamcinolone greater than about 30%, not greater than about 25%, not and triamcinolone derivative compositions, the triamcino greater than about 20%, not greater than about 15%, not lone and triamcinolone derivative is retained at the desired greater than about 10%, or not greater than about 5% of the Site of application for a longer period of time as compared T. exhibited by the non-nanoparticulate triamcinolone or to conventional triamcinolone and triamcinolone derivative triamcinolone derivative composition. dosage forms. 0091 Preferred triamcinolone and triamcinolone deriva 0.083. In one embodiment of the invention, the therapeu tive compositions of the invention exhibit, in comparative tically effective amount of the nanoparticulate triamcinolone pharmacokinetic testing with a non-nanoparticulate triam and triamcinolone derivative compositions is /6, /5, /4, /3, or cinolone or triamcinolone derivative composition, adminis % of the therapeutically effective amount of a non-nanopar tered at the same dosage, a C, which is at least about 50%, ticulate triamcinolone and triamcinolone derivative compo at least about 100%, at least about 200%, at least about Sition. 300%, at least about 400%, at least about 500%, at least 0084. Such lower doses are preferred as they may about 600%, at least about 700%, at least about 800%, at decrease or eliminate adverse effects of the drug. In addition, least about 900%, at least about 1000%, at least about Such lower doses decrease the cost of the dosage form and 1100%, at least about 1200%, at least about 1300%, at least may increase patient compliance. about 1400%, at least about 1500%, at least about 1600%, at least about 1700%, at least about 1800%, or at least about 0085 B. Pharmacokinetic Profiles of the Nanoparticulate 1900% greater than the C exhibited by the non-nanopar Triamcinolone and Triamcinolone Derivative Compositions ticulate triamcinolone or triamcinolone derivative composi of the Invention tion. 0.086 The invention also preferably provides triamcino 0092 Preferred triamcinolone and triamcinolone deriva lone and triamcinolone derivative compositions having a tive compositions of the invention exhibit, in comparative desirable pharmacokinetic profile when administered to pharmacokinetic testing with a non-nanoparticulate triam mammalian Subjects. cinolone or triamcinolone derivative composition, adminis 0087. The desirable pharmacokinetic profile of the triam tered at the same dosage, an AUC which is at least about cinolone and triamcinolone derivative compositions prefer 25%, at least about 50%, at least about 75%, at least about ably includes, but is not limited to: (1) a T for triamci 100%, at least about 125%, at least about 150%, at least nolone or a triamcinolone derivative composition, when about 175%, at least about 200%, at least about 225%, at assayed in the plasma of a mammalian Subject following least about 250%, at least about 275%, at least about 300%, administration, that is preferably less than the T for a at least about 350%, at least about 400%, at least about non-nanoparticulate triamcinolone or triamcinolone deriva 450%, at least about 500%, at least about 550%, at least tive composition, administered at the same dosage; (2) a about 600%, at least about 750%, at least about 700%, at C. for triamcinolone or a triamcinolone derivative compo least about 750%, at least about 800%, at least about 850%, Sition, when assayed in the plasma of a mammalian Subject at least about 900%, at least about 950%, at least about following administration, that is preferably greater than the 1000%, at least about 1050%, at least about 1100%, at least C for a non-nanoparticulate triamcinolone or triamcino about 1150%, or at least about 1200% greater than the AUC lone derivative composition, administered at the same doS exhibited by the non-nanoparticulate triamcinolone or tri age; and/or (3) an AUC for triamcinolone or a triamcinolone amcinolone derivative composition. derivative composition, when assayed in the plasma of a 0093. Any formulation giving the desired pharmacoki mammalian Subject following administration, that is prefer netic profile is Suitable for administration according to the ably greater than the AUC for a non-nanoparticulate triam present methods. Exemplary types of formulations giving cinolone or triamcinolone derivative composition, adminis Such profiles are liquid dispersions, gels, aerosols, oint tered at the same dosage. ments, creams, Solid dose forms, etc. of nanoparticulate 0088. The desirable pharmacokinetic profile, as used triamcinolone and triamcinolone derivatives. herein, is the pharmacokinetic profile measured after the 0094) C. The Pharmacokinetic Profiles of the Nanopar initial dose of triamcinolone or triamcinolone derivative. ticulate Triamcinolone and Triamcinolone Derivative Com The compositions can be formulated in any way as described positions of the Invention are Preferably not Substantially below and as known to those of skill in the art. Affected by the Fed or Fasted State of the Subject Ingesting 0089. The use of conventional non-nanoparticulate for the Compositions mulations of triamcinolone and triamcinolone derivatives 0095 The invention encompasses nanoparticulate triam for treatment of asthma, allergic rhinitis, Skin disorders and cinolone and triamcinolone derivative compositions wherein other inflammation-related conditions is not ideal due to preferably the pharmacokinetic profile of the triamcinolone delayed onset of action. In contrast, the nanoparticulate or triamcinolone derivative is not substantially affected by triamcinolone and triamcinolone derivative compositions of the fed or fasted State of a Subject ingesting the composition. the invention exhibit faster therapeutic effects. This means that there is no Substantial difference in the 0090 Preferred triamcinolone and triamcinolone deriva quantity of triamcinolone or triamcinolone derivative tive compositions of the invention exhibit, in comparative absorbed or the rate of triamcinolone or triamcinolone US 2004/014 1925 A1 Jul. 22, 2004 derivative absorption when the nanoparticulate triamcino invention is that the compositions redisperse Such that the lone and triamcinolone derivative compositions are admin effective average particle size of the redispersed triamcino istered in the fed versus the fasted State. Thus, the nanopar lone and triamcinolone derivative particles is less than about ticulate triamcinolone and triamcinolone derivative 2 microns. This is significant, because, if upon administra compositions of the invention can Substantially eliminate the tion the nanoparticulate triamcinolone and triamcinolone effect of food on the pharmacokinetics of triamcinolone and derivative particles present in the compositions of the inven triamcinolone derivative. tion do not redisperse to a Substantially nanoparticulate 0096. In another embodiment of the invention, the phar particle size, then the dosage form may lose the benefits macokinetic profile of the triamcinolone and triamcinolone afforded by formulating triamcinolone and triamcinolone derivative compositions of the invention, when administered derivatives into a nanoparticulate particle size. to a mammal in a fasted State, is bioeduivalent to the 0103) This is because nanoparticulate triamcinolone and pharmacokinetic profile of the same triamcinolone or triam triamcinolone derivative compositions benefit from the cinolone derivative composition administered at the same Small particle size; if the nanoparticulate triamcinolone and dosage, when administered to a mammal in a fed State. triamcinolone derivative particles do not redisperse into the “Bioecquivalency” is preferably established by a 90% Con Small particle sizes upon administration, then "clumps' or fidence Interval (CI) of between 0.80 and 1.25 for both C. agglomerated triamcinolone and triamcinolone derivative and AUC under U.S. Food and Drug Administration particles are formed. With the formation of Such agglomer (USFDA) regulatory guidelines, or a 90% CI for AUC of ated particles, the bioavailability of the dosage form may between 0.80 to 1.25 and a 90% CI for C of between 0.70 fall. to 1.43 under the European Medicines Evaluation Agency 0104 Moreover, preferably the nanoparticulate triamci (EMEA) regulatory guidelines (T is not relevant for nolone and triamcinolone derivative compositions of the bioeduivalency determinations under USFDA and EMEA invention exhibit dramatic redispersion of the triamcinolone regulatory guidelines). and triamcinolone derivative particles upon administration 0097. Preferably the difference in AUC (e.g., absorption) to a mammal, Such as a human or animal, as demonstrated of the nanoparticulate triamcinolone or triamcinolone by reconstitution in a biorelevantaqueous media. Preferably, derivative compositions of the invention, when administered upon reconstitution in a biorelevant aqueous media, the in the fed versus the fasted State, is less than about 100%, compositions of the invention redisperse Such that the effec less than about 90%, less than about 80%, less than about tive average particle size of the redispersed triamcinolone 70%, less than about 60%, less than about 50%, less than and triamcinolone derivative particles is less than about 2 about 40%, less than about 35%, less than about 30%, less microns. Such biorelevant aqueous media can be any aque than about 25%, less than about 20%, less than about 15%, ous media that exhibit the desired ionic Strength and pH, less than about 10%, less than about 5%, or less than about which form the basis for the biorelevance of the media. The 3%. desired pH and ionic Strength are those that are representa 0098. In addition, preferably the difference in C of the tive of physiological conditions found in the human body. nanoparticulate triamcinolone and triamcinolone derivative Such biorelevant acqueous media can be, for example, aque compositions of the invention, when administered in the fed ous electrolyte Solutions or aqueous Solutions of any Salt, versus the fasted State, is less than about 100%, less than acid, or base, or a combination thereof, which exhibit the about 90%, less than about 80%, less than about 70%, less desired pH and ionic Strength. than about 60%, less than about 50%, less than about 40%, 0105 Biorelevant pH is well known in the art. For less than about 35%, less than about 30%, less than about example, in the Stomach, the pH ranges from Slightly leSS 25%, less than about 20%, less than about 15%, less than than 2 (but typically greater than 1) up to 4 or 5. In the Small about 10%, less than about 5%, or less than about 3%. intestine the pH can range from 4 to 6, and in the colon it can 0099 Finally, preferably the difference in the T of the range from 6 to 8. Biorelevant ionic Strength is also well nanoparticulate triamcinolone and triamcinolone derivative known in the art. Fasted State gastric fluid has an ionic compositions of the invention, when administered in the fed strength of about 0.1 M while fasted state intestinal fluid has versus the fasted State, is less than about 100%, less than an ionic Strength of about 0.14. See e.g., Lindahl et al., about 90%, less than about 80%, less than about 70%, less “Characterization of Fluids from the Stomach and Proximal than about 60%, less than about 50%, less than about 40%, Jejunum in Men and Women.” Pharm. Res., 14(4): 497-502 less than about 30%, less than about 20%, less than about (1997). 15%, less than about 10%, less than about 5%, less than 0106. It is believed that the pH and ionic strength of the about 3%, or essentially no difference. test Solution is more critical than the Specific chemical 0100 Benefits of a dosage form which substantially content. Accordingly, appropriate pH and ionic Strength eliminates the effect of food include an increase in Subject values can be obtained through numerous combinations of convenience, thereby increasing Subject compliance, as the Strong acids, Strong bases, Salts, Single or multiple conjugate Subject does not need to ensure that they are taking a dose acid-base pairs (i.e., weak acids and corresponding Salts of either with or without food. that acid), monoprotic and polyprotic electrolytes, etc. 0101 D. Redispersibility Profiles of the Nanoparticulate 0107 Representative electrolyte solutions can be, but are Triamcinolone and Triamcinolone Derivative Compositions not limited to, HCl Solutions, ranging in concentration from of the Invention about 0.001 to about 0.1 M, and NaCl solutions, ranging in concentration from about 0.001 to about 0.1M, and mixtures 0102) An additional feature of the nanoparticulate triam thereof. For example, electrolyte Solutions can be, but are cinolone and triamcinolone derivative compositions of the not limited to, about 0.1M HCl or less, about 0.01 M HCl US 2004/014 1925 A1 Jul. 22, 2004

or less, about 0.001M HCl or less, about 0.1M NaCl or less, No. 6,428,814 for “Bioadhesive Nanoparticulate Composi about 0.01 M NaCl or less, about 0.001M NaCl or less, and tions Having Cationic Surface Stabilizers,” which is spe mixtures thereof. Of these electrolyte solutions, 0.01 M HCl cifically incorporated by reference. and/or 0.1M NaCl, are most representative of fasted human 0115 The bioadhesive triamcinolone and triamcinolone physiological conditions, owing to the pH and ionic Strength derivative compositions of the invention are useful in any conditions of the proximal gastrointestinal tract. Situation in which it is desirable to apply the compositions 0108 Electrolyte concentrations of 0.001M HCl, 0.01 M to a biological Surface. The bioadhesive triamcinolone and HCl, and 0.1M HCl correspond to pH 3, pH 2, and pH 1, triamcinolone derivative compositions preferably coat the respectively. Thus, a 0.01 M HCl solution simulates typical targeted Surface in a continuous and uniform film which is acidic conditions found in the stomach. A Solution of 0.1 M invisible to the naked human eye. NaCl provides a reasonable approximation of the ionic 0116 Bioadhesive nanoparticulate triamcinolone and tri Strength conditions found throughout the body, including the amcinolone derivative compositions Slow the transit of the gastrointestinal fluids, although concentrations higher than composition. As a result, Some triamcinolone and triamci 0.1 M may be employed to simulate fed conditions within nolone derivative particles likely would adhere to the the human GI tract. mucosa, prolonging exposure to the drug, thereby increasing 0109 Exemplary solutions of salts, acids, bases or com absorption and the bioavailability of the administered dos binations thereof, which exhibit the desired pH and ionic age in situ. Strength, include but are not limited to phosphoric acid/ phosphate Salts+Sodium, potassium and calcium Salts of 0117) F. Low Viscosity chloride, acetic acid/acetate Salts+Sodium, potassium and 0118 Liquid dosage forms of conventional microcrystal calcium Salts of chloride, carbonic acid/bicarbonate Salts+ line or non-nanoparticulate triamcinolone and triamcinolone Sodium, potassium and calcium Salts of chloride, and citric derivatives can be expected to be a relatively large Volume, acid/citrate SaltS+Sodium, potassium and calcium Salts of Viscous Substance which may not be well accepted by chloride. patient populations. Moreover, Viscous Solutions can be 0110. In other embodiments of the invention, the redis problematic in parenteral administration because these Solu persed triamcinolone and triamcinolone derivative particles tions require a Slow Syringe push and can Stick to tubing. of the invention (redispersed in an aqueous, biorelevant, or Similarly, Viscous Solutions cannot be readily formulated any other Suitable media) have an effective average particle into a fine and/or uniform mist for spray administration (e.g. size of less than about 1900 nm, less than about 1800 nm, nasal and topical spray). In addition, conventional formula less than about 1700 nm, less than about 1600 nm, less than tions of poorly water-Soluble active agents, Such as triam about 1500 nm, less than about 1400 nm, less than about cinolone and triamcinolone derivatives, tend to be unsafe for 1300 nm, less than about 1200 nm, less than about 1100 nm, intravenous administration techniques, which are used pri less than about 1000 nm, less than about 900 nm, less than marily in conjunction with highly water-Soluble Substances. about 800 nm, less than about 700 nm, less than about 600 0119 Liquid dosage forms of the nanoparticulate triam nm, less than about 500 nm, less than about 400 nm, less cinolone and triamcinolone derivative compositions of the than about 300 nm, less than about 250 nm, less than about invention provide Significant advantages over liquid dosage 200 nm, less than about 150 nm, less than about 100 nm, less forms of conventional triamcinolone and triamcinolone than about 75 nm, or less than about 50 nm, as measured by derivatives microcrystalline compound. The low Viscosity light-scattering methods, microScopy, or other appropriate and Silky texture of liquid dosage forms of the nanoparticu methods. late triamcinolone and triamcinolone derivative composi tions of the invention result in advantages in both prepara 0111 Redispersibility can be tested using any suitable tion and use. These advantages include, for example: (1) means known in the art. See e.g., the example Sections of better Subject compliance due to the perception of a lighter U.S. Pat. No. 6,375,986 for “Solid Dose Nanoparticulate formulation which is easier to consume and digest; (2) ease Compositions Comprising a Synergistic Combination of a of dispensing because one can use a cup or a Syringe; (3) Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuc potential for formulating a higher concentration of triamci cinate.” nolone and triamcinolone derivatives resulting in a Smaller 0112 E. Bioadhesive Nanoparticulate Triamcinolone and dosage Volume and thus leSS Volume for the Subject to Triamcinolone Derivative Compositions consume or apply; and (4) easier overall formulation con 0113 Bioadhesive nanoparticulate triamcinolone and tri CCS. amcinolone derivative compositions of the invention com 0120 Liquid triamcinolone and triamcinolone derivative prise at least one cationic Surface Stabilizer, which are dosage forms which are easier to consume are especially described in more detail below. Bioadhesive formulations of important when considering juvenile patients, terminally ill triamcinolone and triamcinolone derivatives exhibit excep patients, and elderly patients. Viscous or gritty formulations, tional bioadhesion to biological Surfaces, Such as mucous and those that require a relatively large dosage Volume, are and mucous membranes. not well tolerated by these patient populations. Liquid oral 0114. In the case of bioadhesive nanoparticulate triamci dosage forms can be particularly preferably for patient nolone and triamcinolone derivative compositions, the term populations who have difficulty consuming tablets, Such as “bioadhesion' is used to describe the adhesion between the infants and the elderly. nanoparticulate triamcinolone and triamcinolone derivative 0121 The viscosities of liquid dosage forms of nanopar compositions and a biological Substrate (i.e., gastrointestinal ticulate triamcinolone and triamcinolone derivatives accord mucin, lung tissue, nasal mucosa, etc.). See e.g., U.S. Pat. ing to the invention are preferably less than about /200, leSS US 2004/014 1925 A1 Jul. 22, 2004

than about/175, less than about/150, less than about /125, leSS filtered. This obviates the need for heat sterilization, which than about 1/100, less than about /75, less than about /so, or can harm or degrade triamcinolone or a triamcinolone less than about /25 of a liquid oral dosage form of non derivative, as well as result in crystal growth and particle nanoparticulate triamcinolone and triamcinolone derivative aggregation. compositions, at about the same concentration per ml of 0128 Sterile filtration can be difficult because of the triamcinolone or triamcinolone derivative. required Small particle size of the composition. Filtration is 0.122 Typically the viscosity of liquid nanoparticulate an effective method for Sterilizing homogeneous Solutions triamcinolone or triamcinolone derivative dosage forms of when the membrane filter pore size is less than or equal to the invention, at a shear rate of 0.1 (1/s), measured at about about 0.2 microns (200 nm) because a 0.2 micron filter is 20° C., is from about 2000 mPa is to about 1 mPa's, from sufficient to remove essentially all bacteria. Sterile filtration about 1900 mPa's to about 1 mPats, from about 1800 mPa's is normally not used to Sterilize Suspensions of micron-sized to about 1 mPats, from about 1700 mPa is to about 1 mPats, triamcinolone and triamcinolone derivatives because the from about 1600 mPa is to about 1 mPa's, from about 1500 triamcinolone and triamcinolone derivative particles are too mPa's to about 1 mPas, from about 1400 mPa's to about 1 large to pass through the membrane pores. mPats, from about 1300 mPa's to about 1 mPats, from about 0129. Sterile nanoparticulate triamcinolone and triamci 1200 mPa's to about 1 mPas, from about 1100 mPa is to nolone derivative dosage forms are particularly useful in about 1 mPas, from about 1000 mPa's to about 1 mPats, treating immunocompromised patients, infants or juvenile from about 900 mPa is to about 1 mPats, from about 800 patients, and the elderly, as these patient groups are the most mPa's to about 1 mPas, from about 700 mPa's to about 1 Susceptible to infection caused by a non-Sterile liquid dosage mPats, from about 600 mPa's to about 1 mPas, from about form. 500 mPa's to about 1 mPas, from about 400 mPa is to about 1 mPats, from about 300 mPa's to about 1 mPats, from about 0.130. Because the nanoparticulate triamcinolone and tri 200 mPa's to about 1 mPas, from about 175 mPa is to about amcinolone derivative compositions of the invention, for 1 mPats, from about 150 mPa's to about 1 mPats, from about mulated into a liquid dosage form, can be Sterile filtered, and 125 mPa's to about 1 mPas, from about 100 mPa is to about because the compositions can have a very Small effective 1 mPas, from about 75 mPa is to about 1 mPas, from about average particle size, the compositions are Suitable for 50 mPa's to about 1 mPas, from about 25 mPa's to about 1 parenteral administration. mPats, from about 15 mPa is to about 1 mPats, from about 10 0131 H. Combination Pharmacokinetic Profile Compo mPa's to about 1 mPats, or from about 5 mPa is to about 1. Sitions mPa's. Such a viscosity is much more attractive for subject consumption and may lead to better overall Subject compli 0.132. In yet another embodiment of the invention, a first CC. nanoparticulate triamcinolone or triamcinolone derivative composition providing a desired pharmacokinetic profile is 0123 Viscosity is concentration and temperature depen co-administered, Sequentially administered, or combined dent. Typically, a higher concentration results in a higher with at least one other triamcinolone or triamcinolone Viscosity, while a higher temperature results in a lower derivative composition that generates a desired different Viscosity. Viscosity as defined above refers to measurements pharmacokinetic profile. More than two triamcinolone or taken at about 20° C. (The viscosity of water at 20° C. is 1 triamcinolone derivative compositions can be co-adminis mPas.) The invention encompasses equivalent Viscosities tered, sequentially administered, or combined. While the measured at different temperatures. first triamcinolone or triamcinolone derivative composition 0.124. Another important aspect of the invention is that has a nanoparticulate particle Size, the additional one or the nanoparticulate triamcinolone and triamcinolone deriva more triamcinolone or triamcinolone derivative composi tive compositions of the invention, formulated into a liquid tions can be nanoparticulate, Solubilized, or have a micro dosage form, are not turbid. “Turbid,” as used herein refers particulate particle size. to the property of particulate matter that can be seen with the 0.133 For example, a first triamcinolone or triamcinolone naked eye or that which can be felt as “gritty.” The nano derivative composition can have a nanoparticulate particle particulate triamcinolone and triamcinolone derivative com Size, conferring a short Ta, and typically a higher C. positions of the invention, formulated into a liquid dosage This first triamcinolone or triamcinolone derivative compo form, can be poured out, extracted from a container, or Sition can be combined, co-administered, or Sequentially Sprayed through an atomizer as easily as water, whereas administered with a second composition comprising: (1) liquid dosage forms of non-nanoparticulate or Solubilized triamcinolone or a triamcinolone derivative having a larger triamcinolone and triamcinolone derivatives are expected to (but still nanoparticulate as defined herein) particle size, and exhibit notably more "sluggish characteristics. therefore exhibiting slower absorption, a longer T, and 0.125 The liquid formulations of this invention can be typically a lower C, or (2) a microparticulate or Solubi formulated for dosages in any Volume but preferably equiva lized triamcinolone or triamcinolone derivative composi lent or Smaller Volumes than a liquid dosage form of tion, exhibiting a longer T lax and typically a lower C. non-nanoparticulate triamcinolone and triamcinolone 0134) The second, third, fourth, etc., triamcinolone or derivative compositions. triamcinolone derivative compositions can differ from the first, and from each other, for example: (1) in the effective 012.6 G. Sterile Filtered Nanoparticulate Triamcinolone average particle sizes of triamcinolone or triamcinolone and Triamcinolone Derivative Compositions derivative; or (2) in the dosage of triamcinolone or triam 0127. The nanoparticulate triamcinolone and triamcino cinolone derivative. Such a combination composition can lone derivative compositions of the invention can be Sterile reduce the dose frequency required. US 2004/014 1925 A1 Jul. 22, 2004

0135) If the second triamcinolone or triamcinolone 0141 Examples of representative active agents useful in derivative composition has a nanoparticulate particle Size, this invention include, but are not limited to, acyclovir, then preferably the triamcinolone or triamcinolone deriva alprazolam, altretamine, amiloride, amiodarone, benz tive particles of the Second composition have at least one tropine meSylate, bupropion, cabergoline, candesartan, Surface Stabilizer associated with the Surface of the drug cerivastatin, chlorpromazine, ciprofloxacin, cisapride, particles. The one or more Surface Stabilizers can be the clarithromycin, clonidine, clopidogrel, cyclobenzaprine, same as or different from the Surface stabilizer(s) present in cyproheptadine, delavirdine, desmopressin, diltiazem, dipy the first triamcinolone or triamcinolone derivative compo ridamole, dolasetron, enalapril maleate, enalaprilat, famoti Sition. dine, felodipine, furazolidone, glipizide, irbesartan, keto 0.136 Preferably where co-administration of a “fast-act conazole, lanSoprazole, loratadine, loxapine, mebendazole, ing formulation and a “longer-lasting formulation is mercaptopurine, milrinone lactate, minocycline, mitox desired, the two formulations are combined within a Single antrone, nelfinavir meSylate, nimodipine, norfloxacin, olan composition, for example a dual-release composition. Zapine, omeprazole, penciclovir, pimozide, tacolimus, quazepam, raloxifene, rifabutin, rifampin, risperidone, riza 0137) I. Combination Active Agent Compositions triptan, Saquinavir, Sertraline, Sildenafil, acetyl-Sulfisox 0.138. The invention encompasses the nanoparticulate tri azole, temazepam, thiabendazole, thioguanine, trandolapril, amcinolone and triamcinolone derivative compositions of triamterene, trimetrexate, troglitaZone, trovafloxacin, Vera the invention formulated or co-administered with one or pamil, vinblastine Sulfate, mycophenolate, atovaquone, more non-triamcinolone or triamcinolone derivative active atovaquone, proguanil, ceftazidime, cefuroxime, etoposide, agents. Methods of using Such combination compositions terbinafine, thalidomide, fluconazole, amsacrine, dacarba are also encompassed by the invention. The non-triamcino Zine, teniposide, and acetylsalicylate. lone or triamcinolone derivative active agents can be present 0142. A description of these classes of active agents and in a crystalline phase, an amorphous phase, a Semi-crystal a listing of Species within each class can be found in line phase, a Semi-amorphous phase, or a mixture thereof. Martindale's The Extra Pharmacopoeia, 31 Edition (The 0.139. The compound to be administered in combination Pharmaceutical Press, London, 1996), specifically incorpo with nanoparticulate triamcinolone and triamcinolone rated by reference. The active agents are commercially derivative compositions of the invention can be formulated available and/or can be prepared by techniques known in the Separately from the nanoparticulate triamcinolone or triam art. cinolone derivative composition or co-formulated with the 0143 Exemplary nutraceuticals or dietary supplements nanoparticulate triamcinolone or triamcinolone derivative include, but are not limited to, lutein, folic acid, fatty acids composition. Where a nanoparticulate triamcinolone or tri (e.g., DHA and ARA), fruit and vegetable extracts, Vitamin amcinolone derivative composition is co-formulated with a and mineral Supplements, phosphatidylserine, lipoic acid, Second active agent, the Second active agent can be formu melatonin, glucosamine/chondroitin, Aloe Vera, Guggul, lated in any Suitable manner, Such as immediate-release, glutamine, amino acids (e.g., arginine, iso-leucine, leucine, rapid-onset, Sustained-release, or dual-release form. lysine, methionine, phenylanine, threonine, tryptophan, and 0140. Such non-triamcinolone or non-triamcinolone valine), green tea, lycopene, whole foods, food additives, derivative active agents can be, for example, a therapeutic herbs, phytonutrients, antioxidants, flavonoid constituents of agent. A therapeutic agent can be a pharmaceutical agent, fruits, evening primrose oil, flax Seeds, fish and marine including a biologic. The active agent can be Selected from animal oils, and probiotics. Nutraceuticals and dietary a variety of known classes of drugs, including, for example, Supplements also include bio-engineered foods genetically nutraceuticals, amino acids, proteins, peptides, nucleotides, engineered to have a desired property, also known as “phar anti-obesity drugs, central nervous System Stimulants, caro mafoods.” tenoids, corticosteroids, elastase inhibitors, anti-fungals, oncology therapies, anti-emetics, analgesics, cardiovascular 0144) Exemplary nutraceuticals and dietary Supplements agents, anti-inflammatory agents, Such as NSAIDS and are disclosed, for example, in Roberts et al., Nutraceuticals: COX-2 inhibitors, anthelmintics, anti-arrhythmic agents, The Complete Encyclopedia of Supplements, Herbs, Vita antibiotics (including penicillins), anticoagulants, antide mins, and Healing Foods (American Nutraceutical ASSocia preSSants, antidiabetic agents, antiepileptics, antihistamines, tion, 2001), which is specifically incorporated by reference. antihypertensive agents, antimuscarinic agents, antimyco Dietary Supplements and nutraceuticals are also disclosed in bacterial agents, antineoplastic agents, immunosuppres Physicians Desk Reference for Nutritional Supplements, Sants, antithyroid agents, antiviral agents, anxiolytics, Seda 1st Ed. (2001) and The Physicians' Desk Reference for tives (hypnotics and neuroleptics), astringents, alpha Herbal Medicines, 1st Ed. (2001), both of which are also adrenergic receptor blocking agents, beta-adrenoceptor incorporated by reference. A nutraceutical or dietary Supple blocking agents, blood products and Substitutes, cardiac ment, also known as a phytochemical or functional food, is inotropic agents, contrast media, corticosteroids, cough Sup generally any one of a class of dietary Supplements, Vita pressants (expectorants and mucolytics), decongestants, mins, minerals, herbs, or healing foods that have medical or diagnostic agents, diagnostic imaging agents, diuretics, pharmaceutical effects on the body. dopaminergics (antiparkinsonian agents), haemostatics, 0145. In a particularly preferred embodiment, nanopar immunological agents, lipid regulating agents, muscle relax ticulate triamcinolone and triamcinolone derivative compo ants, parasympathomimetics, parathyroid calcitonin and Sitions are combined with at least one antihistamine. Useful biphosphonates, prostaglandins, radio-pharmaceuticals, SeX antihistamines include, for example, feXofenadine, azelas hormones (including Steroids), anti-allergic agents, stimu tine, hydoxyZine, diphenhydramine, loratadine, chlorphe lants and anoretics, Sympathomimetics, thyroid agents, niramine maleate, cyproheptadine, promethazine, phenyle vasodilators, and Xanthines. phrine tannate, acrivastine, and cetirizine. US 2004/014 1925 A1 Jul. 22, 2004

0146 In a further particularly preferred embodiment, local (powders, creams, ointments or drops), buccal, intra nanoparticulate triamcinolone and triamcinolone derivative cisternal, intraperitoneal, topical administration, and the compositions are combined with at least one decongestant. like. Useful decongestants include, for example, pseudoephe drine, Oxymetazoline, Xylometazoline, naphazoline, nap O155 A. Triamcinolone and Triamcinolone Derivatives hazoline, and tetrahydrozoline. 0156 As used herein, “triamcinolone” refers to ((11 B, 0147 In an additional preferred embodiment, nanopar ticulate triamcinolone and triamcinolone derivative compo 16D)-9-fluoro-11, 17, 18, 21-dihydroxy-pregna-1,4-diene-3, Sitions are combined with at least one bronchodilator, Such 20-dione or a Salt thereof having the following chemical as short-acting and long-acting agonists, anticholinergics, Structure: and theophylline. Useful short-acting beta2-agonists include pirbuterol and albuterol. Long-acting beta2-agonists include formoteroll, Salmeterol and albuterol. Useful anticholin ergics include ipratropium bromide. 0.148. In yet another embodiment, the compositions of the invention are combined with an anti-fungal agent, Such as amphotericin B, nyStatin, fluconazole, ketoconazole, terbin afine, itraconazole, imidazole, triazole, ciclopiroX, clotrima Zole, and miconazole. 014.9 Finally, in a preferred embodiment of the inven tion, the compositions of the invention can be combined with an immunosuppressant, Such as for treatment required O157. “Triamcinolone derivatives” refers to any chemical following organ transplantation. derivative of triamcinolone and includes, but is not limited 0150 J. Miscellaneous Benefits of the Nanoparticulate to, triamcinolone acetonide ((11 B,16C)-9-fluoro-11,21-dihy Triamcinolone and Triamcinolone Derivative Compositions droxy-16,17-1-methylethylidenebis(oxy)-pregna-1,4-di of the Invention ene-320-dione) having following chemical structure: 0151. The nanoparticulate triamcinolone and triamcino lone derivative compositions preferably exhibit an increased rate of dissolution as compared to microcrystalline or non nanoparticulate forms of triamcinolone or triamcinolone derivatives. In addition, the nanoparticulate triamcinolone and triamcinolone derivative compositions preferably exhibit improved performance characteristics for oral, intra venous, Subcutaneous, or intramuscular injection, Such as higher dose loading and Smaller tablet or liquid dose Vol umes. Moreover, the nanoparticulate triamcinolone and tri amcinolone derivative compositions of the invention do not require organic Solvents or pH extremes. 0158 “Triamcinolone derivatives” also includes, but is 0152 II. Triamcinolone and Triamcinolone Derivative not limited to, triamcinolone diacetate ((11f8,16C)-16,21 Compositions bis(acetyloxy)-9-fluoro-11,17-dihydroxypregna-1,4-diene 0153. The invention provides compositions comprising 3,20-dione) having the following chemical structure: nanoparticulate triamcinolone and triamcinolone derivative particles and at least one Surface Stabilizer. The Surface stabilizers are preferably associated with the surface of the triamcinolone or triamcinolone derivative particles. Surface stabilizers useful herein do not chemically react with the triamcinolone and triamcinolone derivative particles or itself. Preferably, individual molecules of the surface stabi lizer are essentially free of intermolecular croSS-linkages. The compositions can comprise two or more Surface Stabi lizers. 0154) The present invention also includes nanoparticulate triamcinolone and triamcinolone derivative compositions together with one or more non-toxic physiologically accept able carriers, adjuvants, or vehicles, collectively referred to as carriers. The compositions can be formulated for parenteral injection (i.e., intravenous, intramuscular, or Sub 0159) “Triamcinolone derivatives” includes, but is not cutaneous), oral administration (in Solid, liquid, or aerosol limited to, triamcinolone hexacetonide ((11B,16C)-21-(3, (i.e., pulmonary or nasal form), Vaginal, nasal, rectal, ocular, 3dimethyl-1-oxobutoxy)-9-fluoro-11-hydroxy-16,17-(1- US 2004/014 1925 A1 Jul. 22, 2004 14 methylethylidene)bis(oxy)-pregna-1,4-diene-3,20-dione), ypropylcellulose, polyvinylpyrrolidone, Sodium lauryl Sul having the following chemical Structure: fate, dioctylsulfoSuccinate, gelatin, casein, lecithin (phos phatides), dextran, gum acacia, cholesterol, tragacanth, Stearic acid, benzalkonium chloride, calcium Stearate, glyc CHOCOCH2C(CH3)3. erol monoStearate, cetoStearyl alcohol, cetomacrogol emul Sifying wax, Sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol etherS Such as cetomacrogol 1000), poly oxyethylene castor oil derivatives, polyoxyethylene Sorbitan fatty acid esters (e.g., the commercially available TweenS(R) such as e.g., Tween 20E) and Tween 808) (ICI Speciality Chemicals)); polyethylene glycols (e.g., Carbowaxs 3550(R) and 9340E (Union Carbide)), polyoxyethylene stearates, col loidal Silicon dioxide, phosphates, carboxymethylcellulose calcium, carboxymethylcellulose Sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose 0160 Finally, “triamcinolone derivatives” includes, but phthalate, noncrystalline cellulose, magnesium aluminium is not limited to, triamcinolone benetonide ((11B,16C)-21 silicate, triethanolamine, polyvinyl alcohol (PVA), 4-(1,1,3, 3-(benzoylamino)-2-methyl-1-oxopropoxy-9-fluoro-11 3-tetramethylbutyl)-phenol polymer with ethylene oxide and hydroxy-16,17-(1-methylethylidene)bis(oxy)-pregna-1,4- formaldehyde (also known as tyloxapol, Superione, and diene-3,20-dione) having the following chemical structure: triton), poloxamers (e.g., Pluronics F68(R) and F1086, which are block copolymers of ethylene oxide and propylene oxide); poloxamines (e.g., Tetronic 9080E, also known as Poloxamine 9080E), which is a tetrafunctional block copoly mer derived from Sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Wyandotte Cor poration, Parsippany, N.J.)); Tetronic 15086) (T-1508) (BASF Wyandotte Corporation), Tritons X-2008), which is an alkyl aryl polyether sulfonate (Rohm and Haas); Crod

estas F-110(E), which is a mixture of Sucrose Stearate and Sucrose distearate (Croda Inc.), p-isononylphenoxypoly (glycidol), also known as Olin-IOG(R) or Surfactant 10-G(R) (Olin Chemicals, Stamford, Conn.); Crodestas SL-40E (Croda, Inc.); and SA90HCO, which is CH,CH(CON(CH4)-CH(CHOH)(CHOH). (East man Kodak Co.); decanoyl-N-methylglucamide; n-decyl B-D-glucopyranoside; n-decyl B-D-maltopyranoside; n-dodecyl B-D-glucopyranoside; n-dodecyl B-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-B-D-glucopyrano Side; n-heptyl B-D-thioglucoside; n-hexyl B-D-glucopyrano Side; nonanoyl-N-methylglucamide; n-noyl B-D-glucopyra noSide; octanoyl-N-methylglucamide; n-octyl-f-D- 0.161 Triamcinolone and triamcinolone derivatives can glucopyranoside; octyl B-D-thioglucopyranoside, PEG be in a crystalline phase, an amorphous phase, a Semi derivatized phospholipid, PEG-derivatized cholesterol, crystalline phase, a Semi-amorphous phase, or a mixtures PEG-derivatized cholesterol derivative, PEG-derivatized thereof. vitamin A, PEG-derivatized vitamin E, lysozyme, random copolymers of vinyl pyrrollidone and vinyl acetate, and the 0162 B. Surface Stabilizers like. 0163 The choice of a surface stabilizer for triamcinolone 0166 Depending upon the desired method of adminis and triamcinolone derivatives is non-trivial and requires tration, bioadhesive formulations of nanoparticulate triam extensive experimentation to realize a desirable formulation. cinolone and triamcinolone derivatives can be prepared by Accordingly, the present invention is directed to the Surpris Selecting one or more cationic Surface Stabilizers that impart ing discovery that triamcinolone and triamcinolone deriva bioadhesive properties to the resultant composition. Useful tive nanoparticulate compositions can be made. cationic Surface Stabilizers are described below. 0164 Combinations of more than one surface stabilizer 0.167 Examples of useful cationic Surface stabilizers can be used in the invention. Useful Surface stabilizers include, but are not limited to, polymers, biopolymers, which can be employed in the invention include, but are not polysaccharides, cellulosics, alginates, phospholipids, and limited to, known organic and inorganic pharmaceutical nonpolymeric compounds, Such as Zwitterionic Stabilizers, excipients. Such excipients include various polymers, low poly-n-methylpyridinium, anthryul pyridinium chloride, molecular weight oligomers, natural products, and Surfac cationic phospholipids, chitosan, polylysine, polyvinylimi tants. Surface Stabilizers include nonionic, cationic, Zwitte dazole, polybrene, polymethylmethacrylate trimethylammo niumbromide bromide (PMMTMABr), hexyldesyltrimethy rionic, and ionic Surfactants. lammonium bromide (HDMAB), polyvinylpyrrolidone-2- 0.165 Representative examples of other useful surface dimethylaminoethyl methacrylate dimethyl Sulfate, 1.2 Stabilizers include hydroxypropyl methylcellulose, hydrox Dipalmitoyl-sn-Glycero-3-Phosphoethanolamine-N-Ami US 2004/014 1925 A1 Jul. 22, 2004 no(Polyethylene Glycol)2000 (sodium salt) (also known as polymers, Such as polydiallyl dimethylammonium chlo DPPE-PEG(2000)-Amine Na) (Avanti Polar Lipids, Alabas ride and poly-N-methyl vinyl pyridinium chloride; and ter, Ala.), Poly(2-methacryloxyethyl trimethylammonium cationic guar. bromide) (Polysciences, Inc., Warrington, Pa.) (also known 0169. Such exemplary cationic surface stabilizers and as S1001), poloxamines such as Tetronic 9080E), also known other useful cationic Surface Stabilizers are described in J. as Poloxamine 908E), which is a tetrafunctional block CroSS and E. Singer, Cationic Surfactants: Analytical and copolymer derived from Sequential addition of propylene Biological Evaluation (Marcel Dekker, 1994); P and D. oxide and ethylene oxide to ethylenediamine (BASF Wyan Rubingh (Editor), Cationic Surfactants: Physical Chemistry dotte Corporation, Parsippany, N.J.), lysozyme, long-chain (Marcel Dekker, 1991); and J. Richmond, Cationic Surfac polymerS Such as alginic acid, carrageenan (FMC Corp.), tants: Organic Chemistry, (Marcel Dekker, 1990). and POLYOX (Dow, Midland, Mich.). 0170 Nonpolymeric cationic surface stabilizers are any 0168 Other useful cationic stabilizers include, but are not nonpolymeric compound, Such as benzalkonium chloride, a limited to, cationic lipids, Sulfonium, phosphonium, and carbonium compound, a phosphonium compound, an OXO quarternary ammonium compounds, Such as Stearyltrim nium compound, a halonium compound, a cationic organo metallic compound, a quarternary phosphorous compound, a ethylammonium chloride, benzyl-di(2-chloroethyl)ethylam pyridinium compound, an anilinium compound, an ammo monium bromide, coconut trimethyl ammonium chloride or nium compound, a hydroxylammonium compound, a pri bromide, coconut methyl dihydroxyethyl ammonium chlo mary ammonium compound, a Secondary ammonium com ride or bromide, decyl triethyl ammonium chloride, decyl pound, a tertiary ammonium compound, and quarternary dimethyl hydroxyethyl ammonium chloride or bromide, ammonium compounds of the formula NRRRR''. For C-dimethyl hydroxyethyl ammonium chloride or bro compounds of the formula NR. R.R.R.'": mide, coconut dimethyl hydroxyethyl ammonium chloride or bromide, myristyl trimethyl ammonium methyl Sulphate, 0171 (i) none of R-R are CH; lauryl dimethyl benzyl ammonium chloride or bromide, 0172 (ii) one of R-R is CH; lauryl dimethyl(ethenoxy) ammonium chloride or bromide, N-alkyl(Cs)dimethylbenzyl ammonium chloride, 0173 (iii) three of R-R are CH; N-alkyl(Cs)dimethyl-benzyl ammonium chloride, N-tet 0.174 (iv) all of R-R are CH; radecylidmethylbenzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and (C- 0175 (v) two of R-R are CH, one of R-R is 14)dimethyl 1-napthylmethyl ammonium chloride, trimethy CHCH, and one of R-R4 is an alkyl chain of lammonium halide, alkyl-trimethylammonium Salts and Seven carbon atoms or less, dialkyl-dimethylammonium Salts, lauryl trimethyl ammo 0176 (vi) two of R-R are CH, one of R-R is nium chloride, ethoxylated alkyamidoalkyldialkylammo CHCH, and one of R-R is an alkyl chain of nium Salt and/or an ethoxylated trialkyl ammonium Salt, nineteen carbon atoms or more; dialkylbenzene dialkylammonium chloride, N-didecyldim 0177 (vii) two of R-R are CH and one of R-R ethyl ammonium chloride, N-tetradecyldimethylbenzyl is the group CH (CH), where n>1; ammonium, chloride monohydrate, N-alkyl(C) dim ethyl 1-naphthylmethyl ammonium chloride and dode 0178 (viii) two of R-R are CH, one of R-R is cyldimethylbenzyl ammonium chloride, dialkyl benzene CHCH, and one of R-R comprises at least one alkyl ammonium chloride, lauryl trimethyl ammonium heteroatom; chloride, alkylbenzyl methyl ammonium chloride, alkyl 0179 (ix) two of R-R are CH, one of R-R is benzyl dimethyl ammonium bromide, C2, C, C17 trim CHCH, and one of R-R comprises at least one ethyl ammonium bromides, dodecylbenzyl triethyl ammo halogen; nium chloride, poly-diallyldimethylammonium chloride 0180 (x) two of R-R are CH, one of R-R is (DADMAC), dimethyl ammonium chlorides, alkyldimethy CHCH, and one of R-R comprises at least one lammonium halogenides, tricetyl methyl ammonium chlo cyclic fragment; ride, decyltrimethylammonium bromide, dodecyltriethylam monium bromide, tetradecyltrimethylammonium bromide, 0181 (xi) two of R-R are CH and one of R-R is methyl trioctylammonium chloride (ALIQUAT 336 TM), a phenyl ring; or POLYOUAT 10TM, tetrabutylammonium bromide, benzyl 0182 (xii) two of R-R are CH and two of R-R trimethylammonium bromide, choline esters (Such as cho are purely aliphatic fragments. line esters of fatty acids), benzalkonium chloride, Stearalko nium chloride compounds (such as Stearyltrimonium chlo 0183 Such compounds include, but are not limited to, ride and Di-Stearyidimonium chloride), cetyl pyridinium behenalkonium chloride, benzethonium chloride, cetylpyri bromide or chloride, halide Salts of quaternized polyoxy dinium chloride, behentrimonium chloride, lauralkonium ethylalkylamines, MIRAPOLTM and ALKAQUATTM chloride, cetalkonium chloride, cetrimonium bromide, cet (Alkaril Chemical Company), alkyl pyridinium salts; rimonium chloride, cethylamine hydrofluoride, chlorallyl amines, Such as alkylamines, dialkylamines, alkanolamines, methenamine chloride (Quaternium-15), distearyldimonium polyethylenepolyamines, N,N-dialkylaminoalkyl acrylates, chloride (Quaternium-5), dodecyl dimethyl ethylbenzyl and vinyl pyridine, amine Salts, Such as lauryl amine acetate, ammonium chloride(Quaternium-14), Quaternium-22, Stearyl amine acetate, alkylpyridinium Salt, and alkylimida Quaternium-26, Quaternium-18 hectorite, dimethylaminoet Zolium Salt, and amine oxides, imide azolinium Salts, pro hylchloride hydrochloride, cysteine hydrochloride, dietha tonated quaternary acrylamides, methylated quaternary nolammonium POE (10) oletyl ether phosphate, diethano US 2004/014 1925 A1 Jul. 22, 2004 lammonium POE (3)oleyl ether phosphate, tallow alkonium PH102; lactose Such as lactose monohydrate, lactose anhy chloride, dimethyl dioctadecylammoniumbentonite, Stear drous, and Pharmatose(RDCL21; dibasic calcium phosphate alkonium chloride, domiphen bromide, denatonium ben Such as Emcompress(E); mannitol, Starch, Sorbitol; Sucrose; Zoate, myristalkonium chloride, laurtrimonium chloride, and glucose. ethylenediamine dihydrochloride, guanidine hydrochloride, pyridoxine HCl, iofetamine hydrochloride, meglumine 0194 Suitable disintegrants include lightly crosslinked hydrochloride, methylbenzethonium chloride, myrtrimo polyvinyl pyrrollidone, corn Starch, potato Starch, maize nium bromide, oleyltrimonium chloride, polyguaternium-1, Starch, and modified Starches, croScarmelloSe Sodium, croSS procainehydrochloride, cocobetaine, Stearalkonium bento poVidone, Sodium Starch glycolate, and mixtures thereof. nite, Stearalkoniumhectonite, Stearyl trihydroxyethyl propy 0.195 Examples of effervescent agents are effervescent lenediamine dihydrofluoride, tallowtrimonium chloride, and couples Such as an organic acid and a carbonate or bicar hexadecyltrimethyl ammonium bromide. bonate. Suitable organic acids include, for example, citric, tartaric, malic, fumaric, adipic, Succinic, and alginic acids 0184 Most of these surface stabilizers are known phar and anhydrides and acid Salts. Suitable carbonates and maceutical excipients and are described in detail in the bicarbonates include, for example, Sodium carbonate, Handbook of Pharmaceutical Excipients, published jointly Sodium bicarbonate, potassium carbonate, potassium bicar by the American Pharmaceutical Association and The Phar bonate, magnesium carbonate, Sodium glycine carbonate, maceutical Society of Great Britain (The Pharmaceutical L-lysine carbonate, and arginine carbonate. Alternatively, Press, 2000), specifically incorporated by reference. only the Sodium bicarbonate component of the effervescent 0185. The surface stabilizers are commercially available couple may be present. and/or can be prepared by techniques known in the art. 0196. D. Nanoparticulate Triamcinolone and Triamcino 0186 Preferred surface stabilizers include, but are not lone Derivative Particle Size limited to, a random copolymer of vinyl pyrrollidone and 0.197 As used herein, particle size is determined on the vinyl acetate, such as Plasdone(R) S-630 (ISP Technologies, basis of the weight average particle size as measured by Inc.), Sodium lauryl Sulfate (SLS), lysozyme, tyloxapol, and conventional particle size measuring techniques well known combinations thereof. to those skilled in the art. Such techniques include, for 0187 C. Pharmaceutical Excipients example, Sedimentation field flow fractionation, photon cor relation spectroScopy, light Scattering, and disk centrifuga 0188 Pharmaceutical compositions according to the tion. invention may also comprise one or more binding agents, filling agents, lubricating agents, Suspending agents, Sweet 0198 The compositions of the invention comprise triam eners, flavoring agents, preservatives, buffers, wetting cinolone and/or triamcinolone derivative particles which agents, disintegrants, effervescent agents, and other excipi have an effective average particle size of less than about ents. Such excipients are known in the art. 2000 nm (i.e., 2 microns), less than about 1900 nm, less than less than about 1800 nm, less than about 1700 nm, less than 0189 Examples of filling agents are lactose monohy about 1600 nm, less than about 1500 nm, less than about drate, lactose anhydrous, and various Starches, examples of 1400 nm, less than about 1300 nm, less than about 1200 nm, binding agents are various celluloses and croSS-linked poly less than about 1100 nm, less than about 1000 nm, less than Vinylpyrrolidone, microcrystalline cellulose, Such as about 900 nm, less than about 800 nm, less than about 700 Avice1(R) PH101 and Avicel(R) PH102, microcrystalline cel nm, less than about 600 nm, less than about 500 nm, less lulose, and silicified microcrystalline cellulose (ProSolv than about 400 nm, less than about 300 nm, less than about SMCCTM). 250 nm, less than about 200 nm, less than about 150 nm, less 0190. Suitable lubricants, including agents that act on the than about 140 nm, less than about 130 nm, less than about flowability of the powder to be compressed, are colloidal 120 nm, less than about 110 nm, less than about 100 nm, less Silicon dioxide, Such as AeroSilf) 200, talc, Stearic acid, than about 90 nm, less than about 80 nm, less than about 70 magnesium Stearate, calcium Stearate, and Silica gel. nm, less than about 60 nm, or less than about 50 nm, when measured by the above-noted techniques. 0191 Examples of Sweeteners are any natural or artificial Sweetener, Such as Sucrose, Xylitol, Sodium Saccharin, cycla 0199. By “an effective average particle size of less than mate, aspartame, and acSulfame. Examples of flavoring about 2000 nm it is meant that at least 50% of the agents are Magnasweet(R) (trademark of MAFCO), bubble nanoparticulate triamcinolone and/or triamcinolone deriva gum flavor, and fruit flavors, and the like. tive particles have a weight average particle size of less than about 2000 nm, when measured by the above-noted tech 0.192 Examples of preservatives are potassium Sorbate, niques. In other embodiments of the invention, at least about methylparaben, propylparaben, benzoic acid and its Salts, 70%, at least about 90%, at least about 95%, or at least about other esters of parahydroxybenzoic acid Such as butylpara 99% of the nanoparticulate triamcinolone and triamcinolone ben, alcohols Such as ethyl or benzyl alcohol, phenolic and/or triamcinolone derivative particles have a particle size compounds Such as phenol, or quarternary compounds Such of less than the effective average, by weight, i.e., less than as benzalkonium chloride. about 2000 nm, less than about 1900 nm, less than less than 0193 Suitable diluents include pharmaceutically accept about 1800 nm, less than about 1700 nm, etc. able inert fillers, Such as microcrystalline cellulose, lactose, 0200. If the nanoparticulate triamcinolone or triamcino dibasic calcium phosphate, Saccharides, and/or mixtures of lone derivative composition is combined with a micropar any of the foregoing. Examples of diluents include micro ticulate triamcinolone or triamcinolone derivative, or micro crystalline cellulose, such as AVicel(R) PH101 and Avicel(R) particulate non-triamcinolone or non-triamcinolone US 2004/014 1925 A1 Jul. 22, 2004 derivative active agent composition, then Such a composi cipitation of Nanoparticulate Pharmaceutical Agents, U.S. tion is either Solubilized or has an effective average particle Pat. No. 5,543,133 for “Process of Preparing X-Ray Con size of greater than about 2 microns. By “an effective trast Compositions Containing Nanoparticles; U.S. Pat. No. average particle size of greater than about 2 microns' it is 5,534.270 for “Method of Preparing Stable Drug Nanopar meant that at least 50% of the microparticulate triamcino ticles;” U.S. Pat. No. 5,510,118 for “Process of Preparing lone or triamcinolone derivative, or non-triamcinolone or Therapeutic Compositions Containing Nanoparticles,' and non-triamcinolone derivative, particles have a particle size U.S. Pat. No. 5,470,583 for “Method of Preparing Nano of greater than about 2 microns, by weight, when measured particle Compositions Containing Charged Phospholipids to by the above-noted techniques. In other embodiments of the Reduce Aggregation,” all of which are specifically incorpo invention, at least about 70%, at least about 90%, at least rated by reference. about 95%, or at least about 99%, by weight, of the 0208 Following milling, homogenization, precipitation, microparticulate triamcinolone or triamcinolone derivative, etc., the resultant nanoparticulate triamcinolone or triamci or non-triamcinolone or non-triamcinolone derivative, par nolone derivative composition can be utilized in Solid or ticles have a particle size greater than about 2 microns. liquid dosage formulations, Such as controlled release for 0201 In the present invention, the value for D50 of a mulations, Solid dose fast melt formulations, aerosol formu nanoparticulate triamcinolone or triamcinolone derivative lations, nasal formulations, lyophilized formulations, tab composition is the particle size below which 50% of the lets, capsules, Solid lozenge, powders, creams, ointments, triamcinolone or triamcinolone derivative particles fall, by etc. weight. Similarly, D90, D95, and D99 are the particle sizes 0209 A. Milling to Obtain Nanoparticulate Triamcino below which 90%, 95%, and 99%, respectively, of the lone and Triamcinolone Derivatives Dispersions triamcinolone or triamcinolone derivative particles fall, by weight. 0210 Milling triamcinolone and/or a triamcinolone derivative to obtain a nanoparticulate dispersion comprises 0202 E. Concentration of Nanoparticulate Triamcino dispersing triamcinolone and/or a triamcinolone derivative lone and Triamcinolone Derivatives and Surface Stabilizers in a liquid dispersion media in which the triamcinolone 0203 The relative amounts of triamcinolone or a triam and/or triamcinolone derivative is poorly soluble, followed cinolone derivative and one or more Surface Stabilizers can by applying mechanical means in the presence of grinding vary widely. The optimal amount of the individual compo media to reduce the particle size of the triamcinolone and/or nents can depend, for example, upon the particulate triam triamcinolone derivative to the desired effective average cinolone Selected, and the hydrophilic lipophilic balance particle size. The dispersion media can be, for example, (HLB), melting point, and the Surface tension of water water, Safflower oil, ethanol, t-butanol, glycerin, polyethyl ene glycol (PEG), hexane, or glycol. Water is a preferred Solutions of the Stabilizer, etc. dispersion media. 0204. The concentration of triamcinolone or a triamcino 0211 The triamcinolone and/or triamcinolone derivative lone derivative can vary from about 99.5% to about 0.001%, particles can be reduced in Size in the presence of at least one from about 95% to about 0.1%, or from about 90% to about Surface Stabilizer. Alternatively, the triamcinolone and/or 0.5%, by weight, based on the total combined dry weight of triamcinolone derivative particles can be contacted with one the triamcinolone or triamcinolone derivative and at least or more Surface Stabilizers after attrition. Other compounds, one Surface Stabilizer, not including other excipients. Such as a diluent, can be added to the triamcinolone or 0205 The concentration of at least one surface stabilizer triamcinolone derivative/Surface Stabilizer composition dur can vary from about 0.5% to about 99.999%, from about ing the Size reduction process. Dispersions can be manufac 5.0% to about 99.9%, or from about 10% to about 99.5%, by tured continuously or in a batch mode. weight, based on the total combined dry weight of the triamcinolone or triamcinolone derivative and at least one 0212 B. Precipitation to Obtain Nanoparticulate Triam Surface Stabilizer, not including other excipients. cinolone and Triamcinolone Derivatives Compositions 0213 Another method of forming the desired nanopar 0206 III. Methods of Making Nanoparticulate Triamci ticulate triamcinolone and/or triamcinolone derivative com nolone and Triamcinolone Derivatives Formulations position is by microprecipitation. This is a method of 0207. The nanoparticulate triamcinolone and triamcino preparing Stable dispersions of poorly Soluble active agents lone derivative compositions can be made using, for in the presence of one or more Surface Stabilizers and one or example, milling, homogenization, or precipitation tech more colloid Stability enhancing Surface active agents free of niques. Exemplary methods of making nanoparticulate any trace toxic Solvents or Solubilized heavy metal impuri active agent compositions are described in the 684 patent. ties. Such a method comprises, for example: (1) dissolving Methods of making nanoparticulate active agent composi triamcinolone and/or a triamcinolone derivative in a Suitable tions are also described in U.S. Pat. No. 5,518,187 for Solvent; (2) adding the formulation from Step (1) to a “Method of Grinding Pharmaceutical Substances; U.S. Pat. Solution comprising at least one Surface Stabilizer; and (3) No. 5,718,388 for “Continuous Method of Grinding Phar precipitating the formulation from Step (2) using an appro maceutical Substances; U.S. Pat. No. 5,862.999 for priate non-solvent. The method can be followed by removal “Method of Grinding Pharmaceutical Substances; U.S. Pat. of any formed Salt, if present, by dialysis or diafiltration and No. 5,665,331 for “Co-Microprecipitation of Nanoparticu concentration of the dispersion by conventional means. late Pharmaceutical Agents with Crystal Growth Modifiers;” Dispersions can be manufactured continuously or in a batch U.S. Pat. No. 5,662,883 for “Co-Microprecipitation of mode. Nanoparticulate Pharmaceutical Agents with Crystal 0214) C. Homogenization to Obtain Nanoparticulate Tri Growth Modifiers;” U.S. Pat. No. 5,560,932 for “Micropre amcinolone and/or Triamcinolone Derivative Compositions US 2004/014 1925 A1 Jul. 22, 2004

0215 Exemplary homogenization methods of preparing 0223 Exemplary skin disorders that can be treated with nanoparticulate active agent compositions are described in the compositions of the invention include, but are not limited U.S. Pat. No. 5,510,118, for “Process of Preparing Thera to, contact dermatitis, atopic dermatitis, psoriasis, eczema, peutic Compositions Containing Nanoparticles.” and general dermatitis. Exemplary arthritic conditions that can be treated with the compositions of the invention 0216 Such a method comprises dispersing particles of include, but are not limited to, Osteoarthritis, acute nonspe triamcinolone and/or a triamcinolone derivative in a liquid cific Osteoarthritis, posttraumatic osteoarthritis, and rheuma dispersion media in which the particles are poorly Soluble, toid arthritis. Exemplary intestinal disorders that can be followed by Subjecting the dispersion to homogenization to treated with the compositions of the invention include, but reduce the particle size of the triamcinolone and/or triam are not limited to, ulcerative colitis, colitis, gastroenteritis, cinolone derivative to the desired effective average particle irritable bowel disorder, and Crohn's disease. Exemplary size. The dispersion media can be, for example, water, types of cancer or neoplastic diseases that can be treated Safflower oil, ethanol, t-butanol, glycerin, polyethylene gly with the compositions of the invention include, but are not col (PEG), hexane, or glycol. Water is a preferred dispersion limited to, lupus, leukemias, and lymphoma. media. 0224 Compositions suitable for parenteral injection may 0217. The triamcinolone and/or triamcinolone derivative comprise physiologically acceptable Sterile aqueous or non particles can be reduced in size in the presence of at least one aqueous Solutions, dispersions, Suspensions or emulsions, Surface Stabilizer. Alternatively, the triamcinolone and tri and Sterile powders for reconstitution into Sterile injectable amcinolone derivative particles can be contacted with one or Solutions or dispersions. Examples of Suitable aqueous and more Surface stabilizers either before or after attrition. Other nonaqueous carriers, diluents, Solvents, or vehicles includ compounds, Such as a diluent, can be added to the triamci ing water, ethanol, polyols (propyleneglycol, polyethylene nolone or triamcinolone derivative/Surface Stabilizer com glycol, glycerol, and the like), Suitable mixtures thereof, position either before, during, or after the Size reduction vegetable oils (Such as olive oil) and injectable organic proceSS. Dispersions can be manufactured continuously or in esterS Such as ethyl oleate. Proper fluidity can be maintained, a batch mode. for example, by the use of a coating Such as lecithin, by the 0218 IV. Methods of Using Nanoparticulate Triamcino maintenance of the required particle size in the case of lone and Triamcinolone Derivative Formulations dispersions, and by the use of Surfactants. 0219. The method of the invention comprises adminis 0225. The nanoparticulate compositions may also contain tering to a Subject an effective amount of a composition adjuvants Such as preserving, wetting, emulsifying, and comprising nanoparticulate triamcinolone and/or a triamci dispensing agents. Prevention of the growth of microorgan nolone derivative. The triamcinolone and/or triamcinolone isms can be ensured by various antibacterial and antifungal derivative compositions of the present invention can be agents, Such as parabens, chlorobutanol, phenol, Sorbic acid, administered to a Subject via any conventional means and the like. It may also be desirable to include isotonic including, but not limited to, orally, rectally, ocularly, agents, Such as Sugars, Sodium chloride, and the like. Pro parenterally (e.g., intravenous, intramuscular, or Subcutane longed absorption of the injectable pharmaceutical form can ous), intracisternally, pulmonary, intravaginally, intraperito be brought about by the use of agents delaying absorption, neally, locally (e.g., powders, ointments or drops), or as a Such as aluminum monoStearate and gelatin. buccal or nasal Spray. 0226 Solid dosage forms for oral administration include, 0220 AS used herein, the term “subject” is used to mean but are not limited to, powder aerosols, capsules, tablets, an animal, preferably a mammal, including a human or pills, powders, and granules. In Such Solid dosage forms, the non-human. The terms patient and Subject may be used active agent is admixed with at least one of the following: (a) interchangeably. one or more inert excipients (or carriers), Such as Sodium citrate or dicalcium phosphate; (b) fillers or extenders, Such 0221) The compositions of the invention are useful in as Starches, lactose, Sucrose, glucose, mannitol, and Silicic treating conditions or disorders where a glucocorticoid is acid; (c) binders, Such as carboxymethylcellulose, alignates, typically used. In addition, the compositions of the invention gelatin, polyvinylpyrrolidone, Sucrose, and acacia; (d) are useful in treating conditions or disorders where a Ste humectants, Such as glycerol; (e) disintegrating agents, Such roidal anti-inflammatory agent is typically used, Such as in as agar-agar, calcium carbonate, potato or tapioca Starch, treat Swelling, heat, redness, and/or pain. The compositions alginic acid, certain complex Silicates, and Sodium carbon of the invention can also be administered with other drugs to ate, (f) Solution retarders, Such as paraffin, (g) absorption prevent rejection of transplanted organs and to treat certain accelerators, Such as quaternary ammonium compounds, (h) types of cancer. wetting agents, Such as cetyl alcohol and glycerol monostearate; (ii) adsorbents, Such as kaolin and bentonite; 0222 Exemplary conditions or disorders that can be and () lubricants, Such as talc, calcium Stearate, magnesium treated with the compositions of the invention include, but Stearate, Solid polyethylene glycols, Sodium lauryl Sulfate, or are not limited to, arthritis, Skin disorders, blood disorders, mixtures thereof. For capsules, tablets, and pills, the dosage kidney disorders, eye disorders, thyroid disorders, intestinal forms may also comprise buffering agents. disorders, allergies, asthma, bronchial asthma, cancer, neo plastic diseases, tendinitis, allergic reactions, Seasonal aller 0227 Liquid dosage forms for oral administration gic rhinitis, perennial allergic rhinitis, oral inflammation, include pharmaceutically acceptable aerosols, emulsions, oral lesions, oral ulcers, burSitis, epicondylitis, keloids, Solutions, Suspensions, Syrups, and elixirs. In addition to the endocrine disorders, herpes Zoster ophthalmicus, hemolytic active agent, the liquid dosage forms may comprise inert anemia, and acute rheumatic carditis. diluents commonly used in the art, Such as water or other US 2004/014 1925 A1 Jul. 22, 2004

Solvents, Solubilizing agents, and emulsifiers. Exemplary 0234. A nanoparticulate colloidal dispersion (NCD) of emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl car triamcinolone acetonide having 5% (w/w) triamcinolone bonate, ethyl acetate, benzyl alcohol, benzyl benzoate, pro acetonide and 0.5% (w/w) tyloxapol was milled for 1 hour pyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, under high energy milling conditions in a DYNCR-Mill KDL Such as cottonseed oil, groundnut oil, corn germ oil, olive (Willy A. Bachofen AG, Maschinenfabrik, Basel, Switzer oil, castor oil, and Sesame oil, glycerol, tetrahydrofurfuryl land) equipped with a 150 cc batch milling chamber and alcohol, polyethyleneglycols, fatty acid esters of Sorbitan, or using 500 um polymeric attrition media (Dow Chemical, mixtures of these Substances, and the like. Midland Mich.). 0228 Besides such inert diluents, the composition can 0235. The final (weight) mean particle size of the triam also include adjuvants, Such as wetting agents, emulsifying cinolone acetonide particles was 182 nm, with D50<173 nm, and Suspending agents, Sweetening, flavoring, and perfum D90<262 nm, and D95<296 nm, as measured using a Horiba ing agents. LA-910 Laser Scattering Particle Size Distribution Analyzer 0229. One of ordinary skill will appreciate that effective (Horiba Instruments, Irvine, Calif.) and a 0.01% w/w solu amounts of triamcinolone and triamcinolone derivatives can tion of benzalkonium chloride as the dispersing medium. be determined empirically and can be employed in pure 0236. The average particle size of the triamcinolone form or, where Such forms exist, in pharmaceutically accept acetonide dispersion increased by 54 nm to 236 nm, with able Salt, ester, or prodrug form. Actual dosage levels of D50<225 nm, D90<325 nm, and D95<364 nm, after storage triamcinolone and triamcinolone derivative in the nanopar at room temperature for 24 hours, as shown in Table 1. ticulate compositions of the invention may be varied to Particle size was measured using a Horiba LA-910 Laser obtain an amount of triamcinolone or triamcinolone deriva Scattering Particle Size Distribution Analyzer (Horiba tive that is effective to obtain a desired therapeutic response Instruments, Irvine, Calif.). for a particular composition and method of administration. The Selected dosage level therefore depends upon the TABLE 1. desired therapeutic effect, the route of administration, the potency of the administered triamcinolone or triamcinolone Triamcinolone Initial Dnean after derivative, the desired duration of treatment, and other Sample Ref. Acetonide tyloxapol Dmean 24 hrs storage factors. Sample 1 5.0% O.5% 182 mm 236 mm 0230 Dosage unit compositions may contain Such amounts of Such Submultiples thereof as may be used to make up the daily dose. It will be understood, however, that 0237) This example demonstrates that nanoparticulate the Specific dose level for any particular patient will depend triamcinolone compositions can be made, and that compo upon a variety of factors: the type and degree of the cellular Sitions having tyloxapol as a Surface Stabilizer may exhibit or physiological response to be achieved; activity of the Slight particle size growth over time. Specific agent or composition employed; the Specific agents or composition employed; the age, body weight, general EXAMPLE 2 health, Sex, and diet of the patient; the time of administra 0238. The purpose of this example was to prepare dis tion, route of administration, and rate of excretion of the persions of nanoparticulate triamcinolone acetonide, and to agent; the duration of the treatment; drugs used in combi test the prepared compositions for Stability. Stability was nation or coincidental with the Specific agent; and like determined by Static light Scattering methods to Verify factors well known in the medical arts. whether or not larger crystals of triamcinolone or triamci 0231. It will be apparent to those skilled in the art that nolone derivative formed. various modifications and variations can be made in the 0239). A nanoparticulate colloidal dispersion (NCD) of methods and compositions of the present invention without triamcinolone acetonide having 5% (w/w) triamcinolone departing from the Spirit or Scope of the invention. Thus, it acetonide, 0.5% (w/w) tyloxapol, and 0.5% (w/w) sodium is intended that the present invention cover the modifications chloride as a crystal growth inhibitor was milled for 2 hours and variations of this invention provided they come within under high energy milling conditions in a DYNO(R-Mill the Scope of the appended claims and their equivalents. KDL (Willy A. Bachofen AG, Maschinenfabrik, Basel, 0232 The following examples are given to illustrate the Switzerland) equipped with a 150 cc batch milling chamber present invention. It should be understood, however, that the and using 500 um polymeric attrition media (Dow Chemi invention is not to be limited to the Specific conditions or cal, Midland, Mich.). details described in these examples. Throughout the Speci 0240 The final (weight) mean particle size of the triam fication, any and all references to a publicly available cinolone acetonide particles was 149 nm, with D90<212 nm, document, including a U.S. patent, are specifically incorpo as measured using a Horiba LA-910 Laser Scattering Par rated by reference. ticle Size Distribution Analyzer (Horiba Instruments, Irvine, EXAMPLE 1. Calif.) and a 0.5% w/w solution of sodium chloride as the 0233. The purpose of this examples was to prepare dis dispersing medium. persions of nanoparticulate triamcinolone acetonide, and to 0241. In the presence of 0.5% w/w Sodium chloride as a test the prepared compositions for Stability. Stability was crystal growth inhibitor, the average particle size of the determined by Static light Scattering methods to Verify triamcinolone acetonide dispersion increased by only 16 mm whether or not larger crystals of triamcinolone acetonide to 165 nm (D90<243 nm) after storage at room temperature formed. for 24 h as shown in Table 2. US 2004/014 1925 A1 Jul. 22, 2004

Technologies, Inc.) and 0.05% (w/w) sodium lauryl sulfate TABLE 2 (SLS) (Spectrum) was prepared by dissolving 0.85 g of polymer and 4.30 g of a 1% SLS solution in 76.10 g of Sample Triamcinolone Initial Dnean after deionized water. The stabilizer Solution was mixed with 4.26 Ref. Acetonide tyloxapol NaCl Dean 24 hrs storage g of triamcinolone acetonide (5% w/w) and charged into the Sample 2 5% 0.5% 0.5%. 149 mm 165 nm. chamber of a DYNO(E)-Mill Type KDL media mill (Willy Bachofen AG, Basel, Switzerland) along with 500 micron polymeric media (PolyMill(R) 500; Dow Chemical, Midland, 0242. The results of Examples 1 and 2 show that nano Mich.). The mill was operated for 2 hours. particulate triamcinolone compositions can be made. In addition, the results of Examples 1 and 2 demonstrate that 0250. Upon completion of milling, the milled triamcino nanoparticulate triamcinolone acetonide compositions hav lone acetonide particles had a mean particle size of 121 nm, ing tyloxapol as a Surface Stabilizer may benefit from the with a D90 of 194 nm, as measured using a Horiba LA-910 addition of a crystal growth inhibitor, Such as Sodium Laser Scattering Particle Size Distribution Analyzer (Horiba chloride. Instruments, Irvine, Calif.). 0251. It will be apparent to those skilled in the art that EXAMPLE 3 various modifications and variations can be made in the 0243 The purpose of this example was to prepare a methods and compositions of the present invention without nanoparticulate triamcinolone acetonide composition using departing from the Spirit or Scope of the invention. Thus, it is intended that the present invention cover the modifications lysozyme as a Surface Stabilizer. and variations of this invention provided they come within 0244 Lysozyme, also known as muramidase, N-acetyl the Scope of the appended claims and their equivalents. muramylhydrolase, and globulin G1, has a molecular weight of about 14,400. It is a mucolytic enzyme with antibiotic What is claimed is: properties first discovered by A. Fleming, Proc. Roy. Soc. 1. A composition comprising: London, 93B:306 (1922). Although lysozyme has antibiotic (a) particles of at least one triamcinolone or a Salt thereof, properties, it is a large molecule that is not particularly wherein the triamcinolone particles have an effective useful as a drug. It can be applied topically, but cannot rid average particle size of less than about 2000 nm, and the entire body of disease because it is too large to travel between cells. (b) at least one surface stabilizer. 2. The composition of claim 1, wherein the triamcinolone 0245 An aqueous dispersion of 1% (w/w) lysozyme and is Selected from the group consisting of triamcinolone, 5% (w/w) triamcinolone acetonide was charged into a triamcinolone acetonide, triamcinolone diacetate, triamcino NanoMillTM (Elan Drug Delivery) equipped with a 10 cc lone hexacetonide, and triamcinolone benetonide. batch chamber. The mill speed was 2500 rpm, and the 3. The composition of claim 2, wherein the triamcinolone temperature during milling was maintained at 5 C. The is triamcinolone acetonide. triamcinolone acetonide/lysozyme mixture was milled for 4. The composition of claim 1, wherein the triamcinolone 30 min. is Selected from the group consisting of a crystalline phase, 0246 Following milling, the mean particle size, D50, and an amorphous phase, a Semi-crystalline phase, a Semi D90 were measured for the milled triamcinolone acetonide amorphous phase, and mixtures thereof. composition using a Horiba LA-910 Laser Scattering Par 5. The composition of claim 1, wherein the effective ticle Size Distribution Analyzer (Horiba Instruments, Irvine, average particle Size of the triamcinolone particles is Calif.). The milled triamcinolone acetonide composition selected from the group consisting of less than about 1900 was also evaluated via a microscope to detect any aggrega nm, less than about 1800 nm, less than about 1700 nm, less tion. The results are shown below in Table 3. than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about TABLE 3 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than Mean D50 D90 Mill Time about 700 nm, less than about 600 nm, less than about 500 Compound (nm) (nm) (nm) Microscope (hr) nm, less than about 400 nm, less than about 300 nm, less Triamcinolone 114 107 172 Stable 0.5 than about 250 nm, less than about 200 nm, less than about acetomide 100 nm, less than about 75 nm, and less than about 50 nm. 6. The composition of claim 1, wherein the composition is formulated for administration Selected from the group 0247 The results demonstrate that stable nanoparticulate consisting of oral, pulmonary, rectal, ophthalmic, colonic, triamcinolone compositions can be made. parenteral, intracisternal, intravaginal, intraperitoneal, local, buccal, nasal, and topical administration. EXAMPLE 4 7. The composition of claim 1 formulated into a dosage form Selected from the group consisting of liquid disper 0248. The purpose of this example was to prepare a Sions, Sachets, lozenges, oral Suspensions, gels, aerosols, nanoparticulate triamcinolone acetonide composition com ointments, creams, tablets, capsules, and powders. prising a copolymer of vinyl pyrrollidone and Vinyl acetate 8. The composition of claim 1 formulated into a dosage and Sodium lauryl Sulfate as Surface Stabilizers. form Selected from the group consisting of controlled release 0249 An aqueous solution of 1% (w/w) Plasdone(R) formulations, fast melt formulations, lyophilized formula S-630 (60% vinyl pyrrolidone and 40% vinyl acetate) (ISP tions, delayed release formulations, extended release formu US 2004/014 1925 A1 Jul. 22, 2004

lations, pulsatile release formulations, and mixed immediate 16. The composition of claim 13, wherein the surface release and controlled release formulations. Stabilizer is Selected from the group consisting of cationic 9. 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 10. The composition of claim 1, wherein the triamcino trimethyl ammonium bromide, phosphonium compounds, lone or a Salt thereof is present in an amount Selected from quarternary ammonium compounds, benzyl-di(2-chloroeth the group consisting of from about 99.5% to about 0.001%, yl)ethylammonium bromide, coconut trimethyl ammonium from about 95% to about 0.1%, and from about 90% to about chloride, coconut trimethyl ammonium bromide, coconut 0.5%, by weight, based on the total combined dry weight of methyl dihydroxyethyl ammonium chloride, coconut methyl the triamcinolone or Salt thereof and at least one Surface dihydroxyethyl ammonium bromide, decyl triethyl ammo Stabilizer, not including other excipients. nium chloride, decyl dimethyl hydroxyethyl ammonium 11. The composition of claim 1, wherein the at least one chloride, decyl dimethyl hydroxyethyl ammonium chloride Surface Stabilizer is present in an amount Selected from the bromide, C2-sdimethyl hydroxyethyl ammonium chloride, group consisting of from about 0.5% to about 99.999% by C-dimethyl hydroxyethyl ammonium chloride bromide, weight, from about 5.0% to about 99.9% by weight, and coconut dimethyl hydroxyethyl ammonium chloride, coco from about 10% to about 99.5% by weight, based on the nut dimethyl hydroxyethyl ammonium bromide, myristyl total combined dry weight of the triamcinolone or Salt trimethyl ammonium methyl Sulphate, lauryl dimethylben thereof and at least one Surface Stabilizer, not including other Zyl ammonium chloride, lauryl dimethylbenzyl ammonium excipients. bromide, lauryl dimethyl(ethenoxy) ammonium chloride, 12. The composition of claim 1, comprising at least two lauryl dimethyl (ethenoxy) ammonium bromide, Surface Stabilizers. N-alkyl(Cs)dimethylbenzyl ammonium chloride, 13. The composition of claim 1, wherein the surface N-alkyl(Cs)dimethyl-benzyl ammonium chloride, N-tet Stabilizer is Selected from the group consisting of an anionic radecylidimethylbenzyl ammonium chloride monohydrate, Surface Stabilizer, a cationic Surface Stabilizer, a Zwitterionic dimethyl didecyl ammonium chloride, N-alkyl and (C- Surface Stabilizer, and an ionic Surface Stabilizer. 14)dimethyl 1-napthylmethyl ammonium chloride, trimethy 14. The composition of claim 13, wherein the at least one lammonium halide, alkyl-trimethylammonium Salts, Surface Stabilizer is selected from the group consisting of dialkyl-dimethylammonium Salts, lauryl trimethyl ammo cetyl pyridinium chloride, gelatin, casein, phosphatides, nium chloride, ethoxylated alkyamidoalkyldialkylammo dextran, glycerol, gum acacia, cholesterol, tragacanth, nium Salt, an ethoxylated trialkyl ammonium Salt, dialkyl Stearic acid, benzalkonium chloride, calcium Stearate, glyc benzene dialkylammonium chloride, N-didecyidimethyl erol monoStearate, cetostearyl alcohol, cetomacrogol emul ammonium chloride, N-tetradecyldimethylbenzyl ammo Sifying wax, Sorbitan esters, polyoxyethylene alkyl ethers, nium, chloride monohydrate, N-alkyl(C1-)dimethyl polyoxyethylene castor oil derivatives, polyoxyethylene Sor 1-naphthylmethyl ammonium chloride, dodecyldimethyl bitan fatty acid esters, polyethylene glycols, dodecyl trim benzyl ammonium chloride, dialkyl benzenealkyl ammo ethyl ammonium bromide, polyoxyethylene Stearates, col nium chloride, lauryl trimethyl ammonium chloride, alkyl loidal Silicon dioxide, phosphates, Sodium dodecylsulfate, carboxymethylcellulose calcium, hydroxypropyl celluloses, benzyl methyl ammonium chloride, alkylbenzyl dimethyl hypromellose, carboxymethylcellulose Sodium, methylcel ammonium bromide, C2 trimethyl ammonium bromides, lulose, hydroxyethylcellulose, hypromellose phthalate, non C. trimethyl ammonium bromides, C, trimethyl ammo crystalline cellulose, magnesium aluminum Silicate, trietha nium bromides, dodecylbenzyl triethyl ammonium chloride, nolamine, polyvinyl alcohol, polyvinylpyrrolidone, 4-(1,1, poly-diallyldimethylammonium chloride (DADMAC), dim 3,3-tetramethylbutyl)-phenol polymer with ethylene oxide ethyl ammonium chlorides, alkyldimethylammonium halo and formaldehyde, poloxamers, poloxamines, a charged genides, tricetyl methyl ammonium chloride, decyltrimethy phospholipid, dioctylsulfoSuccinate, dialkylesters of Sodium lammonium bromide, dodecyltriethylammonium bromide, SulfoSuccinic acid, Sodium lauryl Sulfate, alkyl aryl poly tetradecyltrimethylammonium bromide, methyl trioctylam ether Sulfonates, mixtures of Sucrose Stearate and Sucrose monium chloride, POLYOUAT 10TM, tetrabutylammonium distearate, p-isononylphenoxypoly-(glycidol), decanoyl-N- bromide, benzyl trimethylammonium bromide, choline methylglucamide; n-decyl B-D-glucopyranoside; n-decyl esters, benzalkonium chloride, Stearalkonium chloride com B-D-maltopyranoside; n-dodecyl B-D-glucopyranoside; pounds, cetyl pyridinium bromide, cetyl pyridinium chlo n-dodecyl 3-D-maltoside; heptanoyl-N-methylglucamide; ride, halide Salts of quaternized polyoxyethylalkylamines, n-heptyl-B-D-glucopyranoside; n-heptyl B-D-thioglucoside; MIRAPOLTM, ALKAQUATTM, alkyl pyridinium salts; n-hexyl B-D-glucopyranoside; nonanoyl-N-methylglucam amines, amine Salts, amine oxides, imide azolinium Salts, ide; n-noyl B-D-glucopyranoSide; octanoyl-N-methylgluca protonated quaternary acrylamides, methylated quaternary mide; n-octyl-B-D-glucopyranoside, octyl B-D-thioglucopy polymers, and cationic guar. ranoside; lysozyme, PEG-phospholipid, PEG-cholesterol, 17. The composition of claim 1, comprising as a Surface PEG-cholesterol derivative, PEG-vitamin A, and random Stabilizer a random copolymer of vinyl pyrrollidone and copolymers of vinyl acetate and Vinyl pyrrolidone. Vinyl acetate, Sodium lauryl Sulfate, lysozyme, tyloxapol, or 15. The composition of claim 13, wherein the at least one a combination thereof. cationic Surface Stabilizer is Selected from the group con 18. The composition of any of claims 13, 15, 16, or 17, Sisting of a polymer, a biopolymer, a polysaccharide, a wherein the composition is bioadhesive. cellulosic, an alginate, a nonpolymeric compound, and a 19. The composition of claim 1, further comprising at phospholipid. least one additional triamcinolone composition having an US 2004/014 1925 A1 Jul. 22, 2004 22 effective average particle size which is different that the 26. The composition of claim 23, wherein the brochodi effective average particle size of the triamcinolone compo lator is Selected from the group consisting of Short-acting Sition of claim 1. beta2-agonists, long-acting beta2-agonists, anticholinergics, 20. The composition of claim 1, additionally comprising and theophyllines. one or more non-triamcinolone active agents. 27. The composition of claim 23, wherein the anti-fungal 21. The composition of claim 20, wherein said additional agent is Selected from the group consisting of amphotericin one or more non-triamcinolone active agents are Selected B, nyStatin, fluconazole, ketoconazole, terbinafine, itracona from the group consisting of nutraceuticals, amino acids, Zole, imidazole, triazole, ciclopiroX, clotrimazole, and proteins, peptides, nucleotides, anti-obesity drugs, central miconazole. nervous System Stimulants, carotenoids, corticosteroids, 28. The composition of claim 1, wherein upon adminis elastase inhibitors, anti-fungals, oncology therapies, anti tration to a mammal the triamcinolone particles redisperse emetics, analgesics, cardiovascular agents, anti-inflamma Such that the particles have an effective average particle size tory agents, anthelmintics, anti-arrhythmic agents, antibiot of less than about 2 microns. ics, anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, anti 29. The composition of claim 28, wherein upon admin muscarinic agents, antimycobacterial agents, antineoplastic istration the composition redisperses Such that the triamci agents, immunosuppressants, antithyroid agents, antiviral nolone particles have an effective average particle size agents, anxiolytics, Sedatives, astringents, alpha-adrenergic selected from the group consisting of less than about 1900 receptor blocking agents, beta-adrenoceptor blocking nm, less than about 1800 nm, less than about 1700 nm, less agents, blood products, blood Substitutes, cardiac inotropic than about 1600 nm, less than about 1500 nm, less than agents, contrast media, corticosteroids, cough Suppressants, about 1400 nm, less than about 1300 nm, less than about decongestants, diagnostic agents, diagnostic imaging agents, 1200 nm, less than about 1100 nm, less than about 1000 nm, diuretics, dopaminergics, haemoStatics, immunological less than about 900 nm, less than about 800 nm, less than agents, lipid regulating agents, muscle relaxants, parasym about 700 nm, less than about 600 nm, less than about 500 pathomimetics, parathyroid calcitonin, parathyroid biphos nm, less than about 400 nm, less than about 300 nm, less phonates, prostaglandins, radio-pharmaceuticals, SeX hor than about 250 nm, less than about 200 nm, less than about mones, anti-allergic agents, Stimulants, anoretics, 150 nm, less than about 100 nm, less than about 75 nm, and Sympathomimetics, thyroid agents, vasodilators, and Xan less than about 50 nm. thines. 30. The composition of claim 1, wherein the composition 22. The composition of claim 20, wherein said additional redisperses in a biorelevant media Such that the triamcino one or more non-triamcinolone active agents are Selected lone particles have an effective average particle size of leSS from the group consisting of acyclovir, alprazolam, altre than about 2 microns. tamine, amiloride, amiodarone, benztropine meSylate, 31. The composition of claim 30, wherein the biorelevant bupropion, cabergoline, candesartan, cerivastatin, chlorpro media is Selected from the group consisting of water, acque mazine, ciprofloxacin, cisapride, clarithromycin, clonidine, ous electrolyte Solutions, aqueous Solutions of a Salt, aque clopidogrel, cyclobenzaprine, cyproheptadine, delavirdine, ous Solutions of an acid, aqueous Solutions of a base, and deSmopressin, diltiazem, dipyridamole, dolasetron, enalapril combinations thereof. maleate, enalaprilat, famotidine, felodipine, furazolidone, 32. The composition of claim 30, wherein the composi glipizide, irbeSartan, ketoconazole, lanSoprazole, loratadine, tion redisperses in a biorelevant media Such that the triam loxapine, mebendazole, mercaptopurine, milrinone lactate, cinolone particles have an effective average particle size minocycline, mitoxantrone, nelfinavir meSylate, nimo selected from the group consisting of less than about 1900 dipine, norfloxacin, olanzapine, omeprazole, penciclovir, nm, less than about 1800 nm, less than about 1700 nm, less pimozide, tacolimus, quazepam, raloxifene, rifabutin, than about 1600 nm, less than about 1500 nm, less than rifampin, risperidone, rizatriptan, Saquinavir, Sertraline, about 1400 nm, less than about 1300 nm, less than about Sildenafil, acetyl-Sulfisoxazole, temazepam, thiabendazole, 1200 nm, less than about 1100 nm, less than about 1000 nm, thioguanine, trandolapril, triamterene, trimetrexate, troglita less than about 900 nm, less than about 800 nm, less than Zone, trovafloxacin, Verapamil, vinblastine Sulfate, myco about 700 nm, less than about 600 nm, less than about 500 phenolate, atovaquone, atovaquone, proguanil, ceftazidime, nm, less than about 400 nm, less than about 300 nm, less cefuroxime, etoposide, terbinafine, thalidomide, flucona than about 250 nm, less than about 200 nm, less than about Zole, amsacrine, dacarbazine, teniposide, and acetylsalicy 150 nm, less than about 100 nm, less than about 75 nm, and late. less than about 50 nm. 23. The composition of claim 20, further comprising at 33. The composition of claim 1, wherein the T of the least one antihistamine, decongestant, bronchodilator, anti triamcinolone composition, when assayed in the plasma of fungal, anti-cancer agent, or immunosuppreSSant. a mammalian Subject following administration, is less than 24. The composition of claim 23, wherein the antihista the T exhibited by a non-nanoparticulate composition of mine is Selected from the group consisting of feXofenadine, the same triamcinolone, administered at the same dosage. aZelastine, hydoxy Zine, diphenhydramine, loratadine, chlo 34. The composition of claim 33, wherein the T is rpheniramine maleate, cyproheptadine, promethazine, phe Selected from the group consisting of not greater than about nylephrine tannate, acrivastine, and cetirizine. 90%, not greater than about 80%, not greater than about 25. The composition of claim 23, wherein the deconges 70%, not greater than about 60%, not greater than about tant is Selected from the group consisting of pseudoephe 50%, not greater than about 30%, not greater than about drine, Oxymetazoline, Xylometazoline, naphazoline, nap 25%, not greater than about 20%, not greater than about hazoline, and tetrahydrozoline. 15%, not greater than about 10%, and not greater than about US 2004/014 1925 A1 Jul. 22, 2004 23

5% of the T exhibited by a non-nanoparticulate compo between 0.80 and 1.25 for AUC and a 90% confidence Sition of the same triamcinolone, administered at the same Interval of between 0.70 to 1.43 for C. dosage. 44. The composition of claim 1 formulated into a liquid 35. The composition of claim 1, wherein the C of the dosage form, wherein the dosage form has a Viscosity of leSS triamcinolone composition, when assayed in the plasma of than about 2000 mPats, measured at 20° C., at a shear rate a mammalian Subject following administration, is greater of 0.1 (1/s). than the C exhibited by a non-nanoparticulate composi 45. The composition of claim 44, having a Viscosity at a tion of the Same triamcinolone, administered at the same shear rate of 0.1 (1/s), measured at 20° C., selected from the dosage. group consisting of from about 2000 mPa is to about 1 mPats, 36. The composition of claim 35, wherein the C is from about 1900 mPa is to about 1 mPas, from about 1800 Selected from the group consisting of at least about 50%, at mPa's to about 1 mPas, from about 1700 mPa's to about 1 least about 100%, at least about 200%, at least about 300%, mPas, from about 1600 mPa's to about 1 mPats, from about at least about 400%, at least about 500%, at least about 1500 mPa's to about 1 mPats, from about 1400 mPa is to 600%, at least about 700%, at least about 800%, at least about 1 mPas, from about 1300 mPa's to about 1 mPats, about 900%, at least about 1000%, at least about 1100%, at from about 1200 mPa's to about 1 mPas, from about 1100 least about 1200%, at least about 1300%, at least about mPa's to about 1 mPas, from about 1000 mPa's to about 1 1400%, at least about 1500%, at least about 1600%, at least mPas, from about 900 mPa is to about 1 mPats, from about about 1700%, at least about 1800%, or at least about 1900% 800 mPa's to about 1 mPas, from about 700 mPa is to about greater than the C. exhibited by a non-nanoparticulate 1 mPas, from about 600 mPa's to about 1 mPas, from about composition of the same triamcinolone, administered at the 500 mPa's to about 1 mPas, from about 400 mPa is to about Same dosage. 1 mPas, from about 300 mPa's to about 1 mPas, from about 37. The composition of claim 1, wherein the AUC of the 200 mPa's to about 1 mPas, from about 175 mPa is to about triamcinolone composition, when assayed in the plasma of 1 mPas, from about 150 mPa's to about 1 mPas, from about a mammalian Subject following administration, is greater 125 mPa's to about 1 mPas, from about 100 mPa is to about than the AUC exhibited by a non-nanoparticulate composi 1 mPas, from about 75 mPa is to about 1 mPats, from about tion of the Same triamcinolone, administered at the same 50 mPa's to about 1 mPas, from about 25 mPa is to about 1 dosage. mPas, from about 15 mPa's to about 1 mPats, from about 10 38. The composition of claim 37, wherein the AUC is mPa's to about 1 mPas, and from about 5 mPa's to about 1 selected from the group consisting of at least about 25%, at mPa S. least about 50%, at least about 75%, at least about 100%, at 46. The composition of claim 44, wherein the viscosity of least about 125%, at least about 150%, at least about 175%, the dosage form is Selected from the group consisting of leSS at least about 200%, at least about 225%, at least about than about /200, less than about /100, less than about /50, leSS 250%, at least about 275%, at least about 300%, at least than about 1/35, and less than about /10 of the viscosity of a about 350%, at least about 400%, at least about 450%, at liquid dosage form of a non-nanoparticulate composition of least about 500%, at least about 550%, at least about 600%, the same triamcinolone, at about the same concentration per at least about 750%, at least about 700%, at least about ml of triamcinolone. 750%, at least about 800%, at least about 850%, at least 47. The composition of claim 44, wherein the viscosity of about 900%, at least about 950%, at least about 1000%, at the dosage form is Selected from the group consisting of leSS least about 1050%, at least about 1100%, at least about than about 5%, less than about 10%, less than about 15%, 1150%, or at least about 1200% greater than the AUC less than about 20%, less than about 25%, less than about exhibited by a non-nanoparticulate composition of the same 30%, less than about 35%, less than about 40%, less than about 45%, less than about 50%, less than about 55%, less triamcinolone, administered at the same dosage. than about 60%, less than about 65%, less than about 70%, 39. The composition of claim 1 which does not produce less than about 75%, less than about 80%, less than about Significantly different absorption levels when administered 85%, and less than about 90% of the viscosity of a liquid under fed as compared to fasting conditions. dosage form of a non-nanoparticulate composition of the 40. The composition of claim 39, wherein the difference Same triamcinolone, at about the same concentration per ml in absorption of the triamcinolone composition of the inven of triamcinolone. tion, when administered in the fed versus the fasted State, is 48. A method of making a triamcinolone composition Selected from the group consisting of less than about 100%, comprising contacting particles of a triamcinolone or a Salt less than about 90%, less than about 80%, less than about thereof with at least one Surface stabilizer for a time and 70%, less than about 60%, less than about 50%, less than under conditions Sufficient to provide a triamcinolone com about 40%, less than about 30%, less than about 25%, less position having an effective average particle size of less than than about 20%, less than about 15%, less than about 10%, about 2000 nm. less than about 5%, and less than about 3%. 49. The method of claim 48, wherein the triamcinolone is 41. The composition of claim 1, wherein administration of Selected from the group consisting of triamcinolone, triam the composition to a human in a fasted State is bioeduivalent cinolone acetonide, triamcinolone diacetate, triamcinolone to administration of the composition to a Subject in a fed hexacetonide, and triamcinolone benetonide. State. 50. The method of claim 49, wherein the triamcinolone is 42. The composition of claim 41, wherein “bioeduiva triamcinolone acetonide. lency” is established by a 90% confidence Interval of 51. The method of claim 48, wherein said contacting between 0.80 and 1.25 for both C and AUC. comprises grinding. 43. The composition of claim 41, wherein “bioeduiva 52. The method of claim 51, wherein said grinding lency” is established by a 90% confidence Interval of comprises wet grinding. US 2004/014 1925 A1 Jul. 22, 2004 24

53. The method of claim 48, wherein said contacting and formaldehyde, poloxamers, poloxamines, a charged comprises homogenizing. phospholipid, dioctylsulfoSuccinate, dialkylesters of Sodium 54. The method of claim 48, wherein said contacting SulfoSuccinic acid, Sodium lauryl Sulfate, alkyl aryl poly comprises: ether Sulfonates, mixtures of Sucrose Stearate and Sucrose distearate, p-isononylphenoxypoly-(glycidol), decanoyl-N- (a) dissolving the particles of a triamcinolone or salt methylglucamide; n-decyl B-D-glucopyranoside; n-decyl thereof in a Solvent; B-D-maltopyranoside; n-dodecyl B-D-glucopyranoside; (b) adding the resulting triamcinolone Solution to a Solu n-dodecyl 3-D-maltoside; heptanoyl-N-methylglucamide; tion comprising at least one Surface Stabilizer; and n-heptyl-B-D-glucopyranoside; n-heptyl B-D-thioglucoside; (c) precipitating the Solubilized triamcinolone/Surface sta n-hexyl B-D-glucopyranoside; nonanoyl-N-methylglucam bilizer composition by the addition of a non-Solvent. ide; n-noyl B-D-glucopyranoSide; octanoyl-N-methylgluca 55. The method of claim 48, wherein the triamcinolone or mide; n-octyl-B-D-glucopyranoside; octyl B-D-thioglucopy Salt thereof is Selected from the group consisting of a ranoside; lysozyme, PEG-phospholipid, PEG-cholesterol, crystalline phase, an amorphous phase, a Semi-crystalline PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin phase, a Semi-amorphous phase, and mixtures thereof. E, and random copolymers of vinyl acetate and Vinyl pyr 56. The method of claim 48, wherein the effective average rolidone. particle size of the triamcinolone particles is Selected from 62. The method of claim 60, wherein the at least one the group consisting of less than about 1900 nm, less than cationic Surface Stabilizer is Selected from the group con about 1800 nm, less than about 1700 nm, less than about Sisting of a polymer, a biopolymer, a polysaccharide, a 1600 nm, less than about 1500 nm, less than about 1000 nm, cellulosic, an alginate, a nonpolymeric compound, and a less than about 1400 nm, less than about 1300 nm, less than phospholipid. about 1200 nm, less than about 1100 nm, less than about 900 63. The method of claim 60, wherein the Surface stabilizer nm, less than about 800 nm, less than about 700 nm, less is Selected from the group consisting of cationic lipids, than about 600 nm, less than about 500 nm, less than about polymethylmethacrylate trimethylammonium bromide, Sul 400 nm, less than about 300 nm, less than about 250 nm, less fonium compounds, polyvinylpyrrollidone-2-dimethylami than about 200 nm, less than about 100 nm, less than about noethyl methacrylate dimethyl sulfate, hexadecyltrimethyl 75 nm, and less than about 50 nm. ammonium bromide, phosphonium compounds, quarternary 57. The method of claim 48, wherein the triamcinolone or ammonium compounds, benzyl-di(2-chloroethyl)ethylam Salt thereof is present in an amount selected from the group monium bromide, coconut trimethyl ammonium chloride, consisting of from about 99.5% to about 0.001%, from about coconut trimethyl ammonium bromide, coconut methyl 95% to about 0.1%, and from about 90% to about 0.5%, by dihydroxyethyl ammonium chloride, coconut methyl dihy weight, based on the total combined dry weight of the droxyethyl ammonium bromide, decyl triethyl ammonium triamcinolone or a Salt thereof and at least one Surface chloride, decyl dimethyl hydroxyethyl ammonium chloride, Stabilizer, not including other excipients. decyl dimethyl hydroxyethyl ammonium chloride bromide, 58. The method of claim 48, wherein the at least one C-dimethyl hydroxyethyl ammonium chloride, C2 Surface Stabilizer is present in an amount Selected from the 15 dimethyl hydroxyethyl ammonium chloride bromide, group consisting of from about 0.5% to about 99.999%, coconut dimethyl hydroxyethyl ammonium chloride, coco from about 5.0% to about 99.9%, and from about 10% to nut dimethyl hydroxyethyl ammonium bromide, myristyl about 99.5% by weight, based on the total combined dry trimethyl ammonium methyl Sulphate, lauryl dimethylben weight of the triamcinolone or a Salt thereof and at least one Zyl ammonium chloride, lauryl dimethylbenzyl ammonium Surface Stabilizer, not including other excipients. bromide, lauryl dimethyl(ethenoxy) ammonium chloride, 59. The method of claim 48, utilizing at least two surface lauryl dimethyl(ethenoxy) ammonium bromide, N-alkyl stabilizers. (Cs)dimethylbenzyl ammonium chloride, N-alkyl(C. 60. The method of claim 48, wherein the Surface stabilizer 1s)dimethyl-benzyl ammonium chloride, N-tetradecylidm is Selected from the group consisting of an anionic Surface ethylbenzyl ammonium chloride monohydrate, dimethyl Stabilizer, a cationic Surface Stabilizer, a Zwitterionic Surface didecyl ammonium chloride, N-alkyl and (C1-)dimethyl Stabilizer, and an ionic Surface Stabilizer. 1-napthylmethyl ammonium chloride, trimethylammonium 61. The method of claim 60, wherein the at least one halide, alkyl-trimethylammonium Salts, dialkyl-dimethy Surface Stabilizer is Selected from the group consisting of lammonium Salts, lauryl trimethyl ammonium chloride, cetyl pyridinium chloride, gelatin, casein, phosphatides, ethoxylated alkyamidoalkyldialkylammonium Salt, an dextran, glycerol, gum acacia, cholesterol, tragacanth, ethoxylated trialkyl ammonium Salt, dialkylbenzene dialky Stearic acid, benzalkonium chloride, calcium Stearate, glyc lammonium chloride, N-didecyldimethyl ammonium chlo erol monoStearate, cetostearyl alcohol, cetomacrogol emul ride, N-tetradecyldimethylbenzyl ammonium, chloride Sifying wax, Sorbitan esters, polyoxyethylene alkyl ethers, monohydrate, N-alkyl(C-)dimethyl 1-naphthylmethyl polyoxyethylene castor oil derivatives, polyoxyethylene Sor ammonium chloride, dodecyldimethylbenzyl ammonium bitan fatty acid esters, polyethylene glycols, dodecyl trim chloride, dialkyl benzenealkyl ammonium chloride, lauryl ethyl ammonium bromide, polyoxyethylene Stearates, col trimethyl ammonium chloride, alkylbenzyl methyl ammo loidal Silicon dioxide, phosphates, Sodium dodecylsulfate, nium chloride, alkylbenzyl dimethyl ammonium bromide, carboxymethylcellulose calcium, hydroxypropyl celluloses, C. trimethyl ammonium bromides, Cs trimethyl ammo hypromellose, carboxymethylcellulose Sodium, methylcel nium bromides, C, trimethyl ammonium bromides, dode lulose, hydroxyethylcellulose, hypromellose phthalate, non cylbenzyl triethyl ammonium chloride, poly-diallyldimethy crystalline cellulose, magnesium aluminum Silicate, trietha lammonium chloride (DADMAC), dimethyl ammonium nolamine, polyvinyl alcohol, polyvinylpyrrolidone, 4-(1,1, chlorides, alkyldimethylammonium halogenides, tricetyl 3,3-tetramethylbutyl)-phenol polymer with ethylene oxide methyl ammonium chloride, decyltrimethylammonium bro US 2004/014 1925 A1 Jul. 22, 2004 25 mide, dodecyltriethylammonium bromide, tetradecyltrim group consisting of from about 0.5% to about 99.999% by ethylammonium bromide, methyl trioctylammonium chlo weight, from about 5.0% to about 99.9% by weight, and ride, POLYQUAT 10TM, tetrabutylammonium bromide, from about 10% to about 99.5% by weight, based on the benzyl trimethylammonium bromide, choline esters, benza total combined dry weight of the triamcinolone or a Salt Ikonium chloride, Stearalkonium chloride compounds, cetyl thereof and at least one Surface Stabilizer, not including other pyridinium bromide, cetyl pyridinium chloride, halide Salts excipients. of quaternized polyoxyethylalkylamines, MIRAPOLTM, 75. The method of claim 66, utilizing at least two surface ALKAQUATTM, alkyl pyridinium salts; stabilizers. amines, amine Salts, amine oxides, imide azolinium Salts, 76. The method of claim 66, wherein at least one Surface protonated quaternary acrylamides, methylated quater Stabilizer is Selected from the group consisting of an anionic nary polymers, and cationic guar. Surface Stabilizer, a cationic Surface Stabilizer, a Zwitterionic 64. The composition of claim 1, comprising as a Surface Surface Stabilizer, and an ionic Surface Stabilizer. Stabilizer a random copolymer of vinyl pyrrollidone and 77. The method of claim 76, wherein at least one Surface Vinyl acetate, Sodium lauryl Sulfate, lysozyme, tyloxapol, or Stabilizer is Selected from the group consisting of cetyl a combination thereof. pyridinium chloride, gelatin, casein, phosphatides, dextran, 65. The method of any of claims 60, 62, 63, or 64, wherein glycerol, gum acacia, cholesterol, tragacanth, Stearic acid, the composition is bioadhesive. benzalkonium chloride, calcium Stearate, glycerol 66. A method of treating a Subject in need comprising monoStearate, cetoStearyl alcohol, cetomacrogol emulsify administering to the Subject an effective amount of a com ing wax, Sorbitan esters, polyoxyethylene alkyl ethers, poly position comprising: oxyethylene castor oil derivatives, polyoxyethylene Sorbitan fatty acid esters, polyethylene glycols, dodecyl trimethyl (a) particles of a triamcinolone or a salt thereof, wherein ammonium bromide, polyoxyethylene Stearates, colloidal the triamcinolone particles have an effective average Silicon dioxide, phosphates, Sodium dodecylsulfate, car particle size of less than about 2000 nm, and boxymethylcellulose calcium, hydroxypropyl celluloses, (b) at least one Surface Stabilizer. hypromellose, carboxymethylcellulose Sodium, methylcel 67. The method of claim 66, wherein the triamcinolone is lulose, hydroxyethylcellulose, hypromellose phthalate, non Selected from the group consisting of triamcinolone, triam crystalline cellulose, magnesium aluminum Silicate, trietha cinolone acetonide, triamcinolone diacetate, triamcinolone nolamine, polyvinyl alcohol, polyvinylpyrrolidone, 4-(1,1, hexacetonide, and triamcinolone benetonide. 3,3-tetramethylbutyl)-phenol polymer with ethylene oxide 68. The method of claim 67, wherein the triamcinolone is and formaldehyde, poloxamers, poloxamines, a charged triamcinolone acetonide. phospholipid, dioctylsulfoSuccinate, dialkylesters of Sodium 69. The method of claim 66, wherein the triamcinolone or SulfoSuccinic acid, Sodium lauryl Sulfate, alkyl aryl poly a Salt thereof is Selected from the group consisting of a ether Sulfonates, mixtures of Sucrose Stearate and Sucrose crystalline phase, an amorphous phase, a Semi-crystalline distearate, p-isononylphenoxypoly-(glycidol), decanoyl-N- phase, a Semi-amorphous phase, and mixtures thereof. methylglucamide; n-decyl B-D-glucopyranoside; n-decyl 70. The method of claim 66, wherein the effective average B-D-maltopyranoside; n-dodecyl B-D-glucopyranoside; particle size of the triamcinolone particles is Selected from n-dodecyl 3-D-maltoside; heptanoyl-N-methylglucamide; the group consisting of less than about 1900 nm, less than n-heptyl-B-D-glucopyranoside; n-heptyl B-D-thioglucoside; about 1800 nm, less than about 1700 nm, less than about n-hexyl B-D-glucopyranoside; nonanoyl-N-methylglucam 1600 nm, less than about 1500 nm, less than about 1400 nm, ide; n-noyl B-D-glucopyranoSide; octanoyl-N-methylgluca less than about 1300 nm, less than about 1200 nm, less than mide; n-octyl-B-D-glucopyranoside; octyl B-D-thioglucopy about 1100 nm, less than about 1000 nm, less than about 900 ranoside; lysozyme, PEG-phospholipid, PEG-cholesterol, nm, less than about 800 nm, less than about 700 nm, less PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin than about 600 nm, less than about 500 nm, less than about E, and random copolymers of vinyl acetate and Vinyl pyr 400 nm, less than about 300 nm, less than about 250 nm, less rolidone. than about 200 nm, less than about 100 nm, less than about 78. The method of claim 76, wherein at least one cationic 75 nm, and less than about 50 nm. Surface Stabilizer is Selected from the group consisting of a 71. The method of claim 66, wherein the composition is polymer, a biopolymer, a polysaccharide, a cellulosic, an formulated for administration Selected from the group con alginate, a nonpolymeric compound, and a phospholipid. Sisting of oral, pulmonary, rectal, opthalmic, colonic, 79. The method of claim 76, wherein the Surface stabilizer parenteral, intracisternal, intravaginal, intraperitoneal, local, is Selected from the group consisting of benzalkonium buccal, nasal, and topical administration. chloride, polymethylmethacrylate trimethylammonium bro 72. The method of claim 66, 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 73. The method of claim 66, wherein the triamcinolone or nium compounds, quarternary ammonium compounds, ben Salt thereof is present in an amount Selected from the group Zyl-di(2-chloroethyl)ethylammonium bromide, coconut tri consisting of from about 99.5% to about 0.001%, from about methyl ammonium chloride, coconut trimethyl ammonium 95% to about 0.1%, and from about 90% to about 0.5%, by bromide, coconut methyl dihydroxyethyl ammonium chlo weight, based on the total combined dry weight of the ride, coconut methyl dihydroxyethyl ammonium bromide, triamcinolone or Salt thereof and at least one Surface Stabi decyl triethyl ammonium chloride, decyl dimethyl hydroxy lizer, not including other excipients. ethyl ammonium chloride, decyl dimethyl hydroxyethyl 74. The method of claim 66, wherein the at least one ammonium chloride bromide, C-dimethyl hydroxyethyl Surface Stabilizer is present in an amount Selected from the ammonium chloride, C2-dimethyl hydroxyethyl ammo US 2004/014 1925 A1 Jul. 22, 2004 26 nium chloride bromide, coconut dimethyl hydroxyethyl agents, diagnostic imaging agents, diuretics, dopaminergics, ammonium chloride, coconut dimethyl hydroxyethyl ammo haemostatics, immunological agents, lipid regulating agents, nium bromide, myristyl trimethyl ammonium methyl Sul muscle relaxants, parasympathomimetics, parathyroid cal phate, lauryl dimethyl benzyl ammonium chloride, lauryl citonin, parathyroid biphosphonates, prostaglandins, radio dimethyl benzyl ammonium bromide, lauryl dimethyl pharmaceuticals, SeX hormones, anti-allergic agents, Stimu (ethenoxy), ammonium chloride, lauryl dimethyl(ethenoxy), lants, anoretics, Sympathomimetics, thyroid agents, ammonium bromide, N-alkyl (Cs)dimethylbenzyl vasodilators, and Xanthines. ammonium chloride, N-alkyl(Cs)dimethyl-benzyl 84. The method of claim 82, wherein said additional one ammonium chloride, N-tetradecylidmethylbenzyl ammo or more non-triamcinolone active agents are Selected from nium chloride monohydrate, dimethyl didecyl ammonium the group consisting of acyclovir, alprazolam, altretamine, chloride, N-alkyl and (C1-)dimethyl 1-napthylmethyl amiloride, amiodarone, benztropine meSylate, bupropion, ammonium chloride, trimethylammonium halide, alkyl-tri cabergoline, candesartan, cerivastatin, chlorpromazine, methylammonium Salts, dialkyl-dimethylammonium Salts, ciprofloxacin, cisapride, clarithromycin, clonidine, clopi lauryl trimethyl ammonium chloride, ethoxylated alkyami dogrel, cyclobenzaprine, cyproheptadine, delavirdine, des doalkyldialkylammonium Salt, an ethoxylated trialkyl mopressin, diltiazem, dipyridamole, dolasetron, enalapril ammonium Salt, dialkylbenzene dialkylammonium chloride, maleate, enalaprilat, famotidine, felodipine, furazolidone, N-didecyldimethyl ammonium chloride, N-tetradecyldim glipizide, irbeSartan, ketoconazole, lanSoprazole, loratadine, ethylbenzyl ammonium, chloride monohydrate, loxapine, mebendazole, mercaptopurine, milrinone lactate, N-alkyl(C2)dimethyl 1-naphthylmethyl ammonium minocycline, mitoxantrone, nelfinavir meSylate, nimo chloride, dodecyldimethylbenzyl ammonium chloride, dipine, norfloxacin, olanzapine, omeprazole, penciclovir, dialkyl benzenealkyl ammonium chloride, lauryl trimethyl pimozide, tacolimus, quazepam, raloxifene, rifabutin, ammonium chloride, alkylbenzyl methyl ammonium chlo rifampin, risperidone, rizatriptan, Saquinavir, Sertraline, ride, alkylbenzyl dimethyl ammonium bromide, C trim Sildenafil, acetyl-Sulfisoxazole, temazepam, thiabendazole, ethyl ammonium bromides, Cs trimethyl ammonium bro thioguanine, trandolapril, triamterene, trimetrexate, troglita mides, C, trimethyl ammonium bromides, dodecylbenzyl Zone, trovafloxacin, Verapamil, vinblastine Sulfate, myco triethyl ammonium chloride, poly-diallyldimethylammo phenolate, atovaquone, atovaquone, proguanil, ceftazidime, nium chloride (DADMAC), dimethyl ammonium chlorides, cefuroxime, etoposide, terbinafine, thalidomide, flucona alkyldimethylammonium halogenides, tricetyl methyl Zole, amsacrine, dacarbazine, teniposide, and acetylsalicy ammonium chloride, decyltrimethylammonium bromide, late. dodecyltriethylammonium bromide, tetradecyltrimethylam 85. The method of claim 82, further comprising admin monium bromide, methyl trioctylammonium chloride, istering at least one antihistamine, decongestant, bronchodi POLYOUAT 10TM, tetrabutylammonium bromide, benzyl lator, anti-fungal, anti-cancer agent, or immunOSuppreSSant. trimethylammonium bromide, choline esters, benzalkonium 86. The method of claim 85, wherein the antihistamine is chloride, Stearalkonium chloride compounds, cetyl pyri Selected from the group consisting of feXofenadine, azelas dinium bromide, cetyl pyridinium chloride, halide Salts of tine, hydoxyZine, diphenhydramine, loratadine, chlorphe quaternized polyoxyethylalkylamines, MIRAPOLTM, niramine maleate, cyproheptadine, promethazine, phenyle ALKAQUATM, alkyl pyridinium salts; amines, amine salts, phrine tannate, acrivastine, and cetirizine. amine oxides, imide azolinium Salts, protonated quaternary 87. The method of claim 85, wherein the decongestant is acrylamides, methylated quaternary polymers, and cationic Selected from the group consisting of pseudoephedrine, guar. oxymetazoline, Xylometazoline, naphazoline, naphazoline, 80. The method of claim 66, comprising as a surface and tetrahydrozoline. Stabilizer a random copolymer of vinyl pyrrollidone and 88. The method of claim 85, wherein the bronchodilator Vinyl acetate, Sodium lauryl Sulfate, lysozyme, tyloxapol, or is Selected from the group consisting of Short-acting beta2 a combination thereof. agonists, long-acting beta2-agonists, anticholinergics, and 81. The method of any of claims 76, 78,79, or 80, wherein theophyllines. the composition is bioadhesive. 89. The method of claim 85, wherein the anti-fungal agent 82. The method of claim 66, additionally comprising is Selected from the group consisting of amphotericin B, administering one or more non-triamcinolone active agents. nyStatin, fluconazole, ketoconazole, terbinafine, itracona 83. The method of claim 82, wherein said additional one Zole, imidazole, triazole, ciclopiroX, clotrimazole, and or more non-triamcinolone active agents are Selected from miconazole. the group consisting of nutraceuticals, amino acids, proteins, 90. The method of claim 66, wherein the T of the peptides, nucleotides, anti-obesity drugs, central nervous triamcinolone composition, when assayed in the plasma of System Stimulants, carotenoids, corticosteroids, elastase a mammalian Subject following administration, is less than inhibitors, anti-fungals, oncology therapies, anti-emetics, the T for a non-nanoparticulate composition of the same analgesics, cardiovascular agents, anti-inflammatory agents, triamcinolone, administered at the same dosage. anthelmintics, anti-arrhythmic agents, antibiotics, antico 91. The method of claim 90, wherein the T is selected agulants, antidepressants, antidiabetic agents, antiepileptics, from the group consisting of not greater than about 90%, not antihistamines, antihypertensive agents, antimuscarinic greater than about 80%, not greater than about 70%, not agents, antimycobacterial agents, antineoplastic agents, greater than about 60%, not greater than about 50%, not immunosuppressants, antithyroid agents, antiviral agents, greater than about 30%, not greater than about 25%, not anxiolytics, Sedatives, astringents, alpha-adrenergic receptor greater than about 20%, not greater than about 15%, not blocking agents, beta-adrenoceptor blocking agents, blood greater than about 10%, and not greater than about 5% of the products, blood Substitutes, cardiac inotropic agents, con T exhibited by the non-nanoparticulate composition of trast media, corticosteroids, cough Suppressants, diagnostic the same triamcinolone, administered at the same dosage. US 2004/014 1925 A1 Jul. 22, 2004 27

92. The method of claim 66, wherein the C of the about 40%, less than about 30%, less than about 25%, less triamcinolone composition, when assayed in the plasma of than about 20%, less than about 15%, less than about 10%, a mammalian Subject following administration, is greater less than about 5%, and less than about 3%. than the C for a non-nanoparticulate composition of the 98. The method of claim 66, wherein administration of the Same triamcinolone, administered at the same dosage. composition to a human in a fasted State is bioeduivalent to 93. The method of claim 92, wherein the C is selected administration of the composition to a human in a fed State. from the group consisting of at least about 50%, at least 99. The method of claim 98, wherein “bioeduivalency” is about 100%, at least about 200%, at least about 300%, at established by a 90% Confidence Interval of between 0.80 least about 400%, at least about 500%, at least about 600%, and 1.25 for both C and AUC. at least about 700%, at least about 800%, at least about 100. The method of claim 98, wherein “bioequivalency” 900%, at least about 1000%, at least about 1100%, at least is established by a 90% Confidence Interval of between 0.80 about 1200%, at least about 1300%, at least about 1400%, and 1.25 for AUC and a 90% Confidence Interval of between at least about 1500%, at least about 1600%, at least about 0.70 to 1.43 for C. 1700%, at least about 1800%, or at least about 1900% 101. The method of claim 66, wherein the subject is a greater than the C exhibited by the non-nanoparticulate human. formulation of the Same triamcinolone, administered at the 102. The method of claim 66, wherein the method is used Same dosage. to treat indications where glucocorticoids are typically used. 94. The method of claim 66, wherein the AUC of the 103. The method of claim 66, wherein the method is used triamcinolone composition, when assayed in the plasma of to treat indications where Steroidal anti-inflammatory agents a mammalian Subject following administration, is greater are typically used. than the AUC for a non-nanoparticulate composition of the 104. The method of claim 66, wherein the method is used Same triamcinolone, administered at the same dosage. to treat indications Selected from the group consisting of 95. The method of claim 94, wherein the AUC is selected arthritis, Skin disorders, blood disorders, kidney disorders, from the group consisting of at least about 25%, at least eye disorders, thyroid disorders, intestinal disorders, aller about 50%, at least about 75%, at least about 100%, at least gies, asthma, bronchial asthma, cancer, neoplastic diseases, about 125%, at least about 150%, at least about 175%, at tendinitis, allergic reactions, Seasonal allergic rhinitis, least about 200%, at least about 225%, at least about 250%, perennial allergic rhinitis, oral inflammation, oral lesions, at least about 275%, at least about 300%, at least about oral ulcers, bursitis, epicondylitis, keloids, endocrine disor 350%, at least about 400%, at least about 450%, at least ders, herpes Zoster ophthalmicus, hemolytic anemia, and about 500%, at least about 550%, at least about 600%, at acute rheumatic carditis. least about 750%, at least about 700%, at least about 750%, 105. The method of claim 104, wherein the skin disorder at least about 800%, at least about 850%, at least about is Selected from the group consisting of contact dermatitis, 900%, at least about 950%, at least about 1000%, at least atopic dermatitis, psoriasis, eczema, and general dermatitis. about 1050%, at least about 1100%, at least about 1150%, or 106. The method of claim 104, wherein the arthritic at least about 1200% greater than the AUC exhibited by the condition is Selected from the group consisting of Osteoar non-nanoparticulate composition of the same triamcinolone, thritis, acute nonspecific osteoarthritis, posttraumatic administered at the same dosage. Osteoarthritis, and rheumatoid arthritis. 96. The method of claim 66, wherein the triamcinolone 107. The method of claim 104, wherein the intestinal composition does not produce significantly different absorp disorder is Selected from the group consisting of ulcerative tion levels when administered under fed as compared to colitis, colitis, gastroenteritis, irritable bowel disorder, and fasting conditions. Crohn's disease. 97. The method of claim 96, wherein the difference in 108. The method of claim 66, wherein the method is used absorption of the triamcinolone composition of the inven to treat indications Selected from the group consisting of tion, when administered in the fed versus the fasted State, is asthma, Seasonal allergic rhinitis, and perennial allergic Selected from the group consisting of less than about 100%, rhinitis. less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than