WO2018193423A1

WO2018193423A1 - Oral pharmaceutical compositions of corticosteroids

Info

Publication number: WO2018193423A1
Application number: PCT/IB2018/052771
Authority: WO
Inventors: Robert F. WOOLLEY; Eliana Martins LIMA; Thais Leite NASCIMENTO; Rayane Santa Cruz ANTONINO; Edilson RIBEIRO
Original assignee: Ferring B.V.
Priority date: 2017-04-21
Filing date: 2018-04-20
Publication date: 2018-10-25

Abstract

Described herein are oral pharmaceutical compositions of corticosteroids that undergo a sol- gel transition, as well as methods of making such oral pharmaceutical compositions, and therapeutic methods using them. The compositions typically comprise a corticosteroid, a solvent for the corticosteroid and a thermoreversible polymer. The compositions are particularly useful for treating inflammatory conditions of the esophagus, such as eosinophilic esophagitis.

Description

ORAL PHARMACEUTICAL COMPOSITIONS OF CORTICOSTEROIDS

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

[0001] This application claims the priority benefits under 35 USC § 119(e) to U.S.

provisional application 62/488,462, filed April 21, 2017, the entire contents of which are incorporated herein by reference in their entirety.

FIELD

[0002] Described herein are oral pharmaceutical compositions of corticosteroids that undergo a sol-gel transition, as well as methods of making such oral pharmaceutical compositions, and therapeutic methods using them.

BACKGROUND

[0003] Eosinophilic esophagitis (EoE) is a clinicopathologic disease characterized by upper intestinal symptoms and the finding of more than 15 or 20 eosinophils in the esophageal epithelium, unresponsive to proton pump inhibitor treatment. The pathogenesis of EoE is still not clear, but a growing body of evidence has established that this condition represents a T cell-mediated immune response involving several pro-inflammatory mediators and chemo- attractants known to regulate eosinophilic accumulation in the esophagus, such as IL-4, IL-5, IL-3, eotaxin-1, eotaxin-2, and eotaxin-3.

[0004] EoE prevalence seems to be worldwide (prevalence estimated at 43/100,000 inhabitants; incidence estimated at 7.4/100,000 inhabitants) but the patient population diagnosed with eosinophilic esophagitis appears to be increasing. Food impaction and dysphagia are the most common presenting symptoms in older children and adults. EoE pathogenesis is likely to be associated with allergen sensitization in predisposed individuals. EoE has a strong familial pattern based on the growing clinical literature. Approximately 8% of pediatric patients with EoE have at least one sibling or parent with EoE as well. In addition, it has been recently reported that three adult brothers with dysphagia were found to have EoE. Taken together, EoE appears to demonstrate a strong familial pattern with a much higher prevalence in siblings. [0005] There is no specific treatment available for EoE, but some physicians prescribe budesonide and fluticasone pumps and/or dry powder to be swallowed. Several issues exist for finding a proper treatment for EoE. For example, a lack of dosage standardization compromises treatment efficacy. Additionally, patients have a difficult time adhering to treatment (such as budesonide and fluticasone pumps and/or dry powder) due to poor product taste and stomach pain and gas resulting from air ingestion. Furthermore, budesonide and fluticasone pumps and/or dry powder can also lead to cavities and oral moniliasis.

[0006] Thus, there remains a need for oral pharmaceutical compositions of corticosteroids suitable for use in treating EoE.

SUMMARY

[0007] Provided herein are oral pharmaceutical compositions comprising (a) a

corticosteroid, (b) a solvent for the corticosteroid, and (c) a thermoreversible polymer, wherein the composition is a liquid at room temperature and a gel at body temperature.

[0008] Also provided are oral pharmaceutical compositions comprising: (a) a

corticosteroid, (b) a solvent selected from one or more of propylene glycol, ethylene glycol, sorbitol, and cyclodextrin, and (c) a polymer selected from one or more of Poloxamer 407; Poloxamer 338; Poloxamer 188; Pluronic F68; Pluronic F127; and Pluronic F98. In some embodiments, the polymer comprises Poloxamer 407.

[0009] In any embodiments of the compositions described herein, the composition may comprise micelles that comprise the polymer, corticosteroid, and solvent.

[0010] In any embodiments of the compositions described herein, the composition may be a liquid at 25°C and a gel at 37°C.

[0011] In any embodiments of the compositions described herein, the composition may have a sol-gel transition temperature of from 25 to 32°C, or from 27 to 32°C, or from 29 to 32°C.

[0012] In any embodiments of the compositions described herein, the corticosteroid may be selected from one or more of budesonide, fluticasone, and ciclesonide. In some embodiments, the corticosteroid is budesonide. In some embodiments, the corticosteroid is fluticasone. In some embodiments, the corticosteroid is ciclesonide.

[0013] In any embodiments of the compositions described herein, the corticosteroid may be present in an amount of 0.001 to 10% w/w or 0.01 to 10% w/w of the composition. In some embodiments, the polymer is present in an amount of 15-30%) w/w of the composition.

[0014] In any embodiments of the compositions described herein, the solvent may be present in an amount of 0.2 to 10%> w/w of the composition.

[0015] In some embodiments of any of the compositions described herein, the polymer is Poloxamer 407 and is present in an amount of 15-30%) w/w of the composition. In some embodiments, the polymer is Poloxamer 407 and is present in an amount of from 15 to 17% w/w, or from 15.5 to 16.5% w/w, of the composition.

[0016] In some embodiments of any of the compositions described herein, the solvent is propylene glycol and is present in an amount of 0.2 to 10%> w/w, or 3 to 7% w/w, or 4 to 6%> w/w of the composition.

[0017] In some embodiments of any of the compositions described herein, the

corticosteroid is budesonide and is present in an amount of 0.001 to 10%> w/w, the polymer is Poloxamer 407 and is present in an amount of 15-30%) w/w, and the solvent is propylene glycol and is present in an amount of 0.2 to 10%> w/w of the composition. In some embodiments, the corticosteroid is budesonide and is present in an amount of 0.01 to 10%> w/w, the polymer is Poloxamer 407 and is present in an amount of 15-30%) w/w, and the solvent is propylene glycol and is present in an amount of 4 to 6%> w/w of the composition.

[0018] In some embodiments of any of the compositions described herein, the

corticosteroid is fluticasone and is present in an amount of 0.001 to 10%> w/w, the polymer is Poloxamer 407 and is present in an amount of 15-30%) w/w, and the solvent is propylene glycol and is present in an amount of 0.2 to 10%> w/w of the composition. In some embodiments, the corticosteroid is fluticasone and is present in an amount of 0.01 to 10%> w/w, the polymer is Poloxamer 407 and is present in an amount of 15-30%) w/w, and the solvent is propylene glycol and is present in an amount of 4 to 6%> w/w of the composition. [0019] In some embodiments of any of the compositions described herein, the corticosteroid is ciclesonide and is present in an amount of 0.001 to 10% w/w, the polymer is Poloxamer 407 and is present in an amount of 15-30%) w/w, and the solvent is propylene glycol and is present in an amount of 0.2 to 10%> w/w of the composition. In some embodiments, the corticosteroid is ciclesonide and is present in an amount of 0.01 to 10%> w/w, the polymer is Poloxamer 407 and is present in an amount of 15-30%) w/w, and the solvent is propylene glycol and is present in an amount of 4 to 6%> w/w of the composition.

[0020] In any embodiments of any of the compositions described herein, the composition further comprises water and, optionally, one or more additional pharmaceutically acceptable excipients. In some embodiments, the composition comprises one or more additional pharmaceutically acceptable excipients in an amount of 0.01-10%) w/w of the composition. In some embodiments, the composition comprises one or more additional pharmaceutically acceptable excipients selected from preservatives, such as methyl-p-hydroxybenzoate.

Additionally, or alternatively, in some embodiments, the composition comprises one or more additional pharmaceutically acceptable excipients selected sweeteners, such as acesulfame potassium.

[0021] In any embodiments of any of the compositions described herein, the composition may adhere to the esophagus. In some embodiments, the compositions adhere to the esophagus for at least 30 minutes, or for at least 45 minutes, or for at least 60 minutes.

[0022] Also provided are methods of treating an inflammatory condition of the esophagus, such as eosinophilic esophagitis, comprising orally administering any oral pharmaceutical composition as described herein.

[0023] Also provided are uses of a corticosteroid in the manufacture of a medicament for treating an inflammatory condition of the esophagus, such as eosinophilic esophagitis, wherein the medicament comprises any oral pharmaceutical composition as described herein.

[0024] Also provided are methods of preparing any oral pharmaceutical composition as described herein, comprising (a) dissolving the corticosteroid in the solvent; (b) mixing the corticosteroid solution with the polymer; and (c) optionally, adding water and, optionally, one or more additional pharmaceutically acceptable excipients. [0025] Also provided are methods of preparing any oral pharmaceutical composition as described herein, comprising (a) dispersing the polymer in water and chilling the polymer dispersion; (b) dissolving the corticosteroid in the solvent; (c) mixing the corticosteroid solution with the polymer dispersion; (d) increasing the temperature of the mixture until the mixture becomes a gel; (e) cooling the gel until the gel becomes a liquid; and (f) optionally, adding water and, optionally, one or more additional pharmaceutically acceptable excipients.

BRIEF DESCRIPTION OF THE DRAWINGS

[0026] FIGS. 1 A-1D are transmission electron microscope (TEM) images of a composition as described herein at 25°C. FIG. 1 A is a magnification of 29000x; FIG. IB is a

magnification of 62000x; FIG. 1C is a magnification of lOOOOOx; FIG. ID is a magnification of 200000x.

[0027] FIGS. 2A-2B are TEM images of a composition as described herein at 37°C. FIG. 2A is a magnification of 62000x; FIG. 2B is a magnification of lOOOOOx.

[0028] FIGS. 3A-B are ex vivo images of the gastrointestinal tract of animals four hours after treatment with 20 μΐ of a composition as described herein (FIG. 3 A) and 20 μΐ 1 of a control composition (with IR780 dye) (FIG. 3B).

[0029] FIGS. 4A-D are ex vivo images of the esophagus of animals four hours after treatment with 20 μΐ of a composition as described herein (FIGS. 4A-B) and 20 μΐ of a control composition (with IR780 dye) (FIGS. 4C-D).

DETAILED DESCRIPTION

[0030] Described herein are oral pharmaceutical compositions comprising a corticosteroid, methods of making such oral pharmaceutical compositions, and therapeutic methods using them. The compositions undergo a sol-gel transition as described herein, and typically comprise a corticosteroid, a solvent, and a thermoreversible polymer capable of undergoing a sol-gel transition. In particular embodiments, the compositions are liquids at room temperature and gels at body temperature. In accordance with these embodiments, the compositions can be readily ingested as liquids, after which they transition to a gel state in which they may exhibit increased adhesion to mucosal surfaces, such as mucosal surfaces of the esophagus. Thus, in some embodiments, the compositions provide local delivery of corticosteroid to the esophagus. Further, in embodiments where the compositions adhere to mucosal surfaces, such as mucosal surfaces of the esophagus, they provide prolonged delivery of corticosteroid to the esophagus. These embodiments may offer particular advantages in the context of treating EoE, by providing local and prolonged delivery of corticosteroid to the site of pathology.

Definitions

[0031] Technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art of pharmaceutical compositions to which the present disclosure pertains, unless otherwise defined. Reference is made herein to various methodologies known to those of ordinary skill in the art. Suitable materials and/or methods known to those of ordinary skill in the art can be utilized in carrying out the present disclosure. However, specific materials and methods are described. Materials, reagents and the like to which reference is made in the following description and examples are obtainable from commercial sources, unless otherwise noted.

[0032] As used herein, the singular forms "a," "an," and "the" designate both the singular and the plural, unless expressly stated to designate the singular only.

[0033] As used herein, the term "about" means that the number or range is not limited to the exact number or range set forth, but encompass values around the recited number or range as will be understood by persons of ordinary skill in the art depending on the context in which the number or range is used. Unless otherwise apparent from the context or convention in the art, "about" means up to plus or minus 10% of the particular term.

[0034] As used herein, "subject" denotes any mammal, including humans. For example, a subject may be suffering from or at risk of developing a condition that can be diagnosed, treated or prevented with a corticosteroid, or may be taking a corticosteroid for other purposes.

[0035] The terms "administer," "administration," or "administering" as used herein refer to (1) providing, giving, dosing and/or prescribing, such as by either a health professional or his or her authorized agent or under his direction, and (2) putting into, taking or consuming, such as by a health professional or the subject.

[0036] The terms "treat", "treating" or "treatment", as used herein, include alleviating, abating or ameliorating a disease or condition or one or more symptoms thereof, whether or not the disease or condition is considered to be "cured" or "healed" and whether or not all symptoms are resolved. The terms also include reducing or preventing progression of a disease or condition or one or more symptoms thereof, impeding or preventing an underlying mechanism of a disease or condition or one or more symptoms thereof, and achieving any therapeutic and/or prophylactic benefit.

[0037] As used herein, the phrase "therapeutically effective amount" refers to a dose that provides the specific pharmacological effect for which the drug is administered in a subject in need of such treatment. It is emphasized that a therapeutically effective amount will not always be effective in treating the conditions described herein, even though such dose is deemed to be a therapeutically effective amount by those of skill in the art. For convenience only, exemplary doses and therapeutically effective amounts are provided below with reference to human subjects. Those skilled in the art can adjust such amounts in accordance with standard practices as needed to treat a specific subject and/or condition/disease.

COMPOSITIONS

[0038] Described herein are oral pharmaceutical compositions comprising a corticosteroid, methods of making such oral pharmaceutical compositions, and therapeutic methods using them. The compositions typically undergo a sol-gel transition as described herein, and comprise a corticosteroid, a solvent, and a thermoreversible polymer capable of undergoing a sol-gel transition.

[0039] As noted above, in particular embodiments the compositions described herein undergo a sol-gel transition. For example, in particular embodiments, the compositions are liquids at room temperature and gels at body temperature. In some embodiments, the compositions are liquids at temperatures of about 20-25°C (typical room temperatures) or lower and gels at temperatures of about 36.5-37.5°C (typical body temperatures) or greater. In some embodiments, the compositions are liquids at temperatures of about 23 °C or lower and gels at temperatures of about 37°C or greater. In some embodiments, the compositions are liquids at 20°C and gels at 37°C. In some embodiments, the compositions undergo a sol- gel transition at a temperature of about 25-32°C or 27-32°C or 29-32°C.

[0040] As noted above, the compositions typically comprise corticosteroid,

thermoreversible polymer, and solvent. While not wanting to be bound by theory or mechanism of action, it is believed that thermoreversible polymer molecules present in the composition form micelles which comprise solubilized (dissolved) corticosteroid. Thus, in some embodiments, the compositions comprise micelles that comprise thermoreversible polymer, corticosteroid, and solvent. The micelles may be present well-below the sol-gel temperature. For example, micelles may be observed at temperatures of about 10-20°C.

[0041] In some embodiments the gel form of the compositions described herein exhibit a viscosity or mucoadhesive strength such that they adhere to mucosal surfaces, such as the esophagus. In some embodiments, the composition adheres to the esophagus for at least 15 minutes, or at least 20 minutes, or at least 25 minutes, or at least 30 minutes, or at least 35 minutes, or at least 40 minutes, or at least 45 minutes, or at least 50 minutes, or at least 55 minutes, or at least 60 minutes, or at least 65 minutes, or at least 75 minutes, or at least 75 minutes, after administration. In some embodiments, the composition adheres to the esophagus for at least 30 minutes after administration. In some embodiments, the

composition adheres to the esophagus for at least 45 minutes after administration. In some embodiments, the composition adheres to the esophagus for at least 60 minutes after administration. In some embodiments, the composition adheres to the esophagus for at least 75 minutes after administration.

[0042] As used herein, the term "mucoadhesive strength" refers to the force required to remove the oral pharmaceutical composition from a mucin disc using a texturometer TA.XT Plus equipment (Stable Micro Systems) as illustrated in the examples. In some embodiments, the gel form of the compositions described herein exhibit a mucoadhesive strength of from about 5 g to about 15 g. In some embodiments, the mucoadhesive strength is from about 7 g to about 14 g, about 8 g to about 12 g, about 9 g to about 11 g, or from about 10 g to about 11 g. In some embodiments, the mucoadhesive strength is about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 g. In some embodiments, the mucoadhesive strength is about 11 g. [0043] While not wanting to be bound by theory, it is believed that these mucoadhesive properties enhance the therapeutic effect of the compositions, such as by providing improved and/or prolonged contact between the corticosteroid-composition and target treatment site, such as esophageal tissue, for improved drug delivery and/or prolonged effect.

Thermoreversible Polymer

[0044] As noted above, the compositions described herein include a polymer capable of undergoing a sol-gel transition, i.e., a thermoreversible polymer. Thermoreversible polymers are polymers that exhibit a temperature-dependent transition from a "sol" state (e.g., a liquid or primarily liquid-like state) to a "gel" stated (e.g., to a state exhibiting gel properties such as elasticity). The temperature at which a polymer (or composition) undergoes a transition from a sol state to a gel state is referred to as the sol-gel temperature. In general, the sol-gel temperature of a polymer is inversely proportional to its molecular weight, with lower molecular weight polymers exhibiting higher sol-gel temperatures. The sol-gel temperature of a composition will depend on the components of the composition as a whole, including the relative amount of thermoreversible polymer, and the identity and amounts of other components. Moreover, different components may have different effects on a compositions ability to exhibit a sol-gel transition, such as if one or more components interferes with ability of the polymer molecules to organize and form cross-linkages.

[0045] One class of pharmaceutically acceptable thermoreversible polymers that exhibit this property are poloxamers, which are block copolymers of polyoxyethylene (also referred to as poly(ethylene oxide) or poly(ethylene glycol) blocks) and polyoxypropylene (also referred to as poly(propylene oxide) or poly(propylene glycol) blocks). Poloxamers typically have a central polyoxypropylene block flanked on each side by polyoxyethylene blocks. Pharmaceutically acceptable poloxamers are known in the art and commercially available.

[0046] Thus, in some embodiments, the thermoreversible polymer comprises a poloxamer, e.g., a polymer having a central polyoxypropylene block flanked on each side by

polyoxyethylene blocks. In some embodiments, the thermoreversible polymer is one or more selected from Poloxamer 407 (also known as Pluronic F127), Poloxamer 338, Poloxamer 188, Pluronic F68, and Pluronic F98. In accordance with conventional nomenclature for "Poloxamers," the first two numbers x 100 correspond to the approximate molecular mass of the polyoxvpropylene block, while the last number x 10 corresponds to the relative content of polyoxy ethylene. Thus, for example, Po!oxamer 407 is a polyoxyethylene-polyoxypropylene- polyoxy ethylene tri-block polymer with an approximate polyoxvpropylene molecular mass of 4,000 g/mol and a 70% polyoxyethylene content; Poloxamer 338 is a polyoxyethylene- polyoxypropylene- polyoxyethylene tri-block polymer with an approximate

polyoxypropylene molecular mass of 3300 g/mol and a 80% polyoxyethylene content, and Poloxamer 188 is a polyoxyethylene-polyoxypropylene- polyoxyethylene tri-block polymer with an approximate polyoxypropylene molecular mass of 1800 g/mol and a 80%

polyoxyethylene content. Thus, in some embodiments, the thermoreversible polymer is selected from polyoxyethylene-polyoxypropylene- polyoxyethylene tri-block polymers with an approximate polyoxypropylene molecular mass of 4,000 g/mol and a 70%

polyoxyethylene content; polyoxyethylene-polyoxypropylene- polyoxyethylene tri-block polymers with an approximate polyoxypropylene molecular mass of 3300 g/mol and a 80% polyoxyethylene content, and polyoxyethylene-polyoxypropylene- polyoxyethylene tri-block polymers with an approximate polyoxypropylene molecular mass of 1800 g/mol and a 80% polyoxyethylene content.

[0047] The amount of thermoreversible polymer present in the composition can be selected and controlled to achieve the target sol-gel temperature and/or other desired properties of the composition, such as adhesion to mucosal surfaces. Exemplary amounts are discussed in more detail below.

[0048] For example, in some embodiments, the thermoreversible polymer is present in an amount from about 10% to about 30% w/w of the composition. In some embodiments, the thermoreversible polymer is present in an amount from about 10% to about 25%, or about 15% to about 25%, or about 15% to about 20%, or about 10% to about 20%, or about 10% to about 18%), or about 10% to about 17%, or about 10% to about 16%, or about 10% to about 15%) w/w of the composition. In some embodiments, the sol -gel polymer is present in an amount of about 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22% , 23%, 24%, or 25% w/w of the composition. [0049] For example, in some embodiments, the thermoreversible polymer comprises a poloxamer, which is present in an amount from about 10% to about 30% w/w of the composition. In some embodiments, the poloxamer is present in an amount from about 10% to about 25%, or about 15% to about 25%, or about 15% to about 20%, or about 10% to about 20%), or about 10% to about 18%, or about 10% to about 17%, or about 10% to about 16%), or about 10% to about 15% w/w of the composition. In some embodiments, the poloxamer is present in an amount of about 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25% w/w of the composition.

[0050] In some embodiments, the thermoreversible polymer comprises Poloxamer 407. In some embodiments, Poloxamer 407 is present in in amount from about 10% to about 30%, or about 15%) to about 25%, or about 15% to about 20%, or about 10% to about 18%, or about 10% to about 17%, or about 10% to about 16%, or about 10% to about 15% w/w of the composition. In some embodiments, Poloxamer 407 is present in an amount of about 10% to about 30%) w/w of the composition. In some embodiments, Poloxamer 407 is present in an amount of about 15% to about 30% w/w of the composition. In some embodiments, Poloxamer 407 is present in an amount of about 15%, 15.5%, 16%, 16.5%, or 17% w/w of the composition. In some embodiments, Poloxamer 407 is present in an amount of from 15 to 17%) w/w of the composition. In some embodiments, Poloxamer 407 is present in an amount of from 15.5 to 16.5% w/w of the composition. In some embodiments, Poloxamer 407 is present in an amount of about 16% w/w of the composition.

Corticosteroids

[0051] The compositions described herein may comprise any one or more pharmaceutically acceptable corticosteroids, such as any one or more corticosteroids pharmaceutically acceptable for oral administration, such as topically active steroids. Non-limiting examples of suitable corticosteroids include one or more selected from budesonide, fluticasone, cicelsonide, cortisone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, amcinonide, desonide, fluocinolone acetonide, fluocinonide, halcinonide, triamcinolone acetonide, beclometasone, betamethasone, dexamethasone, fluocortolone, halometasone, mometasone, flunisolide, ciclesonide, and fludrocortisone, and

pharmaceutically acceptable salts and esters of each thereof. [0052] In some embodiments, a composition as described herein comprises budesonide. Budesonide has the molecular formula C25H34O6, a molecular weight of 430.53, and the chemical name

16,17-butylidenebis(oxy)-l l,21-dihydroxy-, (11β, 16a)-pregna-l,4-diene-3, 20-dione. It is registered under CAS Registry Number 51333-22-3 and Einecs 257-139-7.

[0053] In some embodiments, a composition as described herein comprises fluticasone. Fluticasone has the molecular formula C22H27F3O4S, a molecular weight of 444.51, and the chemical name 6a,9a-difluoro-l ip, 17a-dihydroxy-16a-methyl-21-thia-21- fluoromethylpregna-l,4-dien-3, 20-dione. Fluticasone is registered under CAS Registry Number 90566-53-3.

[0054] In some embodiments, a composition as described herein comprises ciclesonide. Ciclesonide has the molecular formula C32H4407, a molecular weight of 540.69 g/mol, and the chemical name (11β, 16α)-16, 17-[[(R)-cyclohexylmethylene]^/5(oxy)]-l l-hydroxy-21- (2-methyl-l-oxopropoxy)- pregna-1, 4-diene-3, 20-dione. Ciclesonide is registered under CAS Registry Number 126544-47-6.

[0055] In some embodiments, a composition as described herein comprises budesonide. In some embodiments, a composition as described herein comprises fluticasone. In some embodiments, a composition as described herein comprises ciclesonide.

[0056] Pharmaceutically acceptable salts and esters of corticosteroids are known in the art. Exemplary pharmaceutically acceptable salts include acid addition salts, such as

hydrochloride salts. Any pharmaceutically acceptable salt can be used, such as sodium and calcium salts. Other non-limiting exemplary salts include salts formed with a carboxylic acid group, alkali metal salts, and alkaline earth metal salts. Non-limiting examples of pharmaceutically acceptable esters include straight chain or branched Ci-Ci₈ alkyl esters, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, hexyl, heptyl, octyl, nonyl, decyl, lauryl, myristyl, cetyl, and stearyl, and the like; straight chain or branched C₂-C18 alkenyl esters, including vinyl, allyl, undecenyl, oleyl, linolenyl, and the like; C₃-C₈ cycloalkyl esters, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, and the like; aryl esters, including phenyl, toluoyl, xylyl, naphthyl, and the like; alicyclic esters, including menthyl and the like; or aralkyl esters, including benzyl, phenethyl, and the like.

[0057] The compositions described herein may include a therapeutically effective amount of corticosteroid. The therapeutically effective amount may depend on the specific corticosteroid being used, the subject being treated, the condition being treated, the desired effect, and the intended duration of therapeutic effect of the compositions. Compositions comprising more than one corticosteroid may include a therapeutically effective amount of each corticosteroid, or an amount of one or more of the corticosteroids that is not

therapeutically effective on its own, but the amount of all corticosteroids present is therapeutically effective.

[0058] In some embodiments, the corticosteroid is present in an amount of from about 0.001% to about 10% w/w of the composition. In some embodiments, the corticosteroid is present in an amount of from about 0.01% to about 0.5%, or about 1.0%, or about 1.5%, or about 2.0%, or about 2.5% or about 3.0%, or about 3.5%, or about 4.0%, or about 4.5%, or about 5.0%, or about 6.0%, or about 7.0%, or about 8.0%, or about 9.0%, or about 10% w/w of the composition. In some embodiments, the corticosteroid is present in an amount of from about 0.01% to about 0.03%, or about 0.04%, or about 0.05%, or about 0.06%, or about 0.07%, or about 0.08%, or about 0.09%, or about 0.1%, or about 0.2%, or about 0.3%, or about 0.4%), w/w of the composition. In some embodiments, the corticosteroid is present in an amount of from about 0.01 to about 0.1% w/w of the composition. In some embodiments, the corticosteroid is present in an amount of about 0.05% w/w the composition.

[0059] In some embodiments of compositions comprising more than one corticosteroid, the amount of each is selected independently of the other. In some such embodiments, the composition may include one of these amounts of each corticosteroid. In other embodiments of compositions comprising more than one corticosteroid, the amount of each is selected to complement the other. In some such embodiments, the compositions may have a total corticosteroid content corresponding to one of these amounts. Other embodiments of compositions comprising more than one corticosteroid also are contemplated. [0060] In some embodiments, the corticosteroid comprises budesonide. In some embodiments, the budesonide is present in an amount of from about 0.001% to about 10%> w/w of the composition, or from about 0.01%> to about 0.5%, or about 1.0%, or about 1.5%, or about 2.0% w/w of the composition. In some embodiments, the budesonide is present in amount of from about 0.01% to about 0.03%, or about 0.04%, or about 0.05%, or about 0.06%, or about 0.07%, or about 0.08%, or about 0.09%, or about 0.1% w/w of the composition. In some embodiments, the budesonide is present in an amount of from about 0.001%) to about 10% w/w of the composition. In some embodiments, the budesonide is present in an amount of from about 0.01 to 0.1% w/w of the composition.

[0061] In some embodiments, the corticosteroid comprises fluticasone. In some embodiments, the fluticasone is present in an amount of from about 0.001%) to about 10% w/w of the composition, or from about 0.01% to about 0.5%, or about 1.0%, or about 1.5%, or about 2.0% w/w of the composition. In some embodiments, the fluticasone is present in amount of from about 0.01% to about 0.03%, or about 0.04%, or about 0.05%, or about 0.06%, or about 0.07%, or about 0.08%, or about 0.09%, or about 0.1% w/w of the composition. In some embodiments, the fluticasone is present in an amount of from about 0.001%) to about 10% w/w of the composition. In some embodiments, the fluticasone is present in an amount of from about 0.01 to 0.1% w/w of the composition.

[0062] In some embodiments, the corticosteroid comprises ciclesonide. In some embodiments, the ciclesonide is present in an amount of from about 0.001%) to about 10% w/w of the composition, or from about 0.01% to about 0.5%, or about 1.0%, or about 1.5%, or about 2.0% w/w of the composition. In some embodiments, the ciclesonide is present in amount of from about 0.01% to about 0.03%, or about 0.04%, or about 0.05%, or about 0.06%, or about 0.07%, or about 0.08%, or about 0.09%, or about 0.1% w/w of the composition. In some embodiments, the ciclesonide is present in an amount of from about 0.001%) to about 10% w/w of the composition. In some embodiments, the ciclesonide is present in an amount of from about 0.01 to 0.1% w/w of the composition.

[0063] In some embodiments, the corticosteroid is present at a concentration of from about 0.1 mg/ml to about 1.0 mg/ml. In some embodiments, the corticosteroid is present at a concentration of from about 0.1 to about 0.2 mg/ml, or about 0.3 mg/ml, or about 0.4 mg/ml, or about 0.5 mg/ml, or about 0.6 mg/ml, or about 0.7 mg/ml, or about 0.8 mg/ml, or about 0.9 mg/ml. In some embodiments, the corticosteroid is present at a concentration of from about 0.2 mg/ml to about 0.8 mg/ml; or from about 0.3 mg/ml to about 0.7 mg/ml; or from about 0.4 mg/ml to about 0.5 mg/ml. In some embodiments, the corticosteroid is present at a concentration of about 0.5 mg/ml. In some embodiments of compositions comprising more than one corticosteroid, the amount of each is selected independently of the other. In some such embodiments, the composition may include one of these amounts of each corticosteroid. In other embodiments of compositions comprising more than one corticosteroid, the amount of each is selected to complement the other. In some such embodiments, the compositions may have a total corticosteroid content corresponding to one of these amounts. Other embodiments of compositions comprising more than one corticosteroid also are

contemplated.

[0064] In some embodiments, the corticosteroid comprises budesonide. In some embodiments, the budesonide is present at a concentration of from about 0.1 mg/ml to about 1.0 mg/ml. In some embodiments, the budesonide is present at a concentration of from about 0.1 to about 0.2 mg/ml, or about 0.3 mg/ml, or about 0.4 mg/ml, or about 0.5 mg/ml, or about 0.6 mg/ml, or about 0.7 mg/ml, or about 0.8 mg/ml, or about 0.9 mg/ml. In some

embodiments, the budesonide is present at a concentration of from about 0.2 mg/ml to about 0.8 mg/ml; or from about 0.3 mg/ml to about 0.7 mg/ml; or from about 0.4 mg/ml to about 0.5 mg/ml. In some embodiments, the budesonide is present at a concentration of about 0.5 mg/ml.

[0065] In some embodiments, the corticosteroid comprises fluticasone. In some

embodiments, the fluticasone is present at a concentration of from about 0.1 mg/ml to about 1.0 mg/ml. In some embodiments, the fluticasone is present at a concentration of from about 0.1 to about 0.2 mg/ml, or about 0.3 mg/ml, or about 0.4 mg/ml, or about 0.5 mg/ml, or about 0.6 mg/ml, or about 0.7 mg/ml, or about 0.8 mg/ml, or about 0.9 mg/ml. In some

embodiments, the fluticasone is present at a concentration of from about 0.2 mg/ml to about 0.8 mg/ml; or from about 0.3 mg/ml to about 0.7 mg/ml; or from about 0.4 mg/ml to about 0.5 mg/ml. In some embodiments, the fluticasone is present at a concentration of about 0.5 mg/ml. [0066] In some embodiments, the corticosteroid comprises ciclesonide. In some embodiments, the ciclesonide is present at a concentration of from about 0.1 mg/ml to about 1.0 mg/ml. In some embodiments, the ciclesonide is present at a concentration of from about 0.1 to about 0.2 mg/ml, or about 0.3 mg/ml, or about 0.4 mg/ml, or about 0.5 mg/ml, or about 0.6 mg/ml, or about 0.7 mg/ml, or about 0.8 mg/ml, or about 0.9 mg/ml. In some

embodiments, the ciclesonide is present at a concentration of from about 0.2 mg/ml to about 0.8 mg/ml; or from about 0.3 mg/ml to about 0.7 mg/ml; or from about 0.4 mg/ml to about 0.5 mg/ml. In some embodiments, the ciclesonide is present at a concentration of about 0.5 mg/ml.

Solvent

[0067] As noted above, the compositions described herein also include a solvent. In some embodiments, the solvent is compatible with both the corticosteroid(s) and the

thermoreversible polymer(s). In some embodiments, the solvent is a solvent for the corticosteroid(s). Examples of suitable solvents include but are not limited to propylene glycol, ethylene glycol, sorbitol, cyclodextrin, glycerin, and mygliol, and mixtures of any two or more thereof. In some embodiments, the solvent is propylene glycol.

[0068] The amount of solvent present in the composition can be selected and controlled to provide solubilization of the corticosteroid (and other components that may be present), and achieve the target sol-gel temperature and/or other desired properties of the composition, such as adhesion to mucosal surfaces. Exemplary amounts are discussed in more detail below.

[0069] For example, the solvent may be present in an amount from about 0.2 to about 10% w/w of the composition. In some embodiments, the solvent is present in an amount from about 0.5% to about 9%, or about 1% to about 8%, or about 3% to about 7%, or about 4% to about 6%) w/w of the composition.

[0070] In some embodiments, the solvent comprises propylene glycol. In some

embodiments the propylene glycol is present in an amount of from about 0.2 to about 10%, or about 0.5%) to about 9%, or about 1% to about 8%, or about 3% to about 7%, or about 4% to about 6%) w/w of the composition. In some embodiments, the propylene glycol is present in an amount of about 0.2% to about 10% w/w of the composition. In some embodiments, the propylene glycol is present in an amount from about 3% to about 7% w/w of the composition. In some embodiments, the propylene glycol is present in an amount from about 4% to about 6% w/w of the composition. In some embodiments, the propylene glycol is present in an amount of about 5% w/w of the composition.

Other Components

[0071] The compositions described herein typically further comprise water and, optionally, one or more optional pharmaceutically acceptable excipients.

[0072] Examples of optional pharmaceutically acceptable excipients include but are not limited to preservatives, sweeteners, antioxidants, chelating agents, colorants, flavoring agents, and/or pH adjusting agents.

[0073] Non-limiting examples of preservatives include methyl-p-hydroxybenzoate, potassium sorbate, C₁₂ to C₁₅ alkyl benzoates, alkyl p-hydroxybenzoates, propyl and butyl p- hydroxybenzoates, aloe vera extract, ascorbic acid, benzalkonium chloride, benzoic acid, benzoic acid esters of Cg to C₁₅ alcohols, butylated hydroxytoluene, castor oil, cetyl alcohols, chlorocresol, citric acid, cocoa butter, coconut oil, diazolidinyl urea, diisopropyl adipate, dimethyl polysiloxane, DMDM hydantoin, ethanol, fatty acids, fatty alcohols, hexadecyl alcohol, hydroxybenzoate esters, iodopropynyl butyl carbamate, isononyl iso-nonanoate, jojoba oil, lanolin oil, methylparaben, mineral oil, oleic acid, olive oil, poly ethers,

polyoxypropylene butyl ether, polyoxypropylene cetyl ether, silicone oils, sodium propionate, sodium benzoate, sodium bisulfite, disodium metabi sulfite, sorbic acid, stearic fatty acid, vitamin E, vitamin E acetate and derivatives, esters, salts and mixtures thereof. In some embodiments, the preservative is or includes methyl-p-hydroxybenzoate.

[0074] Non-limiting examples of sweeteners include acesulfame potassium, sorbitol, rebaudioside A, rebaudioside B, rebaudioside C, rebaudioside D, rebaudioside E,

rebaudioside F, dulcoside A, dulcoside B, rubusoside, stevia, stevioside, mogroside IV, mogroside V, sorbitol, Luo Han Guo sweetener, siamenoside, monatin and its salts (monatin SS, RR, RS, SR), curculin, glycyrrhizic acid and its salts, thaumatin, monellin, mabinlin, brazzein, hernandulcin, phyllodulcin, glycyphyllin, phloridzin, trilobatin, baiyunoside, osladin, polypodoside A, pterocaryoside A, pterocaryoside B, mukurozioside, phlomisoside I, periandrin I, abrsoside A, cyclocarioside I, sucralose, acesulfame potassium and other salts, aspartame, alitame, saccharin, neohesperidin dihydrochalcone, cyclamate, neotame, N— [N- [3-(3-hydroxy-4-methoxyphenyl)propyl]-L-a-aspartyl]-L-phenylalanine 1-methyl ester, N— [N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-a-aspartyl]-L-phenylalanine 1-methyl ester, N— [N-[3-(3-methoxy-4-hydroxyphenyl)propyl]-L-a-aspartyl]-L-phenylalanine 1- methyl ester, and salts and combinations thereof. In some embodiments, the sweetener is or includes acesulfame potassium.

[0075] Non-limiting examples of antioxidants include glutathione, quinolines, polyphenols, carotenoids, sodium metabi sulphite, tocopherol succinate, propyl galate, butylated hydroxy toluene, butyl hydroxy anisol, flavanoids, and a vitamin C source. Non-limiting examples of vitamin C sources may include ascorbic acid; ascorbyl palmitate; dipalmitate L-ascorbate; sodium L-ascorbate-2-sulfate; an ascorbic salt, such as sodium, potassium, or calcium ascorbate; and mixtures thereof.

[0076] Non-limiting examples of chelating agents include ethylenediaminetetraacetic acid (EDTA) and citric acid, hydrates thereof, salts thereof, and hydrates of the salts thereof.

Examples of such chelating agents include ethylenediaminetetraacetic acid disodium salt, ethylenediaminetetraacetic acid disodium salt dihydrate, and citric acid monohydrate.

Various combinations of chelating agents can be used if desired.

[0077] Non-limiting examples of colorants include commercially available pigments such as FD&C Blue #1 Aluminum Lake, FD&C Blue #2, other FD&C Blue colors, titanium dioxide, iron oxide, and/or combinations thereof.

[0078] Non-limiting examples of flavoring agents include berry flavor, root beer flavor, cream flavor, chocolate flavor, peppermint flavor, spearmint flavor, butterscotch flavor, and wintergreen flavor and combinations thereof. Suitable berry flavoring agents include black cherry, strawberry, cherry, blueberry, raspberry and the like.

[0079] Non-limiting examples of pH-adjusting agents include acetate buffers,

aminomethylamine buffers, ammonium hydroxide, benzoate buffers, borate buffers, carbonate buffers, citrate buffers, diethylamine buffers, diisopropylamine buffers, hydrochloric acid, lactic acid buffers, perchloric acid, aphosphate buffers, tartric acid, triethylamine buffers, proprioate buffers, sodium hydroxide,

tetrahydroxypropylethylendiamine buffers, citric acid, and mixtures thereof.

[0080] The identities and amounts of the excipients can be selected and adjusted to achieve the desired effect while retaining the desired properties of the composition as a whole. In some embodiments, the oral pharmaceutical composition comprises about 0.01% to about 10%, or about 0.03% to about 9%, or about 0.05% to about 7%, or about 0.01% to about 3%, or about 0.02% to about 2.5%, or about 0.03% to about 2.5%, or about 0.05% to about 2.5%, or about 0.1% to about 2%, or about 0.1% to about 1.5%, or about 1% to about 1.5% w/w of excipients. In some embodiments, the oral pharmaceutical composition may comprise about 0.01%) to about 10%) w/w of excipients.

[0081] In some embodiments, the compositions include one or more preservatives.

Additionally or alternatively, in some embodiments, the compositions include one or more sweeteners and/or flavoring agents. In some embodiments, the compositions include one or more preservatives and one or more sweeteners and/or flavoring agents. In some

embodiments, the composition includes potassium sorbate as a preservative and acesulfame potassium and sorbitol as sweeteners. In some embodiments, the composition includes methyl-p-hydroxybenzoate as a preservative and acesulfame potassium as a sweetener.

Methods of Manufacture

[0082] Also provided herein are processes for making the compositions described herein. In general, the compositions can be made by methods known in the art, in view of the following guidance.

[0083] In general, the compositions are made by combining the corticosteroid, solvent, and thermoreversible polymer, and water, and any other optional excipients being used.

[0084] In some embodiments, the corticosteroid is dissolved in the solvent before being mixed with the thermoreversible polymer. In such embodiments, the amount and identity of solvent used is such that the corticosteroid remains in solution when added to the

thermoreversible polymer, and does not precipitate. Thus, in some embodiments, a method of making a composition as described herein comprises (a) dissolving a corticosteroid in a solvent and (b) mixing the corticosteroid solution with a thermoreversible polymer. In some embodiments, the methods further comprise adding water and, optionally, one or more optional excipients to the composition.

[0085] In some embodiments, a method of making a composition as described herein comprises dissolving budesonide in propylene glycol, mixing the budesonide solution with Poloxamer 407, and adding water acesulfame potassium, and methyl-p-hydroxybenzoate.

[0086] In some embodiments, the thermoreversible polymer is at a temperature below room temperature when mixed with the corticosteroid. For example, the thermoreversible polymer may be prepared and held in an ice bath prior to use. In accordance with such embodiments, the polymer and corticosteroid solution can be mixed in a liquid state, and then the temperature can be increased to induce micellization, which is believed to solubilize the corticosteroid in the polymeric formulation.

[0087] For example, a composition may be prepared as follows: dispersing a thermoreversible polymer in water and chilling the polymer dispersion to below room temperature;

dissolving the corticosteroid in a solvent;

mixing the corticosteroid solution with the polymer dispersion;

increasing the temperature of the mixture until the mixture becomes a gel;

cooling the gelled mixture until the mixture becomes a liquid; and

optionally, adding water and, optionally, adding one or more additional

pharmaceutically acceptable excipients.

[0088] For example, in specific embodiments, a composition may be prepared as follows:

• The thermoreversible polymer is prepared by dispersing in water and chilling.

In some embodiments, the chilling is to 4 °C. In some embodiments, the chilling is overnight. • The corticosteroid solution is prepared by dissolving the corticosteroid in the solvent, such as in an ultrasound bath. In some embodiments, the ultrasound bath accelerates the dissolution of the corticosteroid in the solvent.

• The corticosteroid solution is added to the thermoreversible polymer dispersion under stirring. In some embodiments, the stirring is conducted at 700 rpm.

• The temperature is then increased to induce micellization and gel formation.

In some embodiments, the corticosteroid solution may be heated with a heating plate. In some embodiments, the corticosteroid solution in an industrial scale may be heated with a heated water circulation in a processing reactor jacket. For example, in some embodiments, the temperature is increased to 40 °C to induce micellization.

• Then, the composition is cooled to achieve a liquid state. For example, in some embodiments, the gel is cooled to below 20 °C, whereby a liquid state is achieved.

• Then, when the composition is in a liquid state, water and any optional

excipients are optionally added under stirring. In some embodiments, the stirring is conducted at 500 rpm. In some embodiments, water is added to achieve the desired concentration of the thermoreversible polymer.

Therapeutic Methods

[0089] Also provided herein are methods of administering a corticosteroid to a subject in need thereof, comprising orally administering to the subject a composition as described herein. In some embodiments, the method is effective to deliver the corticosteroid to the esophagus of the subject.

[0090] In some embodiments, the method is effective to provide prolonged delivery of corticosteroid to the esophagus of the subject, such as delivery for at least 15 minutes, or at least 20 minutes, or at least 25 minutes, or at least 30 minutes, or at least 35 minutes, or at least 40 minutes, or at least 45 minutes, or at least 50 minutes, or at least 55 minutes, or at least 60 minutes, or at least 65 minutes, or at least 75 minutes, or at least 75 minutes.

[0091] In any embodiments, the subject may be suffering from or at risk of developing an inflammatory condition of the upper gastrointestinal tract, particularly the esophagus. In some embodiments, the subject may be suffering from or at risk of developing eosinophilic esophagitis (EoE). In some embodiments, the subject may be a child (e.g., up to 18 years, including up to 10 years) or an adult.

[0092] In embodiments related to the treatment of EoE, suitable doses of budesonide may be up to 1 mg/day for children younger than 10 years and up to 2 mg daily for older patients, suitable doses of fluticasone may be 440 μg to 880 μg twice daily for adults and 88 μg to 440 μg two to four times a day for children (up to the maximum adult dose), and suitable doses of ciclesonide may be about to 320 μg twice a day for children. Treatment may comprise repeated doses one to four times a day, and may be continued for 1 day or longer, 3 days or longer, 7 days or longer, one week or longer, two weeks or longer, three weeks or longer, four weeks or longer, five weeks or longer, six weeks or longer, seven weeks or longer, or eight weeks or longer.

[0093] Also provided herein are methods of treating an inflammatory condition of the esophagus, including eosinophilic esophagitis, comprising orally administering to a subject in need thereof a composition as described herein. As noted above, a suitable subject may be suffering from one or more inflammatory conditions of the esophagus, including eosinophilic esophagitis.

[0094] The methods may comprise administering the composition as described herein one or more times per day, such as one, two, three, four, five, or more, times per day.

[0095] Also provided are uses of a corticosteroid in the preparation of a medicament for orally administering the corticosteroid to an esophagus of a subject in need thereof, wherein the medicament comprises an oral pharmaceutical composition as described herein. Also provided are uses of a corticosteroid in the preparation of a medicament for treating an inflammatory condition of the esophagus, such as eosinophilic esophagitis, wherein the medicament comprises an oral pharmaceutical composition as described herein. [0096] Also provided are oral pharmaceutical compositions as described herein for orally administering a corticosteroid to an esophagus of a subject in need thereof. Also provided are oral pharmaceutical compositions as described herein for treating an inflammatory condition of the esophagus, such as eosinophilic esophagitis.

EXAMPLES

[0097] The following specific examples are included as illustrative of the compositions described herein. These examples are in no way intended to limit the scope of the disclosure. Other aspects of the disclosure will be apparent to those skilled in the art to which the disclosure pertains.

Example 1 : Preparation of Sol-Gel Budesonide Composition

[0098] The solubility of budesonide in propylene glycol was determined to be 11 mg/ml at room temperature. Based on this information and other experimentation, it was determined that a propylene glycol content of 5% w/w should be sufficient to solubilize budesonide in the composition.

[0099] To prepare a budesonide composition as described herein, Poloxamer 407 was dispersed in water and chilled at 4 °C overnight. Budesonide was then dissolved in propylene glycol in an ultrasound bath at room temperature. The budesonide solution was then added to the Poloxamer 407 dispersion under stirring at 700 rpm. The temperature of the mixture was then raised to 40 °C to induce micellization and sol-gel transition. The gel was then chilled to below 20 °C so that the gel transitioned back into a liquid. To the liquid composition, water and excipients such as acesulfame potassium and methyl-p- hydroxybenzoate were added under stirring. The composition obtained was liquid at room temperature. Example 2: Physicochemical Characterization of Sol-Gel Budesonide Compositions

[0100] A composition having the following components was prepared by methodology described above:

[0101] Similar compositions having 15% or 17% Poloxamer 407 also were prepared.

[0102] The sol-gel transition temperature of the compositions was determined by methodology known in the art using by microrheology and RHEOLASER® LAB

(Formulaction) equipment. For example, 20 mL of test composition was subjected to heating for evaluation of viscoelastic parameters, G(elastic modulus) and G"(viscous modulus). The sol-gel temperature was defined as the temperature at which the values of the viscoelastic modules are between the solution and gel values. Sol-gel temperature determination was performed in triplicate for each formulation.

[0103] The compositions prepared with 16% Poloxamer 407 exhibited a sol-gel transition temperature of about 32°C. In contrast, compositions prepared with 15% Poloxamer 407 exhibited a sol-gel transition at about 39°C, while compositions prepared with 17%

Poloxamer 407 exhibited a sol-gel transition at about 29°C.

[0104] The mucoadhesive force of the compositions was determined by methodology known in the art, by measuring the force required to remove the composition from a mucin disc using a texturometeter (TA.XT plus, Stable Micro Systems, Surrey, UK). For example, to prepare a mucin disc, 250 mg of mucin was weighed and compressed with 140-150 kg force. The mucin disc was fixed on a 0.5R cylindrical probe and hydrated with 5% mucin solution for 2 minutes. Then, 10 mL of test composition was placed in a Petri dish and maintained at 37°C ± 0.5 to begin the test. The probe containing the mucin disc was lowered to the test composition at a constant speed (0.1 mm/s) and a force of 5 g was applied. The mucin disc and test composition were kept in contact for 60 seconds, after which the probe was lifted 15 mm. The force required to remove the probe from being in contact with the test composition was used as a measure of the mucoadehsive force.

[0105] The compositions prepared with 16% Poloxamer 407 exhibited a mucoadhesive force of 10.88 g. In contrast, compositions prepared with 15% Poloxamer 407 exhibited a mucoadhesive force of 5.27 g, while compositions prepared with 17% Poloxamer 407 exhibited a mucoadhesive force of 14.58 g.

Example 3 : Morphological Characterization of Sol-Gel Budesonide Compositions

[0106] A composition having the following components was prepared by methodology described above:

[0107] Morphological characterization was performed at 25 °C by transmission election microscopy (TEM), and showed micellization. See FIGS. 1 A-1D. Morphological characterization was performed at 37 °C revealed dehydration of the micelles and the gelation process. See FIGS. 2A-2B.

[0108] These figures confirm that budesonide was completely solubilized and molecularly dispersed in the composition, since no budesonide crystals are visible. This indicates that all the budesonide is fully available for contact with and delivery to the esophageal tissue. Example 4: Dynamic Gelling

[0109] A dynamic gelling experiment was conducted to mimic in vivo conditions. Aliquots of 1 ml of the compositions described above were applied by a syringe to a heated 40 cm glass tube (37°C) positioned at 90°, and displacement of each composition was assessed.

[0110] The composition with 15% Poloxamer 407 did not form a gel, traveled the entire length of the tube, and drained out of the tube. The composition with 16% Poloxamer 407 traveled about 25 cm along the tube over a period of about 3 seconds, during which time gelation was occurring. The composition with 17% Poloxamer 407 traveled about 15 cm along the tube over a period of about 2 seconds.

[0111] These results indicate that compositions with different sol-gel temperatures below 37°C will form a gel more or less quickly at 37°C, indicating that compositions having a target gelation time at a given temperature (e.g., body temperature) can be prepared by controlling the sol-gel temperature of the composition. These results also indicate that a Poloxamer 407 content of about 16% w/w is suitable for delivering budesonide to the esophagus, based on typical travel time to the esophagus after oral administration.

Example 5: In Vivo Mucoadhesion

[0112] A composition having the following components was prepared by methodology described above:

[0113] An in vivo study was carried out to verify the mucoadhesion of a 16% Poloxamer 407 composition as described above. The composition was fluorescently labeled using 3 mg/ml IR-780, and a volume of 100 μΙ_, was orally administered to Swiss mice (25 g ±). The extent and duration of adhesion in the gastrointestinal tract were evaluated using fluorescence images acquired by tomography. [0114] It was not possible to observe the presence of the composition in the gastrointestinal tract, possibly due to an insufficient concentration of the fluorescent marker to emit a signal detectable through the animal body. However, ex vivo imaging evidenced mucoadhesion along the gastrointestinal tract, particularly in the esophagus (see FIGS. 3A-B and FIGS. 4A- D). FIGS. 3 A-B show ex vivo images of the gastrointestinal tract of animals four hours after treatment with 20 μΐ of the above formulation (FIG. 3 A) or a control composition prepared without budesonide but with the fluorescent dye IR-780 (FIG. 3B). FIGS. 4A-D show ex vivo images of the esophagus of animals four hours after treatment with 20 μΐ of the above formulation (FIGS. 4A-B) or control composition (FIGS. 4C-D).

Claims

WHAT IS CLAIMED IS:

1. An oral pharmaceutical composition comprising:

(a) a corticosteroid,

(b) a solvent for the corticosteroid, and

(c) a thermoreversible polymer that undergoes a sol-gel transition, wherein the composition is a liquid at room temperature and a gel at body temperature.

2. An oral pharmaceutical composition compri

(a) a corticosteroid,

(b) a solvent selected from one or more of propylene glycol, ethylene glycol, sorbitol, and cyclodextrin, and

(c) a polymer selected from one or more of Poloxamer 407; Poloxamer 338; Poloxamer 188; Pluronic F68; Pluronic F127; and Pluronic F98.

3. The composition of claim 1 or 2, wherein the composition comprises micelles that comprise the polymer, corticosteroid, and solvent.

4. The composition of any one of claims 1-3, wherein the composition is a liquid at 25°C and a gel at 37°.

5. The composition of any one of claims 1-4, wherein the composition has a sol- gel transition temperature of from 25 to 32°C.

6. The composition of any one of claims 1-4, wherein the composition has a sol- gel transition temperature of from 29 to 32°C.

7. The composition of any one of claims 1-6, wherein the polymer comprises Poloxamer 407.

8. The composition of any one of claims 1-7, wherein the corticosteroid is selected from one or more of budesonide, fluticasone, and ciclesonide.

9. The composition of any one of claims 1-7, wherein the corticosteroid is budesonide.

10. The composition of any one of claims 1-7, wherein the corticosteroid is fluticasone.

11. The composition of any one of claims 1-10, wherein the corticosteroid is present in an amount of 0.001 to 10% w/w of the composition.

12. The composition of any one of claims 1-10, wherein the corticosteroid is present in an amount of 0.01 to 10%> w/w of the composition.

13. The composition of any one of claims 1-12, wherein the polymer is present in an amount of 15-30%) w/w of the composition.

14. The composition of any one of claims 1-13, wherein the solvent is present in an amount of 0.2 to 10%> w/w of the composition.

15. The composition of any one of claims 1-14, wherein the polymer is

Poloxamer 407 and is present in an amount of 15-30%) w/w of the composition.

16. The composition of any one of claims 1-15, wherein the solvent is propylene glycol and is present in an amount of 0.2 to 10%> w/w of the composition.

17. The composition of any one of claims 1-15, wherein the solvent is propylene glycol and is present in an amount of 3 to 7% w/w of the composition.

18. The composition of any one of claims 1-15, wherein the solvent is propylene glycol and is present in an amount of 4 to 6%> w/w of the composition.

19. The composition of any one of claims 1-7, wherein the corticosteroid is budesonide and is present in an amount of 0.001 to 10%> w/w, the polymer is Poloxamer 407 and is present in an amount of 15-30%) w/w, and the solvent is propylene glycol and is present in an amount of 0.2 to 10%> w/w of the composition.

20. The composition of any one of claims 1-7, wherein the corticosteroid is budesonide and is present in an amount of 0.01 to 10% w/w, the polymer is Poloxamer 407 and is present in an amount of 15-30%) w/w, and the solvent is propylene glycol and is present in an amount of 4 to 6%> w/w of the composition.

21. The composition of any one of claims 1-7, wherein the corticosteroid is fluticasone and is present in an amount of 0.001 to 10%> w/w, the polymer is Poloxamer 407 and is present in an amount of 15-30%) w/w, and the solvent is propylene glycol and is present in an amount of 0.2 to 10%> w/w of the composition.

22. The composition of any one of claims 1-7, wherein the corticosteroid is fluticasone and is present in an amount of 0.01 to 10%> w/w, the polymer is Poloxamer 407 and is present in an amount of 15-30%) w/w, and the solvent is propylene glycol and is present in an amount of 4 to 6%> w/w of the composition.

23. The composition of any one of claims 1-22, wherein the polymer is Poloxamer 407 and is present in an amount of 15 to 17% w/w of the composition.

24. The composition of any one of claims 1-22, wherein the polymer is Poloxamer 407 and is present in an amount of 15.5 to 16.5% w/w of the composition.

25. The composition of any one of claims 1-24, further comprising water and, optionally, one or more additional pharmaceutically acceptable excipients.

26. The composition of claim 25, comprising one or more additional

pharmaceutically acceptable excipients in an amount of 0.01-10%) w/w of the composition.

27. The composition of claim 25 or 26, comprising one or more additional pharmaceutically acceptable excipients selected from preservatives.

28. The composition of claim 26, wherein the preservative is or comprises methyl-p-hydroxybenzoate.

29. The composition of any one of claims 25-28, comprising one or more additional pharmaceutically acceptable excipients selected from sweeteners.

30. The composition of claim 29, wherein the sweetener is or comprises acesulfame potassium.

31. The composition of any one of the preceding claims, wherein the composition adheres to the esophagus.

32. The composition of claim 31, wherein the compositions adheres to the esophagus for at least 30 minutes.

33. The composition of claim 31, wherein the compositions adheres to the esophagus for at least 45 minutes.

34. The composition of claim 31, wherein the compositions adheres to the esophagus for at least 60 minutes.

35. The composition of any one of claims 1-34, for treating an inflammatory condition of the esophagus.

36. The composition of any one of claims 1-34, for treating eosinophilic esophagitis.

37. A method of treating an inflammatory condition of the esophagus, comprising orally administering a composition of any one of claims 1-34 to a subject in need thereof.

38. A method of treating eosinophilic esophagitis, comprising orally administering a composition of any one of claims 1-34 to a subject in need thereof.

39. Use of a corticosteroid in the manufacture of a medicament for treating an inflammatory condition of the esophagus, wherein the medicament comprises a composition of any one of claims 1-34.

40. Use of a corticosteroid in the manufacture of a medicament for treating eosinophilic esophagitis, wherein the medicament comprises a composition of any one of claims 1-34.

41. A method of preparing a composition of any one of claims 1-34, comprising:

(a) dissolving the corticosteroid in the solvent;

(b) mixing the corticosteroid solution with the polymer; and

(c) optionally, adding water and, optionally, one or more additional pharmaceutically acceptable excipients.

42. A method of preparing a composition of any one of claims 1-34, comprising:

(a) dispersing the polymer in water and chilling the polymer dispersion to below room temperature;

(b) dissolving the corticosteroid in the solvent;

(c) mixing the corticosteroid solution with the polymer dispersion;

(d) increasing the temperature of the mixture until the mixture becomes a gel;

(e) cooling the gelled mixture until the mixture becomes a liquid; and

(f) optionally, adding water and, optionally, one or more additional pharmaceutically acceptable excipients.