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.

Esophageal inflammation disorders are gaining increased recognition in both adults and children. One example is eosinophilic esophagitis (EE or EoE), which is an emerging, and fast-growing disorder characterized by high levels of eosinophils in the esophagus, as well as basal zone hyperplasia. EoE is thought to be provoked, in at least a subset of patients, by food allergies or airborne allergen exposure (1-5, 44). EoE 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 EoE 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 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. In one series, 15% of EoE patients had concurrent developmental delay (45).

Although EoE 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 EoE often mimic those of GERD and include vomiting, dysphagia, pain and food impaction (8, 14, 17-20). However, treatment of EoE and GERD differ and it is important to distinguish between them, particularly as untreated EoE may be associated with esophageal narrowing in 10-30% of cases (14, 18, 20, 21). The overlap of GERD and EoE symptoms is common; failure to respond to high PPI GERD treatment may be one diagnostic guideline for EoE (42). The common occurrence regarding misdiagnosis of EoE for GERD often results in delayed treatment for patients with EoE. (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 or EoE, 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 for 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, an isotonic agent, a surfactant, and an excipient.

In certain embodiments, the corticosteroid is, by way of non-limiting example, fluticasone propionate. 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 gram of composition.

In some embodiments, the preservative is, by way of non-limiting example, benzalkonium chloride. In certain embodiments, the preservative is present in the composition in an amount of about 0.0002% to about 0.03% w/w of the composition.

In some embodiments, the isotonic agent is, by way of non-limiting example, dextrose. In certain embodiments, the surfactant is, by way of non-limiting example, polysorbate 80. In some embodiments, the excipient is an excipient that increases the interaction of the composition with a surface of the gastrointestinal tract (e.g., the mucosa and/or epithelium of the gastrointestinal tract or of a specific site of the gastrointestinal tract, such as the esophagus). In certain embodiments, the excipient that increases the interaction of the composition with a surface of the gastrointestinal tract (e.g., the mucosa and/or epithelium of the gastrointestinal tract or of a specific site of the gastrointestinal tract, such as the esophagus) is a viscosity enhancing agent. In some embodiments, the viscosity enhancing agent is selected from, by way of non-limiting example, microcrystalline cellulose, carboxymethyl cellulose sodium and a combination thereof. In certain specific embodiments, the viscosity enhancing agent is a combination of microcrystalline cellulose and carboxymethyl cellulose sodium. In other specific embodiments, the viscosity enhancing agent is carboxymethyl cellulose sodium. In some embodiments, a corticosteroid containing composition of the present invention comprises a second excipient. In certain embodiments, the second excipient is selected from, by way of non-limiting example, an excipient that increases the interaction of the composition with a surface of the gastrointestinal tract (e.g., the mucosa and/or epithelium of the gastrointestinal tract or of a specific site of the gastrointestinal tract, such as the esophagus), a binder, a filler, a disintegrant, a diluent, a carrier a vehicle and combinations thereof. In certain specific embodiments, the second excipient that increases the interaction of the composition with a surface of the gastrointestinal tract (e.g., the mucosa and/or epithelium of the gastrointestinal tract or of a specific site of the gastrointestinal tract, such as the esophagus) is a second viscosity enhancing agent.

In some embodiments, the composition further comprises a fragrance. In specific embodiments, the fragrance is, by way of non-limiting example, phenylethyl alcohol. In some embodiments, the fragrance is present in the composition in an amount of about 0.0005 to about 0.4% w/w of the composition.

In certain embodiments, the vehicle is present in the composition in an amount of about 50% to about 99.5% w/w of the composition. In some embodiments, the vehicle is selected from a liquid vehicle, a solid vehicle and combinations thereof. In certain embodiments, the solid vehicle is selected from, by way of non-limiting example, talc, bentonite, kaolin calcium carbonate, and combinations thereof. In some embodiments, the liquid vehicle is selected from, by way of non-limiting example, water, ethanol, an organic solvent, an oil and combinations thereof.

In some embodiments, the composition is formulated as a suspension of microfine corticosteroid particles suspended in an aqueous vehicle. In certain embodiments, the composition has a pH of about 5 to about 7.

In some embodiments, the composition further comprising a sweetener, a flavoring agent or a combination thereof.

In specific embodiments, the corticosteroid is microfine fluticasone propionate, the preservative is benzalkonium chloride, the isotonic agent is dextrose, the surfactant is polysorbate 80, the fragrance is phenylethyl alcohol, and the excipient that increases the interaction of the composition with a surface of the gastrointestinal tract (e.g., the mucosa and/or epithelium of the gastrointestinal tract or of a specific site of the gastrointestinal tract, such as the esophagus) is a combination of microcrystalline cellulose and carboxymethyl cellulose sodium. In some specific embodiments, the corticosteroid is microfine fluticasone propionate, the preservative is a combination of benzalkonium chloride and phenylethyl alcohol, the isotonic agent is dextrose, the surfactant is polysorbate 80, and the excipient that increases the interaction of the composition with a surface of the gastrointestinal tract (e.g., the mucosa and/or epithelium of the gastrointestinal tract or of a specific site of the gastrointestinal tract, such as the esophagus) is a combination of microcrystalline cellulose and carboxymethyl cellulose sodium. In more specific embodiments, the composition further comprises an aqueous vehicle. In even more specific embodiments, the composition is formulated as a suspension of microfine corticosteroid particles suspended in the aqueous vehicle. In some specific embodiments, the composition has a pH of about 5 to about 7. In certain embodiments, the composition further comprises a second excipient that increases the interaction of the composition with a surface of the gastrointestinal tract (e.g., the mucosa and/or epithelium of the gastrointestinal tract or of a specific site of the gastrointestinal tract, such as the esophagus).

In some embodiments, the benzalkonium chloride is present in the composition in an amount of about 0.0002% to about 0.03% w/w of the composition and the phenylethyl alcohol is present in the composition in an amount of about 0.0005 to about 0.4% w/w of the composition.

In certain embodiments, the present invention provides for methods of administering about 0.25 mg to about 3 mg of corticosteroid per day.

In some embodiments, the present invention provides for methods of treating inflammation of the esophagus. In certain embodiments, the present invention provides for methods of treating, preventing or alleviating and/or methods of treating, preventing or alleviating individuals diagnosed with eosinophilic esophagitis, an inflammatory bowel disease involving the esophagus, Crohn\'s disease, coeliac disease, eosinophilic duodenitis, functional dyspepsia, 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, epithelial hyperplasia, basal cell hyperplasia, elongated papillae, dilated vessels in papillae, fungal esophagitis (e.g., Candida, turolopsis, histoplasma Aspergillus, etc.), viral esophagitis (e.g., HSV, CMV, V2V), bacterial esophagitis (e.g., tuberculosis, actinomycosis, syphlis), corrosive esophagitis, radiation esophagitis, chemotherapy esophagitis, graft vs. host disease, a skin disease with esophageal involvement (e.g., bullous pemphigoid, pemphigus vulgaris, epidermolysis bollosa, Stevens-Johnson syndrome), Behçet\'s disease, sarcoidosis, idiopathic esophagitis, eosinophilic gastritis, Ménétrier\'s disease, parasitic gastritis, lymphocytic esophagitis, inflammatory bowel disease-associated esophagitis, parasitic gastritis, or post-surgery inflammation. In specific embodiments, the present invention provides for methods of treating, preventing or alleviating and/or methods of treating, preventing or alleviating gastrointestinal disorders in individuals diagnosed with eosinophilic esophagitis. In some embodiments, the present invention provides for methods of treating, preventing or alleviating and/or methods of treating, preventing or alleviating individuals diagnosed with gastroesophageal reflux disease (GERD), nonerosive reflux disease (NERD), or erosive esophagitis.