RU2805936C1 - Mucoadhesive pharmaceutical compositions based on corticosteroids - Google Patents

Abstract

FIELD: pharmaceutical industry.

SUBSTANCE: group of inventions relates to a mucoadhesive composition and a method of treating one or more inflammatory conditions of the esophagus, eosinophilic esophagitis or inflammatory bowel disease. A mucoadhesive pharmaceutical composition based on a corticosteroid containing the following ingredients: (a) budesonide in an amount of 0.02–0.06 wt./wt.% of the composition, (b) glycerin in an amount of 40–70 wt./wt.% of the composition, (c) xanthan gum in an amount of 0.25–1.5 wt./wt.% of the composition, and (d) propylene glycol in an amount of not more than 20 wt./wt.% of the composition, the composition having a pH of 4.5 to 7. A method of treating one or more inflammatory conditions of the esophagus, eosinophilic esophagitis or inflammatory bowel disease, comprising administering the above-described composition to a subject in need thereof.

EFFECT: above composition characterized by good mucoadhesive properties and stability, has local activity and prevents unwanted systemic effects by minimizing the penetration of the active ingredient through the mucous membrane.

15 cl, 8 dwg, 5 ex, 7 tbl

Description

RELATED APPLICATIONS

[0001] This application claims the benefit of European Application No. 19150077.6, filed January 2, 2019, and US Provisional Application No. 62/749878, filed October 24, 2018, the entire contents of which are incorporated herein by reference.

TECHNICAL FIELD

[0002] This document describes mucoadhesive pharmaceutical compositions based on corticosteroids, as well as methods for preparing such compositions and therapeutic methods for using them.

BACKGROUND OF THE INVENTION

[0003] Eosinophilic esophagitis (EoE) is a clinicopathological disease characterized by upper bowel symptoms and the presence of more than 15 or 20 eosinophils in the esophageal epithelium that is refractory to treatment with proton pump inhibitors. The pathogenesis of EoE is still incompletely understood, but there is growing evidence that the condition represents a T cell immune response involving several proinflammatory mediators and chemoattractants known to regulate eosinophil accumulation in the esophagus, such as IL-4, IL-5, IL-3, eotaxin-1, eotaxin-2 and eotaxin-3.

[0004] EoE appears to be common worldwide (prevalence estimated at 43/100,000 inhabitants; incidence estimated at 7.4/100,000 inhabitants), but the population of patients diagnosed with eosinophilic esophagitis appears to be increasing. Food impaction and dysphagia are the most common symptoms in older children and adults. The pathogenesis of EoE appears to be associated with allergen sensitization in susceptible individuals. Based on a growing number of publications in the clinical literature, hereditary factors make a high contribution to the development of EoE. Approximately 8% of pediatric patients with EoE have at least one sibling or parent also with EoE. In addition, EoE was recently reported to be found in three adult brothers with dysphagia. Taken together, hereditary factors appear to make a high contribution to the development of EoE, with a much higher prevalence in siblings.

[0005] There is no specific treatment available for EoE, but some physicians prescribe budesonide and fluticasone using inhalers and/or oral dry powder. There are several challenges when finding appropriate treatment for EoE. For example, the effectiveness of treatment is reduced due to lack of standardization of dosage. In addition, patients have difficulty adhering to treatment regimens (eg, budesonide and fluticasone via inhaler and/or dry powder) due to the poor taste of the product, as well as pain and gas in the stomach due to swallowing air. Moreover, budesonide and fluticasone, administered via inhalers and/or as a dry powder, can also lead to cavity formation and the development of oral candidiasis.

[0006] Therefore, there remains a need for corticosteroid-based oral pharmaceutical compositions suitable for use in the treatment of EoE.

[0007] Many inflammatory diseases of the intestinal wall are caused by or are influenced by changes in the intestinal microbiota and/or disrupted interactions between the intestinal microbiota and the intestine. These intestinal inflammations include ulcerative colitis and Crohn's disease, which are now called "inflammatory bowel diseases" (IBD). Ulcerative colitis is a chronic inflammatory disease of the colon of unknown etiology. In its acute stage, it resembles an infectious disease, but no microorganism has been clearly identified as its cause. The disease causes various forms of inflammation of the colon mucosa, which in severe cases spreads to the submucosal layer. As a rule, not only the colon, but also the rectum is affected, but the ileum is affected only in rare cases. The formation of an ulcer and the extent of its spread depend on the stage of development of the disease, but they can often be determined by macroscopic methods (sigmoidoscopy and colonoscopy).

[0008] A related disease, Crohn's disease, also known as regional enteritis or colitis granulomatosa, is most often located in the small intestine (small intestine), especially the ileum, but can also affect the jejunum and any part of the colon, including the rectum gut. In the latter case, when distinguishing Crohn's disease from ulcerative colitis, major diagnostic problems arise. In general, inflammation differs from ulcerative colitis in that it progresses to deeper layers than the mucosa and affects the epithelium to a lesser extent.

[0009] Both diseases are becoming increasingly common, especially in developed countries. In the United States, the incidence of ulcerative colitis is 5-15 cases per 100,000 inhabitants, while the incidence of Crohn's disease is approximately 5 cases per 100,000 inhabitants, and these numbers continue to rise. Therefore, the treatment of IBD has become an important problem in modern medicine.

[0010] Therefore, there remains a need for oral and rectal corticosteroid pharmaceutical compositions suitable for use in the treatment of IBD.

SHORT DESCRIPTION

[0011] Provided herein are mucoadhesive pharmaceutical compositions comprising a corticosteroid dissolved and/or suspended in a mucoadhesive system, wherein the mucoadhesive system comprises a corticosteroid carrier medium, a rheology modifying agent, and optionally an aqueous acidic buffer, wherein the composition has an adhesion function , being 150-350 g/s as assessed by the in vitro texture analysis described herein in Example 2, and/or wherein the composition adheres to the esophageal or rectal mucosa for at least 0.5 minutes after administration, for example, for a period of time ranging from at least 0.5 minutes to no more than 4, 6, 8 or 12 hours or from at least 5 minutes to no more than 4, 6, 8 or 12 hours.

[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 0.01-1% w/w, including 0.01-0.1% w/w of the composition. The corticosteroid may be budesonide and may be present at 0.01-0.1% w/w composition, 0.02-0.06% w/w of the composition, or 0.025% w/w of the composition, or 0.05% w/w of the composition.

[0014] In any embodiments of the compositions described herein, the carrier medium may contain glycerin, or may consist of glycerol, or may contain glycerin and another component, such as propylene glycol. In any embodiments, the carrier medium may be present in an amount of 40-70% w/w of the composition. The carrier medium may be present in an amount of 50% w/w of the composition. The carrier medium may contain glycerin present in an amount of 50% w/w of the composition. In any embodiments containing propylene glycol, propylene glycol may be present in an amount of no more than 20% w/w of the composition, such as from about 0.5% to 20% w/w of the composition, or from about 10% to 20%. w/w of the composition, for example 0.5%, 1%, 5%, 10%, 15% or 20% w/w of the composition. The carrier medium may contain glycerol in an amount of 50% w/w of the composition and propylene glycol in an amount of 0.5-20% w/w of the composition or 10-20% w/w of the composition. The carrier medium may contain glycerin in an amount of 50% w/w of the composition and propylene glycol in an amount of 0.5% w/w of the composition. The carrier medium may contain glycerin in an amount of 50% w/w of the composition and propylene glycol in an amount of 10% w/w of the composition. The carrier medium may contain glycerin in an amount of 50% w/w of the composition and propylene glycol in an amount of 15% w/w of the composition. The carrier medium may contain glycerin in an amount of 50% w/w of the composition and propylene glycol in an amount of 20% w/w of the composition.

[0015] In any embodiments of the compositions described herein, the rheology modifying agent may be present in an amount of 0.25-1.5% w/w of the composition. The rheology modifying agent may be present at 1.0% w/w of the composition.

[0016] In any embodiments of the compositions described herein, the rheology-modifying agent may comprise xanthan gum, or may consist of xanthan gum, or may contain xanthan gum and another rheology-modifying agent. The rheology modifying agent may contain xanthan gum in an amount of 0.25-1.5% w/w of the composition. The rheology modifying agent may contain xanthan gum in an amount of 1.0% w/w of the composition.

[0017] In any embodiments of the compositions described herein, the composition may further comprise an aqueous acidic buffer. In some embodiments, the aqueous acidic buffer is a citric acid buffer or an acetate buffer. In some embodiments, the aqueous acidic buffer is a citric acid-based buffer with a pH of 4.5 to 5.5. In some embodiments, the aqueous acidic buffer is a citric acid buffer with a pH of 5.0.

[0018] In any embodiments of any of the compositions described herein, the composition may optionally further contain one or more additional pharmaceutically acceptable excipients.

[0019]The composition may contain one or more preservatives, such as one or more of methyl p-hydroxybenzoate, potassium sorbate, C₁₂-WITH₁₅alkyl benzoates, alkyl p-hydroxybenzoates, propyl and butyl p-hydroxybenzoates, aloe vera extract, ascorbic acid, benzalkonium chloride, benzoic acid, benzoic acid esters and C₉-WITH₁₅alcohols, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), castor oil, cetyl alcohols, chlorocresol, citric acid, cocoa butter, coconut oil, diazolidinyl urea, diisopropyl adipate, dimethylpolysiloxane, DMDM hydantoin, ethanol, fatty acids, fatty alcohols, hexadecyl alcohol, hydroxybenzoate esters, iodopropynylbutylcarbamate, isononylizonanoate, jojoba oil, lanolin oil, methylparaben, mineral oil, oleic acid, olive oil, polyethers, polyoxypropylene butyl ether, polyoxypropylene cetyl ether, silicone oils, sodium propionate, sodium benzoate, bisulfite sodium, disodium metabisulfite, sorbic acid, stearic fatty acid, vitamin E, vitamin E acetate and their derivatives, esters, salts and mixtures. The one or more preservatives may include one or more preservatives selected from a source of vitamin C, polyaminocarboxylic acid and sulfite. In some embodiments, the one or more preservatives include one or more preservatives selected from ascorbic acid, EDTA or sodium edetate, and sodium bisulfite. In any embodiments containing a preservative, the preservative may be present in an amount of from about 0.01% to about 1.0% w/w of the composition, such as from 0.01% to 1.0%, from 0.01% to 0 .5% and from 0.05% to 0.25%. However, in certain embodiments, the composition is substantially free or free of preservatives, including butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA), i.e. the composition is self-preserving.

[0020] In any embodiments, any of the compositions described herein, the composition may additionally or alternatively still contain one or more antioxidants, such as glutathione, quinolines, polyphenols, carotenoids, sodium metabisulfite, tocopherol succinate, propyl gallate, butylated hydroxytoluene, butylated hydroxyanisole, flavonoids , a source of vitamin C, polyaminocarboxylic acids, sulfites and their derivatives. The one or more antioxidants may include one or more antioxidants selected from a source of vitamin C, polyaminocarboxylic acid and sulfite. In some embodiments, the one or more antioxidants include one or more antioxidants selected from ascorbic acid, EDTA or sodium edetate, and sodium bisulfite. In any embodiments containing an antioxidant, the antioxidant may be present in an amount of from about 0.01% to about 1.0% w/w of the composition, such as from 0.01% to 0.5% and from 0.05% to 0 .25%. In some embodiments, the composition contains a component that acts as both a preservative and an antioxidant.

[0021] Additionally or alternatively, the composition may contain one or more flavors, such as one or more of berry flavor, tutti frutti flavor, caramel flavor, root beer flavor, cream flavor ", chocolate flavor, peppermint flavor, mint flavor, toffee flavor and wintergreen flavor.

[0022] In any embodiments, any of the compositions described herein, the composition may further comprise a sweetener. The sweetener may contain sucralose or may consist of sucralose. In any embodiments containing sucralose, sucralose may be present in an amount of from 0.001% to 0.50% w/w of the composition, including from 0.005% to 0.1% w/w of the composition, from 0.05% to 0 ,50%. w/w of the composition and from 0.01% to 0.05% w/w of the composition. For example, sucralose may be present in an amount of 0.005%, 0.01%, 0.05%, or 0.10% w/w of the composition, such as 0.05% w/w.

[0023] In any of the embodiments of the compositions described herein, the composition may exhibit substantially similar adhesion performance over the temperature range of 20-40°C.

[0024] In any of the embodiments of the compositions described herein, the composition may be pourable at room temperature. In some embodiments, the composition has a viscosity of approximately 3000-9000 cP at room temperature.

[0025]In any embodiments, any of the compositions described herein, the composition may include (a) budesonide in an amount of 0.02-0.06% w/w of the composition, (b) glycerin in an amount of 40-70% w/w of the composition, (c ) xanthan gum in an amount of 0.25-1.5% w/w of the composition, (d) an aqueous citric acid buffer with a pH of 4.5-5.5, (e) optionally sucralose in an amount of 0.001-0.5% w/w of the composition and (f) optionally propylene glycol in an amount of not more than 20% w/w of the composition (e.g. from 0.5% w/w to 20% w/w or from 10% w/w to 20% w/w). In some embodiments, the composition includes sucralose in an amount of 0.05-0.5% w/w of the composition.

[0026] In any embodiments, any of the compositions described herein, the composition may include (a) budesonide in an amount of approximately 0.05% w/w of the composition, (b) glycerin in an amount of approximately 50% w/w of the composition, and (c) xanthan gum in an amount of approximately 1% w/w of the composition.

[0027] In any embodiments, any of the compositions described herein, the composition may be a suspension or solution.

[0028] In any embodiments, any of the compositions described herein, the composition can adhere to mucosal tissue. In any embodiments, any of the compositions described herein, the composition can adhere to esophageal mucosa. In some embodiments, at least a therapeutically effective amount of the composition adheres to the mucosal tissue of the esophagus for at least 0.5 minutes, at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 30 minutes, or for at least 45 minutes or for at least 60 minutes. In any embodiments, any of the compositions described herein, the composition can adhere to rectal mucosal tissue. In some embodiments, at least a therapeutically effective amount of the composition adheres to the rectal mucosa for at least 0.5 minutes, at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 30 minutes or at least 45 minutes, or for at least 60 minutes, such as for a period of no more than 4, 6, 8 or 12 hours.

[0029] In any embodiments, any of the compositions described herein, the composition may have an adhesion work force of 150-350 g/s or 150-300 g/s as assessed by the in vitro texture assay described herein in the Example 2.

[0030] In any embodiments, any of the compositions described herein, the composition may be formulated for oral administration. In any embodiments, any of the compositions described herein may be formulated for rectal administration.

[0031] In any embodiments, the composition may be presented in a single dose package containing 1-10 ml of the composition. In some embodiments, the composition is presented in a single dose package containing 2-5 ml of the composition.

[0032] In any embodiments, the composition may be presented in a multi-dose package. In some embodiments, the multi-dose package contains doses for 1 week of treatment, 2 weeks of treatment, 3 weeks of treatment, 4 weeks of treatment, 1 month of treatment, 2 months of treatment, or 3 months of treatment.

[0033] Methods of treating an inflammatory condition of the esophagus, such as eosinophilic esophagitis, are also provided that involve the oral administration of a mucoadhesive pharmaceutical composition described herein.

[0034] Also provided are methods of treating IBD comprising oral or rectal administration of a mucoadhesive pharmaceutical composition described herein.

[0035] In any embodiments, the composition can be administered to provide a dose of 1 mg to 2 mg of corticosteroid per day. In some embodiments, the dosage is effective for treating an inflammatory condition of the esophagus, such as eosinophilic esophagitis. In some embodiments, the dosage is effective for treating inflammatory bowel disease.

[0036] Also contemplated are uses of a corticosteroid in the manufacture of a medicament for the treatment of an inflammatory condition of the esophagus, such as eosinophilic esophagitis, wherein the medicament comprises a mucoadhesive pharmaceutical composition described herein.

[0037] Also contemplated are uses of a corticosteroid in the manufacture of a medicament for the treatment of IBD, wherein the medicament comprises a mucoadhesive pharmaceutical composition described herein.

[0038] Methods for preparing the mucoadhesive pharmaceutical composition described herein are also provided, comprising preparing a solution or suspension containing a corticosteroid, a carrier medium, a rheology modifying agent, and optionally an aqueous acidic buffer.

BRIEF DESCRIPTION OF GRAPHIC MATERIALS

[0039] In FIG. 1 is a diagram of illustrative manufacturing methods used to produce the composition described herein.

[0040] In FIG. Figure 2 is a diagram showing how adhesion work is an indicator of adhesive ability.

[0041] In FIG. 3 shows the work of adhesion for the following in vitro evaluated compositions: (a) glycerol; (b) glycerin and water (50:50); and (c) water.

[0042] In FIG. Figure 4 shows the time (in seconds) it took to cover an entire 30 cm section of excised pig esophagus with the following compositions: (a) liquid honey; (b) xanthan gum (1% w/w) in glycerin and water (85:15); (c) xanthan gum (1% w/w) in glycerin and water (50:50); and (c) water.

[0043] In FIG. 5A shows the staining and adhesion results of the composition assessed during an in vivo study in rats (rat esophagus) at 5 minutes and at 10 minutes. In FIG. 5B shows the results after 15 minutes and 20 minutes.

[0044] In FIG. 6A shows the relative rheological synergy of the mucin compositions described herein at 22°C. In FIG. 6B shows the relative rheological synergy of the mucin compositions described herein at 37°C.

DETAILED DESCRIPTION

[0045] Described herein are mucoadhesive pharmaceutical compositions containing a corticosteroid, methods for preparing such mucoadhesive pharmaceutical compositions, and therapeutic methods for using them.

[0046] These compositions provide local delivery of a corticosteroid to mucosal tissue, such as esophageal or rectal mucosa. The compositions adhere to mucosal surfaces, such as mucosal surfaces of the esophageal or rectal mucosa, and therefore can provide prolonged delivery of the corticosteroid to the esophagus or rectum. These compositions may have particular advantages in the context of the treatment of EoE or IBD, providing local and sustained delivery of the corticosteroid to the site of pathology.

Definitions

[0047] Technical and scientific terms used herein have the meanings commonly understood by one skilled in the art of pharmaceutical compositions to which this invention relates, unless otherwise indicated. This document contains references to various techniques known to those skilled in the art. Appropriate materials and/or methods known to one skilled in the art can be used to implement the present invention. However, specific materials and methods are described. Materials, reagents, etc. referenced in the following description and examples are available from commercial sources unless otherwise noted.

[0048] As used herein, the singular forms refer to both singular and plural unless only the singular form is explicitly indicated

[0049] As used herein, the term “about” means that the number or range is not limited to an exact number or stated range, but covers values around the stated number or range that would be understood by one skilled in the art depending on the context in which the number or range are used. Unless otherwise obvious from context or art convention, "about" means up to plus or minus 10% of a particular value.

[0050] As used herein, the term “subject” refers to any mammal, including humans. For example, a subject may suffer from or be at risk of developing a condition that can be diagnosed, treated or prevented by a corticosteroid, or may be taking a corticosteroid for other purposes.

[0051] The terms “administer”, “administration” or “administer” as used herein refer to (1) the provision, delivery, administration of a dose and/or administration, for example, by either a healthcare professional or his or her authorized representative, or under its direction, and (2) administration, administration or use, such as by a healthcare professional or subject.

[0052] As used herein, the terms “self-preservative” or “self-preservative” mean a composition that has sufficient antimicrobial activity to be pharmaceutically acceptable without the addition of an additional antimicrobial agent, antioxidant, or preservative. For example, a self-preservative composition can meet the preservative efficacy requirements of the United States Pharmacopoeia ("USP") (eg, USP 41, section <51>) and similar guidelines in other countries, without the addition of an additional antimicrobial agent, antioxidant, or preservative.

[0053] As used herein, the term “substantially free” means that the composition is prepared without the excluded component, although minor or trace amounts may be present as an impurity or by-product.

[0054] The terms “treat,” “treat,” or “cure,” as used herein, include alleviating, mitigating, or ameliorating a disease or condition, or one or more symptoms thereof, regardless of whether the disease or condition is considered “cured.” " or "cured", and regardless of whether all symptoms are eliminated. The terms also include reducing or preventing the development of a disease or condition or one or more symptoms thereof, inhibiting or preventing the mechanism underlying the disease or condition or one or more symptoms thereof, and achieving any therapeutic and/or prophylactic benefit.

[0055] As used herein, the phrase “therapeutically effective amount” refers to a dose that produces the specific pharmacological effect for which the drug is administered to a subject in need of such treatment. It should be emphasized that a therapeutically effective amount will not always be effective in treating the conditions described herein, even if such a dose is considered a therapeutically effective amount by those skilled in the art. For purposes of convenience only, illustrative dosages and therapeutically effective amounts are presented below in relation to human subjects. One skilled in the art can adjust such amounts in accordance with standard practices as necessary to treat a particular subject and/or condition/disease.

COMPOSITIONS

[0056] As noted above, the compositions described herein typically include a corticosteroid in a mucoadhesive system, such as a corticosteroid dissolved and/or suspended in the mucoadhesive system.

Corticosteroids

[0057] The mucoadhesive pharmaceutical compositions described herein may contain any one or more pharmaceutically acceptable corticosteroids, such as any one or more corticosteroids pharmaceutically acceptable for oral administration or rectal administration, such as steroids that are active when administered topically.

[0058] Non-limiting examples of suitable corticosteroids include one or more corticosteroids selected from budesonide, fluticasone, ciclesonide, cortisone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, amcinonide, desonide, fluocinolone acetonide, fluocinonide, galcinonide, triamcinolone a cetonide, beclomethasone, betamethasone , dexamethasone, fluocortolone, halomethasone, mometasone, flunisolide, ciclesonide and fludrocortisone and pharmaceutically acceptable salts and esters of each thereof.

[0059] 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, such as sodium and calcium salts, can be used. 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 and branched chain C ₁ -C ₁₈ alkyl esters including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, hexyl, heptyl, octyl, nonyl, decyl, lauryl, myristyl, cetyl, and stearyl, etc., C ₂ -C ₁₈ alkenyl esters with straight or branched chain, including vinyl, allyl, undecenyl, oleyl, linolenyl, etc., C ₃ -C ₈ cycloalkyl esters, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, etc., aryl esters including phenyl, toluoyl, xylyl, naphthyl, etc., alicyclic esters including menthyl, and the like. or aralkyl esters including benzyl, phenethyl and the like.

[0060] In some embodiments, the composition described herein contains budesonide. Budesonide has the molecular formula C ₂₅ H ₃₄ O ₆ , molecular weight 430.53 and chemical name 16,17-butylidenebis(oxy)-11,21-dihydroxy-(11β,16α)-pregna-1,4-diene-3, 20-dione It is listed under registration number CAS 51333-22-3 and Einecs 257-139-7.

[0061] In some embodiments, the composition described herein contains fluticasone. Fluticasone has the molecular formula C ₂₂ H ₂₇ F ₃ O ₄ S, molecular weight 444.51 and chemical name 6α,9α-difluoro-11β,17α-dihydroxy-16α-methyl-21-thia-21-fluoromethylpregna-1,4- Diene-3,20-dione. Fluticasone is registered under CAS registration number 90566-53-3.

[0062] In some embodiments, the composition described herein contains ciclesonide. Cyclesonide has the molecular formula C ₃₂ H ₄₄ O ₇ , molecular weight 540.69 g/mol and chemical name (11β,16α)-16,17-[[( R )-cyclohexylmethylene] bis (oxy)]-11-hydroxy- 21-(2-methyl-1-oxopropoxy)-pregna-1,4-diene-3,20-dione. Cyclesonide is registered under CAS registration number 126544-47-6.

[0063] The mucoadhesive pharmaceutical compositions described herein may include a therapeutically effective amount of a corticosteroid. The therapeutically effective amount may depend on the particular corticosteroid used, the condition being treated, the route of administration, the subject being treated, the desired effect and the intended duration of the therapeutic effect of the compositions. Compositions containing more than one corticosteroid may include a therapeutically effective amount of each corticosteroid or a quantity of one or more corticosteroids that are not therapeutically effective in themselves, but such amount of all corticosteroids present is therapeutically effective.

[0064] In any embodiments, the corticosteroid may be present in an amount from about 0.001% to about 10% w/w of the composition, such as about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, approximately 0.007%, approximately 0.008%, approximately 0.009%, approximately 0.01%, approximately 0.02%, approximately 0.03%, approximately 0.04%, approximately 0.05%, approximately 0.06%, approximately 0 .07%, approximately 0.08%, approximately 0.09%, approximately 0.1%, approximately 0.2%, approximately 0.3%, approximately 0.4%, approximately 0.5%, approximately 0.6 %, approximately 0.7%, approximately 0.8%, approximately 0.9%, approximately 1%, approximately 2%, approximately 3%, approximately 4%, approximately 5%, approximately 6%, approximately 7%, approximately 8 %, about 9% or about 10% w/w of the composition. The corticosteroid may be 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 approximately 3.5%, or approximately 4.0%, or approximately 4.5%, or approximately 5.0%, or approximately 6.0%, or approximately 7.0%, or approximately 8.0% , or about 9.0%, or about 10% w/w of the composition. The corticosteroid may be 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. The corticosteroid may be present in an amount from about 0.01 to about 1% w/w of the composition. The corticosteroid may be present in an amount of from about 0.01 to about 0.1% w/w of the composition. The corticosteroid may be present in an amount of approximately 0.025% w/w of the composition. The corticosteroid may be present in an amount of approximately 0.05% w/w of the composition.

[0065]In any In embodiments of compositions containing more than one corticosteroid, the amount of each may be selected independently of the other. In some such embodiments, the composition may include one of the above amounts of each corticosteroid. In other embodiments of compositions containing more than one corticosteroid, the amount of each is selected to be complementary to the other. In any such embodiments, the compositions may have a total corticosteroid content corresponding to one of the above amounts. Also provided are embodiments of compositions containing more than one or more than two corticosteroids.

[0066] In embodiments where the corticosteroid is budesonide, budesonide may be 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. Budesonide may be 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% w/w of the composition. Budesonide may be present in an amount from about 0.001% to about 10% w/w of the composition, for example about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008% , approximately 0.009%, for example approximately 0.01%, approximately 0.02%, approximately 0.03%, approximately 0.04%, approximately 0.05%, approximately 0.06%, approximately 0.07%, approximately 0 .08%, approximately 0.09%, approximately 0.1%, approximately 0.2%, approximately 0.3%, approximately 0.4%, approximately 0.5%, approximately 0.6%, approximately 0.7 %, approximately 0.8%, approximately 0.9%, approximately 1%, approximately 2%, approximately 3%, approximately 4%, approximately 5%, approximately 6%, approximately 7%, approximately 8%, approximately 9% or approximately 10% w/w of the composition. Budesonide may be present in an amount from about 0.01 to 1.0% w/w of the composition. Budesonide may be present in an amount of from about 0.01 to 0.1% w/w of the composition. Budesonide may be present in an amount of approximately 0.025% w/w of the composition. Budesonide may be present in an amount of approximately 0.05% w/w of the composition.

[0067] In some embodiments, the corticosteroid comprises fluticasone. In some embodiments, 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 approximately 2.0% w/w of the composition. Fluticasone may be 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% w/w of the composition. Fluticasone may be present in an amount from about 0.001% to about 10% w/w of the composition, for example about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008% , approximately 0.009%, for example approximately 0.01%, approximately 0.02%, approximately 0.03%, approximately 0.04%, approximately 0.05%, approximately 0.06%, approximately 0.07%, approximately 0 .08%, approximately 0.09%, approximately 0.1%, approximately 0.2%, approximately 0.3%, approximately 0.4%, approximately 0.5%, approximately 0.6%, approximately 0.7 %, approximately 0.8%, approximately 0.9%, approximately 1%, approximately 2%, approximately 3%, approximately 4%, approximately 5%, approximately 6%, approximately 7%, approximately 8%, approximately 9% or approximately 10% w/w of the composition. Fluticasone may be present in an amount of from about 0.01 to 1.0% w/w of the composition. Fluticasone may be present in an amount of from about 0.01 to 0.1% w/w of the composition.

[0068] In some embodiments, the corticosteroid includes ciclesonide. In some embodiments, 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 approximately 2.0% w/w of the composition. Ciclesonide may be 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% w/w of the composition. Ciclesonide may be present in an amount from about 0.001% to about 10% w/w of the composition, for example about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008% , approximately 0.009%, for example approximately 0.01%, approximately 0.02%, approximately 0.03%, approximately 0.04%, approximately 0.05%, approximately 0.06%, approximately 0.07%, approximately 0 .08%, approximately 0.09%, approximately 0.1%, approximately 0.2%, approximately 0.3%, approximately 0.4%, approximately 0.5%, approximately 0.6%, approximately 0.7 %, approximately 0.8%, approximately 0.9%, approximately 1%, approximately 2%, approximately 3%, approximately 4%, approximately 5%, approximately 6%, approximately 7%, approximately 8%, approximately 9% or approximately 10% w/w of the composition. Ciclesonide may be present in an amount from about 0.01 to 1.0% w/w of the composition. Ciclesonide may be present in an amount from about 0.01 to 0.1% w/w of the composition.

[0069] In any embodiments, the corticosteroid may be present at a concentration of from about 0.1 mg/ml to about 1.0 mg/ml, such as about 0.1 mg/ml, about 0.2 mg/ml, about 0. 3 mg/ml, approximately 0.4 mg/ml, approximately 0.5 mg/ml, approximately 0.6 mg/ml, approximately 0.7 mg/ml, approximately 0.8 mg/ml, approximately 0.9 mg /ml or approximately 1.0 g/ml. The corticosteroid may be 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 approximately 0.7 mg/ml, or approximately 0.8 mg/ml, or approximately 0.9 mg/ml. The corticosteroid may be 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. The corticosteroid may be present at a concentration of approximately 0.5 mg/ml.

[0070] In embodiments containing more than one corticosteroid, the amount of each can be selected independently of the other. In any such embodiments, the composition may include one of the above concentrations of each corticosteroid. In other embodiments of compositions containing more than one corticosteroid, the amount of each is selected to be complementary to the other. In any such embodiments, the compositions may have a total corticosteroid concentration corresponding to one of the above concentrations. Other embodiments of compositions containing more than one or more than two corticosteroids are also provided.

[0071] In any embodiments where the corticosteroid includes budesonide, budesonide may be present at a concentration of from about 0.1 mg/ml to about 1.0 mg/ml, such as about 0.1 mg/ml, about 0.2 mg /ml, approximately 0.3 mg/ml, approximately 0.4 mg/ml, approximately 0.5 mg/ml, approximately 0.6 mg/ml, approximately 0.7 mg/ml, approximately 0.8 mg/ml , approximately 0.9 mg/ml or approximately 1.0 mg/ml. Budesonide may be 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 approximately 0.7 mg/ml, or approximately 0.8 mg/ml, or approximately 0.9 mg/ml. Budesonide may be 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. Budesonide may be present at a concentration of approximately 0.5 mg/ml.

[0072] In embodiments where the corticosteroid includes fluticasone, fluticasone may be present at a concentration of from about 0.1 mg/ml to about 1.0 mg/ml, such as about 0.1 mg/ml, about 0.2 mg/ml ml, approximately 0.3 mg/ml, approximately 0.4 mg/ml, approximately 0.5 mg/ml, approximately 0.6 mg/ml, approximately 0.7 mg/ml, approximately 0.8 mg/ml, approximately 0.9 mg/ml or approximately 1.0 mg/ml. Fluticasone may be 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 approximately 0.7 mg/ml, or approximately 0.8 mg/ml, or approximately 0.9 mg/ml. Fluticasone may be 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. Fluticasone may be present at a concentration of approximately 0.5 mg/ml.

[0073] In any embodiments where the corticosteroid includes ciclesonide, ciclesonide may be present at a concentration of from about 0.1 mg/ml to about 1.0 mg/ml, such as about 0.1 mg/ml, about 0.2 mg /ml, approximately 0.3 mg/ml, approximately 0.4 mg/ml, approximately 0.5 mg/ml, approximately 0.6 mg/ml, approximately 0.7 mg/ml, approximately 0.8 mg/ml , approximately 0.9 mg/ml or approximately 1.0 mg/ml. Ciclesonide may be 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 approximately 0.7 mg/ml, or approximately 0.8 mg/ml, or approximately 0.9 mg/ml. Ciclesonide may be 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. Ciclesonide may be present at a concentration of approximately 0.5 mg/ml.

Mucoadhesive system

[0074] As noted above, the compositions described herein include a mucoadhesive system capable of adhering to mucosal surfaces, such as esophageal or rectal mucosa.

[0075] Mucoadhesive systems typically contain or consist of a rheology modifying agent, a corticosteroid carrier medium, and optionally an aqueous acidic buffer.

[0076]Non-limiting examples of rheology modifying agents suitable for use in the compositions described herein include xanthan gum, acacia gum, shiraz gum, karaya gum, guar gum, gellan gum, and alginates (e.g. sodium alginate). Other non-limiting examples include carbomers, carboxyethylene polymers and/or polyacrylic acids (such as carbopol 980 or 940 NF, 981 or 941 NF, 1382 or 1342 NF, 5984 or 934 NF, ETD 2020, 2050, 934P NF, 971P NF, 974 PNF , Noveon AA-1 USP); poly(2-hydroxyethyl methacrylate) (PHEMA), poly(methacrylic acid), polyethylene oxides, poloxamers, cellulose derivatives such as hydroxypropyl methylcellulose (HPMC), ethylhydroxyethylcellulose (EHEC), carboxymethylcellulose (CMC), carboxymethylcellulose salts, hydroxypropylcellulose (HPC), hydroxyethylcellulose ( HEC), hydroxyethylmethylcellulose, polyvinylpyrrolidones, chitosans (e.g. chitosan and thiolated chitosan), pectin, gelatin, polyvinyl alcohols and vigum.

[0077] In any embodiments of the compositions described herein, the rheology modifying agent may comprise xanthan gum, or may consist of xanthan gum, or may contain xanthan gum and another rheology modifying agent, such as one or more of those described herein or known in the art.

[0078] In any embodiments of the compositions described herein, the rheology modifying agent may be present in an amount of 0.01-10% w/w of the composition, such as about 0.01%, about 0.02%, about 0.03%, approximately 0.04%, approximately 0.05%, approximately 0.06%, approximately 0.07%, approximately 0.08%, approximately 0.09%, approximately 0.1%, approximately 0.2%, approximately 0 .3%, approximately 0.4%, approximately 0.5%, approximately 0.6%, approximately 0.7%, approximately 0.8%, approximately 0.9%, approximately 1%, approximately 2%, approximately 3 %, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% w/w of the composition. The rheology modifying agent may be present in an amount of from about 0.01% to about 5%, or from about 0.05% to about 4%, or from about 0.1% to about 3%, or about 0.2% to about 2%, or about 0.25% to about 1.5%, or about 0.3% to about 1.2%, or about 0.5% to about 1.0% w/w of the composition. The rheology modifying agent may be present in an amount from about 0.25% to about 1.5% w/w of the composition. The rheology modifying agent may be present at 1.0% w/w of the composition. The rheology modifying agent may be present in an amount of no more than about 3%, or no more than about 1.5%, or no more than about 0.25%, or no more than about 0.1% w/w of the composition.

[0079] In some embodiments, the rheology modifying agent contains xanthan gum, which is present in an amount of 0.25-1.5% w/w of the composition. The rheology modifying agent may contain xanthan gum in an amount of 1.0% w/w of the composition.

Carrier medium

[0080]As noted above, the compositions described herein also contain a corticosteroid carrier medium. As used herein, the term “carrier medium” refers to a pharmaceutically acceptable carrier medium suitable for the intended route of administration (e.g. oral or rectal) in which the corticosteroid may be partially or completely dissolved or suspended, wherein the components of the carrier medium do not have a direct therapeutic effect on the condition(s) for which the composition is administered (e.g. for the specified application(s). In some embodiments, the corticosteroid(s) are suspended in a carrier medium. In some embodiments, the carrier medium is a diluent for the corticosteroid(s). In some embodiments, the corticosteroid(s) are dissolved in a carrier medium. In some embodiments, the corticosteroid(s) are partially suspended and partially dissolved in the carrier medium.

[0081] Examples of suitable carrier media components include, but are not limited to, glycerol and propylene glycol. Additional examples include, but are not limited to, PECEOL™ (glyceryl monooleate, type 40), LABRAFAC™ PG (propylene glycol dicaprylocaprate), PLUROL® OLEIQUE CC497 (polyglyceryl-3-dioleate), LABRAFIL® CS1944 (oleoylpolyoxyl-6-glycerides), diethylene glycol monoethyl ether. Mixtures of any two or more of the above may be used. In some embodiments, the carrier medium contains glycerin, consists of glycerol, or contains glycerin and another medium, such as propylene glycol. In some embodiments, the composition does not include polypropylene glycol. In some embodiments, the composition does not include polyethylene glycol. In some embodiments, the composition does not include polypropylene glycol and does not include polyethylene glycol.

[0082] The amount of carrier medium present in the composition can be selected and controlled to ensure partial or complete solubilization of the corticosteroid and/or other components that may be present and to achieve the desired properties of the composition, such as adhesion to mucosal surfaces. Illustrative quantities are discussed in more detail below. For example, the total amount of carrier medium can be from about 1 to about 90% w/w of the composition, such as about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, approximately 35%, approximately 40%, approximately 45%, approximately 50%, approximately 55%, approximately 60%, approximately 65%, approximately 70%, approximately 75%, approximately 80%, approximately 85% or approximately 90% w/w compositions. The total amount of carrier medium may be from about 25% to about 85%, or from about 30% to about 80%, or from about 35% to about 75%, or from about 40% to about 70%, or from about 45 % to approximately 60% w/w of the composition. The total amount of carrier medium may be approximately 50% w/w of the composition.

[0083]In some embodiments, the carrier medium contains glycerol. Glycerin can be present in an amount from about 1 to about 90% w/w, from about 25% to about 85%, or from about 30% to about 80%, or from about 35% to about 75%, or from about 40% to about 70%, or from about 45% to about 60% w/w of the composition. Glycerin may be present in an amount from about 30% to about 80% w/w of the composition. Glycerin may be present in an amount from about 40% to about 70% w/w of the composition. Glycerin may be present in an amount from about 45% to about 60% w/w of the composition. Glycerin may be present in an amount of about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90% w/w of the composition. Glycerin may be present in an amount of approximately 50% w/w of the composition.

[0084] In some embodiments, the carrier medium contains propylene glycol, which can also act as a penetration enhancer. In some embodiments, propylene glycol is present in an amount of no more than about 40%, or no more than about 30%, or no more than about 20%, or no more than about 15%, w/w of the composition. Propylene glycol may be present in an amount of no more than about 30% w/w of the composition. Propylene glycol may be present in an amount of no more than about 20% w/w of the composition. Propylene glycol may be present in an amount of from about 0.5% to about 40%, from about 0.5% to about 30%, from about 0.5% to about 25%, from about 0.5% to about 20%, from about 0.5% to about 15%, or about 0.5% to about 10% w/w of the composition. Propylene glycol may be present in an amount of about 0.5%, about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40% w/w of the composition .

[0085] In particular embodiments containing propylene glycol, propylene glycol may be present in an amount of no more than 20% w/w of the composition, such as from about 0.5% to 20% w/w of the composition, or from about 10% to 20%. w/w of the composition, for example 0.5%, 1%, 5%, 10%, 15% or 20% w/w of the composition.

[0086] In some embodiments, the composition contains about 40-70% w/w glycerol and up to about 20% w/w propylene glycol, such as about 0.5% to 20% w/w. For example, the composition may contain about 50% w/w glycerol and about 20% w/w propylene glycol.

[0087]Depending on the type and amount of carrier medium used, the compositions described herein can be prepared as a solution or suspension. Thus, in some embodiments, the composition is a suspension (e.g. the corticosteroid is substantially partially dissolved in the vehicle medium), whereas in some embodiments the composition is a solution (e.g. the corticosteroid is essentially completely dissolved in the carrier medium).

pH adjuster

[0088] The mucoadhesive pharmaceutical compositions described herein typically further contain water and optionally a pH adjusting agent. The pH adjusting agent may be in the form of an aqueous buffer, such as an aqueous acid buffer.

[0089] Non-limiting examples of aqueous acidic buffer include citric acid buffers, acetate buffers, benzoate buffers, borate buffers, citrate buffers, carbonate buffers, hydrochloric acid, lactate buffers, perchloric acid, tartaric acid, propionate buffers, and mixtures thereof. In some embodiments, the aqueous acidic buffer is a citric acid-based buffer.

[0090] The pH of the aqueous acidic buffer can be selected and controlled to provide the final composition with the desired pH, which can be adjusted to enhance the chemical stability of the corticosteroid.

[0091] In some embodiments, aqueous acidic buffers may have a pH of from about 1 to about 6, or from about 1.5 to about 5.5, or from about 2 to about 5, or from about 2.5 to about 4, 5, from about 3 to about 4, or from about 4.5 to about 5.5. In some embodiments, the aqueous acidic buffer is a citric acid buffer or an acetate buffer. In some embodiments, the aqueous acidic buffer is a citric acid buffer with a pH of 4.5-5.5. In some embodiments, the aqueous acidic buffer is a citric acid-based buffer with a pH of approximately 5.0, such as pH 5±0.1. In some embodiments, the aqueous acidic buffer is an acetate buffer with a pH of 4.7. For example, for the budesonide compositions described herein, an aqueous acidic buffer with a pH of 4.5-5.5, such as an aqueous citric acid buffer, is suitable.

[0092]The pH of the composition described herein can be selected and controlled to be close to the physiological pH of the esophagus, i.e. slightly acidic to neutral, such as about 4.5 to about 7. In some embodiments, the composition may have a pH of about 4.5, or about 5, or about 5.5, or about 6, or about 6.5, or about 7, and with pH values between any of these values.

Other components

[0093]The mucoadhesive pharmaceutical compositions described herein may optionally further contain one or more optional pharmaceutically acceptable excipients. In any embodiments of the compositions described herein, one or more optional pharmaceutically acceptable excipients may be one or more described herein or known in the art (e.g. described in Roweet al., Handbook of Pharmaceutical Excipients (Pharm. Press 7^th ed. 2012). In some embodiments, any optional pharmaceutically acceptable excipients present do not significantly affect the therapeutic efficacy of the composition. In some embodiments, the pharmaceutically acceptable excipients reduce the risks of developing diseases or conditions associated with long-term use of corticosteroids, such as candidiasis. Additionally or alternatively, in some embodiments, any optional pharmaceutically acceptable excipients present do not significantly affect the mucoadhesive properties of the composition. Optional pharmaceutically acceptable excipients, if present, can be included in the compositions in any suitable amount sufficient to obtain the desired effect of the component without significantly interfering with the desired properties of the compositions, such as their mucoadhesive properties, drug delivery properties and therapeutic properties.

[0094] Examples of optional pharmaceutically acceptable excipients include, but are not limited to, preservatives, sweeteners, antioxidants, chelating agents, coloring agents, penetration enhancers, and/or flavoring agents. The categories of preservatives and antioxidants are not mutually exclusive, as some products can act as both a preservative and an antioxidant.

[0095] Non-limiting examples of preservatives include methyl p-hydroxybenzoate, potassium sorbate, C ₁₂ -C ₁₅ alkyl benzoates, alkyl p-hydroxybenzoates, propyl and butyl p-hydroxybenzoates, aloe vera extract, ascorbic acid, benzalkonium chloride, benzoic acid , benzoic acid esters and C ₉ -C ₁₅ alcohols, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), castor oil, cetyl alcohols, chlorocresol, citric acid, cocoa butter, coconut oil, diazolidinyl urea, diisopropyl adipate, dimethylpolysiloxane, DMDM hydantoin, ethanol, fatty acids, fatty alcohols, hexadecyl alcohol, hydroxybenzoate esters, iodopropynyl butyl carbamate, isononylisonanoate, jojoba oil, lanolin oil, methylparaben, mineral oil, oleic acid, olive oil, polyethers, polyoxypropylene butyl ether, polyoxypropylene cetyl ether , silicone oils, sodium propionate, sodium benzoate, sodium bisulfite, disodium metabisulfite, sorbic acid, stearic fatty acid, vitamin E, vitamin E acetate and their derivatives, esters, salts and mixtures thereof. In some embodiments, the preservative is or includes methyl p-hydroxybenzoate. In some embodiments, the preservative is or includes a source of vitamin C, such as ascorbic acid or a derivative thereof, which includes salts. In some embodiments, the preservative is or includes bisulfite. Non-limiting examples of sulfites include, but are not limited to, sodium bisulfite, sodium metabisulfite, potassium bisulfite, and potassium metabisulfite. In some embodiments, the preservative is or includes sodium metabisulfite. In some embodiments, the preservative is or includes a polyaminocarboxylic acid, such as edetic acid (ethylenediaminetetraacetic acid/EDTA). In some embodiments, the preservative is or includes edetic acid or a derivative thereof, such as a salt. In some embodiments, the preservative is or includes disodium edetate.

[0096] The preservative may be present in any suitable amount, including from about 0.01% to about 1.0%, from about 0.01% to about 0.5%, and from about 0.05% to 0.25 % w/w composition. The preservative may be present in amounts of approximately 0.01%, 0.02%, 0.03%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10% , 0.15%, 0.20%, 0.25%, 0.30%, 0.35%, 0.40%, 0.45%, 0.50%, 0.55%, 0.60% , 0.65%, 0.70%, 0.75%, 0.80%, 0.85%, 0.90%, 0.95% or 1.0% w/w composition. In some embodiments, the preservative is or includes ascorbic acid or a salt thereof and is present in an amount from about 0.01% to about 1.0% w/w of the composition, including any amount between these values, such as 0.01% , 0.02%, 0.03%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.15%, 0.20% , 0.25%, 0.30%, 0.35%, 0.40%, 0.45%, 0.50%, 0.55%, 0.60%, 0.65%, 0.70% , 0.75%, 0.80%, 0.85%, 0.90%, 0.95% or 1.0% w/w of the composition. In some embodiments, the preservative is or includes a bisulfite, such as sodium metabisulfite, and is present in an amount from about 0.05% to about 0.25% w/w of the composition, including any amount between these values, such as 0. 05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.15%, 0.20%, 0.25% w/w composition. In some embodiments, the preservative is or includes edetic acid or a salt thereof, such as disodium edetate, and is present in an amount from about 0.01% to about 0.5% w/w of the composition, including any amount between these amounts eg 0.01%, 0.02%, 0.03%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.15 %, 0.20%, 0.25%, 0.30%, 0.35%, 0.40%, 0.45% or 0.50% w/w of the composition.

[0097] Non-limiting examples of antioxidants include glutathione, quinolines, polyphenols, carotenoids, sodium metabisulfite, tocopherol succinate, propyl gallate, butylated hydroxytoluene, butylated hydroxyanisole, flavonoids, source of vitamin C, polyaminocarboxylic acids, sulfites and derivatives thereof. Non-limiting examples of vitamin C sources for use as a preservative and/or antioxidant include ascorbic acid, ascorbyl palmitate, dipalmitate-L-ascorbate, sodium L-ascorbate-2-sulfate, a salt of ascorbic acid such as sodium, potassium or calcium ascorbate, and the mixtures. In some embodiments, the antioxidant is a source of vitamin C. In some embodiments, the antioxidant is ascorbic acid or a derivative thereof, which includes salts. A non-limiting example of a polyaminocarboxylic acid is edetic acid (ethylenediaminetetraacetic acid/EDTA). In some embodiments, the antioxidant is edetic acid or a derivative thereof, such as a salt. In some embodiments, the antioxidant is disodium edetate. Non-limiting examples of sulfites include, but are not limited to, sodium bisulfite, sodium metabisulfite, potassium bisulfite, and potassium metabisulfite. In some embodiments, the antioxidant is a sulfite. In some embodiments, the preservative is or includes sodium metabisulfite.

[0098] The antioxidant may be present in any suitable amount, including from about 0.01% to about 1.0%, from about 0.01% to about 0.5%, and from about 0.05% to 0.25 % w/w composition. The antioxidant may be present in amounts of approximately 0.01%, 0.02%, 0.03%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10% , 0.15%, 0.20%, 0.25%, 0.30%, 0.35%, 0.40%, 0.45%, 0.50%, 0.55%, 0.60% , 0.65%, 0.70%, 0.75%, 0.80%, 0.85%, 0.90%, 0.95% or 1.0% w/w composition. In some embodiments, the antioxidant is or includes ascorbic acid or a salt thereof and is present in an amount from about 0.01% to about 1.0% w/w of the composition, including any amount between these values, such as 0.01% , 0.02%, 0.03%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.15%, 0.20% , 0.25%, 0.30%, 0.35%, 0.40%, 0.45%, 0.50%, 0.55%, 0.60%, 0.65%, 0.70% , 0.75%, 0.80%, 0.85%, 0.90%, 0.95% or 1.0% w/w of the composition. In some embodiments, the antioxidant is or includes a bisulfite, such as sodium metabisulfite, and is present in an amount from about 0.05% to about 0.25% w/w of the composition, including any amount between these values, such as 0. 05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.15%, 0.20%, 0.25% composition. In some embodiments, the antioxidant is or includes edetic acid or a salt thereof, such as disodium edetate, and is present in an amount from about 0.01% to about 0.5% w/w of the composition, including any amount between these amounts eg 0.01%, 0.02%, 0.03%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.15 %, 0.20%, 0.25%, 0.30%, 0.35%, 0.40%, 0.45% or 0.50% w/w of the composition.

[0099]As noted above, some preservatives are antioxidants and vice versa. Examples of preservatives that also serve as antioxidants include the sulfites discussed above, polyaminocarboxylic acids, and sources of vitamin C. These agents may be present in any suitable amount, including the amounts illustrated above.

[0100] In certain embodiments (e.g., if the composition is self-preservative), the compositions contain substantially no or no preservatives, antioxidants, or both, e.g., no or substantially no one or more or all of the foregoing higher than preservatives, and/or does not contain or is substantially free of one or more or all of the antioxidants listed above. In these embodiments, the compositions may be substantially free or free of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), or both.

[0101] In some embodiments, the compositions may further comprise a penetration enhancer. In some embodiments, the penetration enhancer is or includes propylene glycol. In some embodiments, the penetration enhancer is or includes one or more of propylene glycol PECEOL™ (glyceryl monooleate, type 40), LABRAFAC™ PG (propylene glycol dicaprylocaprate), PLUROL® OLEIQUE CC497 (polyglyceryl-3-dioleate), LABRAFIL® CS1944 (oleoylpolyoxyl-6 -glycerides) and diethylene glycol monoethyl ether.

[0102] Non-limiting examples of sweeteners include sucralose, 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, hernandulcine, phyllodulcine, glycyphylline, phloridzin, trilobatine, Bayunoside, Osladin, Polypodoside A, Pterocaryoside A, Pterocaryoside B, Mucurosioside, Phlomizoside I, Periandrin I, Abrsoside A, Cyclocarioside I and other salts, Aspartame, Alitame, Saccharin, Neohesperidin dihydrochalcone, Cyclamate, Neotame, 1-methyl ester N- [3-(3-hydroxy-4-methoxyphenyl)propyl]-L-α-aspartyl]-L-phenylalanine, N-[N-[3-(3-hydroxy-4-methoxyphenyl)-3 1-methyl ester -methylbutyl]-L-α-aspartyl]-L-phenylalanine, N-[N-[3-(3-methoxy-4-hydroxyphenyl)propyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester , as well as their salts and combinations. The sweetener may be present in any suitable amount, including from about 0.001% to about 0.5%, from about 0.005% to about 0.5%, from about 0.05% to about 0.5%, and from about 0. 01% to about 0.5% w/w of the composition, for example about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009%, approximately 0.01%, approximately 0.02%, approximately 0.03%, approximately 0.04%, approximately 0.05%, approximately 0.06%, approximately 0.07%, approximately 0.08%, approximately 0 .09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, or about 0.5% w/w of the composition. In some embodiments, the sweetener is or includes sucralose. Sucralose may be present in any suitable amount, including from about 0.001% to about 0.5% w/w of the composition, or from about 0.05% to about 0.5% w/w of the composition, from about 0.005% to about 0 .5% or from about 0.01% to about 0.5% w/w of the composition. Suitable amounts of sucralose include, but are not limited to, about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009%, about 0.01%, about 0 .02%, approximately 0.03%, approximately 0.04%, approximately 0.05%, approximately 0.06%, approximately 0.07%, approximately 0.08%, approximately 0.09%, approximately 0.1 %, about 0.2%, about 0.3%, about 0.4%, or about 0.5% w/w of the composition. For example, sucralose may be present in an amount of 0.005%, 0.01% or 0.10% w/w of the composition.

[0103] Non-limiting examples of chelating agents include ethylenediaminetetraacetic acid (EDTA) and citric acid, hydrates thereof, salts thereof, and hydrates of salts thereof. Examples of such chelating agents include ethylenediaminetetraacetic acid disodium, ethylenediaminetetraacetic acid disodium dihydrate, and citric acid monohydrate. Various combinations of chelating agents can be used if required. As noted above, EDTA can also be used as a preservative or antioxidant.

[0104] Non-limiting examples of colorants include commercially available pigments such as FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2, other FD&C Blue colors, titanium dioxide, iron oxide, and/or combinations thereof.

[0105] Non-limiting examples of flavors include berry flavor, tutti frutti flavor, caramel flavor, root beer flavor, cream flavor, chocolate flavor, peppermint flavor ", flavoring additive "mint", flavoring additive "iris" and flavoring additive "wintergreen" and their combinations. Suitable berry flavors include bird cherry, strawberry, cherry, blueberry, raspberry, and the like. In some embodiments, the composition contains a raspberry, tutti-frutti, or caramel flavor.

[0106] The types and amounts of excipients can be selected and adjusted to achieve the desired effect while maintaining the desired properties of the composition as a whole. In some embodiments, the composition includes from about 0.01% to about 10%, or from about 0.03% to about 9%, or from about 0.05% to about 7%, or from about 0.01% to about 3%, or from about 0.02% to about 2.5%, from or about 0.03% to about 2.5%, or from about 0.05% to about 2.5%, or from about 0. 1% to about 2%, or about 0.1% to about 1.5%, or about 1% to about 1.5% w/w excipients. The composition may include from about 0.01% to about 10% w/w excipients, for example about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, approximately 0.06%, approximately 0.07%, approximately 0.08%, approximately 0.09%, approximately 0.1%, approximately 0.2%, approximately 0.3%, approximately 0.4%, approximately 0 .5%, approximately 0.6%, approximately 0.7%, approximately 0.8%, approximately 0.9%, approximately 1%, approximately 2%, approximately 3%, approximately 4%, approximately 5%, approximately 6 %, about 7%, about 8%, about 9% or about 10% w/w excipients. The composition may include from about 0.01% to about 5% w/w excipients. The pharmaceutical composition may contain from about 0.01% to about 1% w/w excipients.

[0107] The mucoadhesive pharmaceutical compositions described herein can be formulated for oral or rectal administration. For example, the composition may be formulated for oral administration by being formulated in dosages and amounts suitable for oral administration with excipients suitable for oral administration, or may be formulated for rectal administration by being formulated in dosages and amounts suitable for rectal administration with excipients , suitable for rectal administration.

[0108] Also provided herein are single-dose packages of compositions for oral or rectal administration, such as a pouch or syringe containing a single dose of the composition. In some embodiments, a single dose package includes from about 1 ml to about 20 ml, from about 1 ml to about 10 ml, from about 2 ml to about 5 ml, including about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 ml and quantities between any of these values.

[0109] Also provided herein are compositions for oral or rectal administration that are formulated for multi-dose packaging, such as pouches or syringes, each containing a dose of the composition. In some embodiments, a multi-dose package includes from about 1 ml to about 20 ml, from about 1 ml to about 10 L, from about 2 ml to about 5 ml, including about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 ml and quantities between any of these values. In some embodiments, the multi-dose package contains doses for 1 week of treatment, 2 weeks of treatment, 3 weeks of treatment, 4 weeks of treatment, 1 month of treatment, 2 months of treatment, or 3 months of treatment.

Mucoadhesive properties

[0110] In any embodiments, the mucoadhesive pharmaceutical compositions described herein have a viscosity or adhesion function that allows them to adhere to mucosal surfaces, such as esophageal or rectal mucosa.

[0111] In some embodiments, a therapeutically effective amount of the composition adheres to the esophageal or rectal mucosa for at least 0.5 minutes, including a period of time from 5 minutes until the next dose is to be administered. Thus, when administered twice daily, a therapeutically effective amount of the composition may adhere for no more than 10 hours or no more than 12 hours. When dosed three times daily, a therapeutically effective amount of the composition may adhere for no more than 6 hours or no more than 8 hours. When dosed four times daily, a therapeutically effective amount of the composition may adhere for no more than 4 hours or no more than 6 hours.

[0112] In some embodiments, a therapeutically effective amount of the composition adheres to the esophageal or rectal mucosa for at least 0.5 minutes, at least 5 minutes, at least 10 minutes, at least 15 minutes, or at least 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 mucosal tissue of the esophagus or rectum for at least 30 minutes after administration. In some embodiments, the composition adheres to the mucosal tissue of the esophagus or rectum for at least 45 minutes after administration. In some embodiments, the composition adheres to the mucosal tissue of the esophagus or rectum for at least 60 minutes after administration. In some embodiments, the composition adheres to the mucosal tissue of the esophagus or rectum for at least 75 minutes after administration.

[0113] In some embodiments, a therapeutically effective amount of the composition adheres to the esophageal or rectal mucosa for a period of time ranging from about 0.5 minutes to about 75 minutes, including about 0.5 minutes, about 5 minutes, about 10 minutes, approximately 15 minutes, approximately 20 minutes, approximately 25 minutes, approximately 30 minutes, approximately 35 minutes, approximately 40 minutes, approximately 45 minutes, approximately 50 minutes, approximately 55 minutes, approximately 60 minutes, approximately 65 minutes and approximately 75 minutes after introduction. In some embodiments, the composition adheres to the mucosal tissue of the esophagus or rectum within approximately 30 minutes after administration. In some embodiments, the composition adheres to the mucosal tissue of the esophagus or rectum within approximately 45 minutes after administration. In some embodiments, the composition adheres to the mucosal tissue of the esophagus or rectum within approximately 60 minutes after administration. In some embodiments, the composition adheres to the mucosal tissue of the esophagus or rectum within approximately 75 minutes after administration.

[0114] In some embodiments, a therapeutically effective amount of the composition adheres to the esophageal or rectal mucosa for a period of time ranging from 0.5 minutes to 12 hours, from 0.5 minutes to 8 hours, from 0.5 minutes to 6 hours or from 0.5 minutes to 4 hours. In some embodiments, a therapeutically effective amount of the composition adheres to the esophageal or rectal mucosa within 0.5 minutes, 5 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 o'clock, 8 o'clock, 9 o'clock, 10 o'clock, 11 o'clock or approximately 12 o'clock. In some embodiments, a therapeutically effective amount of the composition adheres to the esophageal or rectal mucosa for a period of time ranging from 5 minutes to 12 hours, from 5 minutes to 8 hours, from 5 minutes to 6 hours, or from 5 minutes to 4 hours. In some embodiments, a therapeutically effective amount of the composition adheres to the esophageal or rectal mucosa for a period of time ranging from 30 minutes to 12 hours, from 30 minutes to 8 hours, from 30 minutes to 6 hours, or from 30 minutes to 4 hours. In some embodiments, a therapeutically effective amount of the composition adheres to the esophageal or rectal mucosa for a period of time ranging from 45 minutes to 12 hours, from 45 minutes to 8 hours, from 45 minutes to 6 hours, or from 45 minutes to 4 hours. In some embodiments, a therapeutically effective amount of the composition adheres to the esophageal or rectal mucosa over a period of 1-12 hours, 1-8 hours, 1-6 hours, or 1-4 hours.

[0115]As used herein, the term “work of adhesion” refers to the work (force) required to separate a composition from a surface. Adhesion work is a measure of the adhesive ability of a composition, which may be required to resist forces that might separate it from its intended site of action (e.g. such forces as those exerted by saliva, food, liquid and muscle contractions). Adhesion performance can be assessed using techniques known in the art, as illustrated in the examples. For example, adhesion performance can be assessed using a TA-TX2 Texture Analyzer (Stable Micro Systems, UK) at room temperature by applying 1 ml of the composition to a TUFFRYN® HT-450 test membrane with a 0.45 µm filter (hydrophilic polysulfone) (Pall Corp. ) and recording the force required to release the composition as a function of elongation.

[0116] In some embodiments, the mucoadhesive pharmaceutical compositions described herein have an adhesion work force of from about 150 to about 350 g/s, or from 150 to 350 g/s as assessed as set forth in Example 2.

[0117]In some embodiments, the viscosity and/or mucoadhesive properties of the compositions are substantially constant at a biologically relevant temperature in the range of 20-40°C or 30-40°C, as illustrated in FIG. 6A and 6B. The consistency of these properties across these temperature ranges further distinguishes these embodiments from temperature sensitive ones (e.g. thermoreversible) gels.

[0118] Without being bound by theory, these mucoadhesive properties are believed to enhance the therapeutic effect of the compositions, for example, by providing improved and/or prolonged contact between the corticosteroid composition and the target treatment site, such as esophageal tissue or rectal mucosa, to improve delivery and/or prolonged effect of the drug.

[0119] In some embodiments, compositions with the mucoadhesive properties described herein also have viscosity in a fluid form at room temperature and/or body temperature. In certain of these embodiments, the viscosity is from about 1000 to 10,000 cP at room temperature and/or body temperature, such as 3000-9000 cP or 5000-7000 cP at room temperature and/or body temperature.

[0120] With respect to specific embodiments, it has surprisingly been discovered that compositions containing a corticosteroid in a mucoadhesive system containing xanthan gum, glycerin and water (optionally with an acidic buffer such as a citric acid buffer) have an unexpected combination of desired properties, including the manifestation of unexpectedly good mucoadhesion, as well as the presence of self-preserving properties.

[0121] The mucoadhesive pharmaceutical compositions described herein may have good storage stability. For example, the compositions may be stable for at least 1 month under accelerated stability testing conditions, or at least 1 year when stored at room temperature and humidity. The composition can be stable for at least 1 month when stored at 40°C and 75% relative humidity. The composition can be stable for at least 1 year when stored at 25°C and 60% relative humidity.

Illustrative compositions

[0122]In some embodiments, the composition may include (a) budesonide in an amount of 0.02-0.06% w/w of the composition, (b) a carrier medium containing glycerol in an amount of 40-70% w/w of the composition, (c) a modifier rheological properties means containing xanthan gum in an amount of 0.25-1.5% w/w of the composition (for example, 0.5-1.5% w/w or 0.75-1.25% w/w), ( d) optionally an aqueous citric acid buffer with a pH of 4.5-5.5 (for example, with a pH of 5 ± 0.1), (e) optionally sucralose in an amount of 0.05-0.5% w/w of the composition or 0.01-0.5% w/w of the composition and (f) optionally propylene glycol in an amount of more than 20% w/w of the composition (e.g. approximately 0.5%-20% w/w or approximately 10%-20% w/w).

[0123]In some embodiments, the composition may include (a) budesonide in an amount of 0.02-0.06% w/w of the composition, (b) a carrier medium containing glycerol in an amount of 40-70% w/w of the composition, (c) a modifier rheological properties means containing xanthan gum in an amount of 0.25-1.5% w/w of the composition (for example, 0.5-1.5% w/w or 0.75-1.25% w/w), ( d) optionally an aqueous citric acid buffer with a pH of 4.5-5.5 (for example, with a pH of 5 ± 0.1), (e) optionally sucralose in an amount of 0.001-0.5% w/w of the composition and (f) optionally propylene glycol in an amount of not more than 20% w/w of the composition (for example, approximately 0.5%-20% w/w or approximately 10%-20% w/w).

[0124] In some embodiments, the composition may include (a) budesonide in an amount of approximately 0.05% w/w of the composition, (b) glycerin in an amount of approximately 50% w/w of the composition, and (c) a rheology modifying agent comprising xanthan gum in an amount of approximately 1% w/w of the composition.

[0125]In some embodiments, the composition may include (a) fluticasone in an amount of 0.01-0.1% w/w of the composition, (b) a carrier medium containing glycerol in an amount of 40-70% w/w of the composition, (c) a modifier rheological properties means containing xanthan gum in an amount of 0.25-1.5% w/w of the composition (for example, 0.5-1.5% w/w or 0.75-1.25% w/w), ( d) optionally an aqueous citric acid buffer with a pH of 4.5-5.5 (for example, with a pH of 5 ± 0.1), (e) optionally sucralose in an amount of 0.05-0.5% w/w of the composition or 0.01-0.5% w/w of the composition and (f) optionally propylene glycol in an amount of more than 20% w/w of the composition (e.g. approximately 0.5%-20% w/w or approximately 10%-20% w/w).

[0126]In some embodiments, the composition may include (a) fluticasone in an amount of 0.01-0.1% w/w of the composition, (b) a carrier medium containing glycerol in an amount of 40-70% w/w of the composition, (c) a modifier rheological properties means containing xanthan gum in an amount of 0.25-1.5% w/w of the composition (for example, 0.5-1.5% w/w or 0.75-1.25% w/w), ( d) optionally an aqueous citric acid buffer with a pH of 4.5-5.5 (for example, with a pH of 5 ± 0.1), (e) optionally sucralose in an amount of 0.001-0.5% w/w of the composition and (f) optionally propylene glycol in an amount of not more than 20% w/w of the composition (for example, approximately 0.5%-20% w/w or approximately 10%-20% w/w).

[0127] In some embodiments, the composition may include (a) fluticasone in an amount of approximately 0.05% w/w of the composition, (b) glycerin in an amount of approximately 50% w/w of the composition, and (c) a rheology modifying agent comprising xanthan gum in an amount of approximately 1% w/w of the composition.

[0128]In some embodiments, any of the compositions described herein, the composition may include (a) ciclesonide in an amount of 0.01-0.1% w/w of the composition, (b) a carrier medium containing glycerol in an amount of 40-70 wt%. weight of the composition, (c) a rheology modifying agent comprising xanthan gum in an amount of 0.25-1.5% w/w of the composition (for example, 0.5-1.5% w/w or 0.75-1.25 % w/w), (d) optionally an aqueous citric acid buffer with a pH of 4.5-5.5 (e.g. with a pH of 5 ± 0.1), (e) optionally sucralose in an amount of 0.05-0.5% w/w of the composition or 0.01-0.5% w/w of the composition and (f) optionally propylene glycol in an amount of more than 20% w/w of the composition (e.g. approximately 0.5%-20% w/w or approximately 10%-20% w/w).

[0129]In some embodiments, any of the compositions described herein, the composition may include (a) ciclesonide in an amount of 0.01-0.1% w/w of the composition, (b) a carrier medium containing glycerol in an amount of 40-70 wt%. weight of the composition, (c) a rheology modifying agent comprising xanthan gum in an amount of 0.25-1.5% w/w of the composition (for example, 0.5-1.5% w/w or 0.75-1.25 % w/w), (d) optionally an aqueous citric acid buffer with a pH of 4.5-5.5 (e.g. with a pH of 5 ± 0.1), (e) optionally sucralose in an amount of 0.001-0.5% w/w of the composition and (f) optionally propylene glycol in an amount of not more than 20% w/w of the composition (for example, approximately 0.5%-20% w/w or approximately 10%-20% w/w).

[0130] In some embodiments, the composition may include (a) ciclesonide in an amount of approximately 0.05% w/w of the composition, (b) glycerin in an amount of approximately 50% w/w of the composition, and (c) a rheology modifying agent comprising xanthan gum in an amount of approximately 1% w/w of the composition.

Manufacturing methods

[0131] This document also provides methods for preparing the mucoadhesive pharmaceutical compositions described herein. In general, the compositions can be prepared using techniques known in the art, based on the following guidance.

[0132] Typically, compositions are prepared by combining components in a combination and mixing or mixing them. In any embodiments, the mixing may include high shear mixing at low speed or high speed. Mixing can also occur using a propeller-type stirrer or a planetary stirrer.

[0133] Although the components can be combined in any order, in some embodiments, the corticosteroid is mixed with the components of the vehicle before mixing with the rheology modifying agent. In such embodiments, the amount and type of carrier medium used can be selected such that the corticosteroid remains dissolved or suspended when mixed with the rheology modifying agent. In any embodiments, the rheology modifying agent can be mixed with the corticosteroid at room temperature.

[0134]In some embodiments, the corticosteroid is first mixed with the components of the carrier medium, and then other dry components are added (for example, powdered) components of the composition, such as buffers, sweeteners and other excipients, and mix before adding the rheology modifying agent.

[0135] In alternative embodiments, the corticosteroid and other dry components of the composition (eg, buffers, sweeteners, and other excipients) are mixed together with the components of the carrier medium before adding the rheology modifying agent.

[0136]In any of these embodiments, the corticosteroid and optionally other dry components can be first added to the water before adding the vehicle components (eg, glycerol). See for example Fig. 1.

[0137] In any embodiment, the rheology modifying agent can be added with or without additional carrier media components. In embodiments where water is present, additional water may be added after adding the rheology modifying agent.

[0138] Thus, in some embodiments, a method for preparing a composition described herein involves (a) dissolving or suspending a corticosteroid in a carrier medium and (b) mixing the corticosteroid solution or suspension with a rheology modifying agent. In some embodiments, the methods further include adding water. In some embodiments, the methods further include adding an aqueous acidic buffer. In some embodiments, the methods further comprise the addition of one or more optional excipients.

[0139]Thus, in other embodiments, a method for preparing a composition described herein comprises (a) adding the corticosteroid and other dry components of the composition (eg, buffers, sweeteners and other excipients) to water and mixing them; (b) adding the first portion of carrier medium (e.g. glycerin) and stirring; (c) adding a second portion of the carrier medium and the rheology control agent and mixing; and (d) adding water and mixing.See, for example, Fig. 1.

Therapeutic methods

[0140] Also provided herein are methods of administering a corticosteroid to a subject in need thereof, comprising orally or rectally administering to the subject a composition described herein. In some embodiments, the method is effective for delivering a corticosteroid to a subject's esophagus. In some embodiments, the method is effective for delivering a corticosteroid to the rectal or colon mucosa of a subject.

[0141]In some embodiments, such as for the treatment of EoE and IBD, local delivery of the corticosteroid is therapeutically effective. That is, the corticosteroid is active when applied topically to the condition being treated. In such embodiments, it may be advantageous to avoid or minimize systemic delivery, for example to avoid unintended or unwanted systemic effects of the corticosteroid. Therefore, in some embodiments, the composition described herein is formulated for local delivery. However, there may be circumstances (including in the context of treatment of EoE and IBD) where at least partial penetration of the corticosteroid into or through mucosal tissue is necessary for therapeutic efficacy (eg, tissue of the esophagus, rectum, or colon). For example, in some embodiments, at least partial penetration into submucosal tissue may be necessary for therapeutic efficacy. Therefore, in some embodiments, the composition described herein is formulated to achieve at least partial penetration into or through mucosal tissue.

[0142] In some embodiments, the method is effective to provide prolonged delivery of a corticosteroid to the esophagus of a subject, such as delivery over at least 0.5 minutes, 5 minutes, or at least 10 minutes, or 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. In some embodiments, the method is effective to provide sustained delivery of a corticosteroid to the esophagus of a subject, such as delivery over a period of time ranging from about 0.5 minutes to about 75 minutes, including about 0.5 minutes, about 5 minutes, about 10 minutes, approximately 15 minutes, approximately 20 minutes, approximately 25 minutes, approximately 30 minutes, approximately 35 minutes, approximately 40 minutes, approximately 45 minutes, approximately 50 minutes, approximately 55 minutes, approximately 60 minutes, approximately 65 minutes, approximately 70 minutes and approximately 75 minutes.

[0143] In some embodiments, the method is effective to provide sustained delivery of a corticosteroid to the esophagus of a subject, such as delivery over a period of time ranging from 0.5 minute to 12 hours, from 0.5 minute to 8 hours, from 0.5 minute up to 6 hours or from 0.5 minutes to 4 hours. In some embodiments, the method is effective to provide sustained delivery of a corticosteroid to the esophagus of a subject over a period of time ranging from 5 minutes to 12 hours, from 5 minutes to 8 hours, from 5 minutes to 6 hours, or from 5 minutes to 4 hours. In some embodiments, the method is effective to provide sustained delivery of a corticosteroid to the esophagus of a subject over a period of time ranging from 30 minutes to 12 hours, from 30 minutes to 8 hours, from 30 minutes to 6 hours, or from 30 minutes to 4 hours. In some embodiments, the method is effective to provide sustained delivery of a corticosteroid to a subject's esophagus over a period of 45 minutes to 12 hours, 45 minutes to 8 hours, 45 minutes to 6 hours, or 45 minutes to 4 hours. In some embodiments, the method is effective to provide sustained delivery of a corticosteroid to a subject's esophagus over a period of 1-12 hours, 1-8 hours, 1-6 hours, or 1-4 hours. In some embodiments, the method is effective to provide sustained delivery of a corticosteroid to the esophagus of a subject, such as delivery in about 0.5 minutes, about 1 minute, about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, approximately 50 minutes, approximately 1 hour, approximately 2 hours, approximately 3 hours, approximately 4 hours, approximately 5 hours, approximately 6 hours, approximately 7 hours, approximately 8 hours, approximately 9 hours, approximately 10 hours, approximately 11 hours or approximately 12 hours.

[0144] In some embodiments, a therapeutically effective amount of the composition adheres to the esophageal or rectal mucosa for a period of time until the next dose is to be administered. Thus, when administered twice daily, a therapeutically effective amount of the composition may adhere over a period of time of no more than 10 hours or no more than 12 hours, such as from about 1 hour to 10 hours or from about 1 hour to 12 hours. In some embodiments, when administered twice daily, a therapeutically effective amount of the composition may adhere within about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, approximately 9 hours, approximately 10 hours, approximately 11 hours or approximately 12 hours. When dosed three times daily, a therapeutically effective amount of the composition may adhere in no more than 6 hours or no more than 8 hours, such as about 1 hour to 6 hours or about 1 hour to about 8 hours. In some embodiments, when dosed three times daily, a therapeutically effective amount of the composition may adhere in about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, or about 8 hours. When dosed four times daily, a therapeutically effective amount of the composition may adhere in no more than 4 hours or no more than 6 hours, such as about 1 hour to 4 hours or about 1 hour to 6 hours. In some embodiments, when dosed four times daily, a therapeutically effective amount of the composition may adhere in about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, or about 6 hours.

[0145]In some embodiments, the subject may suffer from or be at risk of developing an inflammatory condition of the upper gastrointestinal tract, especially the esophagus. In some embodiments, the subject may have or be at risk of developing eosinophilic esophagitis (EoE). In some embodiments, the subject may be a child (e.g. up to 18 years of age, including up to 10 years of age) or adults.

[0146] In embodiments related to the treatment of EoE, suitable doses of budesonide may be no more than 1 mg/day for children who are less than 10 years of age and no more than 2 mg/day for older patients; suitable doses of fluticasone may be as low as 440 μg up to 880 mcg twice daily for adults and 88 mcg to 440 mcg two to four times daily for children (up to the maximum dose for adults), and appropriate doses of ciclesonide may be approximately 320 mcg twice daily for children. Treatment may include repeated doses one to four times daily and may continue 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.

[0147] In some embodiments, the method is effective to provide prolonged delivery of a corticosteroid to the rectum or colon of a subject, such as delivery over at least 0.5 minutes, at least 5 minutes, at least 10 minutes, or 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 70 minutes, or at least 75 minutes. In some embodiments, the method is effective to provide sustained delivery of a corticosteroid to the rectum or colon of a subject, such as delivery over a period of time ranging from about 0.5 minutes to about 75 minutes, including about 0.5 minutes, 5 minutes, approximately 10 minutes, approximately 15 minutes, approximately 20 minutes, approximately 25 minutes, approximately 30 minutes, approximately 35 minutes, approximately 40 minutes, approximately 45 minutes, approximately 50 minutes, approximately 55 minutes, approximately 60 minutes, approximately 65 minutes, approximately 70 minutes and approximately 75 minutes.

[0148] In some embodiments, the method is effective to provide sustained delivery of a corticosteroid to the rectum or colon of a subject, such as delivery over a period of time ranging from 0.5 minute to 12 hours, from 0.5 minute to 8 hours, from 0 .5 minutes to 6 hours or from 0.5 minutes to 4 hours. In some embodiments, the method is effective to provide sustained delivery of a corticosteroid to the rectum or colon of a subject over a period of time ranging from 5 minutes to 12 hours, from 5 minutes to 8 hours, from 5 minutes to 6 hours, or from 5 minutes to 4 hours. hours. In some embodiments, the method is effective to provide sustained delivery of a corticosteroid to the rectum or colon of a subject over a period of time ranging from 30 minutes to 12 hours, from 30 minutes to 8 hours, from 30 minutes to 6 hours, or from 30 minutes to 6 hours. 4 hours. In some embodiments, the method is effective to provide sustained delivery of a corticosteroid to the rectum or colon of a subject over a period of time ranging from 45 minutes to 12 hours, from 45 minutes to 8 hours, from 45 minutes to 6 hours, or from 45 minutes to 4 hours. hours. In some embodiments, the method is effective to provide sustained delivery of a corticosteroid to the rectum or colon of a subject over 1-12 hours, 1-8 hours, 1-6 hours, or 1-4 hours. In some embodiments, the method is effective to provide sustained delivery of a corticosteroid to the rectum or colon of a subject, such as delivery in about 0.5 minutes, about 1 minute, about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, approximately 50 minutes, approximately 1 hour, approximately 2 hours, approximately 3 hours, approximately 4 hours, approximately 5 hours, approximately 6 hours, approximately 7 hours, approximately 8 hours, approximately 9 hours, approximately 10 hours, approximately 11 hours or approximately 12 hours.

[0149]In some embodiments, a therapeutically effective amount of the composition adheres to the esophageal or rectal mucosa for a period of time until the next dose is to be administered. Thus, when administered twice daily, a therapeutically effective amount of the composition may adhere over a period of time of no more than 10 hours or no more than 12 hours, such as from about 1 hour to 10 hours or from about 1 hour to 12 hours. In some embodiments, when administered twice daily, a therapeutically effective amount of the composition may adhere within about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, approximately 9 hours, approximately 10 hours, approximately 11 hours or approximately 12 hours. When dosed three times daily, a therapeutically effective amount of the composition may adhere in no more than 6 hours or no more than 8 hours, such as about 1 hour to 6 hours or about 1 hour to about 8 hours. In some embodiments, when dosed three times daily, a therapeutically effective amount of the composition may adhere in about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, or about 8 hours. When dosed four times daily, a therapeutically effective amount of the composition may adhere in no more than 4 hours or no more than 6 hours, such as about 1 hour to 4 hours or about 1 hour to 6 hours. In some embodiments, when dosed four times daily, a therapeutically effective amount of the composition may adhere in about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, or about 6 hours. In some embodiments, the subject may suffer from or be at risk of developing an inflammatory condition of the colon and/or rectum. In some embodiments, the subject may suffer from or be at risk of developing IBD, such as ulcerative colitis and Crohn's disease. In some embodiments, the subject may be a child (e.g. up to 18 years of age, including up to 10 years of age) or adults.

[0150] In embodiments related to the treatment of IBD, suitable doses of budesonide may be no more than 1 mg/day for children who are less than 10 years of age and no more than 2 mg/day for older patients; suitable doses of fluticasone may be as low as 440 μg up to 880 mcg twice daily for adults and 88 mcg to 440 mcg two to four times daily for children (up to the maximum dose for adults), and appropriate doses of ciclesonide may be approximately 320 mcg twice daily for children. Treatment may include repeated doses one to four times daily and may continue 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.

[0151] 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 described herein. As noted above, a suitable subject may suffer from one or more inflammatory conditions of the esophagus, including eosinophilic esophagitis.

[0152] Also provided herein are methods of treating an inflammatory bowel condition, including IBD, comprising orally or rectally administering to a subject in need thereof a composition described herein. As noted above, a suitable subject may suffer from one or more inflammatory bowel conditions, including ulcerative colitis and Crohn's disease.

[0153] The methods may involve administering a composition described herein one or more times per day, such as one, two, three, four, five or more times per day.

[0154] Also provided are uses of a corticosteroid in the preparation of a medicament for oral administration of a corticosteroid into the esophagus of a subject in need thereof, the medicament comprising a pharmaceutical composition described herein. Also provided are the uses of a corticosteroid in the preparation of a medicament for the treatment of an inflammatory condition of the esophagus, such as eosinophilic esophagitis, the medicament comprising a pharmaceutical composition described herein.

[0155] Also provided are uses of a corticosteroid in the preparation of a medicament for oral or rectal administration of a corticosteroid into the intestine of a subject in need thereof, the medicament comprising a pharmaceutical composition described herein. Also provided are the uses of a corticosteroid in the preparation of a medicament for treating an inflammatory bowel condition such as IBD, wherein the medicament comprises a pharmaceutical composition described herein.

[0156] Pharmaceutical compositions described herein are also provided for the oral administration of a corticosteroid into the esophagus of a subject in need thereof. Pharmaceutical compositions described herein are also provided for the treatment of an inflammatory condition of the esophagus, such as eosinophilic esophagitis.

[0157] Pharmaceutical compositions described herein are also provided for the oral administration of a corticosteroid to a subject in need thereof. Pharmaceutical compositions described herein are also provided for rectal administration of a corticosteroid to a subject in need thereof. Also provided herein are pharmaceutical compositions for the treatment of an inflammatory bowel condition such as IBD, such as ulcerative colitis and Crohn's disease.

EXAMPLES

[0158] The following specific examples of the compositions described herein are included as illustrative. These examples are not intended to limit the scope of the present invention in any way. Other aspects of the present invention will be apparent to those skilled in the art to which the present invention relates.

Example 1. Preparation of a mucoadhesive composition

[0159] The solubility of budesonide in water at room temperature was determined to be approximately 0.01 mg/ml, approximately 1 mg/ml in glycerol, and approximately 10 mg/ml in propylene glycol at room temperature.

[0160]For production on a laboratory scale (e.g. with batch sizes ranging from 1 to 1000 g) of the budesonide composition described herein, budesonide was mixed with glycerin with or without propylene glycol in an ultrasonic bath at room temperature. Xanthan gum was then added to the budesonide solution with stirring until a macroscopically homogeneous mixture was obtained. A citric acid-based buffer with a pH of approximately 5 and auxiliary substances such as sucralose were added to the liquid composition with stirring. The resulting composition was liquid at room temperature. Compositions without propylene glycol were prepared as a liquid suspension, and compositions with propylene glycol were prepared as a liquid suspension or solution, depending on the amount of propylene glycol.

[0161]In FIG. 1 is a schematic representation of an alternative exemplary production method that can be used to produce the composition described herein on a laboratory scale (e.g. with a batch size of 10 kg). Specifically, (a) budesonide and other dry components of the composition (eg, buffers and sweetener) are added to an amount of water that will be approximately 40% w/w of the final composition and mixed; (b) add an amount of carrier medium (e.g. glycerin), which will constitute approximately 30% w/w of the final composition, and mix; (c) add an amount of carrier medium (e.g. glycerol), which will constitute approximately 20% w/w of the final composition, and a rheology control agent (e.g. xanthan gum) and stir; and (d) add the remaining amount of water and mix.

Example 2. Study of the characteristics of mucoadhesive compositions

[0162] Using the methodology described above, compositions with the following components were prepared

Component w/w% Glycerol 50 Xanthan gum 1 Buffer based on citric acid in sufficient quantity

[0163] Although this composition does not include a corticosteroid, it is believed that the absence of a corticosteroid does not affect the properties assessed below. Moreover, it is believed that the properties described below are also not affected by the addition of small amounts of other excipients that do not significantly affect the physicochemical properties (for example, a sweetener such as sucralose).

Work of adhesion

[0164] The mucoadhesive strength of a composition is assessed by the work of adhesion required to separate the composition from a mucosal tissue sample. In FIG. 2 illustrates how adhesion work is an indicator of adhesive ability.

[0165] Adhesion performance is assessed as described in Skulason S. et al., Proc. Int'l. Control. Rel. Bioact. Mater., 27(2000) #6326, using a TA-TX2 texture analyzer (Stable Micro Systems, United Kingdom) at room temperature and the following parameters and by recording the force required to separate the composition as a function of elongation.

Test sample volume: 1 ml

Test membrane: HT Tuffryn (hydrophilic polysulfone), 25 mm diameter, 0.45 µm pore size (Pall Corporation, Michigan)

Speed before testing: 0.1mm/s

Test speed: 0.1 mm/s

Speed after testing: 0.1mm/s

Applied force: 0.2 N

Return distance: 10mm

Contact time: 10s

Start type: auto - 0.05 N

Container mode used: auto

Data acquisition rate: 500 pulses per second

[0166] In FIG. Figure 3 shows the work of adhesion for the following compositions: (a) glycerin; (b) glycerin and water (50:50); and (c) water. The work of adhesion (the area under the force versus time curve) of composition (b) (the composition described herein) was approximately 185 g/s.

Mucoadhesion - porcine mucosa

[0167] An ex vivo study on porcine mucosa was conducted to test the mucoadhesion of the above composition formulated with glycerol, xanthan gum and aqueous citric acid buffer.

[0168] Porcine esophageal tissue was accessed by opening the esophagus longitudinally in freshly slaughtered animals. The outer layers of muscle were removed to expose the inner epithelial tube. The exposed tissue was stretched on a polystyrene backing at a 12° incline. 1 ml of the composition was applied to the upper part of the tube (beginning) and the time until a length of 10 cm, 20 cm and 30 cm was covered was recorded (the test was carried out at room temperature). Each measurement was repeated in triplicate. The extent and duration of adhesion to porcine mucosal tissue was observed and recorded.

[0169] In FIG. Figure 4 shows the time (in seconds) it took to cover the entire 30 cm segment for the following compositions: (a) liquid honey; (b) xanthan gum (1% w/w) in glycerin and water (85:15); (c) xanthan gum (1% w/w) in glycerin and water (50:50); and (c) water (control). In the case of composition C (50:50 glycerol/water), it took more than 180 seconds to cover the entire 30 cm length.

Mucoadhesion - rats

[0170] An in vivo staining study was performed in rats to evaluate the time-dependent/retention/adhesion and staining intensity of the composition described herein after application to the esophagus of rats.

[0171] This study used Wistar rats, which were further divided into four groups, with rats from each group being sacrificed at the following time points after receiving 100 μl of the test composition: 5 minutes, 10 minutes, 15 minutes and 20 minutes. The test composition used in this study contained the following components: 50% w/w glycerol, 1% w/w xanthan gum, 0.1% w/w sucralose; 0.1% w/w raspberry flavor and 48.8% w/w citric acid pH 5.0 buffer.

[0172] Upon opening, the composition reached the stomach at all times. Therefore, the administered bolus was passed through the esophagus.

[0173] In FIG. 5A shows the results of staining and adhesion of the composition in the rat esophagus after 5 minutes and 10 minutes for each rat tested. In FIG. 5B shows the results of staining and adhesion of the composition in the rat esophagus after 15 minutes and 20 minutes for each rat tested. From these results, it can be seen that in vivo staining was still visible after 20 minutes.

In vitro study of adhesion performance

[0174] To further evaluate the mucoadhesive properties of the compositions were analyzed individually and when mixed with the resulting mucin solutions. The dynamic modulus of elasticity was quantified over a range of frequencies, and one value was entered into the two equations described below to obtain the “rheological synergy parameters” ΔG' and ΔG'/G'.

ΔG' denotes the difference between the actual values of the dynamic modulus of the samples mixed with mucin and the theoretical values, where the theoretical values are defined as the sum of the G' values of the sample and the mucin when analyzed separately.

[0175] Δ G'/G'+1 describes relative rheological synergism as it expresses the relative increase in G' relative to the individual sample and individual mucin. A relative rheological synergy parameter of 1 would indicate that no increase was observed when the sample was mixed with mucin, meaning there was no observable interaction with the mucin solution. Whereas a value greater than one indicates some interaction with mucin; a value of 2, for example, would mean that the measured viscosity of the mucin-mixed sample was twice that expected. A value that is less than one indicates that the interaction is negligible and that the value should be treated as if it were 1, or if the value is significantly less than 1 it could indicate the presence of some negative interaction.

[0176] The following test compositions were used for this study.

Composition 1: 1% w/w xanthan gum, 50% w/w glycerol, 0.1% sucralose and 48.9% citric acid pH 5 buffer.

Formulation 2: 1% w/w xanthan gum, 70% w/w glycerol, 0.1% sucralose and 28.9% citric acid pH 5 buffer.

Composition 3: 1% w/w xanthan gum, 40% w/w glycerol, 0.1% sucralose and 58.9% citric acid pH 5 buffer.

[0177] Mucin solutions were prepared using deionized water and porcine gastric mucin (III) purchased from Sigma Aldrich. The concentration of each solution was adjusted to 10%, and the pH was adjusted to 6.2 with 0.5 M HCl before diluting with deionized water to a final concentration of 6% (w/w) before use.

[0178] 3 g of the resulting mucin solution was mixed with an equal weight amount of the test composition to obtain a final mucin concentration of 3% (w/w).

[0179] For control samples, solutions of mucin and test compositions were diluted to 50% (w/w) of their original concentrations with deionized water.

[0180] Testing was performed on a research rheometer (DHR2, TA Instruments) equipped with a 40 mm parallel plate gauging system and the testing gap was set to 200 µm. A solvent trap lid was used to minimize drying of the sample at exposed edges.

[0181] Testing was performed at two temperatures: 22°C and 37°C. In FIG. 6A shows the relative rheological synergy of the mucin compositions tested at 22°C. In FIG. 6B shows the relative rheological synergy of the mucin compositions tested at 37°C.

[0182] It is also apparent from these results that the mucoadhesive properties of the compositions are essentially unchanged at biologically relevant temperatures in the range of 20-40°C.

Example 3: Penetration studies

[0183]Permeation studies were performed to confirm embodiments that may require at least partial penetration of the corticosteroid, e.g. through tissue of the esophagus, rectum, or colon.

In vitro penetration through human oral epithelium

[0184] Penetration studies using human oral epithelium (HOE) were performed as follows.

[0185] 100 mg of the composition was applied to human oral epithelium (85 μm thickness) and its penetration was tested after 15 minutes, 30 minutes, 45 minutes. and 1 hour at room temperature (usually 20°C to 25°C).

[0186] The compositions evaluated were the following

Composition A Composition B Composition C* Composition D Budesonide 0.05 0.05 0.05 0.05 Glycerol - 50 - - Propylene glycol 40 - - - Xanthan gum 1 1 - - Sucralose 0.25 - - - as needed until 100 citric acid buffer with pH 5.0 purified water honey sucralose suspension * Some patients have used budesonide suspension in honey to treat EOE

[0187] 1.5 ml of maintenance carrier medium was added to each well of a 12-well HOE cell culture plate using an Eppendorf multi-dispenser. The HOE insert was then added to each well and the plate was pre-incubated for 2 hours in a water bath at 35°C. After pre-incubation using a 1.2 x 40 mm needle attached to a plastic syringe, approximately eight drops (~100 mg) of each composition were applied to the inserts. Each condition was tested in triplicate. After 15 minutes, 30 minutes and 45 minutes in each well, the maintenance medium was completely collected using a Pipetman dispenser into an amber glass HPLC vial and replaced with fresh maintenance medium using an Eppendorf multi-dispenser. After 60 minutes, a final draw was made from each well without refilling. Samples were analyzed using HPLC.

[0188] The table below outlines the cumulative delivery results of budesonide after 1 hour of HOE penetration.

Compound Repetition Average absolute cumulative delivery [μg/cm²±SD] Average relative cumulative delivery [%±SD] Stationary flow [µg/cm²h] A
B
C 3
3
3 11.56 ± 0.33
1.03 ± 0.01
0.19 ± 0.06 11.75 ± 0.62
0.92 ± 0.07
0.16 ± 0.06 12.53 ± 0.63
But.
But. D 3 4.10 ± 0.16 3.88 ± 0.58 4.22 ± 0.36

[0189] From the results, it is clear that penetration occurs when budesonide is formulated in propylene glycol, but not in glycerin (or honey, or sucralose slurry). Without being bound by theory, it is believed that budesonide dissolves in propylene glycol (rather than being suspended in glycerol), which facilitates penetration.

Penetration of budesonide formulations in vitro through the porcine esophagus

[0190] Penetration studies using porcine esophagus were performed as follows.

[0191] 1000 mg of the composition was introduced into the porcine esophagus (1000 μm thick) and penetration was tested at 4 hours, 5 hours, 6 hours, 7 hours at room temperature (typically 20°C to 25°C).

[0192] The compositions evaluated were the following

E F G Budesonide 0.05 0.05 0.05 Glycerol 50 - - Propylene glycol - 40 - Xanthan gum 0.5 1 - Sucralose 0.1 0.25 - as needed until 100 purified water citric acid buffer with pH 5.0 honey

[0193] Each formulation was tested in 6 replicates (from 3 different donors). A total of eighteen porcine esophageal samples were used. The thickness of each sample was measured using a micrometer. Samples were placed on glass vertical Franz diffusion cells with a release chamber of approximately 7.0 ml, a donor chamber of 3.0 ml and a diffusion area of 1.77 cm. The receptor solution was phosphate-buffered saline (PBS) supplemented with 2% weight/rev. olet-20, i.e. polyoxyethylene oleyl ether (20) pH 7.4 (FGLAG-S-032), maintained at 37°C throughout the study and stirred at 600 rpm. The study was carried out using a Microette®Plus autosampler. After 2 hours of pre-incubation of the skin samples with the receptor solution, approximately 1 g (565 mg/cm2) of the composition was applied with a plastic syringe to the diffusion surface. To allow the drug to diffuse, it was left under closed conditions for 7 hours. Samples of the receptor solution (1.0 ml) were automatically removed after 4 hours, 5 hours, 6 hours and 7 hours (after filling the 1.5 ml release chamber). Samples were collected in 2 mL amber HPLC glass vials pre-sealed with septum crimp caps. Then the samples, supplemented with 10 μl of 10% trifluoroacetic acid solution, were transferred into Eppendorf microtubes and centrifuged at 13,500 rpm. (on a SIGMA 2-16 P centrifuge) for 5 minutes. Each supernatant (0.8 mL) was transferred into 2 mL amber glass HPLC vials. Samples were analyzed using HPLC.

[0194] From the results it is clear that penetration occurs when budesonide is formulated in propylene glycol, but not in glycerol.

Composition Repetition Average absolute cumulative delivery* [µg/cm²±SD] Average relative cumulative delivery
[%±SD] Stationary flow [µg/cm²h] E 6 But. But. But. F 6 2.859 ± 2.214 0.995 ± 0.769 But. G 6 But. But. But. *No penetration was detected with Composition E or Composition G.

[0195] From the results, it is clear that penetration occurs when budesonide is formulated in propylene glycol, but not in glycerin or honey.

Example 4: Stability studies

[0196] Stability of disclosed compositions containing 0.05% w/w budesonide, 50 or 70% w/w glycerol, 1% w/w xanthan gum and water or aqueous citric acid buffer and optionally sucralose or raspberry flavor ", were evaluated for 24 months at 25°C and 60% relative humidity and at 40°C and 75% relative humidity. Results after one month at 40°C and 75% relative humidity show no change in bioadhesion, good stability against degradation product formation (and no interference from sucralose or raspberry flavor).

Example 5: Additional Stability Studies

[0197] The stability of a composition described herein containing 0.05% w/w budesonide, 50% w/w glycerol, 1% w/w xanthan gum, 0.05% sucralose and an aqueous citric acid buffer was evaluated in for 6 months at 25°C and 60% relative humidity, at 30°C and 75% relative humidity and at 40°C and 75% relative humidity. The tested compositions were stored in airless metered multi-dose dispensers.

[0198] The table below shows the results for various parameters assessed at 0, 3 and 6 months. The results show that the composition was stable. A slight drop in viscosity (<6%) was observed after 3 and 6 months at 40°C and 75% relative humidity, but viscosity remained within the target range as did all other properties.

Parameter Eligibility Criteria Storage condition Storage time (months) °C/%RH 0 3* 6 Description Homogeneous, transparent or slightly opalescent gel 25/60 N.P. N.P. N.P. 30/75 H, Tr N.P. N.P. 40/75 N.P. H, Tr H, Tr pH 4.8-5.8 25/60 N.P. N.P. N.P. 30/75 5.1 N.P. N.P. 40/75 N.P. 5.1 5.2 Viscosity 4500-7500 mPa.s 25/60 N.P. N.P. N.P. 30/75 6233 N.P. N.P. 40/75 N.P. 5976 5857 Specific Gravity 1.07-1.18 25/60 N.P. N.P. N.P. 30/75 1.15 N.P. N.P. 40/75 N.P. N.P. 1.13 BUD analysis Immediately upon release: 90.0-100.0% of label claim
At the end of shelf life: 90.0-100.0% stated on the label 25/60 N.P. 101.0 101.1 30/75 102.5 100.8 100.9 40/75 N.P. 98.8 98.7 ^* For the 3-month time period, the analysis for the 25°C/60% RH and 30°C/75% RH conditions was actually performed after 4 months. NP = not performed; H = homogeneous; Tr = transparent.

[0199] The table below shows the profile of two impurities that have been found to contribute significantly to reduced shelf life (RRT: 0.66 and RRT: 0.69) and total impurities after storage at the specified temperatures and relative humidity. The results of mass spectrometric analysis suggest that these two major impurities have very similar structures, such as epimers, diastereoisomers, or closely related structural isomers. The molecular formula of these impurities in the uncharged state is as follows: C ₂₅ H ₃₄ O ₇ , which corresponds to a molecule that has one additional oxygen atom relative to the original budesonide molecule. As shown below, for each of the impurities assessed, after 6 months of storage at 40°C and 75% relative humidity, the amount of impurities is within normal limits.

Impurity Eligibility Criteria Storage condition Storage time (months) °C/%RH 0 3* 6 RRT: 0.66 ≤ 1.0% (end of shelf life);
any single impurity, NMT 0.2% 25/60 ND 0.12 0.27 30/75 ND 0.24 0.38 40/75 ND 0.47 0.89 RRT: 0.69 ≤ 1.0% (end of shelf life);
any single impurity, NMT 0.2% 25/60 ND 0.07 0.13 30/75 ND 0.14 0.21 40/75 ND 0.26 0.51 Amount of impurities NMT 0.2% (immediately after release);
NMT 1.5%
(at the end of the shelf life) 25/60 ND 0.19 0.40 30/75 ND 0.38 0.59 40/75 ND 0.69 1.40 ^* For the 3-month time period, the analysis for the 25°C/60% RH and 30°C/75% RH conditions was actually performed after 4 months. ND = not determined; RRT = relative retention time; NMT = no more.

[0200] In addition, microbiological testing was carried out before storing the compositions. Each parameter of total aerobic microorganisms (≤10 ² CFU/g), yeast and mold cell counts (≤10 ¹ CFU/g), Pseudomonas aeruginosa counts (absent), and Staphylococcus aureus counts (absent) were within the normal range as stated in brackets.

[0201] When extrapolated from the test results presented above, the compositions have a minimum shelf life of 24 months at 25°C and 60% relative humidity.

[0202] Taken together, the results of these studies indicate that the compositions described herein have good mucoadhesive properties, stability and penetration.

Claims (26)

1. Mucoadhesive pharmaceutical composition based on a corticosteroid, containing: (a) budesonide in an amount of 0.02-0.06% w/w of the composition, (b) glycerin in an amount of 40-70% w/w of the composition, (c) xanthan gum in an amount of 0.25-1.5% w/w of the composition, and (d) propylene glycol in an amount of not more than 20% w/w of the composition, wherein the composition has a pH from 4.5 to 7. 2. The composition according to claim 1, containing an aqueous acid buffer. 3. Composition according to any one of paragraphs. 1-2, containing sucralose in an amount of 0.05-0.5% w/w of the composition. 4. Composition according to any one of paragraphs. 1-3, containing (a) budesonide in an amount of 0.05% w/w of the composition, (b) glycerin in an amount of 50% w/w of the composition, and (c) xanthan gum in an amount of approximately 1% w/w of the composition. 5. The composition according to claim 4, containing sucralose in an amount of 0.05% w/w of the composition. 6. Composition according to any one of paragraphs. 1-5, further comprising one or more of the following: flavoring; preservative, and antioxidant. 7. Composition according to any one of paragraphs. 1-6, where the composition is a suspension. 8. Composition according to any one of paragraphs. 1-6, where the composition is a solution. 9. Composition according to any one of paragraphs. 1-8, where the composition is substantially free of preservatives. 10. The composition according to claim 2, wherein the aqueous acid buffer is a citric acid buffer or an acetate buffer. 11. The composition according to claim 2, wherein the aqueous acid buffer is selected from a citric acid-based buffer. 12. Composition according to any one of paragraphs. 1-11, prepared for oral administration. 13. The composition according to claim 12, presented in a single dose package containing from 1 to 10 ml of the composition. 14. Composition according to any one of paragraphs. 1-11, prepared for rectal administration. 15. A method of treating one or more of an inflammatory condition of the esophagus, eosinophilic esophagitis or inflammatory bowel disease, comprising administering a composition according to any one of claims. 1-14 to the subject in need.