Compositions for the treatment of gastrointestinal inflammation

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 EE or 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.

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).

In certain embodiments, the at least one additional active agent is selected from by way of non-limiting example, a proton pump inhibitor (PPI), a H2 antagonist, a transient lower esophageal sphincter relaxation (TLESR)-reducing agent, a serotonergic agent/prokinetics, a potassium-competitive acid blocker (P-CAB), a mucosal protectant, a histamine H3 agonist, an anti-gastrin agent, mGluR₅ antagonists, acetylcholine modulator, 5HT₄ receptor agonist, 5HT₃ receptor antagonist, 5HT₁ receptor antagonist, antibiotics, and combinations thereof.

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.

In a first aspect, the invention is directed to a composition (e.g., a pharmaceutical composition) suitable for oral administration to a patient. The composition can be in unit dosage form. The composition contains a) a corticosteroid (e.g., budesonide), b) an acid inhibitor present in an amount effective to raise the gastric pH of a patient to at least 3.5, preferably to at least 4, and more preferably to at least 5, when one or more unit dosage forms are administered and c) an excipient or combination of excipients thereof. The excipient preferably increases interaction of the composition with a surface of the gastrointestinal tract (e.g., the surface of the esophagus). Further, the excipient may be a viscosity enhancing agent, a mucoadhesive agent, an absorption enhancer, any other agent that increases the interaction of the composition with a surface of the gastrointestinal tract (e.g., the surface of the esophagus), or a combination thereof of one or more of the preceding excipients. The excipient, or combination of excipients, preferably will increase the interaction (e.g., residence on) of the composition with a surface of the gastrointestinal tract (e.g., the surface of the esophagus) by at least 1.1 fold, at least 1.25 fold, by at least 1.5-fold, by at least 2-fold, by at least 3-fold, by at least 4-fold, or by at least 5-fold as compared to a formulation containing no excipients.

The term “acid inhibitor” refers to agents that inhibit gastric acid secretion and increase gastric pH. However, in preferred embodiments, in treatment with the disclosed compositions, the gastric pH should not exceed 7.5 and preferably should not exceed 7.0.

Specific H2 antagonists or blockers that can be used include, but are not limited to, cimetidine, ranitidine, ebrotidine, pabutidine, lafutidine, loxtidine or famotidine. Other agents that may be used include proton pump inhibitors such as, for example, omeprazole, esomeprazole, pantoprazole, lansoprazole or rabeprazole. In some embodiments, the TLESR-reducing agent is selected from, by way of non-limiting example, GABA_B agonists (e.g., baclofen), cholecystokinin (CCK-A or CCK-1) antagonists, anticholinergic agents, NO synthase inhibitors and combinations thereof. In some embodiments, the serotonergic agent/prokinetic is a 5-HT₄ receptor agonist (e.g., a selective 5-HT₄ receptor agonist) including, by way of non-limiting example, cisapride, mosapride, tegaserod, ATI-7505 and combinations thereof. In some embodiments, potassium competitive acid blocker (P-CAB) is selected from, by way of non-limiting example, soraprazan (BY359), revaprazan (YH1185), AZD0865, CS-526 and combinations thereof. In certain embodiments, mucosal protectants are selected from, by way of non-limiting example, sucralfate. In some embodiments, mucosal protectants include one or more of prostaglandin E₂ (PGE₂), epidermal growth factor (EGF) and/or transforming growth factor-α (TGF-α), or analogs thereof. In a specific embodiment, the mucosal protectant comprises the PGE₂ analog trimoprostil. In some embodiments, the histamine H3 agonist is selected from, by way of non-limiting example, (R)-α-methyl-histamine. In certain embodiments, the anti-gastrin agent is selected from, by way of non-limiting example, cholecystokinin (CCK-B or CCK-2) antagonists. Cholecystokinin (CCK-B or CCK-2) antagonists include, by way of non-limiting example, Z-360

Specific excipients that may effect viscosity and increase interaction with a surface of the gastrointestinal tract (e.g., the surface of the esophagus), include but are not limited to, cellulose (including cellulose derivatives), acacia (gum arabic), agar, aluminum magnesium silicate, sodium alginate, sodium stearate, bladderwrack, bentonite, carbomer, carrageenan, Carbopol, cellulose, microcrystalline cellulose, 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 2004-500) 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, sodium carboxymethyl-cellulose (CMC), silicon dioxide, polyvinylpyrrolidone (PVP: povidone), Splenda® (dextrose, maltodextrin and sucralose) or combinations thereof. In certain embodiments, a viscosity-increasing excipient that may be used is Splenda®.

In addition, excipients that impart mucoadhesive characteristics to a composition, thereby increasing interaction of the composition with a surface of the gastrointestinal tract (e.g., the surface of the esophagus), are also included. Specific mucoadhesive agents that may be used as an excipient include, but are not limited to, at least one soluble polyvinylpyrrolidone polymer (PVP); a water-swellable, but water-insoluble, fibrous, cross-linked carboxy-functional polymer, a crosslinked poly(acrylic acid) (e.g. Carbopol 947P), a carbomer homopolymer, a carbomer copolymer, a hydrophilic polysaccharide gum, maltodextrin, a cross-linked alignate gum gel, a water-dispersible polycarboxylated vinyl polymer, at least two particulate components selected from the group consisting of titanium dioxide, silicon dioxide, and clay, or a mixture 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 mucoadhesive agent is a cellulose.

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.

In some embodiments, the excipient used is a mucoadhesive agent, in others a viscosity enhancing agent, and in yet other embodiments the excipient may be an absorption enhancer. It is also contemplated that the excipient used is a combination of one or more of these agents, or alternatively may not include a mucoadhesive agent, viscosity enhancing or an absorption enhancing agent as the excipient.

In one embodiment, the composition may be administered as a unit dosage form. The term “unit dosage form” as used herein refers to a single entity for drug administration. For example, a single liquid volume combining an acid inhibitor, a corticosteroid and at least one excipient that increases the interaction of the composition with a surface of the gastrointestinal tract (e.g., the surface of the esophagus), would be a unit dosage form. A unit dosage form of the present invention preferably provides for coordinated drug release, in a way that elevates gastric pH and reduces inflammation of the esophagus. In a preferred embodiment, the unit dosage form is a powder for reconstitution or a ready-made suspension for oral administration of the composition. A unit dosage form includes multiple unit dosage formulations, for example, separate vials or containers of powdered formulation ready for reconstitution, with each vial or container comprising one unit dosage form combining an acid inhibitor, a corticosteroid and at least one excipient that increases the interaction of the composition with a surface of the gastrointestinal tract (e.g., the surface of the esophagus). In some embodiments, the acid inhibitor may be coated with a protective layer, for example, an enteric coating, to protect against an acidic environment, such as the stomach, for later delivery at a target area, such as the lower gastrointestinal tract, including the duodenum.

In other embodiments, the composition may be administered in multiple dosage forms. Such dosage forms include the administration of an active agent of the composition separate from a second active agent of the composition. For example, a liquid formulation may comprise a corticosteroid and at least one excipient of the contemplated composition, with a separate liquid, capsule or tablet formulation comprising an acid inhibitor and at least one excipient of the disclosed composition herein.