Compositions for the treatment of gastrointestinal inflammation

Description

BACKGROUND OF THE INVENTION

[0002] Inflammatory diseases of the esophagus are increasingly recognized in both adults and children. One example is eosinophilic esophagitis (EE or EoE), which is an emerging and rapidly developing disorder characterized by high levels of esophageal eosinophils as well as basal hyperplasia. EE (EoE) is believed to be caused, in at least some patients, by food allergies or exposure to air allergens (1-5, 44). The diagnosis of EE (EoE) is often associated with other hypersensitivity, including asthma, rhinitis, and sensitivity to other food and inhalation allergens (39-40). It is often diagnosed in e.g. young children and depends on finding 15 to 20 or more to 24 or more eosinophils per field under a high magnification microscope (eos / hpf). high power field) in esophageal mucosa biopsies (6-12).

[0003] The frequency of EE (EoE) appears to be increasing (15, 35) in parallel with other atopic disorders. The disorder may exhibit symptoms similar to reflux, pain and dysphagia, and clinical symptoms similar to gastroesophageal reflux disease (GERD) (42). Symptoms of EE (EoE) include, for example, abdominal pain, chest pain, choking, difficulty swallowing, failure to develop properly, nausea, reflux not amenable to standard reflux treatment, rash or hives, vomiting, and weight loss. In one series, 15% of patients with EE (EoE) had accompanying developmental delays (45).

[0004] Although EE (EoE) is increasingly diagnosed in developing countries (7, 8, 1316), many aspects of the disease remain unclear, including its etiology, natural history, and optimal treatment. Symptoms of EE (EoE) often mimic those of GERD and include vomiting, dysphagia, pain, and food being stuck in the esophagus (8,14,17-20). However, the treatment of EE (EoE) and GERD is different and it is important to distinguish them, especially since untreated EE (EoE) may be associated with esophageal stricture in 10-30% of cases (14, 18, 20, 21). Overlapping of GERD and EE (EoE) symptoms is common; lack of response to GERD treatment with proton pump inhibitors may be one of the guidelines in the diagnosis of EE (EoE) (42). A common phenomenon of GERD misdiagnosis in EE (EoE) is often delayed treatment of patients with EE. (42).

[0005] Long-term treatment with systemic steroids can cause significant secondary side effects affecting bone growth and development. Although treatment of EE with an IL-5 specific monoclonal antibody has been reported to be successful, it is currently not approved in children (36).

[0006] Current treatments include elimination diets (22, 23) and elemental mixtures (2, 24). Identifying true food allergens can be difficult, and elemental mixtures are often unpalatable, making dietary intervention difficult (1,22). Improvised puffing and swallowing techniques can be difficult for patients, especially younger children, and especially children with developmental delays to operate efficiently. This may result in a lower than effective dose of the steroid administered topically into the esophagus. US 2007/0111978 discloses methods and pharmaceutical compositions used to prevent or alleviate symptoms and inflammation associated with inflammatory diseases including the esophagus.

SUMMARY OF THE INVENTION

The invention relates to a stable oral pharmaceutical composition for use in the treatment or prevention of oesophagitis or symptoms associated therewith, a composition comprising a corticosteroid, a liquid carrier and a mucoadhesive, a mucoadhesive containing maltodextrin and carboxymethyl cellulose (CMC), an oral composition pharmaceutical is chemically and physically stable for at least one month (e.g. under ambient conditions or under inert conditions such as inert gas or vacuum). In some embodiments, the corticosteroid is a topically active corticosteroid. In some embodiments, the corticosteroid is budesonide. In other embodiments, the corticosteroid is fluticasone propionate.

[0008] In some embodiments, when the oral pharmaceutical composition described herein is administered into the esophagus, e.g. orally, at least 50%, 20%, 10%, 9%, 8%, 7%, 6%, 5% , 4%, 3%, 2% or 1% of the orally administered pharmaceutical composition adheres to or is in the esophagus for at least 15 seconds or 1 minute. In some embodiments, when the oral pharmaceutical composition described herein is administered into the esophagus, e.g. by oral administration of at least 50%, 20%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% of the corticosteroid adhered to or located in the esophagus through at least 15 seconds or at least 1 minute. In some embodiments, at least 50%, 20%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the corticosteroid adheres to or is absorbed in the esophagus through at least 15 seconds or after at least 1 minute after administration of an oral pharmaceutical composition described herein into the esophagus, e.g., by oral administration. In some embodiments, administering an oral pharmaceutical composition into the esophagus comprises orally administering and / or swallowing at least a portion of the oral pharmaceutical composition or an oral dose of the pharmaceutical composition.

[0009] In some embodiments, the weight percent of the oral pharmaceutical composition described herein that is adhered to or in the esophagus for 15 seconds or 1 minute after administration into the esophagus, e.g., by oral administration, is greater than the weight percent of the control composition. which adheres to the esophagus for 15 seconds or 1 minute after administration of a control composition into the esophagus, e.g. In some embodiments, the amount of corticosteroid that adheres to or is in the esophagus for 15 seconds or 1 minute after administration into the esophagus, e.g., by oral administration, of an oral pharmaceutical composition described herein is greater than the amount of corticosteroid that adheres to or it is absorbed through the esophagus during 15 seconds or 1 minute after administration into the esophagus, e.g. by oral administration of a control composition. In some embodiments, the amount of corticosteroid that adheres to or is absorbed through the esophagus for 15 seconds or 1 minute after administration into the esophagus, e.g., by oral administration, of an oral pharmaceutical composition described herein is greater than the amount of corticosteroid that adheres to or is absorbed by the esophagus. esophagus for 15 seconds or 1 minute after intra-esophageal administration, for example, orally, of a control composition. In particular embodiments, the control composition described herein contains the same amount of corticosteroid as present in the oral pharmaceutical composition and contains about 4 ml of an aqueous formulation (e.g., Pulmicort® formulation) and 10 packs of Splenda® (distributed by McNeil Nutritionals, LLC Fort Washington, PA 19034-2299) for every 0.5 mg of corticosteroid.

[0010] Also disclosed herein are mucoadhesive agents including the mucoadhesive polysaccharide, carbopol. Carbopolies include, for example, but not limited to, cross-linked acrylic acid polymer, Karbopol Ultrez, and Karbopol 974P. Another mucoadhesive described herein is an alginate, which may be, for example, but not limited to, sodium alginate LF120 and / or sodium alginate H120L. The mucoadhesive according to the invention comprises maltodextrin and carboxymethyl cellulose (CMC). In particular embodiments, maltodextrin does not significantly increase the viscosity of an oral pharmaceutical composition (e.g., compared to an otherwise identical composition that does not contain maltodextrin). In further or alternative embodiments, the maltodextrin is selected for its mucoadhesive properties (e.g. its ability to impart a mucoadhesive nature to an oral pharmaceutical composition). In some embodiments, the oral pharmaceutical composition comprises a second maltodextrin that increases the viscosity of the oral pharmaceutical composition (e.g., as compared to an otherwise identical composition that does not contain the second maltodextrin). In particular embodiments, the second maltodextrin does not significantly affect the mucoadhesive properties of the pharmaceutical composition (e.g., compared to an otherwise identical composition that does not contain the second maltodextrin).

[0011] In some embodiments, the mucoadhesive used in the oral pharmaceutical composition disclosed herein causes an increased viscosity of the oral pharmaceutical composition (e.g., compared to an otherwise identical composition that does not contain a mucoadhesive). In other embodiments, the mucoadhesive does not substantially increase the viscosity of an oral pharmaceutical composition (e.g. compared to an otherwise identical composition which does not contain a mucoadhesive agent).

[0012] In some embodiments, the oral pharmaceutical composition described herein further comprises a second mucoadhesive. In further or alternative embodiments, the oral pharmaceutical composition described herein further comprises a viscosity enhancing agent.

[0013] The pharmaceutical composition of the invention is for use in treating or preventing gastrointestinal inflammation or symptoms of gastrointestinal inflammation in a subject whose gastrointestinal inflammation is inflammation of the esophagus. In particular embodiments, the subject has been diagnosed with eosinophilic esophagitis, inflammatory bowel disease involving the esophagus, Crohn's disease, proximal gastrointestinal pathology (e.g. individuals suffering from gallbladder insufficiency), eosinophilic gastroenteritis, celiac disease, eosinophilic duodenitis, duodenal eosinophilia, functional dyspepsia, indirect oesophagitis, epithelial hyperplasia, basal cell hyperplasia, papillary lengthening, vasodilation in papillomas, fungal esophagitis (e.g. Candida, torulopsis, histoplasma Aspergillus, etc.), viral esophagitis (e.g. HSV, CMV, V2V), bacterial oesophagitis (e.g. tuberculosis, actinomycosis, syphilis), corrosive oesophagitis, radiation oesophagitis, post-chemotherapy oesophagitis, graft versus host disease, oesophageal skin disease (e.g. bullous pemphigoid, pemphigus vulgaris, epidermal bullous, Stevens-Johnson syndrome), Behcet's disease, sarcoidosis, idiopathic esophagitis, eosinophilic gastritis, Menetrier's disease, parasitic gastritis, lymphocytic esophagitis, non-esophagitis inflammation of the intestines, parasitic gastritis, inflammation of the esophagus following ingestion of a corrosive / irritant substance, persistent / recurrent esophageal strictures from any cause including corrosive / irritant ingestion, drug-induced oesophagitis, systemic diseases, congenital diseases, postoperative inflammation or gastrointestinal infections. In more particular embodiments, the subject exhibits eosinophilic esophagitis. In other specific embodiments, the subject has been diagnosed with gastroesophageal reflux disease (GERD), non-erosive gastroesophageal reflux disease (GERD). nonerosive reflux disease (NERD) or erosive esophagitis. In some embodiments, inflammation of the gastrointestinal tract is, for example, but not limited to, inflammation of the stomach and / or small intestine, e.g., a gastrointestinal infection.

[0014] In some embodiments, a pharmaceutical composition for use as described herein comprises administering (e.g., daily or in a dose) to a subject about 0.1 mg to about 20 mg of a corticosteroid, about 0.1 mg to about 10 mg of a corticosteroid, about 0.3 mg to about 5 mg of corticosteroid, about 0.3 mg to about 4 mg of corticosteroid, about 1 to about 2 mg of corticosteroid, about 2 to about 3 mg of corticosteroid, or about 0.25 to about 2.5 mg of corticosteroid.

[0015] In some embodiments, a composition as described herein is administered to a child. In particular embodiments, the child is less than 19 years old, less than 16 years old, less than 12 years old, less than 8 years old, less than 6 years old, less than 4 years old or less than 2 years old. In some embodiments, a composition described herein is administered to an adult.

SHORT DESCRIPTION OF THE DRAWINGS

[0017] The novel features of the invention are set out in detail in the appended claims. A better understanding of the features and advantages of the invention will be obtained by reference to the following detailed description, which sets out illustrative embodiments which make use of the principles of the invention and accompanying drawings including:

[0018] Figure 1 shows the percentage of the composition present in the esophagus as a function of time after oral administration (by measuring the amount of radiolabel in the esophagus).

DETAILED DESCRIPTION OF THE INVENTION

[0019] Also disclosed herein are pharmaceutical compositions for use in treating, preventing or alleviating symptoms and inflammation associated with inflammatory diseases associated with the gastrointestinal tract, including the esophagus, stomach and / or digestive system. The present invention relates to stable oral pharmaceutical compositions for use in treating or preventing esophagitis or symptoms associated therewith in a subject. In some embodiments, a corticosteroid is administered orally to a subject in combination with at least one excipient to increase the mucoadhesive properties of the composition (mucoadhesive). The pharmaceutical composition according to the invention comprises a corticosteroid, a mucoadhesive and a liquid carrier. In further or alternative embodiments, the pharmaceutical composition is suitable for oral administration. In some embodiments, the enhanced mucoadhesive properties of the composition allow the composition to contact the esophagus for an extended period of time after administration.

[0020] In some embodiments, the selected excipient or excipients increases the interaction of the composition with the surface of the gastrointestinal tract (e.g. mucosa and / or epithelium of the digestive tract or a specific site of the digestive tract such as the esophagus) at least 1.02 times, at least 1.05 times, at least 1.1 times, at least 1.2 times times at least 1.25 times, at least 1.5 times, at least 2 times, at least 3 times, at least 4 times or at least 5 times. In some embodiments, the interaction of the composition is increased by at least 1.02 times, at least 1.05 times, at least 1.1 times, at least 1.2 times, at least 1.25 times, at least 1 times. , 5 times, at least 2 times, at least 3 times, at least 4 times, or at least 5 times compared to the esophageal interaction of the composition that occurs after a bolus of the swallowed composition. In some embodiments, increases are measured and compared to a measurement for a similar composition that does not contain excipients or excipients that enhance the interaction of the composition with the gastrointestinal surface. In some instances, the increased interaction of the composition is measured as a function of the amount of the composition present in a selected or target part of the gastrointestinal tract, such as the esophagus (e.g. measured after the bolus has passed through the esophagus, which can be 5 seconds, 6 seconds, 7 seconds, 8 seconds, 9 seconds, 10 seconds, 11 seconds, 12 seconds, 13 seconds, 14 seconds, 15 seconds or so after initially swallowing at least a portion composition). In specific instances, the amount of composition present in the esophagus is measured by any suitable means, e.g., by radiolabelling the composition and measuring the amount of the composition in the esophagus using gamma scintigraphy. The increase in interaction of the composition with the gastrointestinal surface (e.g., esophageal surface) can be measured by measuring the retention time of the material along the length of the gastrointestinal surface (e.g., esophageal surface), the retention time being increased in the presence of the excipient as compared to the absence of the excipient. In another embodiment, an increased interaction can be measured by reducing the physiological symptoms or symptoms of the disease or condition to be treated, including reduction of the total number of eosinophils in the target sample.

[0021] In one aspect of the invention, the use of excipients may act to reduce the amount of active ingredients needed to elicit a response in the absence of excipients. In some embodiments, excipients can reduce the amount of corticosteroid used. Accordingly, the compositions provided herein may provide the added benefit of reducing the amount of active ingredient needed to treat patients afflicted with inflammatory diseases affecting the gastrointestinal tract, including the esophagus, stomach and / or digestive system.

[0022] In some embodiments, the pharmaceutical composition described herein employs an active agent that will increase interaction with the surface of the gastrointestinal tract (eg, a topical corticosteroid).

[0023] A subject suitable for treatment with the compositions disclosed herein may, for example, be diagnosed with a disease or condition involving eosinophilic esophagitis, inflammatory bowel disease involving the esophagus, eosinophilic gastrointestinal infection, Crohn's disease, celiac disease, pathology of the proximal gastrointestinal tract (e.g. . individuals suffering from gallbladder insufficiency), eosinophilic gastroenteritis, celiac disease, eosinophilic duodenitis, duodenal eosinophilia, functional dyspepsia, indirect oesophagitis, epithelial hyperplasia, basal cell hyperplasia, papillary lengthening, vasodilation in papillomas, fungal esophagitis (e.g. Candida, torulopsis, histoplasma Aspergillus, etc.), viral esophagitis (e.g. HSV, CMV, V2V), bacterial oesophagitis (e.g. tuberculosis, actinomycosis, syphilis), corrosive oesophagitis, radiation oesophagitis, post-chemotherapy oesophagitis, graft versus host disease, oesophageal skin disease (e.g. bullous pemphigoid, pemphigus vulgaris, epidermal bullous, Stevens-Johnson syndrome), Behcet's disease, sarcoidosis, idiopathic esophagitis, eosinophilic gastritis, Menetrier's disease, parasitic gastritis, lymphocytic esophagitis, non-esophagitis inflammation of the intestines, parasitic gastritis, inflammation of the esophagus following ingestion of a corrosive / irritant substance, persistent / recurrent esophageal strictures from any cause including corrosive / irritant ingestion, drug-induced oesophagitis, systemic diseases, congenital diseases, postoperative inflammation or gastrointestinal infections. The composition can also be used in the treatment of other gastrointestinal disorders including gastric ulcer and duodenal ulcer, hyperacid secretion diseases such as Zollinger-Ellison syndrome and laryngeal diseases.

[0024] A subject suitable for treatment with the compositions disclosed herein may, for example, be diagnosed with a disease or condition involving eosinophilic esophagitis, inflammatory bowel disease involving esophagus, Crohn's disease, celiac disease, proximal gastrointestinal pathology (e.g. individuals suffering from gallbladder insufficiency), eosinophilic gastroenteritis, celiac disease, eosinophilic duodenitis, duodenal eosinophilia, functional dyspepsia, indirect oesophagitis, epithelial hyperplasia, basal cell hyperplasia, papillary lengthening, vasodilation in papillomas, fungal esophagitis (e.g. Candida, torulopsis, histoplasma Aspergillus, etc.), viral esophagitis (e.g. HSV, CMV, V2V), bacterial oesophagitis (e.g. tuberculosis, actinomycosis, syphilis), corrosive oesophagitis, radiation oesophagitis, post-chemotherapy oesophagitis, eosinophilic obstruction and associated inflammation, graft versus host disease, skin disease with esophagus involvement (e.g. bullous pemphigoid, pemphigus vulgaris, epidermal bullous, Stevens-Johnson syndrome), Behcet's disease, sarcoidosis, idiopathic esophagitis, eosinophilic gastritis, Menetrier's disease, parasitic gastritis, lymphocytic esophagitis, non-esophagitis inflammation of the intestines, parasitic gastritis, inflammation of the esophagus following ingestion of a corrosive / irritant substance, persistent / recurrent esophageal strictures from any cause including corrosive / irritant ingestion, drug-induced oesophagitis, systemic diseases, congenital diseases, postoperative inflammation or gastrointestinal infections. The composition can also be used in the treatment of subjects diagnosed with other gastrointestinal disorders including gastric ulcer and duodenal ulcer, hyperactive acid secretion diseases such as Zollinger-Ellison syndrome and laryngeal diseases. In some embodiments, the compositions disclosed herein are used to treat subjects diagnosed with other gastrointestinal diseases, including, for example, but not limited to, Barrett's esophagus, gastroesophageal reflux disease (GERD), non-erosive gastroesophageal reflux disease (GERD). nonerosive reflux disease (NERD) or erosive esophagitis. In some embodiments, compositions for use in treating, preventing, or alleviating inflammation or symptoms of inflammation include treatment of any of the gastrointestinal disorders described herein. In some embodiments, these include orally administering to a designated subject the corticosteroid-containing compositions described herein.

[0025] The compositions provided herein are intended to treat, prevent and alleviate any chronic inflammatory or malignant conditions that involve the gastrointestinal tract, for example, the esophagus, and are responsive to steroid treatment. The compositions of the invention are useful, for example, in the treatment, prevention and alleviation of inflammation and / or symptoms associated with eosinophilic esophagitis, inflammatory bowel disease involving the esophagus, Crohn's disease, celiac disease, proximal gastrointestinal pathology (e.g. individuals suffering from gallbladder insufficiency), eosinophilic gastroenteritis, celiac disease, eosinophilic duodenitis, duodenal eosinophilia, functional dyspepsia, indirect oesophagitis, epithelial hypertrophy, basal cell hyperplasia, elongation of papillae, vasodilation in papillomas, fungus Candida, torulopsis, histoplasma Aspergillus etc.), viral oesophagitis (e.g. HSV, CMV, V2V), bacterial oesophagitis (e.g. tuberculosis, actinomycosis, syphilis), corrosive oesophagitis, radiation oesophagitis, post-chemotherapy oesophagitis, eosinophilic obstruction of the gastric outlet and related inflammation, graft versus host disease, skin diseases with esophagus involvement (e.g. bullous pemphigoid, pemphigus vulgaris, epidermal blistering, Stevens-Johnson syndrome), Behcet's disease, sarcoidosis, idiopathic esophagitis, eosinophilic gastritis, Menetrier's disease, parasitic gastritis, lymphocytic gastritis related to esophagitis inflammation of the intestines, parasitic gastritis, oesophagitis due to ingestion of a corrosive / irritant substance, persistent / recurrent oesophageal stricture for any reason including ingestion of a corrosive / irritant substance, drug-induced oesophagitis, systemic diseases, congenital diseases, bullous epidermal separation, postoperative inflammation or gastrointestinal infection. The compositions disclosed herein are also useful in treating, preventing or alleviating symptoms and / or inflammation associated with other gastrointestinal diseases or conditions, e.g. treatment. As used herein, inflammation and / or symptoms associated with a disorder or disease disclosed herein include inflammation and / or symptoms associated with, caused by, and / or resulting from the disorder or disease.

[0026] As used herein, unless otherwise stated, terms used include both the singular and the plural of the embodiments. As used herein, the term subject includes any animal. In some embodiments, the animal is a mammal. In some embodiments, the mammal is human. In particular embodiments, the human is adult. In other embodiments, the human is a child (e.g. a child under 12 or a child under 6). In some embodiments, the human is an infant. As used herein, the term treatment method or treatment method can, in some embodiments, include methods of preventing, reducing the incidence, providing prophylactic treatment, treating, and ameliorating. As used herein, an effective amount and a therapeutically effective amount is an amount sufficient to effect a change in inflammatory symptoms or conditions associated with gastrointestinal disorders including esophagitis, eosinophilic esophagitis, GERD, NERD, or erosive esophagitis. As used herein, the term or includes and and or.

[0027] As used herein, the expression treating inflammatory diseases involving the esophagus includes treating the symptoms of such diseases and treating inflammation associated with these diseases.

[0028] In some embodiments as used herein, substantially increasing or influencing comprises increasing or varying, respectively, in an amount, for example, but not limited to, about 10%, 5%, 3%, 2% or 1. %.

Compositions

[0029] In some embodiments, the corticosteroids used in the invention include topically administered steroids, including, for example, budesonide or fluticasone propionate. In some embodiments, the corticosteroids are, for example, but not limited to, aclometasone, amcinomide ("amcinomide), beclomethasone, betamethasone, budesonide, ciclesonide, clobetasol, clobetasone, clocortolone (" c / ocorto / one), clopivortnol, , desoxycorticosterone, desoxymethasone desonide, dexamethasone, diflorazone, diflucortolone, difluprednate, fluclorolone, fludrocortisone, fludroxycortide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin, fluocortolone, fluocortolone fluorometolone, fluperolone, fluticasone, fuprednidene ("fuprednidene), formocortal, halcinonide, halomethasone (" ha / ometasone), hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone butyrate, loteprednolonate, medrisone, mepredazone, methylpredazone, acarbortinone, methylpredazone ("Prednicarbate), prednisone, prednisolone, prednylidene, rimexolone (" remexolone), thixocortol, triamcinolone and ulobetasole ("u / obetaso /), and combinations thereof, pharmaceutically acceptable salts and esters. In a specific embodiment, the corticosteroid is budesonide. In another embodiment, the corticosteroid is a fluticasone ester, e.g. fluticasone propionate.

Provided herein are pharmaceutical compositions for use in the treatment, prevention or alleviation of symptoms and inflammation associated with inflammatory diseases of the gastrointestinal tract, including the upper gastrointestinal tract (e.g., esophagus). Also provided herein are pharmaceutical compositions for the prevention or alleviation of gastrointestinal reflux symptoms and gastric pH increase that are associated with inflammatory diseases of the gastrointestinal tract, including the esophagus.

[0031] In some embodiments, a corticosteroid (e.g., budesonide or fluticasone propionate), which is orally administered in a formulation with enhanced mucoadhesive properties, is delivered, e.g., to the esophagus in an effective dose to reduce inflammation of the esophagus.

[0031] The oral pharmaceutical composition of the invention comprises a corticosteroid and a mucoadhesive. In various aspects, an exemplary corticosteroid is budesonide, 16,17- (butylidenebis (oxy)) - 11,21-dihydroxy-, (11-β, 16-α) -pregna-1,4-diene-3,20-dione. or fluticasone propionate, S- (fluoromethyl) 6α, 9-difluoro-11β-17-dihydroxy-16α-methyl-3-oxoandrosta-1,4-dien-17β-carbothioate, 17-propionate or S- (fluoromethyl) ester of acid (6a, 11β, 16a, 17β) -6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17- (1-oxopropoxy) androsta 1,4-diene-17-carbothioate.

[0033] In some embodiments, the pharmaceutical compositions disclosed herein and used herein include one or more excipients. Excipients useful in the invention include, for example, but not limited to, mucoadhesives, tackifiers, binders, fillers, lubricants, solvents, suspensions, flavoring agents, dyes, sweeteners, preservatives, antioxidants, buffering agents, humectants, chelating agents, surfactants.

[0034] In some embodiments, the corticosteroid (s) used in the invention are used as particles (e.g., corticosteroid particles suspended or dispersed in an aqueous medium). In particular embodiments, the particles are microparticles. In some embodiments, the microparticles have an average diameter of from about 0.1 microns to about 50 microns. In particular embodiments, the microparticles have an average diameter of from about 1 micron to about 20 microns. In some embodiments, at least 95%, at least 98%, or at least 99% of the microparticles are less than 10 microns in diameter.

[0035] In some embodiments, the composition or formulation described herein comprises less than 50% w / w, less than 40% w / w, less than 30% w / w, less than

20% w / w, less than 10% w / w, less than 8% w / w, less than 6% w / w, less than 5% w / w, less than 4% w / w, less than 3% w / w, less than 2% w / w or about 2% w / w, less than 1% w / w, less than 0.5% w / w, less than 0.3% w / w, less than 0 , 2% w / w or about 0.2% w / w undissolved particles. In some embodiments, a composition or formulation as described herein is substantially free of non-corticosteroid molecules.

[0036] In some embodiments, the active corticosteroid described herein is replaced with another active ingredient. In some embodiments, the active ingredient is a therapeutic agent that targets the esophagus, e.g., to treat oesophagitis, mucositis, esophageal cancer, infections (e.g., bacterial or fungal infections) of the esophagus, esophageal wounds and / or injuries, or the like. similar. In some embodiments, the active ingredient is a therapeutic agent that is absorbed systemically through the esophagus. In particular embodiments, a medicament systemically absorbed through the esophagus is an agent that degrades or loses its efficacy in certain instances when present in the stomach, e.g., a therapeutic peptide.

[0037] Mucoadhesives disclosed herein include, for example, but not limited to, soluble polyvinylpyrrolidone (PVP) polymer, carbopol, cross-linked poly (acrylic acid) (e.g., Carbopol 974P), carbomer homopolymer, carbomer copolymer, water-swellable, but water-insoluble, fibrous, cross-linked carboxy-functional polymer, mucoadhesive polysaccharide (e.g. hydrophilic polysaccharide gum), one or more maltodextrins, alginate, cross-linked alginate gum gel, water-dispersible polycarboxylated vinyl polymer. A mucoadhesive agent which is carbopol is also described herein. Also described herein are mucoadhesives selected from the following: Carbopol 974P, Carbopol Ultrez 10, sodium alginate LF120, and sodium alginate H120L. As used herein, a mucoadhesive is an agent that adheres to the surface of the gastrointestinal tract (e.g., the epithelium and / or mucosa of the gastrointestinal tract). Also described herein is a mucoadhesive which is cellulose. The mucoadhesive according to the invention comprises maltodextrin and carboxymethyl cellulose (CMC), e.g. sodium carboxymethyl cellulose (NaCMC). Other mucoadhesive agents disclosed herein include microcrystalline cellulose (MCC) or a combination of CMC and MCC. For example, but not limited to, the mucoadhesive includes a combination of MCC and CMC (e.g., Avicel RC-591). In some embodiments, the CMC / MCC combination (e.g., Avicel® RC-591) is present in the composition in an amount of about 1 mg / ml to about 150 mg / ml, 1 mg / ml to about 75 mg / ml, or about 5 mg / ml. up to about 40 mg / ml. In some embodiments, the CMC / MCC blended weight ratio is between about 1/99 and about 99/1, about 20/80 and about 5/95, or about 15/85 and about 10/90. In a specific embodiment, the CMC is NaCMC and the CMC / MCC blended mass ratio is about 11/89.

[0038] The composition of the invention comprises CMC (e.g. a CMC / MCC mixture) and maltodextrin. In some embodiments, a combination of CMC (e.g., a CMC / MCC mixture) and maltodextrin provides an increased residence time on a diseased or target surface of the gastrointestinal tract (e.g., esophagus) compared to a composition with a similar amount of CMC (e.g., a CMC / MCC mixture) or alone. maltodextrins.

[0039] In some embodiments, the mucoadhesive comprises one or more maltodextrins. In various respects, the physical properties of maltodextrins vary depending, for example, on the dextrose equivalent of a particular maltodextrin. In some aspects, the dextrose equivalent of a specific maltodextrin can affect the viscosity, hygroscopicity, sweetness, moisture, plasticity, solubility, and / or mucoadhesiveness of the maltodextrin. Thus, in various embodiments, maltodextrin is selected based on the specific properties to be imparted to the pharmaceutical composition described herein. In some embodiments, a maltodextrin is selected that enhances the mucoadhesive properties of the composition described herein without substantially increasing the viscosity of the composition (e.g., as compared to an identical composition without maltodextrin). In some embodiments, the oral pharmaceutical composition comprises a second maltodextrin which increases the viscosity of the oral pharmaceutical composition (e.g., as compared to an identical composition not containing the second maltodextrin). In particular embodiments, a second maltodextrin that does not substantially affect the mucoadhesive properties of the pharmaceutical composition (e.g., compared to an identical composition containing no second maltodextrin).

[0040] In some embodiments, the mucoadhesive does not substantially increase the viscosity of an oral pharmaceutical composition (e.g., compared to an identical composition containing no mucoadhesive). In other or alternative embodiments, the mucoadhesive is selected for its mucoadhesive properties (e.g., its ability to impart mucoadhesive properties to an oral pharmaceutical composition).

[0041] In some embodiments, a mucoadhesive agent used in the oral pharmaceutical composition described herein increases the viscosity of the oral pharmaceutical composition (e.g., compared to an identical composition not containing a mucoadhesive). In other embodiments, the mucoadhesive does not substantially increase the viscosity of an oral pharmaceutical composition (e.g., compared to an identical composition containing no mucoadhesive).

[0042] In some embodiments, at least one mucoadhesive is selected and used in a pharmaceutical composition such that the addition of the at least one mucoadhesive does not significantly increase the viscosity of the resulting oral pharmaceutical composition (e.g., as compared to an identical composition containing no mucoadhesive).

[0043] In some embodiments, at least two mucoadhesives are selected and used in a pharmaceutical composition such that the addition of the at least two mucoadhesives does not significantly increase the viscosity of the resulting oral pharmaceutical composition (e.g., compared to an identical composition containing no mucoadhesive). . In some embodiments, the at least one mucoadhesive agent, when used alone in a pharmaceutical composition, would increase the viscosity of the pharmaceutical composition, but together with all the ingredients of the pharmaceutical composition, it does not substantially increase the viscosity of the resulting oral pharmaceutical composition (e.g., compared to an identical composition without mucoadhesive agent). ).

[0044] The SI unit for centipoise (cP) is millipascal second (mPas * s), which is numerically identical. In some embodiments, the composition has a viscosity of at least about 2 centipoise (cP), at least about 5 cP, at least about 10 cP, at least about 20 cP, at least about 25 cP, at least about 35 cP, at least about 40 cP. cP, at least about 50 cP, at least about 200 cP, or at least about 225 cP. In some embodiments, the composition has a viscosity of at least about 100 cps. In certain embodiments, the viscosity of the composition, measured at 25 degrees Celsius, is about 50 cP to about 250,000 cP, about 50 cP to about 70,000 cP, about 50 cP to about 25,000 cP, about 50 cP to about 10,000 cP. , about 50 cP to about 3000 cP, or about 50 cP to about 2000 cP. In one aspect, the viscosity of the composition, as measured at 25 degrees Celsius, is about 25 centipoise (cP) to about 800 cP, about 50 cP to about 800, or about 300 cP to about 800 cP (e.g., measured using a Brookfield viscometer). In another aspect, the viscosity of the composition may be about 100 cps to about 200 cps, about 200 cps to about 300 cps, about 250 cps to about 600 cps, or about 400 cps to about 600 cps. In particular embodiments, the viscosity of the formulation is about 30 cP, about 100 cP, about 200 cP, about 300 cP, about 400 cP, about 500 cP, or about 250,000 cP (e.g., measured using a Brookfield viscometer at 25 degrees Celsius equipped with into an ultra low adapter).

[0045] In some embodiments, the viscosity of the composition is measured at room temperature (about 25 degrees C) with a shear rate of about 13.2 seconds.^-1. In some embodiments, provided herein is a composition having a viscosity under such conditions of at least about 2 centipoise (cP), at least about 5 cP, at least about 10 cP, at least about 20 cP, at least about 25 cP, at least about 30 cP, at least about 35 cP, at least about 40 cP, at least about 50 cP, at least about 200 cP, at least about 225 cP, at least about 250 cP, at least about 300 cP, or at least about 300 cP, or at least about about 400 cP. In some embodiments, the viscosity of the composition under these conditions is about 50 cP to about 250,000 cP, about 50 cP to about 70,000 cP, about 50 cP to about 25,000 cP, about 50 cP to about 10,000 cP, about 50 cP. up to about 3,000 cP, about 50 cP to about 2,000 cP, about 250 cP to about 250,000 cP, about 250 cP to about 70,000 cP, about 250 cP to about 25,000 cP, about 250 cP to about 10,000 cP, about 250 cP to about 3,000 cP, or about 250 cP to about 2,000 cP. In one aspect, the viscosity of the composition, as measured at 25 degrees Celsius, is about 25 centipoise (cP) to about 800 cP, about 50 cP to about 800, or about 300 cP to about 800 cP (e.g., measured using a Brookfield viscometer). In another aspect, the viscosity of the composition under such conditions may range from about 100 cps to about 200 cps, about 200 cps to about 300 cps, about 250 cps to about 600 cps, or about 400 cps to about 600 cps. In particular embodiments, the viscosity of the formulation as measured under these conditions is about 30 cP, about 40 eP, about 100 cP, about 200 cP, about 300 cP, about 400 cP, about 500 cP, or about 250,000 cP.

[0046] In some embodiments, the viscosity of the composition is measured at room temperature (about 25 degrees C) with a shear rate of about 15 seconds.^-1 (e.g., with a gap between the spindle and the sample chamber wall of about 6 mm or more). In some embodiments, a composition is provided herein with a viscosity under such conditions of at least about 150 centipoise (cP), at least about 160 cP, at least about 170 cP, at least about 180 cP, at least about 190 cP, or at least about 200 cP. In some embodiments, the viscosity of the composition under these conditions is about 150 cps to about 250,000 cps, 160 cps to about 250,000 cps, 170 cps to about 250,000 cps, 180 cps to about 250,000 cps, or 190 cps to about 250,000 cps. .

[0047] The mucoadhesive used in any of the compositions described herein includes maltodextrin.

[0048] In some embodiments, the mucoadhesive is substantially or at least partially dissolved in the liquid carrier. In some embodiments, the oral pharmaceutical composition described herein contains less than about 0.1 g or less than about 1 g of maltodextrin for each ml of liquid carrier in the oral pharmaceutical composition. In some cases, the composition or formulation described herein contains less than 2 g maltodextrin / ml of composition, less than 1.5 g of maltodextrin / ml of composition, less than 1 g of maltodextrin / ml of composition, less than 0.5 g of maltodextrin / ml of composition. , less than 0.25 g / ml of maltodextrin / ml of composition, about 0.05 g of maltodextrin / ml of composition to about 0.5 g of maltodextrin / ml of composition, about 0.05 g of maltodextrin / ml of composition to about 0.4 g of maltodextrin / ml of composition, about 0.05 g maltodextrin / mL of composition to about 0.3 g of maltodextrin / mL of composition, about 0.1 g of maltodextrin / mL of composition to about 0.5 maltodextrin / mL of composition to about 0.4 maltodextrin / mL of composition to about 0.3 g maltodextrin / ml of composition, about 0.1 g of maltodextrin / ml of composition, about 0.1 g of maltodextrin / ml of composition, about 0.2 g of maltodextrin / ml of composition to about 0.5 g of maltodextrin / ml of composition, about 0.2 g of maltodextrin / mL of composition to about 0.4 g of maltodextrin / mL of composition, or about 0.2 g of maltodextrin / mL of composition to about 0.3 g of maltodextrin / mL of composition. In some embodiments, the maltodextrin is substantially dissolved in the liquid carrier. In some embodiments, the maltodextrin has dextrose equivalents (DE) of greater than 4, greater than 5, greater than 10, greater than 11, greater than 12, greater than 13, greater than 14, greater than 15, about 15, about 4 to about 10, about 4 to about 9, about 4 to about 8, about 11 to about 20, about 12 to about 19, about 13 to about 18, or about 14 to about 16. In particular embodiments, the first maltodextrin has a DE of about 4 to about 10, about 4 to about 9, or about 4 to about 8 and the second maltodextrin has a DE of about 10 to about 20, about 12 to about 19, or about 13 to about 18. In some embodiments, at least one maltodextrin used in the composition described herein has a molecular weight high enough to increase the solubility of the corticosteroid or increase the suspending capacity of the corticosteroid particles.

[0049] In some embodiments, mucoadhesives are described in, for example, U.S. Patent Nos. 6,638,521, 6,566,363, 6,509,028, 6,348,502, 6.306789, 5,814,330, and

4,900,552.

[0050] Also described herein are mucoadhesives which are at least two components selected from titanium dioxide, silicon dioxide and clay. In some embodiments, where the composition is not further diluted with any fluid prior to administration, the level of silicon dioxide is from about 3% to about 15% by weight of the composition. In some embodiments, the silicon dioxide is selected from, for example, but not limited to, fumed silicon dioxide, precipitated silicon dioxide, coacervated silicon dioxide, silicon dioxide gel, and mixtures thereof. In some embodiments, the clay is selected from, for example, but not limited to, kaolinites, serpentine, smectites, illites, or mixtures thereof. In some embodiments, the clay is selected from, for example, but not limited to, laponite, bentonite, hectorite, saponite, montmorillonite, or mixtures thereof.

In some embodiments, the mucoadhesive is provided in an amount sufficient to ensure exposure of the corticosteroid to the surface of the gastrointestinal tract (e.g., the esophagus) for a sufficient period of time such that symptoms and / or inflammation associated with inflammatory diseases involving the gastrointestinal tract (e.g. .

esophagus, stomach and / or digestive system) were reduced following administration of the oral corticosteroid-containing formulation as a single dose or multiple doses.

[0052] In some embodiments, the mucoadhesive is selected in an amount sufficient to adhere the pharmaceutical composition containing the corticosteroid or reside on the surface of the gastrointestinal tract (e.g., the esophagus surface) for 5 seconds, 10 seconds, 15 seconds, 30 seconds, 45 seconds, or 1 minute after falling on the surface of the gastrointestinal tract (e.g., the esophagus), for example by oral administration. In some embodiments, the mucoadhesive is selected in an amount sufficient to cause the pharmaceutical composition containing the corticosteroid to adhere or reside on the surface of the gastrointestinal tract (e.g., the esophagus surface) for 1.5, 2, 3, 4, 5, 6, 7, 8. 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60 minutes after administration to the surface of the gastrointestinal tract (e.g., to the surface of the esophagus). In some embodiments, the amount of the corticosteroid-containing composition that adheres to the surface of the gastrointestinal tract (e.g. esophageal surface) for 5 seconds, 10 seconds or 0.25; 0.5; 0.75; 1; 1.5; 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60 minutes is at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 95% by weight when applied to the surface of the gastrointestinal tract (e.g. the surface of the esophagus ). In particular embodiments, at least 50% of the pharmaceutical composition adheres to or resides on the surface of the gastrointestinal tract (e.g., esophageal surface) for at least 1 or at least 15 minutes after administration to the gastrointestinal surface (e.g., esophageal surface).

[0053] In some embodiments, the mucoadhesive is selected in an amount sufficient to induce corticosteroid adhesion and / or absorption on the surface of the gastrointestinal tract (e.g., esophageal surface) after 5 seconds, 10 seconds, or 0.25; 0.5; 0.75; 1; 1.5; 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60 minutes after administration to the surface of the gastrointestinal tract (e.g., the esophagus surface) for example by oral administration. In some embodiments, the amount of corticosteroid that adheres to and / or is absorbed on the surface of the gastrointestinal tract (i.e. sum of the amount adhered to or in the esophagus and the amount absorbed by the gastrointestinal tract (inflamed) for 5 seconds, 10 seconds or 0.25; 0.5; 0.75; 1; 1.5; 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60 minutes is at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 95% by weight when applied to the surface of the gastrointestinal tract (e.g. the surface of the esophagus ). In some embodiments, at least 50% of the corticosteroid adheres to and / or is absorbed through the gastrointestinal surface (e.g., esophageal surface) for at least 1 or at least 15 minutes after administration to the gastrointestinal surface (e.g., esophageal surface).

[0054] In particular embodiments, following oral administration of a composition described herein into the esophagus (e.g., after first swallowing or drinking the composition), at least 1%, 2%, 3%, 4%, 5%, 6%, 7 %, 8%, 9%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% by weight of the corticosteroid or the administered composition is present in the esophagus ( e.g. as measured by gamma scintigraphy) after at least 5 seconds, 10 seconds, 15 seconds, 20 seconds, 25 seconds, 30 seconds, 40 seconds, 45 seconds, 50 seconds, or 1; 1.5; 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes after administration of the composition into the esophagus. In some examples, even small differences (e.g., growth) in the time of adherence (e.g. residence time) between formulations can produce therapeutically significant or clinically significant results or improvement.

[0055] In some embodiments, the weight percent of the corticosteroid-containing composition is adhered to or is on the surface of the gastrointestinal tract (e.g., esophageal surface) after 5, 10, 15, 30, or 45 seconds or 1; 1.5; 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60 minutes is greater than (e.g. more than 1.1x, 1 , 2x, 1.3x, 1.4x, 1.5x, 2x, 3x, 4x, 5x) weight percent of a control composition that adheres to the surface of the gastrointestinal tract (e.g. esophagus surface). In some embodiments, the control composition contains the same amount of a corticosteroid, 4 mL of an aqueous formulation, and 10 packs of Splenda® (distributed by McNeil Nutritionals, LLC Fort Washington, PA 19034-2299) for every 0.5 mg, 1 mg, or 2 mg of corticosteroid ( e.g. 2 Pulmicort Respules®, each 2 ml of suspension contains 0.25 mg, 0.5 mg or 1 mg of micronized budesonide). For example, in some embodiments, for a pharmaceutical composition containing budesonide, the control composition comprises 4 ml of Pulmicort® and 10 packs of Splenda®. In some embodiments, the control composition contains the same amount of corticosteroid, 8 ml of the aqueous formulation, and 20 packs of Splenda® (Splenda® packs contain about 1 g and are distributed by McNeil Nutritionals, LLC Fort Washington, PA 19034-2299) for every 0.5 mg. , 1 mg or 2 mg of corticosteroid (e.g. 4 Pulmicort Respules ®, each 2 ml of suspension contains 0.25 mg, 0.5 mg or 1 mg of micronized budesonide). In certain embodiments, the control composition contains the same volume and the same amount of corticosteroid as present in a stable oral pharmaceutical composition, and has a viscosity of about 1 cP at 25 ° C and a shear rate of about 13.2 seconds.^-1 (e.g. Pulmicort Respules®). The formulations described herein as control compositions are also contemplated herein. The weight percent of a corticosteroid-containing composition which adheres to or is on the surface of the gastrointestinal tract (e.g. esophageal surface area) by the total amount of corticosteroid-containing composition that was applied to the surface of the gastrointestinal tract (e.g., esophageal surface) and multiplying the result by 100%. Likewise, the weight percent of a control composition that adheres to the surface of the gastrointestinal tract (e.g. esophageal area) by the total amount of control composition that was applied to the gastrointestinal surface (e.g., esophageal area) and multiplying the result by 100%. In some embodiments, the amount of the corticosteroid that adheres to or is absorbed through the surface of the gastrointestinal tract (e.g., esophageal surface) after 5, 10, 15, 30, or 45 seconds or 1; 1.5; 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60 minutes is greater than (e.g. greater than 1.1x, 1.2x, 1.3x, 1.4x, 1.5x, 2x, 3x 4x, 5x) in the case of a control composition containing the same amount of corticosteroid, e.g. 4 ml of the aqueous formulation and 10 packs of Splenda® for every 0.5 mg or 1 mg of corticosteroid. One pack of Splenda® contains approximately one gram of a mixture containing dextrose, maltodextrin and sucralose.

[0056] In some embodiments, a pharmaceutical composition described herein has improved mucoadhesive properties and reduced viscosity as compared to a control composition containing the same amount of a corticosteroid. In some embodiments, a pharmaceutical composition described herein exhibits substantially similar mucoadhesive properties and reduced viscosity as compared to a control composition. In some embodiments, the pharmaceutical composition described herein adheres to or is located at a site of the gastrointestinal tract (e.g., the esophagus) for greater than or equal to the control composition, and the viscosity is less than or equal to the control composition. In particular embodiments, where the pharmaceutical composition described herein is adjacent to or located at a site of the gastrointestinal tract (e.g. esophagus) for a time equal to that of the control composition, the viscosity of the pharmaceutical composition described herein is lower than that of the control composition. In some embodiments, the control composition used herein comprises 4 ml of Pulmcort® (e.g., 0.25 mg or 0.5 mg of budesonide per 2 ml dose) and 10 packs of Splenda® (e.g., 4 ml of an aqueous formulation and 10 packs of Splenda®). for every 0.5 mg or 1 mg of corticosteroid). In some embodiments, the control composition contains the same amount of corticosteroid, 8 ml of the aqueous formulation, and 20 packs of Splenda® (Splenda® packs contain about 1 g and are distributed by McNeil Nutritionals, LLC Fort Washington, PA 19034-2299) for every 0.5 mg. , 1 mg or 2 mg of a corticosteroid (e.g. 4 Pulmicort Respules®, each 2 ml of suspension contains 0.25 mg, 0.5 mg or 1 mg of micronized budesonide).

[0057] In some embodiments, the adherence and / or absorption of a pharmaceutical composition or corticosteroid as described herein to the surface of the gastrointestinal tract (e.g., esophageal surface) may be determined using scintigraphy or an assay. In some embodiments, such assays are performed in vivo or in vitro. In some embodiments, in vivo scintigraphy may include combining a pharmaceutical composition described herein with a detectable radioisotope, administering a labeled composition to a subject, and detecting and / or measuring adherence of the pharmaceutical composition or corticosteroid to a gastrointestinal surface (e.g., esophageal surface) using a device ( e.g. cameras) that detects and / or measures radioactivity. In some embodiments, in vivo scintigraphy may include combining a corticosteroid as described herein with a detectable radioisotope, formulating a labeled corticosteroid as a composition as described herein, administering the composition to a subject, and detecting and / or measuring adherence of a pharmaceutical composition or corticosteroid to a gastrointestinal surface ( e.g. esophageal surface) using a device (e.g. cameras) that detects and / or measures radioactivity. In some embodiments, an in vitro test for detecting adherence of a pharmaceutical composition or corticosteroid described herein to a gastrointestinal surface (e.g., esophageal surface) may involve administering a composition described herein to a distal strip of gastrointestinal surface tissue (e.g. porcine esophageal tissue) and subjecting the composition to flow of artificial saliva in a direction away from the distal portion of the belt. Determination of adherence of the composition and / or corticosteroid can be done at a given time by detecting the amount of composition and / or corticosteroid in the eluate or the amount of composition and / or corticosteroid remaining on the surface of the gastrointestinal tissue.

[0058] In some embodiments, a pharmaceutical composition described herein (or a corticosteroid administered in a composition described herein) has an esophageal transit time greater than 5, 10, 15, 30, or 45 seconds, or 1; 1.5; 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60 minutes, with esophageal transit time being the delay time from administration (e.g. orally and / or oesophagus) of the pharmaceutical composition described herein until the activity drops to <10% of the peak activity. In some embodiments, a pharmaceutical composition described herein (or a corticosteroid administered in a composition described herein) has a mean esophageal transit time of about 5, 10, 15, 30, or 45 seconds or 1; 1.5; 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60 minutes. In some embodiments, a pharmaceutical composition described herein (or a corticosteroid administered in a composition described herein) exhibits an oesophageal emptying of less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9 %, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99% ten seconds after peak activity.

[0059] Optional viscosity-increasing excipients used in the pharmaceutical compositions described herein include, for example, but not limited to, cross-linked poly (acrylic acid) (e.g. Carbopol 974P), glycerin, carbomer homopolymer, carbomer copolymer, acacia (gum arabic), agar, magnesium aluminum silicate, sodium alginate, sodium stearate, bladder wrack, bentonite, carbomer, carrageenan, Carbopol, cellulose, cellulose (MCC), microcrystalline (MCC) cartilage, dextrose, fork, gelatin, Ghatti gum, guar gum, hectorite, lactose, sucrose, maltodextrin, mannitol, sorbitol, honey, corn starch, wheat starch, rice starch, potato starch, gelatin, sterculia gum, xanthan gum, polyethylene glycol (e.g. PEG 200-4500), gum tragacanth, ethylcellulose, ethylhydroxyethylcellulose, ethylmethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, poly (methacrylate / methacrylate, poly (methacrylate) co-methylcellulose, poly (methacrylate / methacrylate, poly (methacrylate) carbonate, oxyethylcellulose, poly (methacrylate) carbonate, hydroxyethylcellulose, poly (methacrylate) MA), poly (methoxyethyl methacrylate), poly (methoxyethoxyethyl methacrylate), hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose (CMC) (including, e.g., sodium carboxymethyl cellulose (NaCMC)), silicon dioxide, polyvinylpyrrolidone (PVP: povidone), Splenda® (dextrose, maltodextrin, and sucralose), or combinations thereof.

[0060] In some embodiments, the pharmaceutical composition described herein is a non-Newtonian or Newtonian fluid. In some embodiments, the pharmaceutical composition described herein is a non-Newtonian fluid. In particular embodiments, the non-Newtonian fluid is a plastic, pseudoplastic, or dilatation non-Newtonian fluid. In some particular embodiments, the non-Newtonian fluid is thixotropic. In some embodiments, the non-Newtonian fluid composition dilutes with shear and thickens with non-shear. Thus, in some embodiments, provided herein is a fluid pharmaceutical composition which is easy to pour after gentle or moderate shaking. Further, in some embodiments, provided herein is a fluid pharmaceutical composition that is suitable for easy pouring after mild to moderate shaking, and becomes viscous enough after oral administration to allow the pharmaceutical composition to at least partially cover the esophagus and locally deliver a therapeutically effective amount of a corticosteroid to the stomach. esophagus.

[0061] Also disclosed herein are pharmaceutical compositions provided herein for use in the treatment, prevention or alleviation of inflammatory diseases involving the gastrointestinal tract including the esophagus, stomach and / or digestive system. In some embodiments, the pharmaceutical composition is in liquid form. Liquid forms include, for example, but not limited to, emulsions, solutions, suspensions, syrups, slurries, dispersions, colloids. Pharmaceutical compositions are also provided comprising a corticosteroid (e.g. a topical corticosteroid such as e.g. budesonide) and a mucoadhesive in the form of a dissolving tablet, dissolving pad, capsule or gel capsule. In some embodiments, the pharmaceutical composition described herein is in liquid, semi-solid, or solid form. In particular embodiments, the pharmaceutical composition described herein is in a semi-solid form, e.g., a gel, gel matrix, cream, paste, or the like. In some embodiments, the semi-solid forms include a liquid carrier.

[0062] The compositions of the invention are used by individuals of all ages. By subject is meant any animal, e.g., mammal, or, for example, human, including, for example, patients in need of treatment.

[0063] By a subject is meant any animal, for example a mammal or, for example, a human, including, for example, patients in need of treatment. In some embodiments, the human is a child. Children often need treatment because they have the greatest difficulty with the inhalation-swallowing technique. In some embodiments, the methods of the invention are applied to subjects of all ages, including adults.

[0064] In some embodiments, the compositions provided herein are prepared using any suitable source of the active ingredient. In some embodiments, the corticosteroid (e.g., budesonide) used in the compositions described herein is pure corticosteroid (e.g., budesonide). In some embodiments, a pure corticosteroid (e.g., budesonide) is a pure, abundant corticosteroid. In some embodiments, the pure corticosteroid (e.g., budesonide) is a powdered corticosteroid (e.g., budesonide). In particular embodiments, the pure corticosteroid (e.g., budesonide) is a micronized corticosteroid (e.g., budesonide).

[0065] In some embodiments, the corticosteroid is administered in a commercially available formulation. In other embodiments, the corticosteroid is administered in a composition containing a commercially available corticosteroid formulation. For example, in some embodiments, a corticosteroid-containing composition comprises a commercially available formulation and an excipient such as an excipient that imparts mucoadhesive properties to the composition and / or diluent. In some embodiments where the corticosteroid is budesonide, the commercially available formulation is Pulmicort Respules®. In other embodiments, the corticosteroid is budesonide, the commercially available formulation is Rhinocort Aqua®. In some embodiments where the corticosteroid is fluticasone, the commercial formulation is Flonase®. In some embodiments, the ratio of the commercially available formulation to the optional diluent is between about 1: 0.5 and about 1: 100. Diluents include any pharmaceutically acceptable oral diluent including, for example, powder diluents (such as talc) and liquid diluents (such as water, ethanol, and combinations thereof). In some embodiments, the commercially available formulation is Entocort®. In some embodiments, the Entocort® compositions are dissolved and / or dispersed in an aqueous carrier. In particular embodiments, the Entocort® formulation is dispersed in a liquid carrier at a pH sufficient to remove the enteric coating from the budesonide particles. In other embodiments, an Entocort® formulation is pretreated with a solvent at a pH sufficient to remove the enteric coating of the budesonide particles, and then the particles are formulated into a composition as described herein.

[0066] In some embodiments, the corticosteroid-containing composition comprises micronized budesonide, disodium edetate, sodium chloride, sodium citrate, citric acid, polysorbate (e.g., polysorbate 80), water, and optionally one or more excipients, wherein the excipients are selected from those mentioned in this document. In some embodiments, the composition comprises about 0.1 mg to about 1.0 mg budesonide / 2 ml (or about 0.05 mg to about 0.5 mg per gram) of the composition. In some embodiments, the composition comprises about 0.2 mg to about 0.6 mg budesonide / 2 ml (or about 0.1 mg to about 0.3 mg per gram) of the composition. In particular embodiments, the composition comprises about 0.25 mg / 2 ml of the composition. In other particular embodiments, the composition comprises about 0.5 mg / 2 mL of the composition.

[0067] In other embodiments, the corticosteroid-containing composition comprises micronized budesonide, microcrystalline cellulose (MCC), carboxymethyl cellulose (including, e.g., sodium carboxymethyl cellulose), dextrose, polysorbate (e.g., polysorbate 80), optionally disodium edetate, hydrochloric acid and optionally one or more excipients , the excipients being selected from any of those listed herein. In particular embodiments, the composition has a pH of about 4.5. In some embodiments, the composition comprises about 0.1 mg to about 1.0 mg budesonide / g of the composition. In some embodiments, the composition comprises about 0.3 mg to about 0.6 mg budesonide / g of the composition. In particular embodiments, the composition comprises about 0.4 mg or 0.44 mg budesonide / g of the composition. In certain specific embodiments, the composition comprises about 3.8 mg / 8.6 g of the composition. In some embodiments, the composition comprises about 0.1 mg to about 1.0 mg budesonide / ml of the composition (about 0.01 to about 0.1% w / w). In some embodiments, the composition comprises about 0.3 mg to about 0.8 mg budesonide / mL of the composition (about 0.03 to about 0.08% w / w). In particular embodiments, the composition comprises about 0.6 to about 0.7 mg budesonide / mL of composition (about 0.06 to about 0.07% w / w). In more specific embodiments, the composition comprises about 0.63 mg budesonide / mL of composition (about 0.063% w / w).

[0068] In some embodiments, the corticosteroid-containing composition comprises microfine fluticasone propionate, microcrystalline cellulose, carboxymethyl cellulose (including, e.g., sodium carboxymethylcellulose), dextrose, benzalkonium chloride, polysorbate (e.g., polysorbate 80), and optionally polysorbate 80. excipients, where the excipients are selected from those listed in this document. In some embodiments, the composition has a pH of between about 5 and about 7. In some embodiments, the composition comprises about 20 to about 80 µg fluticasone propionate / mg of composition. In some embodiments, the composition comprises about 40 to about 60 µg fluticasone propionate / mg of the composition. In certain embodiments, the composition comprises about 50 µg fluticasone propionate / mg of composition. In some embodiments, the composition comprises about 0.02% w / w sodium benzalkonium and about 0.25% w / w phenylethyl alcohol.

Formulations

[0069] While the compositions of the invention will typically be used in human therapy, in certain embodiments, they are used in veterinary medicine to treat similar or identical diseases. In some embodiments, the compositions are used for the treatment of mammals, including primates and domestic mammals, for example. In some embodiments, the compositions are used, for example, to treat herbivores. The compositions of the invention include geometric and optical isomers.

[0070] Pharmaceutical compositions suitable for use in the present invention include compositions in which the active ingredient or ingredients are contained in an amount effective to achieve its intended purpose.

The exact dose will depend on the route of administration, the form in which the composition is administered, the subject to be treated, the age, weight / height of the subject to be treated, and the preferences and experience of the attending physician. In some embodiments, the optimal concentration of a corticosteroid in the composition depends on the particular corticosteroid used, the characteristics of the patient, and the nature of the inflammation for which treatment is sought. In various embodiments, these factors are determined by those skilled in the medical and pharmaceutical arts in light of the present disclosure.

[0072] In general, a therapeutically effective dose is desired. A therapeutically effective dose refers to the amount of corticosteroid which relieves symptoms and / or inflammation compared to symptoms and / or inflammation before treatment is started. Dosage forms and methods of administering dosage forms containing effective amounts are within the scope of the invention. In various embodiments, the amount of the corticosteroid (e.g. budesonide or fluticasone propionate) used in the method or composition described herein is from about 2.5 to about 400 µg / kg body weight per day, or for example from 5 to 300 µg / kg per day, or for example, it is in the range of 5 to 200 µg / kg per day, or, for example, is in the range of 5 to 100 µg / kg per day, or, for example, is in the range of 10 to 100 µg / kg per day, or, for example, it is in the range of 10-50 μg / kg / day, or, for example, it is in the range of 10-100 µg / kg / day, or is, for example, in the range of 5-50 µg / kg / day, or in an illustrative embodiment it is in the range of 10-60 µg / kg / day. In some embodiments, the amount of the corticosteroid (e.g. budesonide or fluticasone propionate) used in the method, in combination or dose combination disclosed herein includes, for example, but not limited to, about 50 µg to about 500 mg, about 50 µg to about 200 mg, about 50 µg to about 100 mg, about 50 mcg to about 50 mg, about 100 mcg to about 20 mg, about 250 mcg to about 20 mg, about 250 mcg to about 15 mg, about 250 mcg to about 10 mg, about 250 mcg to about 5 mg, about 300 μg to approximately 4 mg, approximately 350 μg to approximately 2 mg, about 250 µg to about 3 mg, or about 500 µg to about 3 mg, about 375 µg to about 1.5 mg, or about 500 µg to about 2 mg, or about 1 mg to about 3 mg. In an illustrative embodiment, the dose is delivered in a sufficient volume for the composition to reach the esophagus in an effective amount. In some embodiments, a composition described herein comprises 1 or more doses. In particular embodiments, the composition described herein is in a multi-unit container. Thus, provided herein is a kit comprising a composition as described herein and a container (e.g., multiple unit container or single unit container). In some embodiments, provided herein is a composition or kit comprising a composition that has from about 2 to about 180, about 10 to about 60, about 14, or about 30 doses.

[0073] In an illustrative embodiment, a dose or amount (including a split dose) of corticosteroid is provided in a composition with a sufficient volume for any of the compositions disclosed herein to reach a target and / or inflamed portion of the gastrointestinal tract, including e.g. esophagus, in an effective amount. In some embodiments, an effective amount of a composition delivered to the esophagus is an amount sufficient to cover or at least partially cover the esophagus and deliver the composition to the affected areas, for example, but not limited to, the lower esophagus, esophagus and stomach junction, stomach, and / or duodenum. In some embodiments, the composition described herein has a volume, for example about 1-50 ml, or for example about 1-40 ml, or for example about 1-30 ml, or for example about 125 ml, or for example about 1-40 ml, for example. 20 ml, or for example about 5-25 ml, or for example about 1020 ml, or for example about 10 ml, or for example about 15 ml, or for example about 20 ml, or for example about 1-15 ml, or e.g. about 1-10 ml, or e.g. about 2-8 ml, or for example about 3-7 ml, or for example about 4-6 ml, or for example about 5 ml, or for example about 6-14 ml, or for example about 8-12 ml, or for example about 9-11 ml, or for example about 10 ml. In more specific embodiments, about 0.25 mg to about 6 mg, about 0.375 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, or about 2 mg a corticosteroid (e.g. of budesonide) is formulated into a single or unit dose of a pharmaceutical composition as described herein, and the single or unit dose has a total volume of about 10-20 ml, or for example about 10 ml, or for example about 15 ml, or for example about 20 ml. or for example about 1-15 ml, or for example about 1-10 ml, or for example about 2-8 ml, or for example about 3-7 ml, or for example about 4-6 ml, or for example about 5 ml, or for example about 6-14 ml, or for example about 8-12 ml, or for example about 9-11 ml, or for example about 10 ml. As discussed herein, the liquid includes liquids, solutions, suspensions, dispersions, or any combination thereof, depending on the solubility and amount of the individual ingredients and the carriers and solvents used. In some embodiments, a suitable palatable dose has a volume sufficient to cover or at least partially cover the esophagus, and in an illustrative embodiment, the volume is sufficient to cover or at least partially cover the esophagus and deliver the corticosteroid to the affected areas, for example, but not limited to, the lower esophagus. , the connection of the stomach and esophagus, stomach and / or duodenum. The composition may be delivered, for example, four times a day, three times a day, twice a day, once a day, every other day, three times a week, twice a week, or once a week. For example, the dose may be divided into multiple doses administered throughout the day, or may be administered, for example, into four, three, two or one doses per day. In some embodiments, more frequent administration (e.g. twice versus once daily) provides shorter overall treatment or faster onset of symptom relief. In one illustrative embodiment, the dose is administered once a day.

[0074] In some embodiments, a dose or composition as described herein is administered with food. In some embodiments, a dose or composition described herein is administered without food. In some embodiments, a dose or composition as described herein is administered after a meal or on an empty stomach. In some embodiments, a dose or composition as described herein is administered in the morning, afternoon, evening, night or time of day combination. In some embodiments, the dose is administered at night. In another aspect, the dose is administered about 30 minutes before bedtime, without food or water following administration of the present composition. In yet another embodiment of the invention, the dose is administered at bedtime, wherein the patient or subject is substantially supine after administration of the composition for at least 30 minutes, at least 1 hour, at least 2 hours, at least 4 hours, or at least 4 hours. at least 8 hours.

Disclosed herein are compositions for use in treating, preventing or alleviating inflammation or symptoms associated with inflammation of the gastrointestinal tract, e.g., esophagus, comprising administering to a subject in need of treatment a single dose of a pharmaceutical composition described herein from a multi-dose container. In particular embodiments, administering a single unit dose from a multi-dose container comprises (1) shaking the multi-dose container, a multi-dose container containing at least one unit dose of a pharmaceutical composition as described herein; (2) pouring (or otherwise dispensing) a single unit dose from a multi-dose container into a delivery device (e.g. devices suitable for human administration, such as a spoon, cup or syringe); and (3) administering the single unit dose to a subject in need thereof. In more specific embodiments, shaking of the multi-dose container is performed until the fluid contained therein reaches a viscosity suitable for pouring (e.g., easy pouring). In particular embodiments, the process further comprises waiting after a single unit dose has been dispensed and before the single unit dose has been administered to a subject in need thereof. In particular embodiments, the waiting time is a time sufficient to allow the composition to achieve a desired viscosity, e.g., a viscosity intended to improve the coating ability of the composition. In some embodiments, the waiting time is e.g. about 3 seconds or more; about 5 seconds or more; about 10 seconds or more; about 15 seconds or more; about 20 seconds or more; about 25 seconds or more; about 30 seconds or more; about 40 seconds or more; about 45 seconds or more; about 50 seconds or more; or about 60 seconds or more. In other specific embodiments, the composition is administered immediately after pouring the composition into the delivery device. In some embodiments, the process includes vigorously shaking the multi-dose container.

[0076] In some embodiments, the initial treatment is, for example, for about 3 days to 2 weeks for an acute condition, or about 4 weeks to about 16 weeks for a chronic condition, or about 8 weeks to about 12 weeks for a chronic condition. In various embodiments, a longer treatment is needed, such as, for example, treatment similar to the chronic treatment of persistent asthma. For example, in some aspects of the invention, patients are treated for up to 6 months or up to one year. In some aspects, the duration of maintenance treatment is greater than one year. In some embodiments, patients are treated on a maintenance or as needed basis during the problematic episode, depending on the severity of the condition. In some embodiments, patients are treated on a rotational therapy basis when treatment is provided for a period of time, and then the patient is off drug for a period of time before treatment is resumed. Upon discontinuation of medication, the patient may not be treated, may be treated with a different drug, or may be treated at a reduced dose. In some embodiments, patients are treated with a higher dose of the composition until the condition improves as desired, and then treatment is continued with a lower dose of the composition.

[0077] In some embodiments, the corticosteroid is present in the pharmaceutical composition described herein in any effective amount. In some embodiments, an effective amount is an amount sufficient to reduce inflammation or symptoms of inflammation associated with inflammatory disease or gastrointestinal (eg, esophagus) disease as compared to the level of inflammation or symptoms associated with inflammatory disease prior to administration of the effective amount. In some embodiments, an effective amount is an amount sufficient to maintain a reduction in inflammation or symptoms of inflammation obtained by any means, including administration of an effective amount sufficient to achieve such reduction. In some embodiments, the effective amount is about 0.05 mg to about 10 mg, about 0.05 mg to about 7.5 mg, about 0.05 mg to about 5 mg, about 0.25 mg to about 3 mg, about 0.25 mg to about 2.5 mg, about 0.5 mg to about 3 mg, about 0.5 mg to about 2 mg, about 0.5 mg to about 0.1 mg, about 0.5 mg to about 5 mg, about 0.5 mg to about 4 mg, about 1 mg to about 4 mg, about 1 mg to about 3 mg, about 2 mg to about 3 mg, or about 2 mg to about 4 mg. In particular embodiments, the effective amount of the corticosteroid is about 0.05 mg, about 0.1 mg, about 0.15 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg. , about 0.37 mg, about 0.375 mg, about 0.7 mg, about 0.8 mg, about 0.75 mg, about 1 mg, about 1.2 mg, about 1.25 mg, about 1.3 mg , about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg , about 6.5 mg, about 7 mg, or about 7.5 mg or more. In some embodiments, the corticosteroid is present in the pharmaceutical composition at a concentration of about 0.01 mg / ml to about 2 mg / ml of the composition. In particular embodiments, the corticosteroid is present in the pharmaceutical composition at a concentration of about 0.01 mg / ml to about 1.5 mg / ml, about 0.03 mg / ml to about 1.5 mg / ml, about 0.05 mg. / mL to about 1.5 mg / mL, or about 0.07 mg / mL to about 1.5 mg / mL. In more specific embodiments, the corticosteroid is present in the pharmaceutical composition at a concentration of about 0.07 mg / ml to about 1 mg / ml.

[0078] Also described herein is a composition comprising a corticosteroid, dextrose, maltodextrin, edetate, citrate, polysorbate 80, optionally a preservative, optionally a flavoring agent, an optional sweetener, at least one additional excipient, and a liquid carrier. In particular embodiments, the composition comprises a preservative. In further or alternative embodiments, the composition comprises a flavoring agent. In further or alternative embodiments, the fluid carrier is an aqueous medium (e.g., water). In particular embodiments, corticosteroid particles (e.g., microparticles) are suspended in an aqueous medium.

[0079] In some embodiments, the corticosteroid is selected from, for example, but not limited to, budesonide, fluticasone propionate, and combinations thereof. In particular embodiments, the corticosteroid (e.g. budesonide or fluticasone propionate) is present in the composition or formulation described herein in an amount of about 0.005 mg / mL to about 1.5 mg / mL or about 0.01 mg / mL to about 1 mg / mL, about 0.01 mg / mL to about 5 mg / ml, about 0.01 mg / ml to about 3 mg / ml, about 0.01 mg / ml to about 2 mg / ml, about 0.01 mg / ml to about 1.5 mg / ml, about 0.05 mg / ml to about 0.5 mg / ml, about 0.05 mg / ml to about 0.4 mg / ml, about 0.07 mg / ml to about 1.5 mg / ml or about 0 , 07 mg / ml to about 1 mg / ml. In more specific embodiments, budesonide is present in an amount of about 0.01 mg / ml to about 3 mg / ml, about 0.01 mg / ml to about 1.5 mg / ml, about 0.05 mg / ml to about 0 , 5 mg / ml, about 0.05 mg / ml to about 0.4 mg / ml, or about 0.07 mg / ml to about 1 mg / ml. In other particular embodiments, the fluticasone propionate is present in an amount of about 0.005 mg / mL to about 1.5 mg / mL, or about 0.01 mg / mL to about 1 mg / mL.

[0080] In some embodiments, the volume of the composition or dose of the composition described herein is an amount sufficient to substantially cover (e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98% or at least 99% of the length of the esophagus of a subject to whom the composition is administered. In some embodiments, the volume of the composition or dose of the composition described herein is about 0.05 ml / cm esophagus length to about 1 ml / cm esophagus length, about 0.1 ml / cm esophagus length to about 0.8 ml / cm esophagus length. esophagus, about 0.2 ml / cm esophagus length to about 0.6 ml / cm esophagus length or about 0.3 ml / cm esophagus length to about 0.5 ml / cm esophagus length, with esophagus length being the length of the subject's esophagus to whom the composition is administered. In some embodiments, the volume of a composition or dose of a composition described herein is based on the esophagus length of a subject (e.g., male, female, or both), which is at the 50th percentile height for their age. Therefore, in some embodiments, the volume of a composition or dose of a composition described herein is about 0.05 ml / cm esophagus length to about 1 ml / cm esophagus length, about 0.1 ml / cm esophagus length to about 0.8 ml / cm. esophagus length, about 0.2 ml / cm esophagus length to about 0.6 ml / cm esophagus length, about 0.3 ml / cm esophagus length to about 0.5 ml / cm esophagus length, about 0.32 ml / cm esophagus length to about 0.41 ml / cm esophagus length or about 0.3 ml / cm esophagus length to about 0.46 ml / cm esophagus length, with esophagus length being the length of an individual's esophagus at the 50th percentile for the age of the subject to whom the composition is administered. In some cases, esophagus length is either the actual length of the subject's esophagus or is calculated from the equation: esophagus length = 1.048 (cm) + (0.167 * height (cm)). In some cases, for example, the 50th percentile height (CDC 2000) for male children at 2 years of age is 87 cm, at 3 years old is 95 cm, at 4 years old is 102 cm, at 5 years old is 109 cm at 6 years old is 115cm, at 7 years old it is 122cm, at 8 years old it is 128cm, at 9 years old it is 134cm, at 10 years old it is 139cm, at 11 years old it is 144cm, at age 12 years old is 149cm, age 13 is 156cm, age 14 is 164cm, age 15 is 170cm, age 16 is 174cm, age 17 is 175cm, and at the age of 18 it is 176 cm.

[0081] Further, in some embodiments, the amount of the therapeutic agent (e.g. of a corticosteroid such as budesonide) in the composition or dose of the composition described herein is about 0.005 mg / cm esophagus length to about 0.3 mg / cm esophagus length, about 0.008 mg / cm esophagus length to about 0.2 mg / cm esophagus length esophagus, about 0.01 mg / cm esophagus length to about 0.15 mg / cm esophagus length, or about 0.015 mg / cm esophagus length to about 0.1 mg / cm esophagus length, wherein the esophagus length is the length of the subject's esophagus. to whom the composition is administered. In some embodiments, the volume of a composition or dose of a composition described herein is based on the esophagus length of a subject (e.g., male, female, or both), which is at the 50th percentile height for their age. Therefore, in some embodiments, the amount of the therapeutic agent (e.g. of a corticosteroid such as budesonide) in the composition or dose of the composition described herein is about 0.005 mg / cm esophagus length to about 0.3 mg / cm esophagus length, about 0.008 mg / cm esophagus length to about 0.2 mg / cm esophagus length esophagus, about 0.01 mg / cm esophagus length to about 0.15 mg / cm esophagus length, or about 0.015 mg / cm esophagus length to about 0.1 mg / cm esophagus length, wherein the esophagus length is the esophagus length of an individual with the 50th percentile height for the age of the subject to whom the composition is administered.

[0082] In some embodiments, any pharmaceutical composition or dose of a pharmaceutical composition described herein is delivered or administered in a volume sufficient for administration of a bolus when administered orally to a subject. In some embodiments, the composition is a volume that does not provide a systemic excess of the active ingredient. In some embodiments, the pharmaceutical composition or dose is delivered in a volume sufficient to provide a bolus when administered to a subject, with the bolus amount at the distal end of the esophagus (e.g., bolus amount prior to, e.g. immediately before, entering or passing the lower esophageal sphincter) is less than 90%, less than 85%, less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10% or less than 5% of the bolus amount entered into the esophagus (e.g. bolus amount after, e.g., immediately after passing through the upper esophageal sphincter). In some embodiments, the bolus amount is defined as a measure of diameter or volume. In some embodiments, the diameter of the sphincter can be determined using gamma scintigraphy. In particular embodiments, the volume of the composition or dose is adjusted to take into account the length and / or diameter of the esophagus of the individual to which the composition or dose is administered.

[0083] In other illustrative embodiments of the invention, the compositions disclosed herein are provided in the form of a lozenge that can be dissolved in the mouth reaching and at least partially covering the esophagus, delivering the composition to the affected areas, including, for example, but not limited to. to the lower esophagus, the junction of the esophagus and stomach, stomach and / or duodenum. A pill or other similar dosage form (e.g. tablet, capsule or other solid form), would dissolve in the mouth or esophagus to form a solution that may then at least partially cover the esophagus and then deliver the composition to the affected areas, including, for example, but not limited to the lower esophagus. junction of the esophagus and stomach, stomach and / or duodenum. Or, in the case of children, infants, or other patients who may have difficulty dissolving the lozenge, the lozenge may be ground or otherwise dissolved in a small volume of water or other pharmaceutically acceptable liquid, for example, to reach the total volume shown in the embodiments of the invention. In other illustrative embodiments of the invention, the compositions disclosed herein are provided in the form of a tablet, capsule or, for example, a gel capsule, designed to be slowly released and delivered to the gastrointestinal tract, including the esophagus.

[0084] In some embodiments, the initial treatment is for, for example, about 3 days to 2 weeks for an acute condition, or about 4 weeks to about 16 weeks for a chronic condition, or about 8 weeks to about 12 weeks for a chronic condition. In various embodiments, a longer treatment is needed, such as, for example, treatment similar to the chronic treatment of persistent asthma. For example, in some aspects of the invention, patients are treated for up to 6 months or up to one year. In some aspects, the duration of maintenance treatment is greater than one year. In some embodiments, patients are treated on a maintenance or as needed basis during the problematic episode, depending on the severity of the condition. In some embodiments, patients are treated on a rotational therapy basis when treatment is provided for a period of time, and then the patient is off drug for a period of time before treatment is resumed. Upon discontinuation of the drug, the patient may not receive treatment, receive another drug, diet, or treat at a reduced dose. In some embodiments, patients are treated with a higher dose of the composition until the condition improves as desired, and then treatment is continued with a lower dose of the composition. In some embodiments, treatment of a patient with a composition as described herein is combined with treatment with another drug and / or diet. In some embodiments, patients receive treatment with a higher dose of the composition until the condition improves as desired, and then treatment is continued with a lower dose of the composition.

[0085] In some embodiments, the treatment described herein comprises intermittent or continuous treatment. In some embodiments, treatment for gastrointestinal inflammation as described herein includes prophylactic treatment of gastrointestinal inflammation (e.g., treatment that prevents the onset of symptoms and / or inflammation). In some embodiments, treatment of gastrointestinal inflammation as described herein includes a method of prolonging and / or maintaining remission of gastrointestinal inflammation by administering or continuing to administer a pharmaceutical composition as described herein after remission of inflammation and / or symptoms of inflammation. In particular embodiments, the prophylactic and / or remission treatment optionally comprises administering a composition as described herein, comprising a reduced amount of corticosteroid compared to the amount of corticosteroid used when the inflammation and / or symptoms of inflammation are not in remission.

[0086] In some embodiments, also disclosed herein is a method of diagnosing a subject with gastroenteritis (e.g., EoE) by administering a pharmaceutical composition described herein and determining the effectiveness of such treatment. In some instances, the subject is a patient who has gastrointestinal inflammation and / or symptoms resistant to at least one acid inhibitor (eg, PPI and / or H2A). In some embodiments, effective treatment of gastrointestinal inflammation with a composition described herein is a positive indicator of the presence of EoE. In some embodiments, this method of diagnosis is used in place of an esophageal biopsy.

[0087] In various embodiments, compositions of the invention include pharmaceutically acceptable salts. Pharmaceutically acceptable salts are generally well known to those skilled in the art and include, for example, but not limited to, acetate, benzenesulfonate, besylate, benzoate, bicarbonate, hydrogen tartrate, bromide, calcium edetate, carnsylate, carbonate, citrate, edetate, edysylate, estolate, esylate , fumarate, gluceptan, gluconate, glutamate, glycol arsanilate, hexyl resorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, mucic acid salt, napsylate, nitrate, pamoate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, basic acetate, succinate, sulfate, tannate, tartrate or theoclate. Other pharmaceutically acceptable salts can be found, for example, in Remington: The Science and Practice of Pharmacy (20th Ed.) Lippincott, Williams and Wilkins (2000). In particular embodiments, pharmaceutically acceptable salts include, for example, acetate, benzoate, bromide, carbonate, citrate, gluconate, hydrobromide, hydrochloride, maleate, mesylate, napsylate, pamoate, phosphate, salicylate, succinate, sulfate, or tartrate. In some embodiments, such salts are used with any of the corticosteroids described herein.

[0088] Depending on the specific conditions treated, the compositions may be formulated as liquid or solid dosage forms and administered systemically or locally. In some embodiments, the agents are delivered in, for example, a timed or sustained slow release form as is known to those skilled in the art. Formulation and administration techniques can be found in Remington: The Science and Practice of Pharmacy (20th Ed.) Lippincott, Williams & Wilkins (2000).

[0089] In addition to the active ingredients, various embodiments of the invention provide pharmaceutical compositions that contain suitable excipients and excipients acceptable to the pharmaceutical industry. For example, in some embodiments, pharmaceutically acceptable excipients and / or adjuvants are used to formulate the corticosteroids disclosed herein in order to practice the invention at dosages suitable for systemic administration and within the scope of the invention. In some embodiments, the corticosteroid is readily formulated with pharmaceutically acceptable excipients and / or excipients well known in the art in dosages suitable for oral administration. Such excipients and / or adjuvants make it possible to formulate the compositions according to the invention in the form of tablets, pills, dragees, capsules, liquids, soft chews, creams, pastes, chewable tablets, gels or gel matrices, syrups, smears, suspensions, gums, lozenges. for consumption by the patient to be treated. In some cases, oral formulations (e.g. suspensions, creams or gel matrices) such that upon oral administration, an intermediate layer is formed between the oral formulation (e.g., suspension, cream or gel matrix) and the gastrointestinal surface (e.g., the esophageal surface). In some instances, an oral formulation (e.g., suspension, cream, or gel matrix) in contact with the gastrointestinal surface (e.g., the esophageal surface) delivers the corticosteroid on and / or across the gastrointestinal surface (e.g. esophageal surface) through the intermediate layer and since oral formulations (e.g., suspensions, creams or gel matrices) contain less corticosteroid near the intermediate layer, a concentration gradient is created. In some instances, aliquots of oral formulations (e.g., suspensions, creams, or gel matrices) with a high concentration of corticosteroid relative to aliquots of oral formulations (e.g. suspensions, creams or gel matrices) near the intermediate layer replenish the corticosteroid in a portion of the oral formulations (e.g., suspensions, creams or gel matrices) near the intermediate layer. In some instances, upon oral administration to a subject of the oral formulation described in the present invention, an intermediate layer is formed between the surface of the gastrointestinal tract (e.g., the surface of the esophagus) and the mixture of the oral formulation (e.g., chewable tablets) and the subject's saliva.

[0090] In some embodiments, pharmaceutical preparations for oral use are obtained by combining corticosteroids with solid excipients, optionally grinding the resulting mixture and processing into granules, after adding a suitable excipient, if desired, to obtain tablets or dragee cores. . Suitable excipients include, for example, but not limited to, fillers, such as sugars or starches, including dextrose, lactose, maltodextrin, sucrose, sucralose, mannitol, or sorbitol; cellulose preparations, for example, corn starch, wheat starch, rice starch, potato starch or combinations thereof. Optionally, disintegrants such as cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate are added. In some embodiments, the pharmaceutical compositions used herein include excipients suitable to make the dissolving tablet palatable, such as sweeteners or flavorings.

[0091] In some embodiments, the pharmaceutical compositions described herein are in liquid form. Excipients suitable for use in the liquid form of a pharmaceutical composition include, for example, those that enhance the mucoadhesive properties of the liquid composition. Optional excipients also include, for example, but not limited to, those that make the liquid composition palatable or increase the viscosity of the liquid composition. Optional excipients that improve the taste include, for example, but not limited to, sugars, including dextrose, lactose, sucrose, sucralose, maltodextrin, mannitol, or sorbitol; honey, combinations thereof or the like.

[0092] Any of the compositions or formulations described herein optionally contain one or more viscosifying agents, optionally include one or more binders, optionally include one or more fillers, optionally include one or more lubricant, optionally include one or more solvents, optionally including one or more suspending agents, optionally containing one or more flavoring agents, optionally containing one or more coloring agents, optionally containing one or more sweetening agents, optionally containing one or more preservatives, optionally containing one or more antioxidants, optionally containing one or more buffering agents, optionally including one or more humectants, optionally contains one or more chelating agents, optionally one or more surfactants or combinations thereof.

Preservatives include, for example, but not limited to, benzalkonium chloride, cetrimide (cetyltrimethylammonium bromide), benzoic acid, benzyl alcohol, para-hydroxybenzoic acid methyl, ethyl, propyl, and butyl esters, chlorhexidine, chlorobutanol, borane, and nitrate, potassium sorbate, sodium benzoate, sorbic acid, thiomersal (mercuric thiosalicylate), combinations thereof or the like. The compositions and formulations described herein optionally include about 0.1% w / w to about 5% w / w, about 0.1% w / w to about 3% w / w, about 0.1% w / w to. about 1% w / w, about 0.1% w / w to about 0.5% w / w, about 0.2% w / w of one or more preservatives.

[0094] Antioxidants include, for example, but not limited to ascorbyl palmitate, butylhydroxyanisole, butylhydroxytoluene, monothioglycerol, sodium ascorbate, sodium formaldehyde sulfoxylate, sodium metabisulfite, BHT, BHA, sodium bisulfite, vitamin E or its EDTA derivatives, edta gallate (EDTA) (e.g. disodium edetate), diethylenetriaminepentaacetic acid (DTPA), triglycolamate (NT), combinations thereof or the like. The compositions and formulations described herein optionally include about 0.01% w / w to about 1% w / w, about 0.01% w / w to about 0.5% w / w, about 0.01% w / w, w to about 0.3% w / w or about 0.01% w / w to about 0.1% w / w of one or more antioxidants.

[0095] Buffering agents include, for example, but not limited to, citrate buffers (ie, citric acid and citrate), phosphate buffers, acetate buffers, combinations thereof, or the like.

[0096] The term citrate as used herein includes all compounds of Formula I wherein each R is independently selected from H and a negative charge (e.g., as a salt or as a dissociated salt or acid). In some embodiments, citrate is selected, for example, but not limited to sodium citrate, citric acid.

<img file="PL2211896T3_D0001.tif" />

Formula

[0097] Humectants include, for example, but not limited to, glycerin, propylene glycol, ethylene glycol, glycerin triacetate, polyols (e.g., sorbitol, xylitol, maltitol, polydextrose). The compositions and formulations described herein optionally include about 0.1% w / w to about 10% w / w, about 1% w / w to about 10% w / w, about 1% to about 8% w / w, or about 5% w / w humectant. In some embodiments, humectants inhibit precipitation and / or crystallization of one or more ingredients of a composition or formulation described herein (e.g., a sweetener, mucoadhesive, or viscosity enhancer).

[0098] Chelating agents include, for example, but not limited to, edetate (EDTA) (eg, disodium edetate), diethylenetriaminepentaacetic acid (DTPA), triglycolamate (NT), or the like. The compositions and formulations described herein optionally include about 0.01% w / w to about 0.5% w / w, about 0.01% w / w to about 0.3% w / w, or about 0.01%. w / w to about 0.1% w / w or about 0.05% w / w of one or more chelating agents.

[0099] As used herein, edetate includes all compounds of formula II where each R is independently selected from H and a negative charge (e.g., as a salt or as a dissociated salt or acid). In some embodiments, the edetate is selected from, for example, but not limited to, disodium edetate, calcium edetate, ethylenediaminetetraacetic acid.

<img file="PL2211896T3_D0002.tif" />

[0100] In some embodiments, sweeteners include, for example, but are not limited to, glycerin, acesulfame potassium (AceK), monoammonium glycyrrhizinate (e.g., Magnasweet®), sucrose, lactose, glucose, fructose, arabinose, xylose, ribose, galactose, and mannose. , dextrose, sorbose, sorbitol, mannitol, maltose, cellobiose, xylitol. In some embodiments, flavorings include, for example, but are not limited to, mint, orange, bubble gum, broadcast gold, grapes, and cherry.

Surfactants include, e.g., anionic, cationic, non-ionic, or dipolar surfactants such as, for example, but not limited to polysorbate (e.g., polysorbate 20, polysorbate 60, polysorbate 40, polysorbate 80, polysorbate 81, polysorbate 85). , polysorbate 120), bile acids or their salts (e.g. sodium taurocholates, sodium deoxytaurocholates, chenodeoxycholic acid and ursodeoxycholic acid), nonoxynol or polyoxyethylene glycol fatty acid esters, pluronics or poloxamers such as Pluronic F68, Pluronic L44, Pluronic L101, combinations thereof or the like. The compositions and formulations described herein optionally include about 0.001% w / w to about 0.5% w / w, about 0.001% w / w to about 0.3% w / w, or about 0.001% w / w to about 0 1% w / w of one or more surfactants.

[0102] Dragee cores are provided with suitable coatings. In some embodiments, concentrated sugar solutions are used for this purpose and optionally include gum arabic, talc, polyvinylpyrrolidone, Carbopol gel, polyethylene glycol (PEG) and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments are optionally added to the tablet or dragee coatings to identify or characterize different combinations of active corticosteroid doses.

[0103] In various embodiments, pharmaceutical preparations that are used orally include filled capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In some embodiments, the filled capsules contain the active ingredient or ingredients mixed with a filler, binder, lubricant, stabilizer, or a combination thereof. Fillers include, for example, but are not limited to, lactose. Binders include, for example, but not limited to, starch. Lubricants include, for example, but not limited to, talc and magnesium stearate. In soft capsules, the corticosteroids may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols (PEG). In addition, stabilizers are optionally added.

[0104] In one embodiment, the invention provides a corticosteroid that has low bioavailability. Due to low bioavailability, a corticosteroid is used in some embodiments of the invention, the corticosteroid remaining in the gastrointestinal tract, for example in the esophagus. In some embodiments, low bioavailability reduces systemic side effects and complications, allowing patients with chronic diseases to be treated for extended periods of time.

[0105] In some embodiments, the pharmaceutical composition or dosage form described herein is a suspension or solution containing a corticosteroid (eg, budesonide). In some embodiments, the compositions (e.g., suspensions or solutions) contain a certain concentration of a corticosteroid (e.g., budesonide) dissolved in a liquid medium (e.g., a solvent or a liquid carrier such as water, alcohol, aqueous alcohol or the like is used). In some embodiments, the amount of corticosteroid (e.g., budesonide) dissolved in the liquid medium (e.g. in a balanced sample) is greater than 4 μg / ml, greater than 5 μg / ml, greater than 10 μg / ml, greater than 15 μg / ml, greater than 20 μg / ml, greater than 21 μg / ml, greater than 22 μg / ml, greater than 23 μg / ml, greater than 24 μg / ml, greater than 25 μg / ml, approximately 25 μg / ml, greater than 30 μg / ml, approximately 25 μg / ml to approximately 80 μg / ml, approx. 30 μg / ml to approx. 80 μg / ml, approx. 30 μg / ml, approx. 35 μg / ml, approx. 40 μg / ml, approx. 45 μg / ml, approx. 50 μg / ml, approx. 55 μg / ml, approx. 60 μg / ml, approximately 65 μg / ml or approximately 70 μg / ml.

[0106] In some embodiments, the compositions described herein contain a certain concentration of budesonide dissolved in a liquid medium (e.g., a solvent or a liquid carrier such as water, alcohol, aqueous alcohol or the like is used). In particular embodiments, the amount of the R epimer dissolved budesonide (compared to the total weight of budesonide) is greater than 28% w / w, greater than 30% w / w, greater than 39% w / w, greater than 40%, about 39- 50%, about 40-50%, less than 38% w / w, about 29% -37% w / w, less than 27% w / w or the like. In some instances, the% epimer is obtained in a composition having a total% R epimer (compared to the total% budesonide) of about 50-55% w / w or about 53-54% w / w. In some instances, sample equilibrium is achieved when the concentration of a corticosteroid (e.g., budesonide) dissolved in the liquid is substantially stable, e.g., 2 days, 3 days, 4 days, 5 days, a week, a month or the like. In certain cases, sample equilibrium is reached after 2 days.

[0107] In some embodiments, the corticosteroid is administered in a commercially available formulation. In other embodiments, the corticosteroid is administered in a composition containing a commercially available corticosteroid formulation and formulated as described herein. For example, in some embodiments, a corticosteroid-containing composition provided herein includes a commercially available formulation and an excipient such as diluents, flavoring, mucoadhesive, viscous agent, binder, filler, lubricant, solvent, suspending agent, colorant, sweetener, preservative, antioxidant, buffering agent, humectant, chelating agent, surfactant, combinations or the like. In some embodiments where the corticosteroid is budesonide, the commercially available formulation is Pulmicort Respules® (distributed by AstraZeneca, e.g., as shown in NDA 20-929). In other embodiments where the corticosteroid is budesonide, the commercially available formulation is Rhinocort Aqua® (distributed by AstraZeneca LP, Wilmington, DE 19850, e.g. as set forth in NDA 20-746, which includes all supplements, herein in their entirety incorporated by reference). In still other embodiments where the corticosteroid is budesonide, the commercially available formulation is Symbicort® (manufactured by AstraZeneca Dunkerque Production, Dunkerque, France, e.g., as set forth in NDA 21-929, which includes all supplements herein in their entirety incorporated herein by reference. ). In some embodiments where the corticosteroid is fluticasone, the commercial formulation is Flanase®. In some embodiments, the ratio of the commercially available formulation to the optional diluent is between about 1: 0.5 and about 1: 100. Diluents include any pharmaceutically acceptable oral diluent including, for example, powder diluents (such as talc) and liquid diluents (such as water, ethanol, and combinations thereof). In some embodiments, the commercially available formulation is Entocort® (manufactured by AstraZeneca AB, S-151 85 Sodertalje, Sweden, distributed by Prometheus Laboratories Inc, San Diego, CA 92121, as set forth in NDA 21-324, which includes all supplements, herein). incorporated herein by reference in its entirety). In some embodiments, the Entocort® formulation is dissolved and / or dispersed in an aqueous vehicle. In particular embodiments, the Entocort® formulation is dispersed in a liquid carrier at a pH sufficient to remove the enteric coating from the budesonide particles. In other embodiments, an Entocort® formulation is pretreated with a solvent at a pH sufficient to remove the intestinal coating from the budesonide particles therein, and the particles are then formulated into a composition as described herein.

[0108] In some embodiments, the corticosteroid composition described herein comprises a corticosteroid, a commercially available formulation, and optionally one or more additional excipients. In some embodiments, the corticosteroid composition described herein comprises a corticosteroid formulated in a manner similar to a commercial fomulation (e.g. one or more active ingredients of the formulation are missing) and, optionally, one or more excipients. One or more additional excipients may be used to obtain the formulation described herein. In particular embodiments, the commercially available formulation is Ultra XCID (manufactured by Matrixx Initiatives, Inc., Phoenix, A2).

[0109] In some embodiments, a composition provided herein comprises or is produced by combining the ingredients shown in any of Tables 1-12. In various embodiments, one or more maltodextrins, dextrose, HEC, CMC, MCC, Carbomer, and HPMC are used.

Table 1: Composition containing budesonide No. 1

<td>Ingredient</td><td>Quantity</td>

<td>Budesonide</td><td>1 mg to 150 mg</td>

<td>CMC, MCC, Carbomer, HPMC and / or HEC</td><td>0.5 g to 10 g</td>

<td>Dextrose</td><td>0 g to 100 g</td>

<td>Maltodextrin</td><td>0 g to 100 g</td>

<td>EDTA (e.g. disodium edetate)</td><td>5 mg to 200 mg</td>

<td>Citric acid</td><td>10 mg to 1 g</td>

<td>Citrate (e.g. sodium citrate)</td><td>10 mg to 2 g</td>

<td>Polysorbate 80 (e.g. Tween 80)</td><td>5 mg to 100 mg</td>

<td>Flavoring agent</td><td>optional</td>

<td>Sweetener</td><td>optional</td>

<td>Preservative</td><td>optional</td>

<td>Water</td><td>qs to 100 ml</td>

Table 2: Composition containing budesonide No. 2

<td>Ingredient</td><td>Quantity</td>

<td>Budesonide</td><td>1 mg to 150 mg</td>

<td>CMC, MCC, Carbomer, HPMC and / or HEC</td><td>0 g to 10 g</td>

<td>Dextrose</td><td>1 g to 100 g</td>

<td>Maltodextrin</td><td>0 g to 100 g</td>

<td>EDTA (e.g. disodium edetate)</td><td>5 mg to 200 mg</td>

<td>Citric acid</td><td>10 mg to 1 g</td>

<td>Citrate (e.g. sodium citrate)</td><td>10 mg to 2 g</td>

<td>Polysorbate 80 (e.g. Tween 80)</td><td>5 mg to 100 mg</td>

<td>Flavoring agent</td><td>optional</td>

<td>Sweetener</td><td>optional</td>

<td>Preservative</td><td>optional</td>

<td>Water</td><td>qs to 100 ml</td>

Table 3: Composition containing budesonide No. 3

<td>Ingredient</td><td>Quantity</td>

<td>Budesonide</td><td>1 mg to 150 mg</td>

<td>CMC, MCC, Carbomer, HPMC and / or HEC</td><td>0 g to 10 g</td>

<td>Dextrose</td><td>0 g to 100 g</td>

<td>Maltodextrin</td><td>1 g to 100 g</td>

<td>EDTA (e.g. disodium edetate)</td><td>5 mg to 200 mg</td>

<td>Citric acid</td><td>10 mg to 1 g</td>

<td>Citrate (e.g. sodium citrate)</td><td>10 mg to 2 g</td>

<td>Polysorbate 80 (e.g. Tween 80)</td><td>5 mg to 100 mg</td>

<td>Flavoring agent</td><td>optional</td>

<td>Sweetener</td><td>optional</td>

<td>Preservative</td><td>optional</td>

<td>Water</td><td>qs to 100 ml</td>

Table 4: Composition containing budesonide No. 4

<td>Ingredient</td><td>Quantity</td>

<td>Budesonide</td><td>0.5 mg to 2 mg</td>

<td>CMC and MCC (e.g. Avicel RC-591)</td><td>0.01 g to 3 g</td>

<td>Dextrose</td><td>0.1 g to 1 g</td>

<td>Maltodextrin</td><td>0.5 g to 2 g</td>

<td>EDTA (e.g. disodium edetate)</td><td>1 mg to 10 mg</td>

<td>Citric acid</td><td>0.1 mg to 100 mg</td>

<td>Citrate (e.g. sodium citrate)</td><td>0.1 mg to 200 mg</td>

<td>Polysorbate 80 (e.g. Tween 80)</td><td>0.1 mg to 10 mg</td>

<td>Cherry flavor</td><td>1 mg to 100 mg</td>

<td>Sweetener</td><td>100 mg to 1 g</td>

<td>Sodium benzoate</td><td>1 mg to 50 mg</td>

<td>Potassium Sorbate</td><td>1 mg to 50 mg</td>

<td>Water</td><td>qs to 5 ml</td>

Table 5: Composition containing budesonide No. 5

<td>Ingredient</td><td>Quantity</td>

<td>Budesonide</td><td>0.5 mg to 2 mg</td>

<td>CMC and MCC (e.g. Avicel RC-591)</td><td>0.02 g to 0.6 g</td>

<td>Dextrose</td><td>0.2 g to 2 g</td>

<td>Maltodextrin</td><td>1 g to 4 g</td>

<td>EDTA (e.g. disodium edetate)</td><td>2 mg to 20 mg</td>

<td>Citric acid</td><td>0.2 mg to 200 mg</td>

<td>Citrate (e.g. sodium citrate)</td><td>0.2 mg to 400 mg</td>

<td>Polysorbate 80 (e.g. Tween 80)</td><td>0.2 mg to 20 mg</td>

<td>Cherry flavor</td><td>2 mg to 200 mg</td>

<td>Sweetener</td><td>200 mg to 2 g</td>

<td>Sodium benzoate</td><td>2 mg to 100 mg</td>

<td>Potassium Sorbate</td><td>2 mg to 100 mg</td>

<td>Water</td><td>qs to 10 ml</td>

Table 6: Composition containing budesonide No. 6

<td>Ingredient</td><td>Amount (mg / ml)</td>

<td>Budesonide</td><td>0.01 to 0.5</td>

<td>CMC and MCC (e.g. Avicel RC-591)</td><td>2 to 100</td>

<td>Dextrose</td><td>10 to 500</td>

<td>Maltodextrin</td><td>10 to 500</td>

<td>EDTA (e.g. disodium edetate)</td><td>0.01 to 10</td>

<td>Citric acid</td><td>0.1 to 10</td>

<td>Citrate (e.g. sodium citrate)</td><td>0.1 to 10</td>

<td>Polysorbate 80 (e.g. Tween 80)</td><td>0.01 to 1</td>

<td>Flavoring (e.g. cherry flavor)</td><td>0.1 to 100</td>

<td>Glycerine</td><td>10 to 100</td>

<td>Acesulfame potassium</td><td>0.1 to 40</td>

<td>Magnasweet 110</td><td>0.1 to 40</td>

<td>Sodium benzoate</td><td>0.1 to 10</td>

<td>Potassium Sorbate</td><td>0.1 to 10</td>

<td>Water</td><td>qs to 1-15 ml</td>

Table 7: Composition containing budesonide No. 7

<td>Ingredient</td><td>Amount (mg / ml)</td>

<td>Budesonide</td><td>about 0.05 to about 0.2</td>

<td>CMC and MCC (e.g. Avicel RC-591)</td><td>5 to 50</td>

<td>Dextrose</td><td>50 to 250</td>

<td>Maltodextrin (M150)</td><td>200 to 500</td>

<td>EDTA (e.g. disodium edetate)</td><td>0.1 to 1</td>

<td>Citric acid</td><td>0.5 to 5</td>

<td>Citrate (e.g. sodium citrate)</td><td>0.2 to 2</td>

<td>Polysorbate 80 (e.g. Tween 80)</td><td>0.01 to 0.4</td>

<td>Flavoring (e.g. cherry flavor)</td><td>1 to 10</td>

<td>Glycerine</td><td>30 to 80</td>

<td>Acesulfame potassium</td><td>1 to 10</td>

<td>Magnasweet 110</td><td>1 to 10</td>

<td>Sodium benzoate</td><td>0.5 to 4</td>

<td>Potassium Sorbate</td><td>0.5 to 4</td>

<td>Water</td><td>qs to 1-15 ml</td>

Table 8: Composition containing budesonide No. 8

<td>Ingredient</td><td>Amount (mg / ml)</td><td>Amount% w / w</td>

<td>Budesonide</td><td> 0,05</td><td> 0,004</td>

<td>Avicel RC-591</td><td> 23,6</td><td> 2</td>

<td>Dextrose</td><td> 118</td><td> 10</td>

<td>Maltodextrin (M150)</td><td> 306,8</td><td> 26</td>

<td>Disodium edetate</td><td> 0,59</td><td> 0,05</td>

<td>Citric acid</td><td> 1,77</td><td> 0,15</td>

<td>Sodium citrate</td><td> 0,59</td><td> 0,05</td>

<td>Polysorbate 80</td><td> 0,12</td><td> 0,01</td>

<td>Cherry flavor</td><td> 5,9</td><td> 0,5</td>

<td>Glycerine</td><td> 59</td><td> 5</td>

<td>Acesulfame potassium</td><td> 5,9</td><td> 0,5</td>

<td>Magnasweet 110</td><td> 5,9</td><td> 0,5</td>

<td>Sodium benzoate</td><td> 2,36</td><td> 0,2</td>

<td>Potassium Sorbate</td><td> 2,36</td><td> 0,2</td>

<td>Water</td><td>qs to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 ml</td><td>qs to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 ml</td>

Table 9: Composition containing budesonide No. 9

<td>Ingredient</td><td>Amount (mg / ml)</td><td>Amount% w / w</td>

<td>Budesonide</td><td> 0,2</td><td> 0,17</td>

<td>Avicel RC-591</td><td> 23,6</td><td> 2</td>

<td>Dextrose</td><td> 118</td><td> 10</td>

<td>Maltodextrin (M150)</td><td> 306,8</td><td> 26</td>

<td>Disodium edetate</td><td> 0,59</td><td> 0,05</td>

<td>Citric acid</td><td> 1,77</td><td> 0,15</td>

<td>Sodium citrate</td><td> 0,59</td><td> 0,05</td>

<td>Polysorbate 80</td><td> 0,12</td><td> 0,01</td>

<td>Cherry flavor</td><td> 5,9</td><td> 0,5</td>

<td>Glycerine</td><td> 59</td><td> 5</td>

<td>Acesulfame potassium</td><td> 5,9</td><td> 0,5</td>

<td>Magnasweet 110</td><td> 5,9</td><td> 0,5</td>

<td>Sodium benzoate</td><td> 2,36</td><td> 0,2</td>

<td>Potassium Sorbate</td><td> 2,36</td><td> 0,2</td>

<td>Water</td><td>qs to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 ml</td><td>qs to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 ml</td>

Table 10: Composition containing # 1 fluticasone

<td>Ingredient</td><td>Quantity</td>

<td>Fluticasone Propionate</td><td>0.5 mg to 150 mg</td>

<td>CMC, MCC, Carbomer, HPMC and / or HEC</td><td>0.5 g to 10 g</td>

<td>Dextrose</td><td>0 g to 100 g</td>

<td>Maltodextrin</td><td>0 g to 100 g</td>

<td>EDTA (e.g. disodium edetate)</td><td>5 mg to 200 mg</td>

<td>Citric acid</td><td>10 mg to 1 g</td>

<td>Citrate (e.g. sodium citrate)</td><td>10 mg to 2 g</td>

<td>Polysorbate 80 (e.g. Tween 80)</td><td>5 mg to 100 mg</td>

<td>Flavoring agent</td><td>optional</td>

<td>Sweetener</td><td>optional</td>

<td>Preservative</td><td>optional</td>

<td>Water</td><td>qs to 100 ml</td>

Table 11: Composition containing # 2 fluticasone

<td>Ingredient</td><td>Quantity</td>

<td>Fluticasone Propionate</td><td>0.5 mg to 150 mg</td>

<td>CMC, MCC, Carbomer, HPMC and / or HEC</td><td>0 g to 10 g</td>

<td>Dextrose</td><td>1 g to 100 g</td>

<td>Maltodextrin</td><td>0 g to 100 g</td>

<td>EDTA (e.g. disodium edetate)</td><td>5 mg to 200 mg</td>

<td>Citric acid</td><td>10 mg to 1 g</td>

<td>Citrate (e.g. sodium citrate)</td><td>10 mg to 2 g</td>

<td>Polysorbate 80 (e.g. Tween 80)</td><td>5 mg to 100 mg</td>

<td>Flavoring agent</td><td>optional</td>

<td>Sweetener</td><td>optional</td>

<td>Preservative</td><td>optional</td>

<td>Water</td><td>qs to 100 ml</td>

Table 12: Composition containing fluticasone # 3

<td>Ingredient</td><td>Quantity</td>

<td>Fluticasone Propionate</td><td>0.5 mg to 150 mg</td>

<td>CMC, MCC, Carbomer, HPMC and / or HEC</td><td>0 g to 10 g</td>

<td>Dextrose</td><td>0 g to 100 g</td>

<td>Maltodextrin</td><td>1 g to 100 g</td>

<td>EDTA (e.g. disodium edetate)</td><td>5 mg to 200 mg</td>

<td>Citric acid</td><td>10 mg to 1 g</td>

<td>Citrate (e.g. sodium citrate)</td><td>10 mg to 2 g</td>

<td>Polysorbate 80 (e.g. Tween 80)</td><td>5 mg to 100 mg</td>

<td>Flavoring agent</td><td>optional</td>

<td>Sweetener</td><td>optional</td>

<td>Preservative</td><td>optional</td>

<td>Water</td><td>qs to 100 ml</td>

Diseases

[0110] In certain embodiments, provided herein are compositions for use in treating, preventing or alleviating inflammation or symptoms associated with inflammation of the gastrointestinal tract, eg, esophagus. In particular embodiments, the composition reduces or ameliorates the symptoms of gastrointestinal inflammation. In more particular embodiments, the gastrointestinal inflammation is eosinophilic esophagitis (EoE). In some embodiments, the composition is for the treatment of inflammation associated with eosinophilic esophagitis (EoE). In some embodiments, the composition is for the treatment of dysphagia associated with eosinophilic esophagitis (EoE). In some embodiments, the composition is for the treatment of inflammation and dysphagia associated with eosinophilic esophagitis (EoE). In some embodiments, the compositions described herein are for the treatment of gastrointestinal diseases or conditions (e.g., upper gastrointestinal disease or condition, including esophageal disease or condition).

[0111] In some embodiments, administration of a composition described herein treats, prevents, or alleviates inflammation or symptoms associated with an inflammatory disease or condition. Gastrointestinal diseases or conditions include, for example, but not limited to, any chronic inflammation or malignant condition that involves the gastrointestinal tract (e.g., upper gastrointestinal tract, esophagus, stomach, and / or gastrointestinal tract) and is susceptible to steroid treatment. In some instances, diseases or conditions treated using the compositions described herein include diseases or conditions of the upper gastrointestinal tract (including upstream diseases and disorders), esophagus, stomach, and / or gastrointestinal tract. The methods of the invention are useful, for example, in treating, preventing, and alleviating inflammation associated with or symptoms of eosinophilic esophagitis, inflammatory bowel disease involving the esophagus, Crohn's disease, corrosive / irritant acute oesophagitis, persistent / recurrent esophageal stricture as a result of ingestion of a corrosive / irritating substance, systemic diseases, congenital diseases, post-operative inflammation or gastrointestinal infection. The methods of the invention are also useful, for example, in treating, preventing, and alleviating inflammation associated with or symptoms of gastroesophageal reflux disease (GERD), non-erosive reflux disease (NERD), Barrett's esophagus, and / or erosive esophagitis.

[0112] It will be understood that reference to treatment herein includes both prophylaxis and treatment of inflammation or other symptoms.

[0113] Also disclosed herein is a composition for use in treating, preventing or alleviating inflammation of the gastrointestinal tract including, for example, but not limited to, the esophagus, stomach and / or digestive system in a subject. In some embodiments, the oral dosage form comprises a liquid carrier and is formulated as, e.g., a goose, suspension, syrup, dispersion, solution, etc.

[0114] In one aspect, the patient is administered a corticosteroid such as, for example, budesonide or fluticasone propionate.

[0115] In some embodiments, the inflammation treated using the compositions described herein is associated with eosinophilic inflammation and / or neutrophilic inflammation. In some embodiments, subjects (e.g. patients) to be treated with the compositions described herein include those diagnosed with eosinophilic esophagitis, inflammatory bowel disease involving the esophagus, Crohn's disease, celiac disease, proximal gastrointestinal pathology (e.g. individuals suffering from gallbladder insufficiency), eosinophilic gastroenteritis, celiac disease, eosinophilic duodenitis, duodenal eosinophilia, functional dyspepsia, indirect oesophagitis, epithelial hyperplasia, basal cell hyperplasia, papillary lengthening, vasodilation in the papillae, fungal esophagitis (e.g. Candida, torulopsis, histoplasma Aspergillus etc.), viral esophagitis (e.g. HSV, CMV, V2V), bacterial oesophagitis (e.g. tuberculosis, actinomycosis, syphilis), corrosive oesophagitis, radiation oesophagitis, post-chemotherapy oesophagitis, graft versus host disease, oesophageal skin disease (e.g. pemphigoid, pemphigus vulgaris, epidermal blistering, Stevens-Johnson syndrome), Behcet's disease, sarcoidosis, idiopathic esophagitis, eosinophilic gastritis, Menetrier's disease, parasitic gastritis, lymphocytic oesophagitis, inflammation of the esophagus intestines, parasitic gastritis, inflammation of the esophagus following ingestion of a corrosive / irritant substance, persistent / recurrent esophageal strictures from any cause including corrosive / irritant ingestion, drug-induced oesophagitis, systemic diseases, congenital diseases, postoperative inflammation or gastrointestinal infections. In one but not exclusive example, the patient has eosinophilic esophagitis. In some embodiments, subjects (e.g. patients) to be treated with compositions described herein include those diagnosed with Barrett's esophagus, gastroesophageal reflux disease (GERD), non-erosive gastroesophageal reflux disease (NERD), and / or erosive esophagitis. In some embodiments, the patient is an adult. In other embodiments, the patient is a child or infant. In various aspects, the patient is a child or infant under the age of 16, under the age of 12, under the age of 8, under the age of 6, under the age of 4, or under the age of 2.

[0116] In some embodiments, the composition is in a unit dosage form for oral administration to a patient. In some embodiments, a unit dose of a corticosteroid is administered using a metering device. In some embodiments, a dose metering device delivers a metered unit dose of a composition described herein to the oropharynx of a subject in need thereof. In some embodiments, the metering device is a metered dose inhaler that is used to deliver a metered unit dose to the oropharynx of a subject (the subject swallows rather than inhales a metered dose unit). In some embodiments, a metering device dispenses a metered unit dose of a composition described herein into a container (e.g. cup), which is then used to orally administer a measured unit dose into the mouth or throat. In some aspects, the subject is administered about 0.01 mg to about 20 mg, about 0.01 mg to about 15 mg, or about 0.01 mg to about 10 mg (e.g., about 0.1-10 mg, about 0.25 mg, -5 mg, about 0.25-2.5 mg, about 1-2 mg, or about 2-3 mg) of corticosteroid per day or per dose. In some embodiments, the corticosteroid is present in the composition or unit dose of the composition described herein in an amount from about 0.01 mg to about 10 mg (e.g., about 0.1-10 mg, about 0.25-5 mg, about 0 , 3-4 mg, about 0.25-2.5 mg, about 1-2 mg, or about 2-3 mg). In some embodiments, the amount of corticosteroid administered daily or in a unit dose is from about 0.5 mg to about 3 mg. In other embodiments, the amount of corticosteroid present in a unit dose or administered daily is between about 1 and about 3 mg, or about 1 mg and about 2 mg, or about 2 and about 3 mg.

[0117] The citation of the above patents, patent applications, publications and documents is not an admission that any of the above is relevant to the art, nor does it constitute any acceptance as to the content or date of such publications or documents.

[0118] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The methods, devices, and materials are now described, although any methods and systems similar or equivalent to those described herein can be used in the practice or testing of the invention. All publications mentioned herein are incorporated by reference to describe and disclose the processes, systems and methodologies that are reported in publications that may be used in connection with the invention. Nothing in this document is to be interpreted as assuming that the invention is not entitled to precede such disclosure on the basis of the prior invention.

[0119] Modifications to the above can be made without departing from the essential aspects of the invention. Although the invention has been described in detail with reference to one or more specific embodiments, it will be appreciated by those skilled in the art that variations can be made to the embodiments specifically disclosed in this application, and that such modifications and improvements are within the scope of the invention. The invention illustratively described herein is suitably practiced in the absence of any element (s) not specifically disclosed herein. Thus, for example, in each case herein, any of the terms comprising, consisting essentially of and consisting of, may be replaced by one of the other two. Thus, the terms and phrases used are used as terms for the description and not as limitation, equivalents of the features shown and described, or parts thereof, are not excluded, and it is contemplated that various modifications are possible within the scope of the invention.

[0120] In some embodiments, provided herein is a multi-unit container containing about 2 to about 180, about 10 to about 60, about 14, or about 30 unit doses of any pharmaceutical composition described herein. In more specific embodiments, each dose comprises about 1 ml to about 25 ml, about 1 ml to about 20 ml, about 7 ml to about 25 ml, about 10 to about 20 ml, about 15 ml, about 20 ml, about 3 to about 7 ml, about 5 ml, about 8 ml to about 12 ml, or about 10 ml. In even more specific embodiments, each dose comprises about 0.1 to about 20 mg, about 0.1 to about 10 mg, about 0.1 to about 7.5 mg, about 0.1 to about 5 mg, about 0 3 to about 4 mg, about 0.25 to about 2.5 mg, about 0.3 mg to about 2 mg, about 0.5 mg to about 1 mg, about 0.7 mg to about 1.5 mg, about 0.375 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, or about 2 mg of a corticosteroid. In some embodiments, provided herein is provided a multi-unit container containing about 10 ml to about 1500 ml, about 50 ml to about 600 ml, about 150 ml, about 300 ml, about 600 ml, or about 1200 ml of any pharmaceutical composition described herein. document. In particular embodiments, the multi-dose container contains about 330 ml or about 55 ml of the composition described herein. In some embodiments, a kit provided herein includes any multi-dose container described herein, a pharmaceutical composition as described herein (e.g., in a volume described), and a delivery device (e.g., syringe, cup, spoon, or the like). In particular embodiments, the delivery device is incorporated into the container (e.g., nebulizer, aerosol generating device, pump, or the like). In some embodiments, the pharmaceutical composition contained in any multi-unit container described herein is physically and chemically stable.

[0121] In some aspects, the patient is administered about 0.1 mg to about 20 mg, about 0.25 mg to about 20 mg, about 0.25 mg to about 15 mg, about 0.25 mg to about 10 mg, or about 0.25 mg to about 5 mg (e.g., about 0.1 to about 5 mg, about 0.3 mg to about 4 mg, about 0.25 to about 2.5 mg, about 0.3 mg to about 2 mg) , about 0.5 mg to about 1 mg, about 0.7 mg to about 1.5 mg, about 0.375 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, or about 2 mg) of a corticosteroid per day. In some embodiments, the corticosteroid is present in a unit dose in an amount from about 0.25 mg to about 5 mg. In some embodiments, the amount of corticosteroid administered daily or in a unit dose is from about 0.3 mg to about 4 mg. In certain embodiments, the amount of administered corticosteroid administered per day or in a unit dose is from about 0.5 mg to about 3 mg. In other embodiments, the amount of corticosteroid present in a unit dose or daily administered is from about 1 to about 3 mg, or from about 1 to about 2 mg, or from about 2 to about 3 mg.

[0122] In some embodiments, any composition or formulation described herein is stable. In particular embodiments, the composition is chemically and physically stable. In some embodiments, the chemical stability is confirmed when the composition comprises at least 80%, 90%, 95%, 98% or 99% of the original amount or amount of corticosteroid and / or optionally additional active ingredient, for example, but not limited to 1 week. , 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, 2 years or for the period of validity. In some embodiments, physical stability is confirmed when the pharmaceutical composition, which is capable of being substantially homogeneous, remains substantially homogeneous (e.g., for at least 1 day, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months). , 6 months, 1 year, 2 years etc.) or substantially regains homogeneity (e.g. by gentle or moderate shaking after being intact for 1 day, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, 2 years etc.). In some embodiments, physical stability is demonstrated when the composition comprises at least 80%, 90%, 95%, 98% or 99% of the initial amount or labeled amount of a corticosteroid and / or an optional additional active ingredient, for example, but not limited to for 2 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, 2 years or for the period of validity. In some embodiments, the uniformity as described herein is evidenced by the uniformity of the dispersed corticosteroid particles throughout the pharmaceutical composition, the uniformity of the dispersed mass of the corticosteroid in the pharmaceutical composition, the uniformity of the concentration of one or more ingredients in the composition throughout the pharmaceutical composition. In some embodiments, gentle or moderate shaking includes, for example, but not limited to shaking, shaking strongly, swirling, gently swirling. In some embodiments, mild or moderate shaking includes shaking without special apparatus. In some embodiments, pharmaceutical composition uniformity refers to dose uniformity (e.g. each dose delivered to or withdrawn from the composition contains a substantially similar amount of corticosteroid or corticosteroid concentrations in at least some or all of the doses of the multi-dose formulation that are substantially similar. In some embodiments, substantially similar ranges, for example, from 20%, 15%, 10%, 7%, 5%, 3%, 2%, or 1%.

[0123] In some embodiments, the dose or volume of the composition administered is adjusted based on the effectiveness of the treatment. In some embodiments, diagnosis of eosinophilic esophagitis is achieved by administering a composition as described herein and determining treatment efficacy. In some embodiments, a composition is used as described herein that has been separately determined to be effective in treating eosinophilic esophagitis. Treatment efficacy can be determined in any suitable manner, including, for example, symptom scoring, gastroscopy (e.g., esophagogastroduodenoscopy), gastrointestinal (e.g., esophageal) biopsy, histological evaluation, or a combination thereof. The process of diagnosing eosinophilic esophagitis and / or determining the effectiveness of treatment includes any suitable process including, for example, but not limited to, the processes set out in Aceves et al., J Allergy Clin Immunol, February 2008; abstract 270 or Aceves et al., Am J Gastroenterol., October 2007, 102 (10): 2271-9.

Also described herein is a process for determining treatment efficacy (e.g., for eosinophilic esophagitis) and scoring clinical symptoms comprising (i) administering a composition described herein to a subject diagnosed or suspected to have eosinophilic esophagitis; and (ii) assessing one or more symptoms in the subject. Symptoms that are optionally scored include, for example, but are not limited to, nausea, vomiting, pain, and heartburn. The total score or change in score is optionally used to diagnose a disorder and / or determine treatment efficacy.

[0125] The process for determining the efficacy of a treatment described herein includes (i) administering a composition described herein to a subject diagnosed or suspected of having inflammation of the gastrointestinal tract (e.g. eosinophilic oesophagitis) and / or related symptoms; (ii) endoscopy of the surface of the gastrointestinal tract of the subject; (iii) a biopsy of the surface tissue of the gastrointestinal tract; and (iv) evaluating the tissue obtained by biopsy, and optionally determining the endoscopic outcome of the biopsied tissues. In particular embodiments, the process further comprises comparing biopsy and / or endoscopic tissue assessments obtained prior to administering the composition to biopsy and / or endoscopic tissue results following administration of the composition.

[0126] Also disclosed herein is a process of diagnosing a subject with gastroenteritis by (i) detecting and / or measuring symptoms in the subject prior to administering to the subject a composition as described herein; (ii) administering to the subject any composition described herein; (iii) detecting and / or measuring symptoms in a subject after administering the composition; and (iv) comparing the symptoms measured or detected before and after administration of the composition described herein. A positive diagnosis occurs when the subject's symptoms are reduced (e.g., by a statistically significant or clinically significant amount). In particular embodiments, the process of diagnosing a subject with gastroenteritis is diagnosing a subject with eosinophilic esophagitis.

Combinations

[0127] As discussed herein, the compositions and formulations described herein contain at least one corticosteroid (eg, budesonide or fluticasone propionate). In some embodiments, a composition or formulation described herein further comprises at least one additional active ingredient. In particular embodiments, a composition or formulation as described herein comprises a therapeutically effective amount of a corticosteroid and a therapeutically effective amount of at least one additional active ingredient. In some embodiments, the at least one additional active is an agent that treats, prevents, or alleviates symptoms and / or inflammation associated with inflammatory diseases involving the gastrointestinal tract (e.g., esophagus). It should be understood that in some instances when a corticosteroid is combined with an additional active ingredient, the therapeutically effective amount of the corticosteroid is less than in the absence of the additional active ingredient.

[0128] In addition, the compositions provided herein are compositions for preventing or ameliorating inflammation of the gastrointestinal tract (e.g., esophagus) in a subject, comprising orally administering to the subject a corticosteroid in combination or combination with at least one additional active ingredient. In some embodiments, the corticosteroid and the at least one additional active ingredient are in a single dosage form. In other embodiments, the corticosteroid and the at least one additional active ingredient are in separate dosage forms and are administered in any manner, including, for example, but not limited to, simultaneously, sequentially, or at different times. For example, in some embodiments, several doses of a corticosteroid composition are administered over a period of time after which the administration of the corticosteroid composition is discontinued and at least one additional active ingredient is administered at least once.

[0129] In some embodiments, at least one additional active ingredient used in the composition, the formulation described herein is a substance that treats, prevents or alleviates symptoms and / or inflammation associated with inflammatory diseases involving the gastrointestinal tract (eg, esophagus). In more specific embodiments, the at least one additional active ingredient is not a second corticosteroid. In some embodiments, the at least one additional active is an acid inhibitor (eg, an H2 and / or PPI antagonist). In some embodiments, the at least one additional active ingredient is, for example, but not limited to, a proton pump inhibitor (PPI), an H2 antagonist, an agent that reduces transient relaxation of the lower esophageal sphincter (PPI). transient lower esophageal sphincter relaxation (TLESR), serotonergic / prokinetic agent, potassium-competitive acid blocker (P-CAB), mucosal protective agent, histamine H3 agonist, anti-gastrin receptor agent, or a combination thereof.

[0130] In some embodiments, a patient receives combined treatment with a composition as described herein and another drug and / or diet.

EXAMPLES

Example 1:

[0131] This example demonstrates the increased interaction between the composition described herein and the esophagus compared to an oral radiolabeled composition by combining Pulmicort Respules® (4 ml) with ^99mTc of pertechnetate and dilute with saline to approximately 7-8 ml (M0). Composition Mo has a viscosity of around cP at 13.2 sec^-1. A population of healthy individuals was administered a radiolabeled oral budesonide (M1) composition. A radiolabeled budesonide (M1) composition prepared in a volume of approximately 7-8 ml by combining Pulmicort Respules®, approximately 10 packs of Splenda® (distributed by McNeil Nutritionals, LLC Fort Washington, PA 19034-2299) and^99mTc of pertechnetate, contains about 7% w / w maltodextrin and has a viscosity of about 200 cP at 13.2 s^-1. A radiolabeled budesonide (M2) composition was prepared in a volume of approximately 7-8 ml by combining Pulmicort Respules®, 70% w / w maltodextrin and^99mTc of pertechnetate with a viscosity of about 1450 cP at 13.2 s^-1. A healthy population was also administered a radiolabeled budesonide composition (Rhinocort Aqua®, M3) having a viscosity of approximately 39 at 13.2 sec.^-1. The increased interaction of the budesonide composition was determined by measuring the amount of radioactive tracer present in the esophagus following oral administration of a viscous budesonide composition. Figure 1 shows the percentage of the composition in the esophagus as a function of time after oral administration (by measuring the amount of radiolabel in the esophagus).

[0132] The area under the curve (AUCr) of the percentage of dose administered as a function of time (% dose * time (min)) is determined from ingestion 50% (i.e. 50% of the administered dose passed from the mouth) to oesophageal activity is peaked and then decreased to 10% of peak value. The area under the curve from t = 0 min to t = 1 min (AUC0-1) and from t = 0 min to t = 2 min (AUC0-2) were also determined. These results (including the ratio of non-sticky sample to sticky sample) are as follows:

<td rowspan="2">Formulation</td><td colspan="2">AUCr</td><td colspan="2">AUC0-1</td><td colspan="2">AUC0-2</td>

<td>geometric mean</td><td>ratio</td><td>geometric mean</td><td>ratio</td><td>geometric mean</td><td>ratio</td>

<td>M0</td><td> 3,95</td><td></td><td> 5,51</td><td></td><td> 6,93</td><td></td>

<td>M1</td><td> 6,33</td><td> 0,62</td><td> 8,84</td><td> 0,62</td><td> 9,41</td><td> 0,74</td>

<td>M2</td><td> 17,67</td><td> 0,22</td><td> 18,91</td><td> 0,29</td><td> 21,94</td><td> 0,32</td>

<td>M3</td><td> 9.39</td><td> 0,42</td><td> 11,07</td><td> 0,5</td><td> 14,16</td><td> 0,49</td>

Example 2:

[0133] This example describes the efficacy and safety of using the once and twice daily budesonide formulation described herein at 5 ml and 7 ml doses in inducing and maintaining remission of disease activity in children with EE. The number of children (e.g., 20 per frequency, amount and dose volume of budesonide) is assessed to determine the highest eosinophil count (eos / hpf) and the mean highest eosinophil count in the group. The score for the highest eosinophil count (eos / hpf) and the mean highest eosinophil count in a group are also determined after treatment. Symptom scores and mean symptom scores are also determined before and after treatment.

[0134] In some instances, subjects who have previously been treated with a proton pump inhibitor, an elimination diet by skin or blood allergy test, an elimination diet, or have refused an elimination diet but still show&gt; 24 eos / hpf on esophageal biopsy are included in the study. Patients are defined as having food or allergenic sensitization if RAST and / or skin tests are positive. No change occurs in long-term therapy used to treat chronic diseases such as asthma or eczema, and none of the children receive concurrent immunomodulatory therapy.

[0135] Endoscopy is performed using an Olympus P160 endoscope (according to RD) and biopsies of the entire esophagus, stomach and duodenum are taken. Eosinophilic esophagitis is diagnosed when at least one esophageal biopsy site has&gt; 24 eos / hpf. Two mucosal biopsies are taken from the proximal esophagus (3 cm below the cricopharyngeal muscle), the distal esophagus (3 cm above the junction of the stomach and esophagus). gastroesophageal junction (GEJ)) and the middle esophagus (center between the cricopharyngeal muscle and the GEJ). Biopsies are routinely performed and evaluated by a pediatric pathologist (RN). The highest number of eosinophils per field at 400x magnification is counted. Basal zone hyperplasia (BZH) has been reported when the basal layer cells extend towards the luminal epithelial surface (&gt; 25% of epithelial thickness).

[0136] Another endoscopy with biopsy is performed after 3-4 months of treatment. Response to treatment was determined with the highest number of eos / hpf in biopsies, and patients were divided into treatment responders (0-7 eos / hpf), partial responders (8-23 eos / hpf) and non-responders (&gt; 24 eos / hpf).

[0137] Endoscopy EE (EoE) score is designed to compare the results obtained before and after treatment. It is calculated on the basis of reports on procedures and photos. Four categories, (1) paleness and less pronounced vessels; (2) furrows and thickened mucosa; (3) white mucosa plaques; (4) concentric rings or tapers. One point is assigned for each category if lesions are detected in 1 or 2 esophageal sites, and two points if lesions are detected throughout the esophagus. The maximum score is 8.

[0138] Patients receive the formulation described herein in an amount of 0.25 to 2 mg per day, and it is not recommended to consume any solids or liquids for 30 minutes after administration. No changes were made to the diet of patients already subject to dietary restrictions.

[0139] The EE clinic (EoE) routinely uses the modified symptom score of children with peptic ulcer disease. Symptom categories include (1) heartburn or regurgitation; (2) abdominal pain or unexplained irritability in younger children; (3) nausea or vomiting; (4) anorexia or early satiety; (5) dysphagia or odynophagia; (6) symptomatic nocturnal awakening; (7) gastrointestinal bleeding (previous 4 months). Each category received 0-2 points with a maximum of 14 points. Zero points are awarded if the symptom is absent; one point if the symptom is mild, does not interfere with daily activities, and 2 points if the symptoms are severe enough to interfere with daily activities. Previous gastrointestinal bleeding is considered mild (1 point) if there is no associated cardiac impairment or anemia, or too severe (2 points) if bleeding is numerous, has resulted in anemia or blood transfusion is required.

[0140] All statistical analysis is performed using the NCSS statistical software package. Two-sided p-values ​​are calculated using paired Student's t-test to compare a patient's mean eos / hpf, Endoscopy EE (EoE) score, and symptom score before and after budosonide treatment. Two-sided unpaired Student's t-test is used to compare the variables in treatment responders and non-responders. Spearman's correlation coefficients are generated using GraphPad Prism software. Results with p values ​​&lt;0.05 are considered statistically significant. The mean and median are generated, both are equivalent, and the means are presented.

[0141] Test subjects. The charts were reviewed for a number of children. All children show&gt; 24 eos / hpf on repeated oesophageal biopsy prior to treatment initiation.

[0142] Treatment. Patients received the described formulation for a specified period of time (e.g., 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, or the like) prior to re-endoscopy. Various patients received budesonide in an amount ranging from 0.25 to 2 mg / day.

[0143] Histology. Prior to treatment, the mean highest eosinophil count is measured for all patients, including the distal, middle, and proximal esophagus. All seats are similarly assessed within the allotted time, and again if required.

[0144] Upper GI Endoscopy. Before treatment, the mean endoscopy EE (EoE) score was determined for all patients. After treatment, the mean endoscopic EE (EoE) result is repeated. Reduction in endoscopic scores (e.g.,&gt; 95%,&gt; 90%,&gt; 85%,&gt; 75%,&gt; 50%,&gt; 25%, or the like) in individual subjects is indicative of successful treatment.

[0145] Symptom Score. Prior to treatment, the mean symptom score for all patients is determined. And then determines again after treatment. A reduction in symptom scores (e.g.,&gt; 95%,&gt; 90%,&gt; 85%,&gt; 75%,&gt; 50%,&gt; 25%, or the like) in subjects is indicative of successful treatment (alone or in conjunction with the above-mentioned decrease). endoscopy result).

[0146] Adults: These parameters are repeated in adults to determine the efficacy and safety of the treatment.

Example 3:

[0147] This example describes the efficacy and safety of once and twice daily budesonide use in the formulation described herein in inducing and maintaining remission of disease activity in subjects (children and / or adults) with GERD. Doses of 0-1 mg, 1-2 mg, 2-3 mg, 3-4 mg, 4-5 mg and 5-6 mg per daily dose are administered once daily, bid or tid in volumes of 3, 5, 7, 10 , 12, 15 or 17.5 ml. Many individuals (e.g. twenty frequency, amount and volume of budesonide dosing) were assessed to determine symptoms before, during and after treatment. Administration is continued for 7 days, 14 days and 28 days. First Measurements include complete resolution of heartburn and regurgitation (e.g., no more than one day with mild heartburn or regurgitation in the 7 days prior to scheduled assessment time point). Secondary Measurements include: Number of days with heartburn (day and night); Number of days with regurgitation (day and night); The number of days without heartburn and regurgitation (24 hours); Combined score for frequency and severity of heartburn and regurgitation and Time to resolution of heartburn / regurgitation symptoms; Worsening of additional GERD symptoms; Quality of life (assessed using PAGI-QOL to PGIC (Patient General Impression of Change); Complete resolution of heartburn; Complete resolution of regurgitation; Moderate severity of heartburn (day and night); Moderate severity of regurgitation (day and night). These symptoms are assessed (e.g., assigning 3 to the most severe symptoms and 0 to no symptoms) and used to determine treatment effectiveness.

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