Corticosteroid compositions

Abstract

Provided herein are methods for treating, 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.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising:
 a. a therapeutically effective amount of corticosteroid,   b. an antioxidant,   c. a buffer,   d. a surfactant,   c. a preservative, a flavoring agent, a sweetener, or a combination thereof,   f. at least one additional excipient, and   g. a liquid vehicle,   wherein the composition is suitable for single or multiple dose administration.   
     
     
         2 . The pharmaceutical composition of  claim 1  comprising:
 a. a therapeutically effective amount of corticosteroid, 
 b. edetate, 
 c. citrate, 
 d. polysorbate 80, 
 e. a preservative, a flavoring agent, a sweetener, or a combination thereof, 
 f. at least one additional excipient, and 
 g. a liquid vehicle, 
 suitable for single or multiple dose administration. 
 
     
     
         3 . The pharmaceutical composition of  claim 1  present in a multiple-unit container and comprising a plurality of unit doses. 
     
     
         4 . The pharmaceutical composition  claim 1 , wherein the composition has a solid, semi-solid, gel, cream, ointment, spreadable, flowable, or paste-like consistency. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the composition regains substantial uniformity upon mild or moderate agitation, swirling, gentle swirling or shaking. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein after storage the composition regains substantial uniformity upon mild or moderate agitation, swirling, gentle swirling or shaking. 
     
     
         7 . The pharmaceutical composition of  claim 6 , wherein after mild or moderate agitation, swirling, gentle swirling or shaking, the composition remains substantially uniform for a convenient period of time. 
     
     
         8 . The pharmaceutical composition of  claim 3 , wherein the composition is a multiple dose formulation. 
     
     
         9 . The pharmaceutical composition of  claim 8 , wherein each dose from the container of the formulation is substantially uniform with regard to each other. 
     
     
         10 . The pharmaceutical composition of  claim 8 , wherein the first and final dose from the container are substantially uniform. 
     
     
         11 . The pharmaceutical composition of  claim 1 , wherein the corticosteroid is readily dispersed throughout the composition upon mild or moderate agitation. 
     
     
         12 . The pharmaceutical composition of  claim 1 , wherein the corticosteroid is readily dispersed throughout the composition upon mild or moderate agitation after storage. 
     
     
         13 . The pharmaceutical composition of  claim 1 , wherein the corticosteroid is easily resuspended in the composition upon mild or moderate agitation. 
     
     
         14 . The pharmaceutical composition of  claim 1 , wherein the corticosteroid is easily resuspended in the composition upon mild or moderate agitation after storage. 
     
     
         15 . The pharmaceutical composition of  claim 1 , wherein the corticosteroid is readily dispersed throughout the composition upon mild or moderate agitation alter storage for one week. 
     
     
         16 . The pharmaceutical composition of  claim 1 , wherein the corticosteroid is readily dispersed throughout the composition upon mild or moderate agitation after storage for one month. 
     
     
         17 . The pharmaceutical composition of  claim 1 , wherein the composition does not cake after storage. 
     
     
         18 . The pharmaceutical composition of  claim 1 , wherein the composition is a dispersion, suspension or solution. 
     
     
         19 . The pharmaceutical composition of  claim 20 , wherein during and after storage, the particles of dispersion or suspension do not cake or aggregate. 
     
     
         20 . The pharmaceutical composition of  claim 1 , wherein the composition is substantially free of non-corticosteroid particles. 
     
     
         21 . The pharmaceutical composition of  claim 1 , wherein the at least one excipient does not enhance the solubility of the corticosteroid in the liquid vehicle. 
     
     
         22 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition is a non-Newtonian fluid. 
     
     
         23 . The pharmaceutical composition of  claim 22 , wherein the non-Newtonian fluid is selected from the group consisting of plastic, pseudo-plastic and dilatant. 
     
     
         24 . The pharmaceutical composition of  claim 23 , wherein the non-Newtonian fluid is pseudo-plastic. 
     
     
         25 . The pharmaceutical composition of  claim 24 , wherein the non-Newtonian fluid is thixotropic. 
     
     
         26 . The pharmaceutical composition of either of  claim 1 , wherein the at least one additional excipient comprises one or more maltodextrin, dextrose, hydroxyethylcellulose (HEC), hydroxypropylmethyl-cellulose (HPMC), carboxymethyl-cellulose (CMC), microcrystalline cellulose (MCC), carbomer or combinations thereof. 
     
     
         27 . The pharmaceutical composition of  claim 1 , wherein the corticosteroid is topically active. 
     
     
         28 . The pharmaceutical composition of  claim 1 , wherein the corticosteroid comprises a plurality of microparticles. 
     
     
         29 . The pharmaceutical composition of  claim 1 , wherein the corticosteroid comprises a plurality of nanoparticles. 
     
     
         30 . The pharmaceutical composition of  claim 1 , wherein the corticosteroid is budesonide. 
     
     
         31 . The pharmaceutical composition of  claim 1 , wherein the corticosteroid is fluticasone propionate. 
     
     
         32 . The pharmaceutical composition of  claim 1 , wherein the liquid vehicle comprises an aqueous medium. 
     
     
         33 . The pharmaceutical composition of  claim 32 , wherein the pharmaceutical composition comprises corticosteroid particles suspended in the aqueous medium. 
     
     
         34 . The pharmaceutical composition of  claim 33 , wherein the corticosteroid particles are microparticles having a mean diameter of about 0.1 microns to about 50 microns. 
     
     
         35 . The pharmaceutical composition of  claim 33 , wherein at least 95%, at least 97%, at least 98%, at least 99% of the corticosteroid particles are microparticles having a diameter of less than about 10 microns. 
     
     
         36 . The pharmaceutical composition of  claim 32 , wherein the corticosteroid is present in an amount of about 0.01 mg/mL to about 1 mg/mL. 
     
     
         37 . The pharmaceutical composition of  claim 32 , wherein the pharmaceutical composition has a volume of about 1 mL to about 20 mL. 
     
     
         38 . The pharmaceutical composition of  claim 37 , wherein the pharmaceutical composition has a volume of about 3 mL to about 12 mL. 
     
     
         39 . The pharmaceutical composition of  claim 37 , wherein the pharmaceutical composition comprises about 0.1 mg to about 20 mg of corticosteroid. 
     
     
         40 . The pharmaceutical composition of  claim 32 , wherein the at least one additional excipient comprises CMC, and wherein the CMC is present in an amount of about 5 mg/mL to about 30 mg/mL. 
     
     
         41 . The pharmaceutical composition of  claim 32 , wherein the at least one additional excipient comprises carbomer, and wherein the carbomer is present in an amount of about 5 mg/mL to about 100 mg/mL. 
     
     
         42 . The pharmaceutical composition of  claim 32 , wherein the at least one additional excipient comprises HPMC, and wherein the HPMC is present in an amount of about 5 mg/mL to about 30 mg/mL. 
     
     
         43 . The pharmaceutical composition of  claim 32 , wherein the at least one additional excipient comprises MCC, and wherein the MCC is present in an amount of about 5 mg/mL to about 30 mg/mL. 
     
     
         44 . The pharmaceutical composition of  claim 32 , wherein the at least one additional excipient comprises a combination of CMC and MCC, wherein the CMC-MCC combination is present in an amount of about 10 mg/mL to about 40 mg/mL, and wherein the CMC/MCC mixed weight ratio is about 11/89. 
     
     
         45 . The pharmaceutical composition of  claim 32 , wherein the at least one additional excipient comprises dextrose, and wherein the dextrose is present in an amount of about 10 mg/mL to about 1 g/mL. 
     
     
         46 . The pharmaceutical composition of  claim 32 , wherein the at least one additional excipient comprises maltodextrin, and wherein the maltodextrin is present in an amount of about 10 mg/mL to about 1 g/mL. 
     
     
         47 . The pharmaceutical composition of  claim 48 , wherein the maltodextrin has a dextrose equivalents of about 13 to about 17. 
     
     
         48 . The pharmaceutical composition of  claim 32 , wherein edetate is present in an amount of about 0.05 mg/mL to about 25 mg/mL. 
     
     
         49 . The pharmaceutical composition of  claim 32 , wherein citrate is present in an amount of about 0.1 mg/mL to about 30 mg/mL. 
     
     
         50 . The pharmaceutical composition of  claim 32 , wherein polysorbate 80 is present in an amount of 0.01 mg/mL to about 1 mg/mL. 
     
     
         51 . The pharmaceutical composition of  claim 2  comprising:
 a. budesonide in an amount of about 0.1 mg/mL to about 0.75 mg/mL, 
 b. edetate in an amount of about 0.05 mg/mL to about 25 mg/mL, 
 c. citrate in an amount of about 0.1 mg/mL to about 30 mg/mL, 
 d. polysorbate 80 in an amount of 0.01 mg/mL to about 1 mg/mL, 
 e. a preservative, 
 f. a flavoring agent, a sweetener, or a combination thereof, 
 g. at least one additional excipient, and 
 h. an aqueous liquid vehicle. 
 
     
     
         52 . The pharmaceutical composition of  claim 51 , wherein the additional excipient is selected from hydroxyethylcellulose (HEC), hydroxypropylmethyl-cellulose (HPMC), carboxymethyl-cellulose (CMC), microcrystalline cellulose (MCC), carbomer and combinations thereof, and wherein the additional excipient is present in an amount of about 5 mg/mL to about 100 mg/mL. 
     
     
         53 . The pharmaceutical composition of  claim 51 , wherein the additional excipient is selected from maltodextrin, dextrose and combinations thereof, and wherein the additional excipient is present in an amount of about 1 mg/mL to about 1.5 g/mL. 
     
     
         54 . The pharmaceutical composition of  claim 51 , wherein the pharmaceutical composition has a total volume of about 1 mL to about 20 mL. 
     
     
         55 . A method of treating, preventing or alleviating inflammation or symptoms associated with inflammation of the gastrointestinal tract comprising orally administering to an individual a pharmaceutical composition comprising:
 a. a therapeutically effective amount of corticosteroid,   b. an antioxidant,   c. a buffer,   d. a surfactant,   e. a preservative, a flavoring agent, a sweetener, or a combination thereof,   f. at least one additional excipient, and   g. a liquid vehicle.   
     
     
         56 . A method of treating, preventing or alleviating inflammation or symptoms associated with inflammation of the gastrointestinal tract of  claim 55 , wherein the pharmaceutical composition comprises:
 a. a therapeutically effective amount of corticosteroid,   b. edetate,   c. citrate,   d. polysorbate 80,   e. a preservative, a flavoring agent, a sweetener, or a combination thereof,   f. at least one additional excipient, and   g. a liquid vehicle.   
     
     
         57 . The method of  claim 55 , comprising administering about 0.1 mg to about 20 mg of corticosteroid per day. 
     
     
         58 . The method of  claim 55 , wherein the inflammation of the gastrointestinal tract is inflammation of the esophagus. 
     
     
         59 . The method of  claim 55 , wherein the inflammation of the gastrointestinal tract is eosinophilic esophagitis, an inflammatory bowel disease involving the esophagus, Crohn's disease, celiac disease, proximal gastrointestinal pathology, eosinophilic gastrointestinal inflammation, celiac disease, eosinophilic duodenitis, duodenal eosinophilia, functional dyspepsia, intermediate esophagitis, epithelial hyperplasia, basal cell hyperplasia, elongated papillae, dilated vessels in papillae, fungal esophagitis, viral esophagitis, bacterial esophagitis, corrosive esophagitis, radiation esophagitis, chemotherapy esophagitis, graft vs. host disease, a skin disease with esophageal involvement, bullous pemphigoid, pemphigus vulgaris, epidermolysis bollosa, Stevens Johnson syndrome, Behçet's disease, sarcoidosis, idiopathic esophagitis, eosinophilic gastritis, Menetrier's disease, parasitic gastritis, lymphocytic esophagitis, inflammatory bowel disease-associated esophagitis, parasitic gastritis, lymphocytic esophagitis, inflammatory bowel disease-associated esophagitis, 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, post-surgery inflammation or gastroenteritis. 
     
     
         60 . The method of  claim 59 , wherein the individual has eosinophilic esophagitis. 
     
     
         61 . The method of  claim 60 , wherein the individual has been diagnosed with gastroesophageal reflux disease (GERD), nonerosive reflux disease (NERD), Barrett's Esophagus or erosive esophagitis. 
     
     
         62 . The method of  claim 55 , wherein the pharmaceutical composition has a viscosity such that when a single dose of the pharmaceutical composition is orally administered to an individual, the pharmaceutical composition at least partially coats the esophagus and topically delivers a therapeutically effective amount of corticosteroid to the esophagus. 
     
     
         63 . The method of  claim 55 , wherein the pharmaceutical composition has a mucoadhesive characteristic such that when a single dose of the pharmaceutical composition is orally administered to an individual, the pharmaceutical composition adheres to the esophageal surface of the individual for a time sufficient to allow topical delivery of a therapeutically effective amount of the corticosteroid to the esophagus. 
     
     
         64 . A kit comprising a multiple unit container and a plurality of doses of a pharmaceutical composition, wherein each dose of the pharmaceutical composition comprises:
 a. a therapeutically effective amount of corticosteroid,   b. edetate,   c. citrate,   d. polysorbate 80,   c. a preservative, a flavoring agent, a sweetener, or a combination thereof,   f. at least one additional excipient, and   g. a liquid vehicle.   
     
     
         65 . The kit of  claim 64 , wherein the at least one additional excipient comprises one or more maltodextrin, dextrose, hydroxyethylcellulose (HEC), hydroxypropylmethyl-cellulose (HPMC), carboxymethyl-cellulose (CMC), microcrystalline cellulose (MCC), carbomer or combinations thereof. 
     
     
         66 . The kit of  claim 64 , wherein the kit comprises about 10 to about 60 doses of the pharmaceutical composition. 
     
     
         67 . The kit of  claim 64 , wherein the kit comprises about 330 mL of the pharmaceutical composition. 
     
     
         68 . The kit of  claim 64 , wherein the kit comprises about 55 mL of the pharmaceutical composition. 
     
     
         69 . The kit of  claim 64 , wherein the kit further comprises a metering device for administering the composition to an individual. 
     
     
         70 . The kit of  claim 69 , wherein the metering device is incorporated into the multiple unit container.