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 December 06, 2007; U.S. Provisional Application No. 61/015,998, filed December 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.

Esophageal inflammation disorders are gaining increased recognition in both adults and children. One example is eosinophilic esophagitis (EE), which is an emerging, and fast-growing disorder characterized by high levels of eosinophils in the esophagus, as well as basal zone hyperplasia. EE is thought to be provoked, in at least a subset of patients, by food allergies or airborne allergen exposure (1-5, 44). EE diagnosis is often associated with other hypersensitivity disorders, including asthma, rhinitis, and other food and aeroallergen inhalant sensitivities (39-40). Diagnosis is often made, e.g., in young children and depends on the finding of 15 to 20 or more to 24 or more eosinophils per high power field (eos/hpf) within esophageal mucosal biopsies (6-12).

In parallel with other atopic disorders, the incidence of BE appears to be increasing (15, 35). The disorder may present with reflux-like symptoms, pain and dysphagia, clinical symptoms similar to the presentation of gastroesophageal reflux disease (“GERD”) (42). Symptoms of EE 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. In one series, 15% of EE patients had concurrent developmental delay (45).

Although EE is becoming more frequently diagnosed throughout developing countries (7, 8, 13-16) many aspects of the disease remain unclear including its etiology, natural history and optimal therapy. Symptoms of EE often mimic those of GERD and include vomiting, dysphagia, pain and food impaction (8, 14, 17-20). However, treatment of EE and GERD differ and it is important to distinguish between them, particularly as untreated EE may be associated with esophageal narrowing in 10-30% of cases (14, 18, 20, 21). The overlap of GERD and EE symptoms is common; failure to respond to high PPI GERD treatment may be one diagnostic guideline for EE (42). The common occurrence regarding misdiagnosis of EE for GERD often results in delayed treatment for patients with EE. (42).

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, this therapy is currently not approved for use in children (36).

Current treatments include elimination diets (22, 23), and elemental formulas (2, 24). 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.

Certain embodiments of the present invention provide a method of treating, preventing or alleviating inflammation of the gastrointestinal tract comprising orally administering to an individual in need thereof a composition comprising a corticosteroid, a preservative, a chelating agent, an isotonic agent, a surfactant, and an excipient that increases the interaction of the composition with a mucosal layer. In some embodiments, the corticosteroid is, by way of non-limiting example, budesonide. In specific embodiments, the corticosteroid is present in the composition in an amount of about 0.01 mg to about 1.0 mg of corticosteroid per gram of composition. In some embodiments, the corticosteroid is present in the composition in an amount of about 0.01 mg to about 1.0 mg of corticosteroid per mL of composition.

In certain embodiments, the present invention provides for methods of administering about 5 mL to about 50 ma of the corticosteroid containing composition to the individual.

In some embodiments, the preservative is, by way of non-limiting example, potassium sorbate. In specific embodiments, the preservative is present in the composition in an amount of about 0.0002% to about 0.5% w/w of the composition. In some embodiments, the chelating agent is, by way of non-limiting example, disodium edetate. In specific embodiments, the chelating agent is present in the composition in an amount of about 0.0005% to about 0.1% w/w of the composition. In certain embodiments, the isotonic agent is, by way of non-limiting example, dextrose. In some embodiments, the surfactant is, by way of non-limiting example, polysorbate 80. In specific embodiments, the surfactant is present in the composition in an amount of about 0.0005% to about 2% w/w of the composition. In certain embodiments, the excipient that increases the interaction of the composition with a mucosal layer is a viscosity modulator and/or modifier. In specific embodiments, the viscosity modulator and/or modifier is selected from, by way of non-limiting example, microcrystalline cellulose, carboxymethyl cellulose sodium and a combination thereof. In more specific embodiments, the viscosity modulator and/or modifier is a combination of microcrystalline cellulose and carboxymethyl cellulose sodium. In some embodiments, the viscosity modulator and/or modifier is present in the composition in about 0.01% to about 3.0% w/w of the composition. In certain embodiments, the viscosity modulator and/or modifier is Avicel® RC-591.

In some embodiments, the composition has a first and a second excipient. In specific embodiments, the second excipient is selected from an excipient that increases the interaction of the composition with a mucosal layer, a binder, a filler, a disintegrant, a diluent, a carrier, a vehicle and combinations thereof. In other embodiments, the second excipient that increases the interaction of the composition with a mucosal layer is a second viscosity modulator and/or modifier. In some embodiments, the second excipient is a vehicle (including a diluent) and is present in the composition in an amount of about 50% to about 99.5% w/w of the composition. In specific embodiments, the vehicle is selected from, by way of non-limiting example, a liquid vehicle, a solid vehicle and combinations thereof. In some embodiments, the vehicle is a solid vehicle and is selected from, by way of non-limiting example, talc, bentonite, kaolin calcium carbonate, and combinations thereof. In certain embodiments, the vehicle is a liquid vehicle and is selected from, by way of non-limiting example, water, ethanol, an organic solvent, an oil (e.g., corn oil) and combinations thereof. In specific embodiments, the corticosteroid containing composition is formulated as a micronized suspension of the corticosteroid in an aqueous vehicle.

In some embodiments, the corticosteroid containing composition has a target pH of about 4.5. In certain embodiments, the target pH of the composition is attained by adding a pH adjusting agent to the composition. In specific embodiments, the pH adjusting agent is, by way of non-limiting example, hydrochloric acid or sodium hydroxide.

In certain embodiments, the corticosteroid containing composition also contains, by way of non-limiting example, a sweetener, a flavoring agent or a combination thereof.

In specific embodiments of the present invention, the corticosteroid containing composition contains budesonide as the corticosteroid, potassium sorbate as the preservative, disodium edetate as the chelating agent, dextrose as the isotonic agent, polysorbate 80 as the surfactant, a combination of microcrystalline cellulose and carboxymethyl cellulose sodium as the excipient that increases the interaction of the composition with a mucosal layer, and hydrochloric acid as the pH adjusting agent. In more specific embodiments, the corticosteroid containing composition contains about 0.01 mg to about 1.0 mg of budesonide per mL of composition, about 0.0002% to about 0.5% w/w of potassium sorbate, about 0.0005% to about 0.1% W/W of disodium edetate, about 0.0005% to about 2% w/w of polysorbate 80, and about 0.01% to about 3.0% w/w of a combination of microcrystalline cellulose and carboxymethyl cellulose sodium In still more specific embodiments, the composition is further comprises an aqueous vehicle. In some embodiments, the corticosteroid containing composition is formulated as a micronized suspension of the budesonide in the aqueous vehicle. In yet more specific embodiments, the composition has a pH of about 4.5. In some embodiments, the composition comprises a second excipient that increases the interaction of the composition with a mucosal layer.

In certain embodiments, a pharmaceutical composition described comprises or a method described herein comprises administering (e.g., per day or per dose) to an individual about 0.1 mg to about 20 mg corticosteroid, about 1 to about 2 mg corticosteroid, about 2 to about 3 mg corticosteroid, or about 0.25- to about 2.5 mg, or about 0.25 to about 3 mg of corticosteroid. In certain embodiments, the methods described herein of treating, preventing or alleviating inflammation of the gastrointestinal tract include treating, preventing or alleviating inflammation of the esophagus. In certain embodiments, the individual has been diagnosed with (or has inflammation associated with), by way of non-limiting example, eosinophilic esophagitis, an inflammatory bowel disease involving the esophagus, Crohn\'s disease, esophageal inflammation secondary to caustic/irritant ingestion, persistent/recurrent esophageal strictures of any cause and including caustic/irritant ingestion, pill-induced esophagitis, systemic diseases, congenital diseases or post-surgery inflammation. In specific embodiments, the individual has been diagnosed with (or has inflammation associated with), by way of non-limiting example, eosinophilic esophagitis. In some embodiments, the individual has been diagnosed with (or has inflammation associated with), by way of non-limiting example, gastroesophageal reflux disease (GERD), nonerosive reflux disease (NERD), or erosive esophagitis. It is to be understood that disclosure of treating an individual diagnosed with or inflammation associated with a certain inflammatory disorder includes a method of treating, preventing or alleviating inflammation associated with the certain inflammatory disorder.

In certain embodiments, the individual treated with the methods disclosed herein is a child or infant. In some embodiments, the child less than 19 years old, less than 16 years old, 12 years old, 8 years old, 6 years old, 4 years old, or 2 years old. In other embodiments, the individual is an adult.

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.