Compositions for the treatment of inflammation of the gastrointestinal tract

This application claims the benefit of U.S. Provisional Application No. 60/987,720, filed Nov. 13, 2007; U.S. Provisional Application No. 61/012,012, filed Dec. 6, 2007; U.S. Provisional Application No. 61/015,998, filed Dec. 21, 2007; U.S. Provisional Application No. 61/019,818, filed Jan. 8, 2008; U.S. Provisional Application No. 61/034,941, filed Mar. 7, 2008; U.S. Provisional Application No. 61/035,348, filed Mar. 10, 2008; U.S. Provisional Application No. 61/054,103, filed May 16, 2008; U.S. Provisional Application No. 61/054,104, filed May 16, 2008; U.S. Provisional Application No. 61/054,105, filed May 16, 2008; U.S. Provisional Application No. 61/054,106, filed May 16, 2008; U.S. Provisional Application No. 61/054,107, filed May 16, 2008; and U.S. Provisional Application No. 61/090,658, filed Aug. 20, 2008, which applications are incorporated herein by reference.

Gastroesophageal reflux disease (GERD) is among the most common gastrointestinal (GI) problems. GERD is caused by abnormal reflux in the esophagus. Heartburn is a common symptom that is indicative of GERD. Other symptoms associated with GERD include, by way of non-limiting example, odynophagia, bitter taste in the mouth, belching, nausea, dysphagia, regurgitation, laryngitis, cough, hoarseness and asthma are also associated with GERD.

Accordingly, certain embodiments of the present invention provide for a method of treating or alleviating the symptoms of or inflammation associated with gastroesophageal reflux disease (GERD). Specifically, some embodiments of the present invention provide for a method of treating or alleviating the symptoms of or inflammation associated with gastroesophageal reflux disease (GERD) in an individual by administering to an individual a therapeutically effective amount of a corticosteroid. In specific embodiments, the gastroesophageal reflux disease treated nonerosive reflux disease (NERD). In other specific embodiments, the gastroesophageal reflux disease is erosive esophagitis (EE). In some embodiments of the present invention, the corticosteroid utilized in the methods described herein is a topical corticosteroid. Specific topical corticosteroid include, by way of non-limiting example, budesonide and fluticasone.

In certain embodiments, the methods described herein include administration of about 0.1 mg to about 20 mg/day; or at least 250 μg/day of the corticosteroid to the individual. In specific embodiments, between about 300 μg/day and about 4 mg/day, or between about 500 μg/day and about 6 mg/day of the corticosteroid is administered to the individual. In more specific embodiments, between about 500 μg/day and about 3 mg/day of the corticosteroid is administered to the individual. In some embodiments, less than 500 μg/day of the corticosteroid is administered to the individual.

In some embodiments, the methods described herein further include administering a therapeutically effective amount of an acid inhibitor to the individual.

In certain embodiments, the acid inhibitor is an H₂RA. In some embodiments, the corticosteroid and H₂RA are administered concurrently. In specific embodiments, the H₂RA is selected for, by way of non-limiting example, cimetidine, famotidine, nizatidine, and ranitidine. In more specific embodiments, the H₂RA is ranitidine. In some embodiments, the H₂RA is administered in an amount of between 1 mg and 500 mg.

In other embodiments, the acid inhibitor is a proton pump inhibitor. In some embodiments, the corticosteroid and the proton pump inhibitor are administered concurrently. In specific embodiments, the proton pump inhibitor is selected from, by way of non-limiting example, omeprazole, hydroxyomeprazole, esomeprazole, tenatoprazole, lansoprazole, pantoprazole, rabeprazole, dontoprazole, habeprazole, perprazole, ransoprazole, pariprazole, leminoprazole, S-tenatoprazole-Na, and dexlansoprazole. In a more specific embodiment, the proton pump inhibitor is omeprazole. In certain embodiments, the proton pump inhibitor is administered in an amount of between 1 mg and 600 mg. Furthermore, in addition to administering therapeutically effective amounts of a corticosteroid and a proton pump inhibitor, certain embodiments of the present invention include methods further comprising administering a therapeutically effective amount of an H₂RA to said individual.

In any of the methods described herein, the present invention includes methods wherein the corticosteroid is administered in the form of a pharmaceutical composition comprising the corticosteroid and at least one excipient. In specific embodiments, such a pharmaceutical composition is viscous. In other embodiments, the pharmaceutical composition is non-viscous. In some embodiments, the excipient increases the interaction of the composition with the individual\'s esophagus. In certain embodiments, the excipient is a viscosity enhancer, a mucoadhesive agent, an absorption enhancing agent, or a combination thereof. As used herein, a mucoadhesive agent is an agent that adheres to a gastrointestinal surface (e.g., either or both of a gastrointestinal epithelia or mucosa).

In some embodiments, the viscosity-enhancing excipient is selected from, by way of non-limiting example, cellulose (including cellulose derivatives), acacia (gum arabic), agar, aluminum magnesium silicate, sodium alginate, sodium stearate, bladderwrack, bentonite, carbomer, carrageenan, Carbopol, cellulose, microcrystalline cellulose (MCC), ceratonia, chondrus, dextrose, furcellaran, gelatin, Ghatti gum, guar gum, hectorite, lactose, sucrose, maltodextrin, mannitol, sorbitol, honey, maize starch, wheat starch, rice starch, potato starch, gelatin, sterculia gum, xanthum gum, polyethylene glycol (e.g. PEG 200-4500), gum tragacanth, ethyl cellulose, ethylhydroxyethyl cellulose, ethylmethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, poly(hydroxyethyl methacrylate), oxypolygelatin, pectin, polygeline, povidone, propylene carbonate, methyl vinyl ether/maleic anhydride copolymer (PVM/MA), poly(methoxyethyl methacrylate), poly(methoxyethoxyethyl methacrylate), hydroxypropyl cellulose, hydroxypropylmethyl-cellulose (HPMC), sodium carboxymethyl-cellulose (CMC), silicon dioxide, polyvinylpyrrolidone (PVP: povidone), Splenda® (distributed by McNeil Nutritionals, LLC Fort Washington, Pa. 19034-2299; comprising dextrose, maltodextrin and sucralose) and combinations thereof. In specific embodiments, the viscosity-enhancing excipient is a combination of MCC and CMC (e.g., Avicel RC-591).

In some embodiments, the viscosity of the pharmaceutical composition is greater than about 2 cP, greater than about 50 cP, about 50 cP to about 800 cP, or about 90 cP to about 200 cP, or about 300 cP to about 800 cP, or about 300 cP to about 500 cP or about 400 cP to about 600 cP, and wherein the viscosity is measured at 25 degrees Celsius. In specific embodiments, the viscosity of the pharmaceutical composition is about 250 cP to about 600 cP.

In certain embodiments, the mucoadhesive agent is selected from, by way of non-limiting example, a soluble polyvinylpyrrolidone polymer (PVP); a water-swellable, but water-insoluble, fibrous, cross-linked carboxy-functional polymer, a cross-linked poly(acrylic acid), a carbomer homopolymer, a carbomer copolymer, a hydrophilic polysaccharide gum, maltodextrin, a cross-linked alignate gum gel, a water-dispersible polycarboxylated vinyl polymer, and combinations thereof. In other embodiments, the mucoadhesive agent is selected from at least of titanium dioxide, silicon dioxide, and clay, and mixtures thereof.

In some embodiments, the absorption enhancing agent is selected from, by way of non-limiting example, acylcarnitines, surfactants, sodium lauryl sulfate, saponins, bile salts or bile acids including but not limited to cholanic acid, chilic acid, deoxycholic acid, glycocholic acid, tautocholic acid, chenodeoxycholic acid, lithocholic acid, ursocholic acid, ursodeoxycholic acid, isourosde oxycholic acid, lagodeoxycholic acid, glycodeoxycholic acid, glycochenodeoxycholic acid, dehydrocholic acid, hyocholic acid, hyodeoxycholic acid, or combinations thereof, dihydrofusidates, fatty acid derivatives, chitosan, carbopol, cellulosic agents, sterols, including but not limited to alcohols structurally related to steroids, including but not limited to cholestanol, coprostanol, cholesterol, epicholesterol, ergosterol, ergocalciferol, or combinations thereof, starch, dextran, cyclodextrin, and combinations thereof.

In certain embodiments, the present invention provides for methods wherein the corticosteroid is administered in a unit dose formulation for oral administration.

In some embodiments, the individual is an adult. In other embodiments, the individual is a child or infant. In certain embodiments, the child or infant is less than 19 years old, less than 12 years old, less than 8 years old, less than 6 years old, less than 4 years old or less than 2 years old.

All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.