(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date PCT (10) International Publication Number 21 June 2007 (21.06.2007) WO 2007/070082 Al (51) International Patent Classification: (74) Agent: YAO, Gene; 2600 Aramark Tower, 1101 Market A61K 9164 (2006.01) Street, Philadelphia, Pennsylvania 19107 (US). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/US2006/0 18000 kind of national protection available): AE, AG, AL, AM, AT,AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, (22) International Filing Date: IMay 2006 (09.05.2006) CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, (25) Filing Language: English KG, KM, KN, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, LY,MA, MD, MG, MK, MN, MW, MX, MZ, NA, NG, NI, (26) Publication Language: English NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SM, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM, ZW (30) Priority Data: 60/679,424 10 May 2005 (10.05.2005) US (84) Designated States (unless otherwise indicated, for every 11/372,857 10 March 2006 (10.03.2006) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (71) Applicant (for all designated States except US): ELAN ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), PHARMA INTERNATIONAL LIMITED [IE/IE]; European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, Monksland, Athlone, County Westmeath (IE). FR, GB, GR, HU, IE, IS, IT, LT, LU, LV,MC, NL, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, (72) Inventors; and GN, GQ, GW, ML, MR, NE, SN, TD, TG). (75) Inventors/Applicants (for US only): DEVANE, John [IE/IE]; Barrymore, Athlone, County Westmeath (IE). Declaration under Rule 4.17: STARK, Paul [GB/TE]; 37 Auburn Heights, Athlone, — of inventorship (Rule 4.17 (iv)) County Westmeath (IE). FANNING, Mall [IE/IE]; 23 Coolevin Park, Coosan, Athlone, County Westmeath Published: (IE). REKHI, Gurvinder [US/US]; 1492 Riverview Run — with international search report Lane, Suwanee, Georgia 30024 (US). JENKINS, Scott [US/US]; 1451 Carolina Place, Downingtown, Pennsyl For two-letter codes and other abbreviations, refer to the "G uid vania 19335 (US). LIVERSIDGE, Gary [US/US]; 258 ance Notes on Codes and Abbreviations" appearing at the beg in Colwyn Terrace, West Chester, Pennsylvania 19380 (US). ning of each regular issue of the PCT Gazette. (54) Title: NANOPARTICULATE AND CONTROLLED RELEASE COMPOSITIONS COMPRISING TEPRENONE (57) Abstract: The present invention is directed to compositions comprising a nanoparticulate teprenone having improved bioavail- ability. The nanoparticulate teprenone particles of the composition have an effective average particle size of less than about 2000 nm and are useful in the prevention and treatment of gastritis and gastric ulcers. The invention also relates to a controlled release composition comprising a teprenone or a nanoparticulate teprenone that in operation delivers the drug in a pulsed or multi-modal manner for the prevention and treatment of gastritis and gastric ulcers. NANOPARTICULATE AND CONTROLLED RELEASE COMPOSITIONS COMPRISING TEPRENONE FIELD OF INVENTION The present invention relates to compositions and methods for the prevention and treatment of gastric disease. In particular, the present invention relates to compositions comprising teprenone-containing particles and methods for making and using such a composition. In an embodiment of the invention, teprenone is in nanoparticulate form. The present invention relates also to novel dosage forms for the controlled delivery of teprenone. BACKGROUND OF INVENTION A. Background Regarding Teprenone Teprenone is an effective therapeutic against gastric disease. A healthy stomach and proper digestive processes require a fine balance of stomach acid and stomach mucosa. However, aging, body condition, and eating habits, among other factors, can disrupt this delicate balance resulting in a reduction in the amount of stomach mucous, and reduced gastric peristalsis. When this occurs, digestion time can increase, leading to conditions such as stomach heaviness and heartburn. Moreover, gastric mucosal lesions as a result of erosion, hemorrhage, redness and edema can lead to gastritis and gastric ulcers. Teprenone increases gastric mucous, and also protects gastric mucosa from stomach acid, thereby helping to restore normal gastric mucosa and treat gastric diseases. Gastritis is not necessarily clear in the special definition thereof in view of the fact that it is usually divided into acute gastritis and chronic gastritis in the discussion thereof. In the present invention, the term is used as including both types of gastritis. Chronic gastritis is usually classified into superficial gastritis and atrophic gastritis, and further into atrophic hyperplastic gastritis, hypertrophic gastritis, etc. Representative examples of chronic gastritis symptoms include anorexia, esophagostenosis, pyrosis, nausea, emesis, epigastrium dysphoria, epigastralgia, and flatulence. Acute gastritis is generally an inflammatory lesion of tunica mucosa ventriculi which is rapidly caused by an endogenous or xenogenic stimulus, and is usually accompanied by erosion. Clinical studies have demonstrated that teprenone has a potent anti-ulcer effect and is very effective against various gastric mucosal lesions. Specifically, teprenone is thought to increase gastric mucus by promoting mucus synthesis and secretion in mucosal epithelial cells. Teprenone also increases gastric mucosal blood flow and has been shown to protect the gastric mucosa from, for example, ethanol-induced injury and increases in lipid peroxide levels. Further, teprenone enhances gastric mucosal cell proliferation and thus helps to maintain the homeostasis of the gastric mucosal cell proliferation zone. Teprenone may be administered as part of a dosage form offered under the registered trademark SELBEX® by Eisai Co., Ltd. of Japan. Its chemical name is 3:2 (5E:5Z) geometric mixture of (9E,13E)-6,10,14,18-tetramethyl-5,9,13,17- nonadecatetraen-2-one. The molecular formula of teprenone is C23H38O and it has a molecular weight of 330.55. The chemical structure of teprenone is: Teprenone occurs as a colorless to pale yellow, oily liquid. It has a slight characteristic odor, and is tasteless. It is miscible with methanol, ethanol (95), acetone, chloroform, and hexane, and is practically insoluble in water. Conventional teprenone is administered orally, either as a capsule or in fine granules, in 50 mg quantities three times daily after a meal. Teprenone is described in, for example, U.S. Pat. No. 4,814,353 for "Therapeutic and Prophylactic Agent for Gastritis". U.S. Pat. No. 4,814,353 describes the teprenone compound and a method for treating gastritis comprising administering a therapeutic amount of teprenone to a patient suffering from gastritis. Teprenone has high therapeutic value for the treatment of patients suffering from gastritis and gastric ulcers. However, given the need to take teprenone three times a day and the further need to take teprenone after meals, strict patient compliance is a critical factor in the efficacy of teprenone in the treatment of gastritis and gastric ulcers. Moreover, such frequent administration often requires the attention of health care workers and contributes to the high cost associated with treatments involving teprenone. Thus, there is a need in the art for teprenone compositions which overcome these and other problems associated with their use in the treatment of gastritis and gastric ulcers. B. Background Regarding Nanoparticulate Compositions Nanoparticulate active agent compositions, first described in U.S. Patent No. 5,145,684 ("the '684 patent"), are particles consisting of a poorly soluble therapeutic or diagnostic agent having adsorbed onto or associated with the surface thereof a non- crosslinked surface stabilizer. The '684 patent does not describe nanoparticulate compositions of teprenone. Methods of making nanoparticulate active agent compositions are described in, for example, U.S. Patent Nos. 5,518,187 and 5,862,999, both for "Method of Grinding Phaπnaceutical Substances;" U.S. Patent No. 5,718,388, for "Continuous Method of Grinding Pharmaceutical Substances;" and U.S. Patent No. 5,510,1 18 for "Process of Preparing Therapeutic Compositions Containing Nanoparticles." Nanoparticulate active agent compositions are also described, for example, in U.S. Patent Nos. 5,298,262 for "Use of Ionic Cloud Point Modifiers to Prevent Particle Aggregation During Sterilization;" 5,302,401 for "Method to Reduce Particle Size Growth During Lyophilization;" 5,3 18,767 for "X-Ray Contrast Compositions Useful in Medical Imaging;" 5,326,552 for "Novel Formulation For Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants;" 5,328,404 for "Method of X-Ray Imaging Using Iodinated Aromatic Propanedioates;" 5,336,507 for "Use of Charged Phospholipids to Reduce Nanoparticle Aggregation;" 5,340,564 for "Formulations Comprising Olin 10-G to Prevent Particle Aggregation and Increase Stability;" 5,346,702 for "Use of Non-Ionic Cloud Point Modifiers to Minimize Nanoparticulate Aggregation During Sterilization;" 5,349,957 for "Preparation and Magnetic Properties of Very Small Magnetic-Dextran Particles;" 5,352,459 for "Use of Purified Surface