HK1225974B - Corticosteroid containing orally disintegrating tablet compositions for eosinophilic esophagitis - Google Patents

Description

Orally disintegrating tablet composition containing a corticosteroid for eosinophilic esophagitis

Cross-related applications

This application claims the benefit under 35 USC §119(e) of U.S. Provisional Patent Application Serial No. 61/874,450, filed September 6, 2013, the disclosure of which is incorporated herein by reference in its entirety for all purposes.

Field of the Invention

The present invention relates to orally administered, low-dose, topically acting corticosteroid compositions useful for treating conditions associated with inflammation of the esophagus.

Background of the Invention

Esophageal inflammatory conditions such as eosinophilic esophagitis (EoE) are characterized by high levels of eosinophils in the esophagus and basal zona hyperplasia, which are becoming more recognized in children and adults. Many aspects of the disease remain unclear, including its etiology, natural history, and optimal treatment. EoE affects people of all ages, but is most common in individuals between the ages of 20 and 50. The symptoms of EoE often mimic those of gastroesophageal reflux disease (GERD) and include vomiting, dysphagia, pain, and food retention. Misdiagnosis of EoE as GERD often occurs, often leading to delayed treatment of EoE patients. Currently, there are no approved locally applied anti-inflammatory drugs for treating conditions associated with inflammation of the upper gastrointestinal tract, particularly inflammatory conditions of the esophagus, i.e., EoE. The disease causes pain, leads to dysphagia, and predisposes patients to food retention and other complications. While systemic treatment with corticosteroids such as prednisolone is effective, they are associated with significant adverse effects such as suppression of the hypothalamic-pituitary-adrenal (HPA) axis as reflected in salivary cortisol levels, general suppression of immune function, and, particularly in children, distressing side effects from long-term systemic exposure including growth retardation, which may lead to reduced height in adulthood.

In contrast, twice-daily EoE treatment involves directing steroid medications to the back of the throat via a metered-dose inhaler (MDI) so that they are not significantly inhaled, and instructing patients to keep their mouths closed during the "puff-and-swallow" treatment and to rinse their mouths immediately after administration without swallowing food or water for two hours after administration. Flushing is recommended because residual medication in the mouth and throat can lead to candidiasis, and swallowing is prohibited because it can wash the medication down the esophagus. In another study, 50% of patients treated with fluticasone propionate (FP) achieved histologic remission, compared to 9% of patients receiving placebo (P=0.047). FP reduced esophageal eosinophil levels, with a more pronounced effect in non-allergic individuals. However, this therapy is particularly problematic for very young children and those with developmental delays, who are unlikely to be able to use the puff-and-swallow technique effectively.

In another randomized, double-blind, placebo-controlled trial evaluating the effect of oral 1 mg budesonide viscous solution (0.5-mg Respule dissolved in 10-15 mL of fluid) twice daily for 15 days in adolescents and adults with active EoE compared to placebo, disease activity was assessed clinically, endoscopically, and histologically before and after treatment. The primary objective was to reduce the mean number of eosinophils in the esophageal epithelium (number per high-power field [hpf] = esophageal eosinophil burden). A 15-day course of budesonide was well tolerated and effectively induced histological and clinical remission in adolescents and adults with active EoE. A 15-day course of treatment significantly reduced the number of eosinophils in the esophageal epithelium in patients given budesonide (from 68.2 eosinophils/hpf to 5.5 eosinophils/hpf; P < 0.0001), but not in the placebo group (from 62.3 eosinophils/hpf to 56.5 eosinophils/hpf; P = 0.48). Dysphagia scores were significantly improved in patients given budesonide compared with those given placebo (5.61 vs. 2.22; P < 0.0001). Based on endoscopic examination, white exudate and red furrows were reversed in patients given budesonide. These dosage forms have not yet been approved by the FDA for commercial use, and oral administration would be cumbersome and likely to produce inconsistent results.

When an oral solid dosage form with a drug load of ≤5% by weight is desired, the drug is either micronized and co-processed by mixing with at least one carrier excipient, or granulated in a fluidized bed or high shear granulator by spraying, preferably with a drug solution, to achieve blend uniformity/homogeneity of the mixture and, subsequently, content uniformity in the finished dosage unit, as required by regulatory requirements (FDA's Draft Guidance for Industry "Powder blend and finished dosage units - stratified in-process dosage unit sampling and assessment," October 2003). Many micronized drugs exhibit a tendency to segregate in the mixture and form larger particles to reduce their high surface energy. The resulting segregation and agglomeration can lead to recurring blend inhomogeneity/inhomogeneity, a primary concern. Segregation and agglomeration, in particular, must be avoided in mixtures containing low-dose drugs with low water solubility, not only during powder mixing but also throughout processing into the finished dosage form (capsule or tablet) to achieve and maintain the desired blend uniformity/homogeneity and/or avoid high solubility variability. Separation of drug particles, especially in direct compression mixtures, is equipment and materials dependent. Therefore, achieving acceptable mixture homogeneity during direct compression blending of low-dose drugs with suitable pharmaceutically acceptable excipients (i.e., drug content <5% by weight in the mixture) and maintaining that mixture homogeneity until processing into finished dosage forms (e.g., tablets or capsules) is extremely challenging (McGinity J.W. et al., Dissolution and uniformity properties of ordered mixes of micronized griseofulvin and a directly compressible excipient. Drug Development and Industrial Pharmacy 1985; 11(4):891-900; Yalkowsky S.H. and Bolton S., Particle size and content uniformity. Pharmaceutical Research. 1990; 7(9):962-966; Ahmad H. and Shah N., Formulation of low dose medicines—Theory and Practice. Amer. Pharm. Rev. 2000; 3(3):1-5; Mahmoudi Z.N. et al., The influence of fillerin blending on the properties of fillerin). uniformity of micronized drugs. Contributed poster, AAPS Annual Meeting (USA) 2010; Mahmoudi Z.N. et al., Effect of drug particle size on blendsegregation and content uniformity. Contributed poster, AAPS Annual Meeting (USA) 2011).

WO 2011041509 discloses an orally administered pharmaceutical composition formulation containing a topically acting corticosteroid in an amount of less than 20 mg. While the working examples of compression mixtures containing only 4% fluticasone propionate by weight do not specifically discuss how to achieve acceptable mixture uniformity, which translates into acceptable content uniformity for the ODT, the fact that fluticasone is granulated with suitable pre-granulated excipients (e.g., rapidly dispersing microparticles containing mannitol and crospovidone) suggests that the purpose of fluticasone granulation is to achieve acceptable content uniformity in the finished tablet. However, the micronized topically acting corticosteroid particles may be present in aggregated granules and, therefore, may not be readily exposed to inflamed EoE tissue following oral administration for rapid induction of EoE remission.

Therefore, there is a need for a low-dose corticosteroid composition having acceptable mixture uniformity/homogeneity (i.e., drug content <5%, particularly <3% by weight in the mixture) during mixing of a topically acting corticosteroid with a suitable pharmaceutically acceptable excipient as a carrier, and maintaining the mixture homogeneity until processing into a finished unit dosage form (e.g., tablet or capsule), wherein the pharmaceutical composition exhibits high content uniformity while being suitable for oral administration to a patient to provide local (rather than systemic) treatment of inflammation of the upper gastrointestinal tract, particularly eosinophilic esophagitis (EoE), because the micronized topically acting corticosteroid particles that have been adsorbed in large quantities on the surface of the carrier are able to rapidly induce relief of EoE.

SUMMARY OF THE INVENTION

The present invention relates to an oral solid pharmaceutical composition comprising a low-dose locally acting corticosteroid and at least one pharmaceutically acceptable carrier for adsorbing the drug, wherein the amount of the drug is less than about 5% by weight (drug weight/composition weight), particularly less than 3%, and the composition has no significant systemic glucocorticoid or mineralocorticoid activity in humans after oral administration. The mixture of the corticosteroid and the carrier has high mixture homogeneity/drug homogeneity, which translates into content uniformity in the finished unit tablets.

The compositions of the present invention may be formulated into orally disintegrating tablets (hereinafter referred to as ODTs) that disintegrate within 30 seconds when tested using the USP <701> Disintegration Test and/or within 60 seconds when placed in a human oral cavity.

The present invention also relates to a process for producing a low-dose pharmaceutical composition comprising adsorbing an optionally micronized topically acting corticosteroid onto at least one pharmaceutically acceptable carrier, such as silicified microcrystalline cellulose, by mixing for a sufficient time and passing through a deagglomeration/comminution mill at least once before mixing with other pharmaceutically acceptable excipients, and then formulating the resulting mixture into a suitable unit dosage form, such as a tablet.

The present invention discloses a method for preparing a pharmaceutical composition comprising a particularly low water solubility, low dose, micronized drug and at least one pharmaceutically acceptable carrier, wherein the drug and the carrier must be mixed for a sufficiently long time using a suitable mixer-comminution mill combination to avoid agglomeration-agglomeration of the drug particles in the mixture not only during powder mixing but also until processing into the finished dosage form (capsule or tablet), to achieve and maintain high mixture uniformity/homogeneity, and/or to achieve high content uniformity in the finished dosage unit, and also to avoid high dissolution variability.

The compositions of the present invention can be used to treat a variety of conditions, including inflammatory conditions of the gastrointestinal tract. Therefore, the present invention also provides a method for treating inflammatory conditions of the upper gastrointestinal tract, particularly in the esophagus (eosinophilic esophagitis), in an individual by a local action with minimal systemic absorption and accompanying corticosteroid-related side effects. The method comprises administering a pharmaceutical composition of the present invention comprising optionally micronized locally acting corticosteroid particles adsorbed on silicified microcrystalline cellulose to an individual to treat eosinophilic esophagitis. Alternatively, the compositions of the present invention may comprise a water-soluble or water-swellable pharmaceutically acceptable excipient, such as a biogel or bioadhesive polymer, that will enhance the bioadhesion of the corticosteroid to the inflamed esophageal mucosa.

Detailed Description of the Figures

FIG1 shows the sampling locations for taking representative samples in a mixer according to the FDA's Draft Guidance for Industry "Powder blend and finished dosage units-stratified in-process dosage unit sampling and assessment" October 2003.

Detailed Description of the Invention

The present invention relates to a solid pharmaceutical composition comprising a corticosteroid in an amount of less than about 5% (weight of drug/weight of composition) and at least one pharmaceutically acceptable carrier for adsorbing the drug, wherein the composition has no significant systemic glucocorticoid or mineralocorticoid activity, and wherein the solid pharmaceutical composition disintegrates within 30 seconds when tested using the USP <701> Disintegration Method. Upon contact with saliva in the oral cavity of a subject or patient in need thereof, the composition disintegrates in about 60 seconds or less.

The solid pharmaceutical composition of the present invention provides a therapeutically effective amount of a topical corticosteroid to inflamed tissues of the upper gastrointestinal tract, particularly to inflamed tissues of the esophagus.

As used above, and throughout the description of the present invention, the following terms shall have the following meanings unless otherwise indicated.

As used herein, the terms "drug,""activeingredient," or "active pharmaceutical ingredient" include pharmaceutically acceptable and topically acting corticosteroids, their pharmaceutically acceptable salts, esters, solvates (including hydrates), polymorphs, stereoisomers, and/or prodrugs, and mixtures thereof. The term "salt" refers to the product formed by reacting a suitable inorganic or organic acid with the "free base" form of the drug. Suitable acids include acids with sufficient acidity to form stable salts, such as acids with low toxicity, such as salts approved for use in humans or animals. Non-limiting examples of acids that can be used to form salts of orally active drugs include inorganic acids such as HCl, H ₃ PO ₄ , H ₂ SO ₄ . Non-limiting examples of organic acids include alkylsulfonic acids and propionic acid.

The term "orally disintegrating tablet," "orally dispersible tablet," or "ODT" refers to a solid dosage form of the present invention that, after administration, rapidly disintegrates in the patient's mouth without chewing. The rate of oral disintegration can vary, but is significantly faster than the rate of oral disintegration of conventional solid dosage forms or chewable solid dosage forms (i.e., tablets or capsules) that are intended to be swallowed immediately after administration.

As used herein, the term "about" refers to a quantity and includes "exactly." For example, "about 30 seconds" includes exactly 30 seconds, as well as values close to 30 seconds (e.g., 25 seconds, 29 seconds, 31 seconds, 35 seconds, etc.). When the term "about" is used in reference to a range of values, the term "about" refers to both the maximum and minimum values of the range (e.g., "about 1-50 μm" means "about 1 μm to about 50 μm").

The term "intimately associated," as used herein to describe the spatial relationship between two or more components of a composition, refers to components that are intimately mixed, for example, in a mixture, coating, or matrix.

Unless otherwise indicated, all percentages and ratios are calculated by weight. Unless otherwise indicated, all percentages and ratios are calculated based on the total composition.

As used herein, the term "no significant systemic glucocorticoid or mineralocorticoid activity" refers to a corticosteroid composition that provides a local effect by local contact with diseased tissue rather than by being absorbed into the circulation. Corticosteroids with high systemic glucocorticoid potency when administered orally include, for example, hydrocortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, or mineralocorticoid potency (e.g., aldosterone (alsosterone)). Corticosteroids that typically have systemic glucocorticoid or mineralocorticoid activity after oral administration can also be used in diluted compositions of the present invention, wherein systemic intake of the corticosteroid is reduced or suppressed.

Suitable topically acting corticosteroids that may be included in the pharmaceutical compositions of the present invention include budesonide, fluticasone, flunisolide, ciclesonide, mometasone, beclomethasone, tixocortsone, and salts or esters thereof and mixtures thereof.

In one specific embodiment, the compositions of the present invention comprise fluticasone. In other embodiments, the compositions of the present invention comprise budesonide. In certain other embodiments, the compositions of the present invention comprise ciclesonide.

In one embodiment, the corticosteroid can be in the form of crystals having an average particle size of about 100 μm or less, about 75 μm or less, about 50 μm or less, more particularly about 25 μm or less, or about 15 μm or less. A particular embodiment of the invention is one in which the corticosteroid is micronized to a mean particle size of less than about 10 μm, less than about 8 μm or less, less than about 6 μm, or particularly less than about 4 μm. Alternatively, such crystals can have a mean particle size in the submicron range (e.g., an average particle size of about <1 μm), i.e., can be used as nanoparticles (e.g., an average particle size in the range of about 1-100 nm).

In another embodiment, the corticosteroid can be present in an amorphous form, for example, in combination with a stabilizer that limits recrystallization of the drug, such as polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose, hydroxyethylcellulose, VA64, sodium lauryl sulfate, Tween surfactants, EPO polymers, and mixtures thereof.

The amount of the corticosteroid present in the pharmaceutical composition of the present invention is selected to maximize the therapeutic benefit from topical application, while minimizing the side effect from systemic absorption. In the case of solid pharmaceutical composition of the present invention, the amount of the corticosteroid in the composition is less than about 5%w/w (drug weight/composition weight). In one embodiment, the amount of the corticosteroid in the pharmaceutical composition is less than about 4%. In another embodiment, it is less than about 3%. In another embodiment, it is less than about 2%, less than about 1.5%, less than about 1%, less than about 0.5% or less by weight. In one embodiment, the amount of the corticosteroid in the pharmaceutical composition is between about 0.50mg and about 18mg. In another embodiment, the amount of the corticosteroid in the pharmaceutical composition is between about 0.75mg and about 12mg. In another embodiment, the amount of the corticosteroid in the pharmaceutical composition is between about 1.5mg and about 9mg. In other embodiments, the amount of corticosteroid is about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.15 mg, about 0.1 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 1 mg, about 1.5 mg, about 2 mg, about 3 mg, about 4 mg, about 4.5 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 12 mg, about 18 mg, and all ranges and subranges therebetween.

In embodiments of the present invention, the rapidly disintegrating compositions of the present invention may include a pharmaceutically acceptable excipient that swells, dissolves, or otherwise promotes the disintegration of the ODT composition, thereby forming a smooth, viscous suspension containing micronized corticosteroid particles to coat the inflamed esophageal mucosa, thereby treating eosinophilic esophagitis. In certain embodiments of the present invention, the total weight of the dosage form is maintained in the range of 300 mg to 900 mg to incorporate as much rapidly dispersing microparticles containing at least one sugar alcohol in combination with at least one disintegrant as possible, thereby maximizing the surface coating of the eosinophilic esophagitis with micronized corticosteroid. In another embodiment, the rapidly dispersing microparticles contain at least one disintegrant in combination with a sugar alcohol and/or sugar. The amount of sugar alcohol and/or sugar in the rapidly dispersing granules ranges from about 99% to 90% or about 95% to 90% of the total weight of the disintegrant-containing granules, including all ranges and subranges therebetween. In one embodiment, the average particle size of the sugar alcohol and/or sugar is about 30 μm or less, for example, about 1-30 μm, about 5-30 μm, about 5-25 μm, about 5-20 μm, about 5-15 μm, about 5-10 μm, about 10-30 μm, about 10-25 μm, about 10-20 μm, about 10-15 μm, about 15-30 μm, about 15-25 μm, about 15-20 μm, about 20-30 μm, about 20-25 μm, or about 25-30 μm.

In one embodiment of the invention, the dosage form has a total weight of 300 mg and comprises about 0.05 mg (0.16%), about 0.75 mg (0.25% w/w), about 1.5 mg (0.5% w/w), about 3 mg (1% w/w), about 4.5 mg (1.5%), about 6 mg (2% w/w), about 9 mg (3% w/w), about 12 mg (4% w/w), about 16 mg (5%) of a corticosteroid.

In another embodiment of the invention, the dosage form has a total weight of 600 mg and comprises about 0.75 mg (0.125% w/w), about 1.5 mg (0.25% w/w), about 3 mg (0.5% w/w), about 4.5 mg (0.75%), about 6 mg (0.1% w/w), about 9 mg (1.5% w/w), about 12 mg (2% w/w), about 18 mg (3% w/w) of a corticosteroid. In one embodiment of the invention, the topically acting corticosteroid is fluticasone propionate and is present in the pharmaceutical composition at a range of about 0.05 mg to about 15 mg, with the drug content being about 0.16% to 5% by weight of the composition.

In another embodiment, the fluticasone propionate is in the range of about 0.75 mg to about 4.5 mg in the composition, and the drug content in the composition is about 0.25% to 1.5% by weight.

In another embodiment, the fluticasone propionate ranges from 0.05 mg to about 18 mg in the composition, and the drug content in the composition is about 0.125% to 5% by weight.

The pharmaceutically acceptable carrier used in the mixture of the present invention is suitable for adsorbing the drug. It should have the properties of an excellent carrier for drying the mixture, improve the flowability and processability of the mixture, and prevent agglomeration. It can also improve the uniformity of the corticosteroid content. It is selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, pregelatinized starch, corn starch, colloidal silicon dioxide, or amorphous magnesium aluminum silicate (commercially available as VEEGUM ^™ or NEUSILIN ^™ ). It is preferably silicified microcrystalline cellulose, which is composed of tightly bound microcrystalline cellulose and colloidal silicon dioxide particles (SMCC: MCC, 98% and CSD, 2%). The use of this ingredient in the composition of the present invention improves the flowability and mixing properties of the corticosteroid mixture; improves the uniformity/homogeneity and physical stability of the formulation during storage and until it is finally processed into a finished dosage form such as a tablet or capsule. In other words, it also avoids or minimizes the potential for demixing and agglomeration of the corticosteroid particles. The presence of the carrier in admixture with the active also ensures reproducible preparation of the compositions of the invention, particularly in the context of direct tableting applications. In one embodiment of the present invention, a low-dose corticosteroid mixture with a carrier is disclosed that exhibits high mixture homogeneity, low potential for aggregation, and excellent flow properties. The mixture is particularly suitable for producing rapidly disintegrating diluted corticosteroid compositions. In one embodiment of the present invention, the mixture comprises fluticasone propionate adsorbed on silicified microcrystalline cellulose and rapidly dispersing microparticles.

The disintegration rate of the compositions of the present invention in the oral cavity of a subject may be on the order of about 60 seconds or less, about 50 seconds or less, about 40 seconds or less, about 30 seconds or less, about 20 seconds or less, or about 10 seconds or less.

The disintegration rate of the solid pharmaceutical composition of the present invention measured using the USP <701> Disintegration Test is about 60 seconds or less, about 45 seconds or less, about 30 seconds or less, about 20 seconds or less, or about 10 seconds or less.

In addition to the corticosteroid and the carrier, the composition or mixture of the oral dosage form of the present invention may further contain a pharmaceutically acceptable ingredient that swells, dissolves, or otherwise promotes disintegration. Such ingredients may include disintegrants, sugar alcohols, sugars, or mixtures thereof, water-soluble polymer binders, biogels, or bioadhesive polymers that can keep the corticosteroid particles adsorbed to the inflamed esophageal tissue longer than in the absence of the ingredients.

In one embodiment, the present invention provides a solid pharmaceutical composition comprising a corticosteroid and a pharmaceutically acceptable biocolloid polymer capable of retaining the corticosteroid longer at inflamed esophageal tissue. Components referred to herein as "biocolloid polymers" or "bioadhesives" are agents that promote the adhesion of corticosteroids to biological surfaces, particularly inflamed mucosa, by gelling under physiological conditions of the GI tract (e.g., when in contact with physiological fluids and/or at physiological temperatures), and include, but are not limited to, the biocolloid polymers listed below.

The biogelling polymer may be a thermosensitive polymer. Suitable thermosensitive polymers include polyacrylamides, such as poly(N-isoacrylamide), and poly(ether-ester) copolymers, such as poly(ethylene glycol-(DL-lactic acid-co-glycolic acid)-ethylene glycol). Such thermosensitive polymers can partially or completely cover the inflamed esophageal tissue while keeping the corticosteroid particles close to or in close contact with the inflamed tissue, thereby increasing local contact of the corticosteroid with the inflamed tissue.

In one embodiment, the compositions of the present invention comprise a bioadhesive, such as a lipid or polymer. Examples of such lipids are glycerophospholipids, such as phosphatidylcholine, and diacylglycerols, such as diolein. Examples of bioadhesive polymers include chitosan, polyorthoesters, and copolymers, terpolymers, and mixtures thereof.

In another embodiment, the solid pharmaceutical composition of the present invention comprises an adhesive. Suitable adhesives include sucrose aluminum sulfate complex, chitosan and derivatives such as trimethyl chitosan, polyvinyl pyrrolidone, methylcellulose, hydroxypropyl cellulose, cross-linked polyacrylic acid copolymers, polyvinyl pyrrolidone, vinyl pyrrolidone-polyvinyl acetate copolymers (e.g., VA 64 from BASF), (poly (ethylene glycol 6000-vinyl caprolactam-vinyl acetate) (13:57:30) copolymer from BASF), polyvinyl alcohol, polyethylene oxide, polyamides, alginic acid and its salts, carrageenan, xanthan gum, ammoniomethacrylate copolymers, CARBOPOL polymers, maltodextrin, pectin, sucralose, and combinations thereof.

In certain embodiments of the solid pharmaceutical compositions of the present invention, the corticosteroid and the adhesive are tightly bound. In one such embodiment, the solid pharmaceutical composition comprises the corticosteroid surrounded or encapsulated by the adhesive. In another such embodiment, the solid pharmaceutical composition comprises the corticosteroid disposed on the surface of the adhesive. In other embodiments, the solid pharmaceutical composition comprises the corticosteroid mixed or granulated with the adhesive.

In certain embodiments of the invention, the solid pharmaceutical composition includes any solid dosage form that rapidly disintegrates in the mouth to form a suspension of powdered corticosteroid that is hypothesized to coat or adhere to the inflamed esophageal mucosa when swallowed.

In one embodiment, the composition of the present invention is in the form of an ODT. The ODT comprises a drug in an amount of less than about 5% (drug weight/composition weight) and a pharmaceutically acceptable carrier, wherein the composition has no significant systemic glucocorticoid or mineralocorticoid activity in humans after oral administration. The drug particles (e.g., as described herein, optionally coated with or optionally combined with a corticosteroid of an adhesive as described herein) are combined with rapidly dispersing microparticles. The rapidly dispersing microparticles comprise sugar alcohols, sugars, or mixtures thereof, and disintegrants alone or in combination with pharmaceutically acceptable additives (e.g., pregelatinized starch, hydroxypropyl cellulose, etc.) having multifunctional activity.

A non-limiting list of suitable disintegrants for use in the rapidly dispersing microgranules includes crospovidone (cross-linked PVP), sodium starch glycolate, cross-linked sodium carboxymethylcellulose, calcium silicate, and low-substituted hydroxypropyl cellulose.

The amount of disintegrant in the ODT typically ranges from about 1% to about 10% by weight.

Sugar alcohol is the hydrogenation formation of carbohydrate, wherein carbonyl (that is, aldehyde or ketone) has been reduced to primary hydroxyl or secondary hydroxyl. Non-limiting examples of suitable sugar alcohol for the rapid dispersion granules of pharmaceutical composition of the present invention include such as arabitol, isomalt, erythritol, glycerol, lactitol, mannitol, sorbitol, xylitol, maltitol and mixtures thereof. Term " sugar (saccharide) " and term " sugar (sugar) " synonymous, include monosaccharide such as glucose, fructose, lactose and ribose, and disaccharide such as sucrose, lactose, maltose, trehalose and cellobiose. In one embodiment, non-limiting examples of suitable sugar for use in composition of the present invention include such as lactose, sucrose, maltose and mixtures thereof. In another embodiment, described rapid dispersion granules include at least one disintegrant combined with sugar alcohol. In another embodiment, described rapid dispersion granules include at least one disintegrant combined with sugar. In another embodiment, described granules comprising disintegrant include at least one disintegrant combined with sugar alcohol and sugar.

The amount of sugar alcohol and/or sugar in the rapidly dispersing granules ranges from about 99% to 90% or about 95% to 90% of the total weight of the granules including the disintegrant, including all ranges and subranges therebetween.

The amount of sugar alcohol and/or sugar in the ODT ranges from about 30% to about 70% by weight.

In one embodiment, the average particle size of the sugar alcohol and/or sugar is 30 μm or less, for example, about 1-30 μm, about 5-30 μm, about 5-25 μm, about 5-20 μm, about 5-15 μm, about 5-10 μm, about 10-30 μm, about 10-25 μm, about 10-20 μm, about 10-15 μm, about 15-30 μm, about 15-25 μm, about 15-20 μm, about 20-30 μm, about 20-25 μm or about 25-30 μm.

The ratio of disintegrant to sugar alcohol, sugar or mixture thereof in the rapidly dispersing microgranules ranges from about 90/10 to about 99/01, for example, about 90/10, about 91/9, about 92/8, about 93/7, about 94/6, about 95/5, about 96/4, about 97/3, about 98/2, about 99/1, including all values, ranges and subranges therebetween.

The corticosteroid particles are usually adsorbed on the carrier. The method for the preparation includes repeatedly mixing the corticosteroid and the carrier so that the mixture is adsorbed on the carrier. Usually micronized corticosteroids (average particle size is less than 10 μm) are used for the following reasons. First, the finished dosage form (such as ODT) is designed to disintegrate rapidly after contact with the saliva in the oral cavity. In order to achieve this, the dosage form (ODT) should preferably have a minimum of 100 mg of rapidly dispersible microparticles, no matter how much the dosage of the corticosteroid is (for example, 0.1 mg, 1 mg, 10 mg or 20 mg). Secondly, in order to achieve the content in the mixture uniformity/homogeneity and the finished unit dosage form in the mixture, the micronized drug particles can be mixed into a single silicified microcrystalline cellulose or a silicified microcrystalline cellulose combined with rapidly dispersible microparticles by at least once mixing and grinding as described in the examples of the different embodiments of the present invention. The first option of incorporating the drug into silicified microcrystalline cellulose will largely prevent agglomeration of the corticosteroid microparticles during transient storage until final processing into finished dosage forms (capsules or tablets), exhibiting high content uniformity and/or low dissolution variability.

Rapidly dispersing granules or granules can be prepared by granulating a disintegrant with a sugar alcohol and/or sugar having an average particle size of not more than about 30 μm as described in U.S. 2005/0232988 or U.S. 2003/0215500. The granulation can be carried out, for example, in a high shear granulator using about 20-25% water as a granulating fluid and, if necessary, wet-milled and dried to produce rapidly dispersing microparticles having an average particle size of not more than about 300 μm (e.g., about 175-300 μm). Alternatively, rapidly dispersing microparticles can be prepared as described in U.S. 13/310,632 by granulating a disintegrant in a fluidized bed granulator in combination with a low level of a pharmaceutically acceptable additive (e.g., starch, hydroxypropyl cellulose, etc.) having a multifunctional activity.

The rapidly disintegrating microparticles present in the ODT help the tablet disintegrate rapidly when placed in the oral cavity, thereby producing a smooth suspension containing corticosteroid drug particles. It is desirable to contain a sufficient amount of rapidly disintegrating microparticles to widely cover the esophageal mucosa. This creates a content uniformity problem in these low-dose ODTs (e.g., 300 mg ODT contains 12 mg or less of corticosteroid). Generally speaking, this problem is overcome by granulation, which involves spraying a dilute solution of the corticosteroid onto a bed of excipient powder. The drug particles are embedded in the granules and therefore may not be exposed to the inflamed mucosa, resulting in poor effectiveness. Surprisingly, it has been observed that by adsorbing the micronized locally acting corticosteroid drug particles onto a pharmaceutically acceptable carrier (e.g., silicified microcrystalline cellulose) before mixing with the rapidly dispersing microparticles and other excipients and compressing into the ODT, not only can the desired content uniformity be achieved, but the probability of the corticosteroid drug particles being exposed to the inflamed mucosa is also greatly enhanced.

The dosage forms described herein may also contain pharmaceutically acceptable excipients commonly used in disintegrating tablet formulations, such as fillers, diluents, glidants, disintegrants, binders, and lubricants.

Examples of suitable fillers, diluents and/or binders include lactose (e.g., spray-dried lactose, for example), microcrystalline cellulose (various grades), hydroxypropyl cellulose, L-hydroxypropyl cellulose (low-substituted), low molecular weight hydroxypropyl methylcellulose (HPMC) (e.g., Methocel ^™ E, F and K from Dow Chemical, Metholose E SH from Shin-Etsu, Ltd), hydroxyethyl cellulose, sodium carboxymethyl cellulose, carboxymethyl hydroxyethyl cellulose and other cellulose derivatives, sucrose, agarose, sorbitol, mannitol, dextrin, maltodextrin, starch or modified starch (including potato starch, corn starch and rice starch), calcium phosphate (e.g., basic calcium phosphate, calcium hydrogen phosphate, dicalcium phosphate hydrate), calcium sulfate, calcium carbonate, sodium alginate and collagen. A preferred filler for the compositions of the present invention is mannitol, for example, spray-dried mannitol.

Examples of suitable disintegrants include crospovidone (cross-linked PVP), sodium starch glycolate, cross-linked sodium carboxymethylcellulose, calcium silicate and low-substituted hydroxypropylcellulose.A preferred disintegrant for use in the compositions of the present invention is crospovidone.

Specific examples of glidants and lubricants include stearic acid, magnesium stearate, calcium stearate or other metal stearates, talc, glyceryl behenate, colloidal silicon dioxide, corn starch, and optionally magnesium stearate or sodium stearyl fumarate (lubricants mixed within the granules or applied externally are used to lubricate the die and punch surfaces). A preferred glidant for the compositions of the present invention is colloidal silicon dioxide, and a preferred lubricant is sodium stearyl fumarate.

The solid pharmaceutical compositions of the present invention may include other dosage forms besides ODTs, wafers, films or other solid dosage forms that rapidly disintegrate in the mouth to form a suspension or dispersion of the corticosteroid that can be easily swallowed to cover the mucosal surface of eosinophilic esophagitis.

For example, the wafer may include dry or freeze-dried compositions, such as oral disintegration or dissolving formulations comprising corticosteroids as active pharmaceutical ingredients prepared using freeze-drying technology (such as, as described in U.S. Patent number 6,316,027). Film dosage forms may include edible films, such as the film dosage forms comprising corticosteroids as active pharmaceutical ingredients described in U.S. Patent number 6,596,298 or U.S. Patent number 6,740,332. In one embodiment of the invention, the solid composition comprises a freeze-dried matrix, wherein the freeze-dried matrix comprises a corticosteroid, a carrier and an excipient. Suitable excipients include mannitol, xylitol, sorbitol, maltitol, maltose, lactose, sucrose, maltose and combinations thereof.

Topical application of corticosteroids to the oral cavity of individuality has been accompanied by candidiasis infection. Although the present invention is designed to promote this type of infection not so easily, in another embodiment of the present invention, the pharmaceutical composition can include an antifungal agent. Suitable antifungal agents include but are not limited to mitotic inhibitor antifungals, pyrimidine analog antifungals, polyene antifungals, benzimidazole antifungals, imidazole antifungals, polyene antifungals, triazole antifungals, thiazole antifungals, allylamine antifungals, echinocandins antifungals, and other "unclassified" recognized in the art but do not fall into the antifungal agents (such as tolnaflate (tolnaflate) and ciclopirox) in any of the above classifications. For example, suitable antifungal agents that can be included in the solid pharmaceutical composition of the present invention include abafungin, amorolfine, anidulafungin, bifonazole, butenafine, butoconazole, candesin, caspofungin, ciclopirox, clotrimazole, econazole, fenticonazole, filipin, fluconazole, flucytosine, griseofulvin, isavuconizole, isoconazole, itraconazole, ketoconazole, micafungin, miconazole, miconazole nitrate, naftifine, natamycin, nystatin, oxiconazole, posaconazole, praconazole, ravuconazole, chelamycin, sertaconazole, sulconazole, terbafen, terconazole, tioconazole, tolnaftate, undecylenic acid, and voriconazole.

In another embodiment, topical application of corticosteroids to the oral cavity of individuality has been accompanied by candidiasis infection. Although the present invention is designed to not so easily promote this type of infection, in another embodiment of the present invention, the pharmaceutical composition can include an antifungal agent. Suitable antifungals include but are not limited to mitotic inhibitor antifungals, pyrimidine analog antifungals, polyene antifungals, benzimidazole antifungals, imidazole antifungals, polyene antifungals, triazole antifungals, thiazole antifungals, allylamine antifungals, echinocandins antifungals, and other "unclassified" antifungals recognized in the art but not falling into any of the above classifications (e.g., tolnaflate and ciclopirox). For example, suitable antifungal agents that can be included in the solid pharmaceutical composition of the present invention include abafungin, amorolfine, anidulafungin, bifonazole, butenafine, butoconazole, candesin, caspofungin, ciclopirox, clotrimazole, econazole, fenticonazole, filipin, fluconazole, flucytosine, griseofulvin, isavuconizole, isoconazole, itraconazole, ketoconazole, micafungin, miconazole, miconazole nitrate, naftifine, natamycin, nystatin, oxiconazole, posaconazole, praconazole, ravuconazole, chelamycin, sertaconazole, sulconazole, terbafen, terconazole, tioconazole, tolnaftate, undecylenic acid, and voriconazole.

In another embodiment, the pharmaceutical composition of the present invention comprises an antiviral agent. Antiviral agents that may be included in the solid pharmaceutical composition of the present invention include interferons, nucleotides and nucleotide reverse transcriptase inhibitors, non-nucleotide reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, fusion inhibitors, maturation inhibitors, guanosine analogs, purine analogs, pyrimidine analogs, and other "unclassified" antiviral drugs recognized in the art that do not fall into any of the above categories (e.g., foscarnet and miltefosine). For example, suitable antifungal agents that can be included in the solid pharmaceutical composition of the present invention include abacavir, acyclovir (also known as acyclovir), adefovir, amantadine, amdosovir, amprenavir, apraviroc, arithiabine, arbidol, atazanavir, bevirimat, BMS-488043, boceprevir, brivudine, cidofovir, DCM205, docosanol, delavirdine, didanosine, durunavir, efavirenz, elvitegravir, elvucitabine, emtricitabine, enfuviridone, epigallocatechin gallate, ethavirine, famciclovir, fosamprenavir, ganciclovir, globoidnan A, fosamprenavir, ganciclovir ... A), griffithsin, ibalizumab, idoxuridine, indinavir, lamivudine, lopinavir, loviride, maraviroc, nelfinavir, nevirapine, oseltamivir, peginterferon alfa-2a, peginterferon alfa-2b, penclovir, peramivir, plerixafor, PRO 140, racivir, raltegrvir, ritonavir, ribavirin, rimantadine, rlipivirine, saquinavir, stampidine, stavudine, tenofovir, tipranavir, TNX-355, trifluridine, tromantanamide, valacyclovir, valganciclovir, vicriviroc, vidarabione, viramidine, vivecon, zalcitabine, zanamivir, and zidovudine.

Tablet dosage forms, including ODT dosage forms, comprising a low-dose strength locally acting corticosteroid and a pharmaceutically acceptable carrier, wherein the amount of the drug is less than about 5% (weight of drug/weight of composition), has no significant systemic glucocorticoid or mineralocorticoid activity in humans after oral administration, disintegrates in less than about 30 seconds (USP method), and has low friability to have sufficient durability to withstand handling, shipping and/or push-through packaging in blister packs. Friability is less than about 1%, for example, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, etc., including all ranges and subranges therebetween).

Different preparation methods can be applied to prepare a corticosteroid mixture with a suitable carrier having mixture homogeneity (ie, acceptable mixture uniformity and also content uniformity suitable for tableting). Mixing of the above ingredients can be achieved both by dry mixing and by granulation.

The present invention also discloses a method for manufacturing an oral composition (e.g., a compressed or compressible mixture having a drug load of about 0.5% to about 3% by weight), wherein achieving and maintaining acceptable mixture uniformity until the compressed or compressible mixture is processed into a finished unit dosage form (e.g., an orally disintegrating tablet) exhibiting acceptable content uniformity is challenging. The method comprises the following steps:

1) preparing the rapidly dispersible microparticles or granules;

2) preparing premix 1 by loading one-quarter of silicified macrocrystalline cellulose (SMCC, a pharmaceutically acceptable carrier), micronized corticosteroid, colloidal silicon dioxide (glidant), and another one-quarter of SMCC into a V-blender and mixing the contents for 10 minutes;

3) preparing premix 2, comprising charging a free-flowing filler (e.g., spray-dried mannitol), premix 1, the remaining half of the SMCC, a disintegrant (e.g., crospovidone), and a sweetener (sucralose powder) into a high shear granulator and mixing the contents for 1 minute with an impeller speed of 300 ± 50 rpm and a chopper speed of 1500 ± 50 rpm;

4) preparing the final compressible mixture by charging half of the rapidly dispersing granules of step 1, a lubricant (e.g., sodium stearyl fumarate), premix 2 of step 3, and the remaining half of the rapidly dispersing granules of step 1 into a V-blender and mixing for 30 minutes, sampling, and mixing for another 10±1 minutes to achieve the mixture uniformity/homogeneity according to regulatory requirements;

5) Preparing orally disintegrating tablets comprising the compressible mixture of step 4 that exhibit acceptable content uniformity according to regulatory requirements.

In one embodiment, the method for manufacturing an orally disintegrating tablet is performed by repeated dry mixing and grinding. The method comprises the following steps:

1) preparing rapidly dispersible microgranules or granules having an average particle size of no greater than about 400 μm by granulating one or more sugar alcohols and/or sugars each having an average particle size of no greater than about 30 μm with a disintegrant (e.g., crospovidone) in the presence of water or an alcohol-water mixture and then drying the granules (fluidized bed equipment or conventional oven);

2) preparing a milled premix 1 by mixing a pharmaceutically acceptable carrier (e.g., silicified microcrystalline cellulose), micronized corticosteroid, and glidant (e.g., colloidal silicon dioxide) in a V-blender at 25 ± 1 rpm for 10 minutes and then grinding through a comminutive mill equipped with a 024R screen (30 mesh openings) at approximately 2400 ± 100 rpm;

3) Prepare milled premix 2 by mixing half of the free-flowing mannitol, premix 1 from step 2, disintegrant (crospovidone) and sweetener (sucralose powder) in a V-blender for 10 minutes and then milling through a comminuted mill equipped with a 024R screen at 2400 ± 100 rpm and rinsing with the remaining half of the free-flowing mannitol;

4) preparing a compressible mixture by mixing the rapidly dispersing granules of step 1, a lubricant (e.g., sodium stearyl fumarate), the milled premix 2 of step 3, and flushed free-flowing mannitol for a total time of 40 minutes;

5) Tablets are prepared by compressing the compressible mixture of step 4.

A method of repeated dry mixing and grinding is the preferred method for preparing the compositions of the present invention.

In the method of the present invention, the different steps and the order of addition of the individual components are important for achieving acceptable mixture uniformity/homogeneity in the compressed mixture and acceptable content uniformity in the finished dosage unit in accordance with regulatory requirements. The tablets obtained by the above method have an appearance, disintegration time, hardness, and brittleness suitable and suitable for ODT to withstand abrasion during transportation in commercial packaging in bulk containers, blisters, or bottles, as well as during transportation in primary/secondary packaging for commercial distribution and the end use and purpose of the present invention. In addition, the tablets manufactured and then packaged in blisters are highly stable under severe and long-term ICH stability conditions.

The solid pharmaceutical composition of the present invention is suitable for oral administration of locally acting corticosteroids to treat inflamed tissues of the upper gastrointestinal tract, such as the esophagus. The use of locally acting corticosteroids for treating conditions associated with inflammation of the gastrointestinal tract is desirable because it produces fewer side effects than highly systemically acting corticosteroids.

Inflammatory conditions of the gastrointestinal tract that can be treated according to the present invention include inflammation of the esophagus, inflammation of the glottis, inflammation of the epiglottis, inflammation of the tonsils, inflammation of the oropharynx, eosinophilic esophagitis, gastroesophageal reflux disease (GERD), non-erosive reflux disease (NERD), erosive esophagitis, Barrett's esophagus, eosinophilic gastroenteritis, hypereosinophilic syndrome, erosive (corrosive) chemical esophagitis, radiation-induced esophagitis, chemotherapy-induced esophagitis, transient drug-induced esophagitis (also known as drug esophagitis), persistent drug-induced esophagitis, Crohn's disease of the esophagus, and pseudomembranous esophagitis.

In a particular embodiment, the pharmaceutical composition of the present invention is suitable for treating inflammatory conditions of the upper gastrointestinal tract, in particular eosinophilic esophagitis.

Thus, the present invention includes pharmaceutical compositions for use as medicaments in the treatment of inflammatory conditions of the gastrointestinal tract.

The present invention also includes methods of administering a solid pharmaceutical composition of the present invention to a patient in need. In one embodiment, the present invention includes methods for treating eosinophilic esophagitis, comprising administering a pharmaceutical composition of the present invention to a patient in need. After administering the solid pharmaceutical composition of the present invention to an individual, the composition disintegrates in the patient's oral cavity. In another embodiment, the present invention includes methods for treating gastroesophageal reflux disease (GERD), non-erosive reflux disease (NERD) or erosive esophagitis, comprising administering a pharmaceutical composition of the present invention to an individual in need. In another embodiment, the present invention includes methods for treating food allergies with identified allergens such as "atopic IBS" and "atopic bowel."

From the foregoing description and the experimental section, it can be seen that the present invention provides several important advantages. The described invention provides low-dose oral compositions, compositions, and dosage forms comprising a corticosteroid and a pharmaceutical carrier characterized by high content uniformity and stability, wherein the corticosteroid microparticles are present in large quantities at or near the surface of the carrier and are therefore likely to be properly disposed for localized treatment of inflammation of the gastrointestinal tract, particularly EoE, upon disintegration of the corticosteroid ODT in the patient's mouth and swallowing of the resulting viscous suspension.

experiment

method

Bulk/tapped density is measured according to USP <616> Method 1.

Particle size distribution (PSD) was measured using an ATM sonic sieve on 5-10 mg samples.

Flowability was tested using a Sotax flow tester on 110 g of material using a standard six-pass pre-vibration/vibration mode; flow properties were expressed as flow index (α'/ _αref ) and as Carr's index.

Moisture content was determined using Karl Fisher titration, or LOD was measured according to USP <921> 1a method.

Mixture uniformity test : Mixture uniformity test was performed by using a sampler to take out 6 random samples from different locations of the final direct compression blend contained in the V-blender or twin shell blender shown in Figure 1. The collected samples were tested for drug content using HPLC stability-indicating method.

Content Uniformity of ODT : Orally disintegrating tablets were randomly sampled at the beginning, middle, and end of each compression cycle and 10 tablets were tested for content uniformity using an HPLC stability-indicating method.

Disintegration was performed according to the USP <701> method. Friability was measured according to the USP <1216> method.

Example

Example 1: Rapid dispersion of microparticles

Rapidly dispersing microparticles were prepared according to the method disclosed in U.S. Patent Publication No. 2003/0215500, published on November 20, 2003, the contents of which are hereby incorporated by reference in their entirety for all purposes. Specifically, D-mannitol (152 kg) (25 from Roquette, France) having an average particle size of about 20 μm or less was mixed with 8 kg of crospovidone (XL-10 from ISP) in a high shear granulator (GMX 600 from Vector), granulated with purified water (about 32 kg), wet milled using a Comil from Quadro, and finally tray dried to provide microparticles having an LOD (loss on drying) of less than about 1.0%. Alternatively, the wet-milled granules were dried in a fluidized bed dryer to provide microparticles having an LOD of less than 1.0% by weight. The dried granules are screened and the oversized material is re-milled to produce rapidly dispersing microparticles having an average particle size in the range of about 175-300 microns.

D-mannitol (93 parts) and crospovidone (5 parts) with a median particle size of <20 μm were granulated by spraying a starch solution (2 parts, Starch from Colorcon) in a top-jet fluidized bed granulator and dried to a loss on drying of <1.0%. The dried granules were sieved through a 20 mesh sieve and, if necessary to produce alternate rapidly dispersing granules, oversized granules were milled and sieved.

Example 2 : Mixture Preparation for 1.5 mg Fluticasone ODT by High Shear Method; Batch 1

Premix 1 was first prepared by mixing one-quarter of silicified microcrystalline cellulose (SMCC marketed as HD90), micronized fluticasone propionate, colloidal silicon dioxide, and another quarter of SMCC in a 1-quart V-blender for 10 ± 1 minutes (see Table 1 for the weights of the individual components of the compressible mixture of ODT, 1.5 mg and 3 mg). A second premix (Premix 2) was prepared by charging PMA 1 with spray-dried mannitol (M200), Premix 1, the remaining half of SMCC, crospovidone, and sucralose powders into the 10 L granulation bowl of a high shear granulator. Mixing was continued at an impeller speed of 300 ± 50 rpm and a chopper speed of 1500 ± 50 rpm for 10 ± 1 minutes to produce Premix 2. Half of the rapidly dispersing microgranules, sodium stearyl fumarate, Premix 2, and the remaining half of the rapidly dispersing microgranules were mixed in an 8-quart V-shell blender and sampled at 30 and 40 minutes for mixture homogeneity testing. The final mix was sampled for bulk/tap density, particle size distribution (PSD), flowability, and moisture testing.

Table 1 Composition of Compressible Fluticasone ODT Mixtures, 1.5 mg and 3 mg

Example 3 : Preparation of mixtures for 1.5 mg and 3 mg fluticasone ODT by repeated mixing and grinding; batches 2, 3, 5

Prepare Premix 1 (see Table 1 for weights of individual components of the compressible mixture of ODT, 1.5 mg and 3 mg) by sequentially charging half of the SMCC, micronized fluticasone propionate, colloidal silicon dioxide, and the remaining half of the SMCC into a 2-quart V-blender and mixing for 10 ± 1 minutes. Pass Premix 1 through a QUADRO Comil equipped with a 024R screen (30 mesh opening) at approximately 2400 ± 100 rpm. Prepare Premix 2 by mixing half of the spray-dried mannitol, milled Premix 1, crospovidone, and sucralose powder in a 4-quart V-blender for 10 ± 1 minutes and milling through a 024R screen. Rinse the Comil by passing the remaining half of the spray-dried mannitol through a 024R screen. Mix half of the fast dispersing granules, sodium stearyl fumarate, milled premix 1, rinsed mannitol, and the remaining half of the fast dispersing granules and sample them for mixture homogeneity at 30 minutes and 40 minutes. The final mixture is sampled for volume/tap density, particle size distribution (PSD), flowability, and moisture content testing.

Example 4 : Mixture uniformity results of Examples 2 and 3

The compressible mixing test results for Examples 2 and 3 are shown in Table 2. The compressed mixtures ODT 1.5 mg (Batch 1) and ODT 1.5 mg (Batch 2), which had been processed using two different equipment combinations (V-blender-high shear granulator and V-blender-comminuted mill), showed similar mixture physical (powder) properties, such as bulk and tap density, particle size distribution, flow properties, and mixture uniformity values, except that the batch that was mixed for 30 minutes showed a slightly higher %RSD.

Table 2: Physical/Mixture Homogeneity Test Results for Fluticasone ODT, 1.5 mg and 3 mg Compressible Mixes

Table 3: Layered Blend Uniformity Results for Fluticasone ODT Compression Blends

Example 5 : Compression of the ODTs of Examples 2 and 3

The compression blends of Examples 2 and 3 were compressed using a rotary tablet press (Manesty Beta Press equipped with a die set of eight 9.5 mm round, flat, and flat-radius edge dies). The average tablet weight was approximately 300 mg. For the compression cycle, the main compression force used was maintained at 5-6 kN, and the pre-compression force was set to 2 ± 0.2 kN (except where noted). During compression, compression speed and force were measured using an SMI tablet pressing instrument. During tableting, tablets were periodically sampled for visual inspection of "appearance," in-process measurements of weight, thickness, hardness, and friability. Additional tablets were also sampled for analytical testing as "composite samples." Details of the compression parameters and tablet properties are shown in Table 4. The tablets were round and tested for potency, content uniformity, and dissolution (greater than 90% release after 45 minutes for all batches); they had a friability of no greater than 0.4%, a hardness of approximately 4 kP, and a disintegration time of less than 30 seconds.

Example 6 : Confirmatory compression blends and ODT batches (ODT 1.5 mg: Batch 3, 3 mg: Batch 5).

For the 1.5 mg and 3.0 mg fluticasone ODT compression blends, blend batches were prepared using a two-iteration mixing and milling process (mixing in a V-shell blender combined with an iterative process using Comil milling) (see Table 1 for composition, and Tables 2 and 3 for physical/mixture uniformity test results and layered blend uniformity results for the confirmatory compression blends. While the bulk and tap density values, particle size distribution, and blend uniformity values for the confirmatory compression blends were similar to those for the corresponding attributes of the ODT compression blend batch ODT 1.5 mg (Batch 2), the estimated flow properties of ODT 1.5 mg (Batch 3) and ODT 3 mg (Batch 5) were not very good. Both compression blend batches were compressed using the same Beta Press equipped with the same die set and at compressibility parameters. During compression of both batches of compression blends, pickling and/or sticking to the punches was observed. Details of the compression parameters and tablet properties are shown in Table 4.

Example 7 : Mixture preparation for 1.5 mg and 3 mg fluticasone ODT by repeated mixing and grinding, 1.5% lubricant by weight, batches 4 and 6

Fluticasone compression blend batches were prepared by first preparing Preblend 1 and Preblend 2 as disclosed in Example 3, then mixing the components of the final blend for 35 minutes without incorporating a lubricant, and for an additional 5 minutes after adding a lubricant (1.5% by weight sodium stearyl fumarate). Both batches of the final blend were sampled for volume/tap density, particle size distribution (PSD), flowability, moisture content, blend uniformity, and layered blend uniformity testing. The results are reported in Tables 2 and 3.

Example 8 : Compression of the ODT of Example 7

Both batches were compressed using the same rotary tablet press equipped with the same die set and under similar compression conditions as disclosed above.

Example 9 : Stability Test

Fluticasone ODT batches 2 (1.5 mg) and 5 (3 mg) were packaged in 30 cc HDPE bottles (30 tablets per bottle) with a synthetic coil and 0.5 g of desiccant (Sorb-it 1/2 g bags). As shown in Tables 5 and 6, all ODTs were stable under stress conditions (40°C/75% RH) for a period of 6 months and under long-term stability conditions (25°C/60% RH) for a period of 9 months. Physical properties such as appearance, hardness, friability, and disintegration time under all stability conditions were also comparable to the initial values of fluticasone ODTs (1.5 mg and 3 mg).

Table 5: Stability data of Fluticasone ODT batch 2 (1.5 mg)

Table 6: Stability data of Fluticasone ODT batch 5 (3 mg)

Example 10 : Preparation of clinical trial materials, batches C1 and C2

Clinical trial batches (fluticasone propionate ODT, 1.5 mg and 3 mg, with 1.5% sodium stearyl fumarate by weight) were prepared by an iterative mixing-milling-mixing process followed by compression as disclosed in Examples 7 and 8. In-process testing results and analytical results for the clinical batches are shown in Tables 7 and 8, respectively. The compressed composition batches exhibited physical (powder) properties similar to those of the feasibility batches, except that the clinical batches had more fine particles passing a 100 mesh sieve (67-76% of the particles were <150 μm in size), compared to 47-57% of the fine particles in the feasibility batches. However, this did not significantly affect the tableting properties of the clinical batches: a slightly higher %RSD for content uniformity and excellent blend uniformity results were observed in batch C-2 (3 mg).

Table 7: Physical/mixture uniformity test results for clinical trial batches, 1.5 mg and 3 mg

Table 8: Physical/Mixture Uniformity Testing Results for Clinical Trial Batches of Fluticasone ODT, 1.5 mg and 3 mg

Example 11 : Stability Data of Clinical Trial Batches of Fluticasone ODT (1.5 mg and 3 mg)

Fluticasone ODT batches (1.5 mg and 3 mg) were packaged in 30-count bottles (30 tablets per bottle) in HDPE bottles with a synthetic coil and 0.5 g of desiccant (Sorb-it 1/2 g bags). As shown in Table 9, all ODTs were stable under stress conditions (40°C/75% RH) for a period of 9 months and under long-term stability conditions (25°C/60% RH) for a period of 24 months. Physical properties such as appearance, hardness, friability, and disintegration time under all stability conditions were also comparable to the initial values of fluticasone ODT (1.5 mg and 3 mg).

Table 9: Stability data for clinical trial batches of fluticasone ODT, 1.5 mg and 3 mg

Example 12 : Clinical testing

A proof-of-concept study was conducted in patients aged 12 to 55 years diagnosed with EoE using clinical batches of ODT-FT 1.5 mg and 3 mg dose strengths.

The doses used were 1.5 mg administered twice daily and 3.0 mg administered once daily. The study also included a placebo group. Eight subjects were recruited per group. The results of the efficacy analysis confirmed that a positive signal of efficacy with the greatest response was seen histologically in reducing the peak eosinophil count per high-power field of view (a marker of disease and an indicator of treatment response). Both the 1.5 mg and 3 mg treatment groups were significantly more effective histologically than the placebo group. The percentage of patients with at least a 30% reduction in overall EoE symptom severity (as measured by patient questionnaires) also showed numerical superiority of both FT-ODTs over placebo. Endoscopic improvements and changes in sulcus formation and vascularity were also seen, which showed the greatest difference between FT-ODT and placebo, indicating a positive anti-inflammatory effect of the formulation.

In conclusion, the FT-ODT of the present invention showed improvement in histology, overall symptoms and overall endoscopic activity.

Example 13 : Preparation of a mixture of 0.75 mg, 4.5 mg and 6 mg fluticasone ODT - Batches 7 to 9

Fluticasone compression blend batches with a drug load of 0.25% by weight were prepared as follows: Premix 1 and Premix 2 were first prepared as described in Example 3. Premix 1 was prepared (see Table 10 for the weights of the individual components of the compression blend of ODT, 0.75 mg, 4.5 mg, and 6 mg) by sequentially charging half of the SMCC, micronized fluticasone propionate, colloidal silicon dioxide, and the remaining half of the SMCC into a 2-quart V-blender and mixing at 25 rpm for 10 ± 1 minutes. Premix 1 was passed through a QUADRO Comil equipped with a 024R screen (30 mesh opening) at approximately 2400 ± 100 rpm. Premix 2 was prepared by mixing half of the spray-dried mannitol, milled Premix 1, crospovidone, and sucralose powder in a 32-quart V-blender at 25 rpm for 10 ± 1 minutes and milling through a 024R screen. The Comil was rinsed by passing the remaining half of the spray-dried mannitol through a 024R screen. Half of the rapidly dispersing microgranules, milled premix 1, rinsed mannose, and the remaining half of the rapidly dispersing microgranules were mixed in a 32-quart V-blender at 25 rpm for 35 minutes without incorporating a lubricant and for an additional 5 minutes after adding a lubricant (1.5% by weight sodium stearyl fumarate).

Example 14 : Preparation of a 30 kg batch size mixture of 1.5 mg fluticasone ODT; Batch 10

The manufacturing process for a fluticasone compression blend with a lower drug load of 0.5% by weight was scaled up to a 30 kg pilot scale. The process essentially consisted of preparing Premix 1 and Premix 2 as described in Example 3. Premix 1 (see Table 10 for weights of individual components of the ODT compressible blend, 1.5 mg) was prepared by sequentially charging half of the SMCC, micronized fluticasone propionate, colloidal silicon dioxide, and the remaining half of the SMCC into a 32-quart V-blender and mixing at 25 rpm for 10 ± 1 minutes. Premix 1 was passed through a QUADRO Comil equipped with a 024R screen (30 mesh opening) at approximately 2400 ± 100 rpm. Premix 2 was prepared by mixing half of the spray-dried mannitol, milled Premix 1, crospovidone, and sucralose powders in a Galley blender with a 113 L full load at 12 rpm for 20 ± 1 minutes and milling through a 024R screen. Rinse the Comil by passing the remaining half of the spray-dried mannitol through a 024R sieve. Mix half of the rapidly dispersing microgranules, the milled premix 1, the rinsed mannitol and the remaining half of the rapidly dispersing microgranules at 12 rpm for a maximum of 40 minutes.

The final blends in Examples 13 and 14 were sampled and subjected to in-process testing according to USP requirements as well as analytical testing for volume/tap density, particle size distribution (PSD), flowability, blend uniformity, and moisture content. This was the first time that a batch of direct compression ODT blends at a drug load of 0.25% by weight was made using a procedure established for blends at a drug load of 0.5% by weight. No technical issues were encountered during manufacturing. The results reported in Table 11 show acceptable physical properties. Although the blend uniformity data indicated a uniform distribution of the active, low potency was evident in Batch 7, which had the lowest drug load, likely due to active loss during mixing/grinding. As shown below, during the pilot-scale compression mixing process, the blends sampled at 20 minutes, 30 minutes, and 40 minutes prior to the incorporation of the lubricant showed acceptable blend uniformity values.

Example 15 : Compression of the ODTs of Examples 13 and 14

As disclosed above for 1.5mg or 3mg ODT, the same rotary tablet press (Beta Press) equipped with the same force feeder and the same die set (B size die, 9.5mm round flat radius edge) was used to compress 0.75mg, 4.5mg and 6mg ODT batches under similar compression conditions. The compressed tablets of 0.75mg, 4.5mg and 6mg met the specifications for tablet weight, disintegration time, brittleness, hardness and thickness. The physical properties of the tablets were similar to and comparable to other dosage specifications. The potency and content uniformity results of 0.75mg ODT showed low potency, confirming the low mixture uniformity results reported above.

The 1.5 mg ODT was compressed using a Korsch XL 400 industrial tablet press equipped with a D die and 9.5 mm round flat radius edges, operating at 1015 tablets per minute. The compressed tablets were observed to meet specifications for tablet weight, disintegration time, friability, hardness, and tablet thickness. The physical properties of the tablets were similar and comparable to those of the same or other dosage strengths produced at small scale. Potency and content uniformity results confirmed the blend uniformity results, resulting in the ODT meeting all product specifications. Results from scaled-up batches have demonstrated that the current small-scale process is scalable at drug loads of 0.5% by weight or higher. Comparable/similar results between dosage strengths and consistency of results between batch sizes at drug loads of at least 0.5% by weight or higher indicate an effective and suitable direct compression manufacturing process for ODT dosage strengths ranging from 1.5 mg to 6 mg, or drug loads of 0.5% to 2% by weight. Such low drug loads have previously been achievable only through spray granulation, where the tablet components are granulated by spraying a drug solution while excluding lubricants.

Table 10: Composition of compression mixes of 0.75 mg (Batch 7), 4.5 mg (Batch 8), 6 mg (Batch 9), and 1.5 mg (Batch 10) fluticasone ODT

Table 11: Physical/Blend Uniformity Test Results for Fluticasone ODT, 0.75 mg, 4.5 mg, and 6 mg Compressed Blends

Table 12: Compression Method Conditions and Chemical/Physical Test Results for Fluticasone ODT

*-->Tested at the beginning, middle and end of compression; ND-->Not Detected

Fluticasone ODT batches 7 (0.75 mg), 8 (4.5 mg), and 9 (6 mg) were tested for stability. These batches were packaged in 30 cc (30 tablets per bottle) HDPE bottles with a synthetic coil and 0.5 g of silica desiccant (Sorb-it 1/2 g bags). All ODTs were stable under stress conditions (40°C/75% RH) for 6 months and under long-term stability conditions (25°C/60% RH) for 9 months. All measurements at given time points (T = 0, 1 month, 2 months, 3 months, 6 months, 9 months) were within the acceptance criteria (disintegration: NMT 30 seconds, assay: NLT 90.0% and NMT 110.0%, individual impurities: NMT 0.5%, total impurities: NMT 1.5%). Physical properties, such as appearance, hardness, friability, and disintegration time, were also comparable to the initial values of the corresponding fluticasone ODTs under all stability conditions.

Although the invention has been described herein with reference to certain specific embodiments, it will be understood that it is capable of further modifications, and this application is intended to cover any variations, uses, and applications of the invention in general accordance with the principles of the invention and including such departures from the present disclosure as come within known or customary means within the art to which the invention pertains and which may be applied to the essential features hereinbefore recited and which fall within the purview of the appended claims.

Claims (47)

1. A pharmaceutical composition in the form of an orally disintegrating tablet comprising: a. a topically acting corticosteroid or a pharmaceutically acceptable salt, ester or polymorph thereof adsorbed on a pharmaceutically acceptable carrier; b. Rapid dispersion of particles, wherein the corticosteroid or a pharmaceutically acceptable salt, ester or polymorph thereof is present in an amount of about 5% or less, wherein "about" refers to the exact value and values close to the exact value, and wherein the pharmaceutically acceptable carrier is selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, pregelatinized starch, corn starch, colloidal silicon dioxide and amorphous magnesium aluminum silicate, wherein the pharmaceutical composition is prepared by a process comprising the steps of: a) preparing the rapidly dispersible microparticles; b) preparing a premix 1 by mixing the pharmaceutically acceptable carrier, the corticosteroid and a glidant; c) preparing a premix 2 by mixing a filler, the premix 1 of step b), a disintegrant, and a sweetener; d) preparing a final compressible mixture by mixing the rapidly dispersing particles of step a), a lubricant, the premix 2 of step c) and a filler; e) preparing the orally disintegrating tablet by compressing the mixture of step d). 2. The pharmaceutical composition according to claim 1, wherein the orally disintegrating tablet disintegrates within 30 seconds when tested for disintegration time using the USP <701> method. 3. The pharmaceutical composition according to claim 1, wherein the orally disintegrating tablet disintegrates within 60 seconds after contact with saliva in the oral cavity of a patient in need thereof. The pharmaceutical composition according to claim 1 , wherein the pharmaceutically acceptable carrier is silicified microcrystalline cellulose. 5. The pharmaceutical composition according to claim 1, wherein the rapidly dispersing microparticles comprise sugar alcohol or sugar or a mixture thereof, and at least one disintegrant. 6. The pharmaceutical composition according to claim 5, wherein the sugar alcohol or sugar and the disintegrant are present in a ratio of sugar alcohol or sugar to disintegrant of 90:10 to 99:1. 7. The pharmaceutical composition of claim 1, wherein the corticosteroid is selected from the group consisting of budesonide, fluticasone, flunisolide, ciclesonide, mometasone, beclomethasone, and salts, esters, and mixtures thereof. 8. The pharmaceutical composition of claim 7, wherein the corticosteroid is fluticasone. 9. The pharmaceutical composition of claim 8, wherein the corticosteroid is fluticasone propionate. 10. The pharmaceutical composition of claim 1, wherein the corticosteroid is present in the composition in an amount of about 3% or less by weight, wherein "about" refers to the exact value and values close to the exact value. 11. The pharmaceutical composition of claim 1, wherein the corticosteroid is present in the composition in an amount of about 1.5% or less by weight, wherein "about" refers to the exact value and values close to the exact value. 12. The pharmaceutical composition of claim 1, wherein the corticosteroid is present in the composition in an amount of about 1% or less by weight, wherein "about" refers to the exact value and values close to the exact value. 13. The pharmaceutical composition of claim 1, wherein the corticosteroid is present in the composition in an amount of about 0.5% or less by weight, wherein "about" refers to the exact value and values close to the exact value. 14. The pharmaceutical composition of claim 1, wherein the corticosteroid is present in the composition in an amount of about 4.5 mg, wherein "about" refers to the exact number and values close to the exact number. 15. The pharmaceutical composition of claim 1, wherein the corticosteroid is present in the composition in an amount of about 3 mg, wherein "about" refers to the exact number and values close to the exact number. 16. The pharmaceutical composition of claim 1, wherein the corticosteroid is present in the composition in an amount of about 1.5 mg, wherein "about" refers to the exact number and values close to the exact number. 17. The pharmaceutical composition of claim 1, wherein the corticosteroid is present in the composition in an amount of about 6 mg, wherein "about" refers to the exact number and values close to the exact number. 18. The pharmaceutical composition of claim 1, wherein the corticosteroid is fluticasone propionate in the composition ranging from 0.05 mg to about 15 mg, with a drug content of about 0.16% to 5% by weight of the composition, wherein "about" refers to the exact value and values close to the exact value. 19. The pharmaceutical composition of claim 1, wherein the corticosteroid is fluticasone propionate in the composition ranging from 0.75 mg to about 4.5 mg at a drug content of about 0.25% to 1.5% by weight of the composition, wherein "about" refers to the exact value and values close to the exact value. 20. The pharmaceutical composition of claim 1, wherein the corticosteroid is fluticasone propionate in the composition ranging from 0.05 mg to about 18 mg at a drug content of about 0.125% to 5% by weight of the composition, wherein "about" refers to the exact value and values close to the exact value. 21. The pharmaceutical composition of claim 1, wherein the corticosteroid is micronized to have a particle size of no greater than 50 microns. 22. The pharmaceutical composition of claim 21, wherein the corticosteroid has an average particle size of no greater than about 10 microns, wherein "about" refers to the exact number and values close to the exact number. 23. The pharmaceutical composition of claim 1, further comprising an adhesive. 24. The pharmaceutical composition of claim 23, wherein the adhesive is selected from the group consisting of sucrose aluminum sulfate complex, chitosan and its derivatives, polyvinyl pyrrolidone, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl ethylcellulose, sodium carboxymethylcellulose, cross-linked polyacrylic acid, cross-linked polyacrylate, aminoalkyl methacrylate copolymer, carbopol polymer, hydrophilic polysaccharide gum, maltodextrin, pectin, xanthan gum, alginic acid, modified alginic acid, and combinations thereof. 25. The pharmaceutical composition according to claim 5, wherein the disintegrant is selected from the group consisting of crospovidone, sodium starch glycolate, cross-linked carboxymethyl cellulose and low-substituted hydroxypropyl cellulose. 26. The pharmaceutical composition of claim 5, wherein the sugar alcohol or sugar is selected from the group consisting of sucralose, lactose, sucrose, maltose, mannitol, sorbitol, xylitol, maltitol, and mixtures thereof. 27. The pharmaceutical composition of claim 1, further comprising a free-flowing sugar alcohol or sugar selected from the group consisting of spray-dried mannitol, spray-dried lactose, and combinations thereof. 28. The pharmaceutical composition of claim 1, further comprising a lubricant selected from the group consisting of magnesium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate, and mixtures thereof. 29. The pharmaceutical composition of claim 1, further comprising at least one antifungal agent. 30. The pharmaceutical composition of claim 1, further comprising at least one antiviral agent. 31. The pharmaceutical composition of claim 5, wherein the rapidly dispersing microparticles further comprise a dual-functional additive, and wherein the ratio of the sugar alcohol or sugar to the disintegrant to the dual-functional additive is 88:10:2 to 98.5:1:0.5. 32. The pharmaceutical composition of claim 31 , wherein the dual-functional additive is selected from the group consisting of pregelatinized starch and hydroxypropyl cellulose. 33. The pharmaceutical composition of claim 5, wherein the corticosteroid has an average particle size of less than about 10 μm, the rapidly dispersing microparticles have an average particle size of less than about 300 μm, and the sugar alcohol and/or sugar has an average particle size of less than about 30 μm, wherein "about" refers to the exact value and values close to the exact value. 34. The pharmaceutical composition of claim 33, wherein the corticosteroid is fluticasone propionate having a particle size of less than 5 microns, the pharmaceutically acceptable carrier is silicified microcrystalline cellulose, the rapidly dispersing microparticles comprise mannitol and crospovidone, and the composition further comprises a free-flowing sugar alcohol and a lubricant, wherein the sugar alcohol is spray-dried mannitol and the lubricant is sodium stearyl fumarate. 35. Use of a pharmaceutical composition according to any preceding claim in the preparation of a medicament for the treatment of inflammatory conditions of the gastrointestinal tract. 36. The use according to claim 35, wherein the condition comprises inflammation of the esophagus. 37. The use according to claim 36, wherein the condition is eosinophilic esophagitis. 38. The use of claim 37, wherein the condition comprises inflammation of the glottis, epiglottis, tonsils or oropharynx. 39. The use of claim 35, wherein the condition is viral or bacterial pharyngitis, gastroesophageal reflux disease (GERD), non-erosive reflux disease (NERD), or erosive esophagitis. 40. A method for preparing the pharmaceutical composition according to claim 1, comprising the following steps: a) preparing the rapidly dispersible microparticles; b) preparing a premix 1 by mixing the pharmaceutically acceptable carrier, the corticosteroid and a glidant; c) preparing a premix 2 by mixing a filler, the premix 1 of step b), a disintegrant, and a sweetener; d) preparing a final compressible mixture by mixing the rapidly dispersing particles of step a), a lubricant, the premix 2 of step c) and a filler; e) preparing the orally disintegrating tablet by compressing the mixture of step d). 41. The method according to claim 40, comprising the steps of: a) preparing the rapidly dispersible microparticles; b) preparing the premix 1 by mixing silicified microcrystalline cellulose, micronized fluticasone propionate and colloidal silicon dioxide; c) preparing premix 2 by mixing mannitol, the premix 1 of step b), crospovidone and sucralose powder; d) preparing a final compressible mixture by mixing the rapidly dispersing granules of step a), sodium stearyl fumarate, the premix 2 of step c), and sugar alcohol or washed mannitol; e) preparing the orally disintegrating tablet by compressing the mixture of step d). 42. The method according to claim 40, comprising the steps of: a) preparing the rapidly dispersible microparticles; b) preparing a premix 1 by charging a mixer with one-fourth of the total amount of the pharmaceutically acceptable carrier, the corticosteroid, the glidant, and another one-fourth of the total amount of the pharmaceutically acceptable carrier, and mixing the resulting combination; c) preparing premix 2 by charging a free-flowing filler, premix 1, the remaining half of the total amount of the pharmaceutically acceptable carrier, the disintegrant, and the sweetener into a high shear granulator, and mixing the resulting combination; and d) preparing a final compressible mixture by charging half the total amount of the rapidly dispersing granules of step a), the lubricant, the premix 2 of step c), and the remaining half the total amount of the rapidly dispersing granules of step a) into a mixer and mixing the resulting combination to provide a compressible mixture; e) preparing an orally disintegrating tablet by compressing the compressible mixture of step d). 43. The method according to claim 42, comprising the steps of: a) preparing the rapidly dispersible microparticles; b) preparing a premix 1 by charging one-quarter of the total amount of silicified microcrystalline cellulose (SMCC), micronized fluticasone propionate, colloidal silicon dioxide, and another one-quarter of the total amount of SMCC into a blender, and mixing the resulting combination; c) preparing premix 2 by charging the spray-dried mannitol, premix 1, the remaining half of the total amount of SMCC, crospovidone, and sucralose powder into a high shear granulator and mixing the resulting combination; d) preparing a final compressible mixture by charging half the total amount of the rapidly dispersing granules of step a), sodium stearyl fumarate, the premix 2 of step c) and the remaining half the total amount of the rapidly dispersing granules of step a) into a V-blender, and mixing the resulting combination; e) preparing an orally disintegrating tablet by compressing the compressible mixture of step d). 44. The method according to claim 40, comprising the steps of: a) preparing the rapidly dispersing microgranules having an average particle size of not more than about 400 μm by granulating one or more sugar alcohols and/or sugars each having an average particle size of not more than about 30 μm with a disintegrant in the presence of water or an alcohol-water mixture and then drying the granules, wherein "about" refers to the exact value and values close to the exact value; b) preparing the milled premix 1 by mixing the pharmaceutically acceptable carrier, corticosteroid and glidant in a mixer and then grinding the resulting mixture through a comminuted mill equipped with a screen having 30 mesh openings; c) preparing a milled premix 2 by mixing half the total amount of the filler which is free-flowing mannitol, the premix 1 from step b), the disintegrant and the sweetener in a mixer, and then grinding the resulting mixture through a comminuted mill equipped with a screen having 30 mesh openings, and rinsing the mill with the remaining half the total amount of free-flowing mannitol; d) preparing a compressible mixture by mixing the rapidly dispersing granules of step a), the lubricant, the milled premix 2 of step c), and flushed free-flowing mannitol; e) preparing an orally disintegrating tablet by compressing the compressible mixture of step d). 45. The method according to claim 44, comprising the steps of: a) preparing rapidly dispersing microgranules or granules having an average particle size of no greater than about 400 μm by granulating one or more sugar alcohols and/or sugars each having an average particle size of no greater than about 30 μm with crospovidone in the presence of water or an alcohol-water mixture and then drying the granules, wherein "about" refers to the exact value recited and values close to the exact value; b) preparing a milled premix 1 by mixing silicified microcrystalline cellulose, micronized fluticasone propionate and colloidal silicon dioxide in a blender and then grinding through a comminuted mill equipped with a screen having 30 mesh openings; c) preparing a milled premix 2 by mixing half the total amount of free-flowing mannitol, the premix 1 from step b), crospovidone and sucralose powder in a mixer, then grinding through a comminuted mill equipped with a screen with 30 mesh openings and rinsing the mill with the remaining half the total amount of free-flowing mannitol; d) preparing a compressible mixture by mixing the rapidly dispersing granules of step a), sodium stearyl fumarate, the milled premix 2 of step c), and the flushed free-flowing mannitol; e) preparing an orally disintegrating tablet by compressing the compressible mixture of step d). 46. The pharmaceutical composition according to claim 1, wherein the corticosteroid or pharmaceutically acceptable salt, ester or polymorph is adsorbed on a pharmaceutically acceptable carrier by a mixing and milling step, wherein the mixing and milling step is performed in the absence of other pharmaceutically acceptable excipients. 47. The pharmaceutical composition of claim 1 or claim 46, wherein the corticosteroid or pharmaceutically acceptable salt, ester or polymorph is not present in agglomerated form with the pharmaceutically acceptable carrier and other pharmaceutically acceptable excipients.