Compositions for the treatment of gastrointestinal inflammation

Abstract

Provided herein are methods for preventing or alleviating the symptoms of and inflammation associated with inflammatory diseases and conditions of the gastrointestinal tract, for example, those involving the esophagus. Also provided herein are pharmaceutical compositions useful for the methods of the present invention.

Description

CROSS-REFERENCE[0001]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.BACKGROUND OF THE INVENTION[0002]Esophageal inflammation disorders are gaining increased reco...

AI Technical Summary

Benefits of technology

[0007]In certain embodiments, the present invention is directed to methods and pharmaceutical compositions for treating, preventing or alleviating the symptoms of and / or inflammation associated with inflammatory diseases involving the gastrointestinal tract, including the esophagus, stomach and / or digestive tract. Provided herein are methods of treating, preventing or alleviating, for example, esophageal inflammation in an individual. In certain embodiments, these methods comprise orally administering to said individual a corticosteroid in association with at least one additional active agent. In some embodiments, provided herein is a pharmaceutical composition comprising a corticosteroid and at least one additional active agent. In specific embodiments, the at least one additional active agent is an agent that treats, prevents, or alleviates the symptoms of and / or inflammation associated with inflammatory diseases involving the gastrointestinal tract. In some embodiments, inflammatory diseases involving the gastrointestinal tract involve, by way of non-limiting example, the esophagus, the stomach and / or the small intestines. In more specific embodiments, the at least one additional active agent is not a second corticosteroid. In certain embodiments, the pharmaceutical composition further comprises a liquid vehicle. In further or alternative embodiments, the pharmaceutical composition is suitable for oral administration. In some embodiments, the composition further comprises an excipient or combination of excipients. In specific embodiments, the excipient or combination of excipients increases the interaction of the composition and / or the corticosteroid and / or the at least one additional active agent with a surface of the gastrointestinal tract (e.g., the surface of the esophagus).

[0009]In certain embodiments, the present invention provides a new method for reducing the risk of gastrointestinal reflux and esophageal inflammation in people taking corticosteroids for pain relief and for other conditions, particularly during treatment. In some embodiments, the present invention provides a method for treating patients presenting with GERD or GERD-like symptoms, but may be afflicted also or instead with non-GERD disease, such as eosinophilic esophagitis (EE or EoE), in a safe and efficient manner. In some embodiments, the method involves the administration of a composition that combines: a) a corticosteroid; b) an acid inhibitor (e.g., a H2 antagonist and / or a PPI) that minimizes the adverse effects of gastrointestinal reflux and c) an excipient or combination of excipients thereof. In some embodiments, the excipient may increase interaction of the composition with the esophagus. Either short or long acting acid inhibitors can be used in the dosage forms. Preferably the excipient allows convenient and efficient administration of the composition while increasing and maintaining interaction of the composition with the affected esophageal area for effective therapeutic treatment.

[0015]Agents that enhance absorption of the composition through a surface of the gastrointestinal tract (e.g., the surface of the esophagus), may also be used to increase the interaction of the compositions disclosed herein with a surface of the gastrointestinal tract (e.g., the surface of the esophagus). Such agents include, but are not limited to, 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, or combinations thereof.

[0020]In a more general sense, the invention includes methods of treating esophageal inflammation, gastrointestinal reflux and / or other related conditions by orally administering a corticosteroid and one or more acid inhibitors at a dose or dose range effective to raise a patients gastric pH to at least 3.5, preferably to at least 4 or and more preferably to at least 5, and to decrease the physiological manifestations, symptoms or appearance of esophageal inflammation, gastrointestinal reflux and / or other related disease or ailment conditions. The patient is administered such compositions in one embodiment in a coordinated dosage form with an excipient that increases interaction of the composition with the esophagus, including but not limited to viscosity enhancing agents, mucoadhesive agents or absorption enhancers, or a combination thereof. In some aspects of the invention, a patient is administered with a single dosage unit form to achieve a therapeutic effect. In other aspects, the patient may be administered the compositions disclosed herein for a single dose, or over a period of time, for example, at least two days, at least a week, at least a month or at least six months in order to achieve the desired therapeutic effect. One of ordinary skill in the art would be knowledgeable as to the dosing amounts and regimen of a patient to achieve a therapeutic effect when treating with the compositions disclosed herein. For example, one of ordinary skill in the medical or pharmaceutical arts may monitor a patient's progress over time using physiological or biochemical markers of esophageal inflammation and GERD further disclosed herein, and adjust or amend a dosing amount and / or dosing regimen depending upon changes in the physiological or physical parameters of the patient to the compositions disclosed herein.

Problems solved by technology

Symptoms of EoE include, for example, abdominal pain, chest pain, choking, difficulty swallowing, failure to thrive, nausea, reflux not relieved by standard anti-flux therapy, skin rash or hives, vomiting, and weight loss.

The common occurrence regarding misdiagnosis of EoE for GERD often results in delayed treatment for patients with EE or EoE.

Long term systemic steroid therapy can result in significant secondary side effects on growth and bone development.

Although treatment with anti-IL-5 monoclonal antibody has been reported to be successful in EE or EoE, this therapy is currently not approved for use in children (36).

Identifying true inciting food allergens can be difficult and elemental formulas are often unpalatable, thereby making dietary interventions complicated (1, 22).

Improvised puff and swallow techniques may be difficult for patients, especially smaller children, and especially children with developmental delays, to perform efficiently.

This may result in a less than effective dose of a topical steroid being delivered to the esophagus.

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