Application of long-acting fluticasone propionate injection suspension for treating and preventing gastrointestinal inflammation

Abstract

Disclosed herein are methods of treating or preventing inflammatory diseases of the gastrointestinal (GI) tract by topical administration of a pharmaceutical composition containing a delayed release composition formulated for extended release of corticosteroids into GI tissue.

Description

Background Art Technical Field

[0001] The present disclosure relates to the use of corticosteroids in treating and preventing inflammation, and more particularly to methods of treating or preventing benign strictures of the gastrointestinal (GI) tract and eosinophilic esophagitis (EoE) using injectable compositions containing sustained-release compositions formulated for prolonged (or delayed) release of the corticosteroid into esophageal tissue.

[0002] Related technical notes

[0003] Eosinophilic esophagitis (EoE) is a rare, chronic immune-mediated disease characterized by inflammation and the accumulation of large numbers of eosinophils within the esophageal epithelium. Eosinophils are recruited to the esophagus, leading to the release of inflammatory cytokines, which in turn cause inflammation. This inflammation is associated with pain, difficulty swallowing, nausea / vomiting, abdominal / chest pain, and food impaction, and in severe cases may require medical attention.

[0004] like Figure 1 As shown, in human subjects (2), EoE-induced inflammation (12) is typically localized to the portion of the esophagus (4) located between the gastroesophageal (GE) junction (8) (above the stomach (10)) and the upper esophageal sphincter (UES) (6).

[0005] Current EoE treatments include non-pharmacological interventions (such as dietary restrictions), mechanical interventions (such as endoscopic dilation), and pharmacological interventions. Pharmacological interventions primarily include the use of swallowed topical corticosteroids (STCs). The U.S. Food and Drug Administration (FDA) has also approved the use of Dupixent for the treatment of people 12 years of age and older. Dupixent is a monoclonal antibody administered subcutaneously. Jorveza is an orodispersible tablet of budesonide that has been approved in Europe but not yet in the United States. The American Gastroenterological Association and the Joint Allergy-Immunology Practice Task Force (AGA-JTF) recommend the use of STCs such as budesonide or fluticasone. The AGA-JTF recommends the use of topical corticosteroids rather than systemic corticosteroids for long-term EoE therapy to prevent long-term complications.

[0006] There are significant problems with the currently available treatments for EoE. Dupixent is only effective in 60% of patients and is associated with upper respiratory tract infections in 18% of patients. In addition, weekly dosing is recommended, which means that compliance and treatment costs are common barriers. Similarly, Jorveza is limited by relapses of the disease in some patients and the need to take it twice a day, which means that compliance is also an issue here. Jorveza patients also suffer from side effects such as oropharyngeal candidiasis, which has been reported in 64% of patients using higher doses and requires them to stop using Jorveza. Other corticosteroid treatments (such as inhalers or aqueous solutions) have also been used, but they also have many problems, including the need for multiple daily doses, poor local absorption, and relapse of the disease after stopping treatment. The topical corticosteroids recommended by AGA-JTF are effective, but are generally only used for short-term treatment and are prone to relapse after discontinuation.

[0007] There is a need for a treatment for EoE that reduces side effects while improving efficacy and patient compliance.

[0008] Benign strictures of the gastrointestinal (GI) tract are pathological conditions characterized by the formation of localized luminal narrowing within the digestive tract that are non-neoplastic and non-malignant in nature. This stricture is typically due to the development of fibrous scar tissue or collagen deposits within the mucosal and submucosal layers of the GI tract wall, resulting in constriction of the luminal cavity. Benign strictures within the GI tract can manifest in various anatomical regions including, but not limited to, the esophagus, stomach, bile duct, small intestine, or large intestine. Typical medical symptoms of benign strictures depend on the location of the stricture and include difficulty swallowing, odynophagia, regurgitation, heartburn or acid reflux, epigastric pain, nausea, vomiting, bloating, changes in bowel habits, and weight loss. Symptoms can range from mild to severe and life-threatening, and in extreme cases, can result in death.

[0009] The strategies currently used to treat benign gastrointestinal stenosis include endoscopic dilatation, drug therapy and surgical intervention. Endoscopic dilatation involves controlling mechanical dilatation via an endoscope to expand the stenosis segment, thereby enhancing the patency of the lumen. Drug therapy generally involves administering anti-inflammatory drugs, particularly in cases associated with inflammatory disorders such as inflammatory bowel disease (IBD), and can reduce inflammation and improve stenosis-related symptoms. In the case of severe stenosis or complications, surgical resection or stricture plasty may be required to remove the affected portion or restore lumen continuity.

[0010] Despite the existence of different strategies for the treatment of benign strictures, there remains a large unmet need for patients with strictures. Summary of the Invention

[0011] Described herein are methods for treating or preventing inflammatory diseases in a subject by administering a delayed-release composition to gastrointestinal (GI) tract tissue by injection, topical application, ingestion, or a combination thereof. Also disclosed are pharmaceutical compositions capable of extending (or delaying) the release of a corticosteroid into healthy or inflamed tissue of the GI tract.

[0012] One embodiment provides a method for treating eosinophilic esophagitis (EoE) in a subject in need thereof, the method being performed by locally administering a therapeutically effective amount of a pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a delayed-release composition formulated to prolong (or delay) the release of a corticosteroid into esophageal tissue. In some embodiments, the pharmaceutical composition is administered by injection into esophageal tissue. In some embodiments, the pharmaceutical composition is injected into esophageal tissue multiple times such that at least two injections occur at different injection sites in the esophageal tissue.

[0013] Another embodiment relates to a method for treating or preventing an inflammatory disease in the GI tract of a subject in need thereof, the method being carried out by locally administering a therapeutically effective amount of a pharmaceutical composition in the subject, wherein the pharmaceutical composition comprises a delayed-release composition formulated for prolonged release of a corticosteroid into GI tract tissue. In some embodiments, the tissue comprises esophageal tissue, gastric tissue, bile duct tissue, small intestinal tissue, large intestinal tissue, or any combination thereof. In some embodiments, administration comprises injecting the pharmaceutical composition into GI tract tissue (such as a benign stricture). BRIEF DESCRIPTION OF THE DRAWINGS

[0014] The following drawings illustrate some embodiments, wherein like reference numerals represent like parts. Embodiments are illustrated by way of example and not limitation in all of the drawings, wherein:

[0015] Figure 1 Shown are human subjects suffering from eosinophilic esophagitis (EoE);

[0016] Figure 2 Schematic representation of core / shell morphology of microparticles;

[0017] Figure 3 The esophagus of a patient is illustrated with a circumferential ring (ring 1) located a distance (d1) above the gastroesophageal (GE) junction. Additional circumferential rings (ring 2, ring 3, and ring 4) located at increasing distances (d2, d3, and d4) above the GE junction are also illustrated.

[0018] Figure 4 An injection site is illustrated positioned along a first ring of the esophagus, the first ring being defined by the circumference of the esophagus at a distance d1 above the gastroesophageal (GE) junction;

[0019] Figure 5 shows a plan view of the esophagus of a subject, wherein multiple injections are performed at injection sites located along a first ring of the esophagus, the first ring being defined by the circumference of the esophagus located a distance d1 above the gastroesophageal (GE) junction;

[0020] Figure 6 illustrates a plan view of the esophagus of a subject wherein multiple injections are performed at injection sites located at different rings along the esophagus such that injections in adjacent rings are relatively offset with respect to each other;

[0021] Figure 7 illustrates a plan view of the esophagus of a subject with multiple injections performed at injection sites positioned at different rings along the esophagus such that injections in adjacent rings are not relatively offset with respect to one another;

[0022] Figure 8 illustrates a plan view of the esophagus of a subject in which multiple injections occur as initial dose injections and subsequent dose injections;

[0023] Figure 9 illustrates a plan view of the esophagus of a subject, wherein multiple injections occur in a spiral pattern relative to the longitudinal axis of the esophagus;

[0024] Figure 10 The pathology of eosinophilic esophagitis (EoE) is illustrated, including the development of a localized stenosis (narrowing) of the esophagus. DETAILED DESCRIPTION

[0025] Described herein are methods for treating or preventing gastrointestinal inflammatory diseases (e.g., benign strictures and eosinophilic esophagitis) by administering a delayed-release composition to the gastrointestinal tissue of a human subject. The pharmaceutical composition containing the delayed-release composition can be administered by injection, topical application, ingestion, or a combination thereof. The following describes a mode of injecting the pharmaceutical composition into esophageal tissue, wherein multiple injections can be performed to administer the delayed-release composition to a controlled area of ​​the esophagus, which may or may not include an area of ​​inflammation.

[0026] definition

[0027] As used herein, the articles "a" and "an" refer to one or to more than one (ie, to at least one) of the grammatical object of the article. For example, "an element" means one element or more than one element.

[0028] As used herein, the term "about" means that the stated parameter may include a deviation of ±10%.

[0029] As used herein, unless expressly stated otherwise, the word "or" means "either / or", but is not limited to "either / or". Conversely, "or" may also mean "and / or".

[0030] As used herein, the terms "active pharmaceutical ingredient," "therapeutic agent," or "drug" mean one or more corticosteroids.

[0031] As used herein, the term "benign stricture" means a narrowing of a portion of the gastrointestinal tract, such as a narrowing of the esophagus, that is not caused by cancer.

[0032] As used herein, the term "biodegradable" means capable of being partially or completely dissolved or decomposed in living tissue (particularly human or other mammalian tissue). Biodegradable compounds can be degraded by any mechanism, including but not limited to hydrolysis, catalysis, and enzymatic action.

[0033] "Blister" refers to a sac-like structure (similar to a blister) with a thin wall that can be filled with fluid.

[0034] "Body cavity" refers to a space or cavity in the body of a vertebrate (including a human) that can be entered by injection. Typically, a body cavity is at least semi-enclosed or completely enclosed by hard tissue or soft tissue (e.g., bone, membrane, ligament structure) that defines the space. Soft tissue is usually present and the soft tissue may have varying degrees of vascularization. More specifically, a body cavity can be a naturally occurring anatomical space, such as esophageal tissue. Additionally, a body cavity can also be a surgically created space (e.g., a pocket for inserting an implant device, soft tissue implant (such as a breast implant), etc.) or any space near an implant that can be entered by injection.

[0035] "Coating solution" refers to a solution of preformed polymer (eg, a commercially available polymer) and is suitable for coating drug cores according to methods known in the art (eg, fluidized bed coating).

[0036] As used herein, the terms "crystalline drug core," "core particle," and "drug core" are used interchangeably to refer to preformed particles comprising a single crystal or multiple crystals of a drug. The drug core is encapsulated by a polymer shell. The core particle may further comprise other compounds, including but not limited to binders, buffers, antioxidants, excipients, and additional active pharmaceutical ingredients. The core particle may be a single large crystal, multiple crystals, or a mixture of the above. In a preferred embodiment, the drug core is substantially pure drug (i.e., at least 90%, or at least 95%, or at least 98% of the entire weight of the drug core is drug). In a preferred embodiment, the drug core is 100% crystalline drug.

[0037] "EC50" is the concentration of a therapeutic agent that provides 50% of the maximum effect, eg, in reducing inflammation or pain.

[0038] The term "esophageal tissue" refers to tissue or body cavity associated with the esophagus of a subject or patient.

[0039] "Local concentration" refers to the concentration of the corticosteroid drug within a body cavity (as defined herein), including the concentration in the tissues or fluids of the body cavity.

[0040] As used herein, the term "microparticles" means particles having an average size of less than 1 mm. Microparticles can be of any solid geometric shape, including but not limited to spheres, needles, ellipsoids, cylinders, polyhedrons, and irregular shapes.

[0041] Microparticles are coated crystalline drug particles. As used herein, microparticles (14) have a "core / shell" morphology. Figure 2 Schematically shown, wherein the drug core (16) is encapsulated by a polymer shell (18), i.e., polymer shell (18). In some embodiments, the polymer shell is a homogeneous polymer coating formed by, for example, a fluidized bed process. See, for example, WO 2014 / 153541. In other embodiments, the polymer shell (18) may include one or more discrete thin coatings (two coatings 20 and 22 are shown) of the same or different polymers formed by, for example, a dipping process. See, for example, WO 2014 / 153541. Importantly, the polymer shell (18) is formed by a polymer coating that is immiscible with the drug core, so that the interface (24) between the drug core and the polymer shell is clear, with minimal drug or polymer (e.g., less than 5%, or less than 1%, or less than 0.5% of the total weight of the drug or polymer should be mixed). Because the drug core contains a highly hydrophobic corticosteroid drug, the polymer shell comprises at least one hydrophilic polymer. In some embodiments, the polymer shell becomes hydrophobic after curing. Although the polymer shell may eventually degrade, it should maintain its structural integrity throughout the sustained-release period.

[0042] A "minimum therapeutically effective amount" is the smallest amount of a therapeutic agent that is capable of producing a therapeutic effect (eg, pain relief or anti-inflammation).

[0043] As used herein, a "patient" or "subject" treated by the methods according to the various embodiments may refer to a human or a non-human animal, such as a primate, a mammal, and a vertebrate.

[0044] "Plasma concentration" refers to the concentration of the corticosteroid drug in plasma or serum. The injectable microparticles are capable of high local release over an extended period of time while maintaining low plasma concentrations, e.g., low enough to minimize HPA axis suppression during the sustained release period.

[0045] Unless expressly specified otherwise, the term "plurality" means "two or more." For example, "multiple times" may simply refer to multiple injections into esophageal tissue.

[0046] As used in this disclosure, the "annulus" of the esophagus is the annular region of the esophagus defined by the circumference of the esophagus a distance above the gastroesophageal (GE) junction.

[0047] The term "subject at high risk of developing benign strictures" refers to subjects with chronic inflammatory processes (such as inflammatory bowel disease), subjects with gastroesophageal lesions (such as gastroesophageal disease or eosinophilic esophagitis), subjects who have previously been treated for benign gastrointestinal strictures, subjects with peptic ulcer disease, subjects with radiation damage, subjects with chemical ingestion, subjects with postoperative complications, subjects with infectious diseases, etc.

[0048] The term "submucosal" refers to the layer of tissue below the mucosa (eg, the lining of certain organs and body cavities that produces mucus).

[0049] When applied to therapeutic agents or drugs (e.g., corticosteroids), the terms "sustained release," "delayed release," or "extended release" are used interchangeably. Sustained release refers to the continued release of the therapeutic agent over an extended period of time after administration of a single dose, thereby providing a prolonged therapeutic effect over the entire release period.

[0050] "Sustained release" is different from bolus administration, in which the total amount of active agent / substance is bioavailable at one time. However, "slow release" may include an initial faster release followed by a slower release over a longer, extended period of time. As discussed in further detail below, the construction of the microparticles is such that the initial rapid release (e.g., burst release) is minimized and the delayed release phase is extended to achieve a nearly constant release profile that is independent of drug concentration. "Sustained release" should provide at least a minimum therapeutically effective amount (as defined herein) of the corticosteroid over the release phase. It should be understood that the minimum therapeutically effective amount of the corticosteroid depends on the severity of the inflammation and / or pain to be addressed.

[0051] Within the scope of the present disclosure, due to the unique structure of the microparticles with core / shell morphology, sustained release of the corticosteroid is achieved. Specifically, the crystalline drug core of the corticosteroid is encapsulated by a polymer shell, which is composed of one or more polymer coatings, each of which is permeable to the corticosteroid. In a preferred embodiment, all layers comprise the same polymer. In other embodiments, two to four layers of polymer are coated on the corticosteroid, and each layer gradually slows down the release of the active ingredient and provides the desired sustained release together. In addition, by adjusting the delivery platform to adapt to the aqueous or sinking environment of the body cavity (e.g., esophageal tissue), sustained release of the corticosteroid is achieved.

[0052] "Sustained-release period" or "extended-release period" refers to the complete release period during which the local concentration of the corticosteroid drug is maintained at or above the minimum therapeutically effective amount. Of course, the desired sustained-release period may vary depending on the disease or condition being treated, the nature of the corticosteroid, and the condition of the particular patient being treated. Therefore, the desired sustained-release period can be determined by the attending physician.

[0053] The phrase "therapeutically effective amount" refers to an amount of a therapeutic agent that produces a degree of inflammation or pain relief in a patient's body cavity (e.g., esophageal wall) when delivered to a body cavity (e.g., submucosal) in the form of coated microparticles as defined herein (at a reasonable benefit / risk ratio applicable to any medical treatment). The effective amount of a therapeutic agent may vary depending on factors such as the type and severity of the inflammation being treated, its progression, the degree of pain experienced by the patient, the specific microparticles administered, the active agent, and / or the size / age / sex of the subject. One of ordinary skill in the art can empirically determine the effective amount of a particular therapeutic agent according to methods known in the art. Unless otherwise indicated, a "therapeutically effective amount" refers to the amount of a therapeutic agent positioned within a body cavity.

[0054] The terms "treating" and "treating" are art-recognized and include treatment of a disease or condition by ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected.

[0055] "Unit dosage form" refers to physically discrete units (e.g., loaded syringes) suitable as unitary dosages for human subjects, each unit containing a predetermined quantity of therapeutic agent and a pharmaceutically acceptable vehicle. The quantity of therapeutic agent is calculated to produce the desired therapeutic effect over the desired period of time.

[0056] "Vehicle" refers to a non-toxic carrier, adjuvant, or solvent in which the microparticles are suspended. The vehicle does not alter or destroy the pharmacological activity of the therapeutic agent formulated with it. Pharmaceutically acceptable carriers or vehicles that can be used in the composition include, but are not limited to, water, saline, hyaluronic acid, carboxymethyl cellulose (CMC), and the like. As used herein, the term "biocompatibility" means the characteristic of not causing toxicity, injury, or immune response when in contact with living tissue (particularly human or other mammalian tissue).

[0057] As used herein, the term "substantially insoluble" means having a solubility of less than 1 part by weight of solute per 1000 parts by weight of solvent or vehicle.

[0058] As used herein, the term "hydrophobic" means having a lower affinity for aqueous solvents than for organic solvents.

[0059] As used herein, the term "hydrophilic" means having a lower affinity for organic solvents than for aqueous solvents.

[0060] As used herein, the recitation of a numerical range for a variable is intended to convey that the present disclosure can be implemented with the variable equal to any value within the range. Thus, for a variable that is discrete in nature, the variable can be equal to any integer value within the numerical range, including the endpoints of the range. Similarly, for a variable that is continuous in nature, the variable can be equal to any real value within the numerical range, including the endpoints of the range. For example, but not limited to, if a variable is discrete in nature, it is described as having a value between 0 and 2, and the variable can take the values ​​0, 1, or 2; and if the variable is continuous in nature, the variable can take the values ​​0.0, 0.1, 0.01, 0.001, or any other real value ≥ 0 and ≤ 2.

[0061] Methods for treating or preventing gastrointestinal inflammation

[0062] The method of the present disclosure includes a method for treating or preventing an inflammatory disease in the gastrointestinal (GI) tract of a subject in need thereof, the method being carried out by locally administering a therapeutically effective amount of a pharmaceutical composition to the subject, wherein the pharmaceutical composition includes a delayed-release composition formulated for prolonged release of a corticosteroid into gastrointestinal tissue. In some embodiments, the tissue includes esophageal tissue, gastric tissue, bile duct tissue, small intestinal tissue, large intestinal tissue, or any combination thereof. In some embodiments, the tissue includes esophageal tissue. In some embodiments, administering includes injecting the pharmaceutical composition into the tissue. For example, administering may involve injecting the pharmaceutical composition into the esophageal tissue. In some embodiments, administering includes injecting the pharmaceutical composition into the tissue at least once submucosally.

[0063] In some embodiments, administration comprises injecting at least one initial dose of the pharmaceutical composition into the tissue. Administration can comprise injecting at least two initial doses of the pharmaceutical composition into the tissue. In some embodiments, administration comprises injecting the pharmaceutical composition into the tissue multiple times, such that at least two injections occur at different injection sites in the tissue. For example, in some embodiments, administration comprises injecting the pharmaceutical composition at least once into an area of ​​inflammation in the gastrointestinal tract, injecting the pharmaceutical composition at least once into an injection site that is not located in the area of ​​inflammation in the gastrointestinal tract, or a combination thereof.

[0064] In some embodiments, the method for treating or preventing inflammation further comprises administering a therapeutically effective amount of the pharmaceutical composition topically to gastrointestinal tissue by subsequent injection. For example, in some embodiments, the method further comprises administering a therapeutically effective amount of the pharmaceutical composition topically to esophageal tissue by subsequent injection.

[0065] Methods for treating inflammatory diseases of the GI tract include methods for treating benign GI stenosis, wherein administering comprises injecting the pharmaceutical composition at least once into at least one benign localized stenosis in the GI tract of a subject. In some embodiments, administering comprises injecting the pharmaceutical composition at least once into GI tissue (e.g., a localized benign stenosis) to form at least one blister containing the delayed-release composition.

[0066] In some embodiments, administration comprises one or more injections of the pharmaceutical composition into a tissue such that each injection independently contains from about 0.1 mg to about 20 mg, or from about 0.5 mg to about 10 mg, or from about 1 mg to about 8 mg, or from about 1 mg to about 6 mg, or from about 2 mg to about 12 mg, or from about 3 mg to about 8 mg, or from about 5 mg to about 20 mg, or from about 5 mg to about 15 mg, or from about 6 mg to about 14 mg, or from about 7 mg to about 18 mg, or from about 7 mg to about 16 mg, or from about 8 mg to about 20 mg, or from about 8 mg to about 16 mg, or from about 9 mg to about 18 mg, or from about 9 mg to about 15 mg, or from about 10 mg to about 20 mg, or from about 10 mg to about 18 mg, or from about 10 mg to about 16 mg of the corticosteroid.

[0067] In some embodiments, the method for treating or preventing inflammation (e.g., localized benign stricture) may include the additional step of administering a topical agent to the gastrointestinal tissue. For example, in some embodiments, the method further comprises administering a topical agent to the esophageal tissue. The topical agent may include an additional corticosteroid.

[0068] In some embodiments, the method for treating or preventing inflammation (e.g., localized stenosis) is performed on a subject suffering from a chronic inflammatory disease. For example, in some embodiments, the subject suffers from inflammatory bowel disease, gastroesophageal disease, peptic ulcer disease, radiation injury, chemical ingestion injury, postoperative complications, infection, or any combination thereof. As explained below, in some embodiments, the subject may suffer from eosinophilic esophagitis (EoE).

[0069] In some embodiments, the methods of the present disclosure are directed to preventing or reducing the development of benign GI stenosis in a subject at high risk of developing such stenosis. For example, in some embodiments, the subject has previously been treated for at least one benign GI stenosis but currently does not have any benign GI stenosis.

[0070] In some embodiments, the methods of the present disclosure involve treating at least one benign GI stenosis in a subject by injecting a pharmaceutical composition into the at least one benign GI stenosis and optionally into tissue surrounding the at least one benign GI stenosis. In some embodiments, the subject has been previously treated with dilation therapy.

[0071] Some embodiments relate to the use of an effective amount of a pharmaceutical composition of the present disclosure in the preparation of a medicament for treating or preventing an inflammatory disease of the gastrointestinal tract in a subject, such as benign GI stenosis, wherein the therapeutically effective amount of the pharmaceutical composition is administered topically in the subject, and wherein the pharmaceutical composition comprises a delayed-release composition formulated for prolonged release of a corticosteroid into the gastrointestinal tissue. Some embodiments relate to a pharmaceutical composition of the present disclosure for treating or preventing an inflammatory disease of the gastrointestinal tract in a subject, such as benign GI stenosis, wherein the therapeutically effective amount of the pharmaceutical composition is administered topically in the subject, and wherein the pharmaceutical composition comprises a delayed-release composition formulated for prolonged release of a corticosteroid into the gastrointestinal tissue.

[0072] The methods of the present disclosure also include a method for treating eosinophilic esophagitis in a subject in need thereof by topically administering to the subject a therapeutically effective amount of a pharmaceutical composition, wherein the pharmaceutical composition comprises a delayed-release composition formulated for extended release of a corticosteroid into esophageal tissue.

[0073] In some embodiments, administration includes injecting the pharmaceutical composition into the esophageal tissue of the subject being treated. Injection can be performed subcutaneously or intradermally from the inside of the esophagus or the outside (e.g., outside) of the esophagus. For example, in some embodiments, the pharmaceutical composition is injected submucosally into the esophageal tissue at least once to administer the delayed-release composition. In other embodiments, the pharmaceutical composition can be topically applied to the subject's esophagus, or can be topically and administered by injection.

[0074] Injecting the pharmaceutical composition into the esophageal tissue may include at least one initial dose injection (for initiating treatment) and may also include at least one secondary (or subsequent) dose injection.

[0075] The dose of corticosteroid contained in each injection can be varied to accommodate different subjects, tissues, and inflammation levels. In some embodiments, administration comprises one or more injections of the pharmaceutical composition into esophageal tissue such that each injection independently contains from about 0.1 mg to about 20 mg of corticosteroid. For example, the dose of corticosteroid contained in each injection can independently range from about 0.1 mg to about 10 mg, or from about 0.5 mg to about 9 mg, or from about 1 mg to about 8 mg, or from about 1 mg to about 6 mg, or from about 2 mg to about 12 mg, or from about 3 mg to about 8 mg, or from about 5 mg to about 20 mg, or from about 5 mg to about 15 mg, or from about 6 mg to about 14 mg, or from about 7 mg to about 18 mg, or from about 7 mg to about 16 mg, or from about 8 mg to about 20 mg, or from about 8 mg to about 16 mg, or from about 9 mg to about 18 mg, or from about 9 mg to about 15 mg, or from about 10 mg to about 20 mg, or from about 10 mg to about 18 mg, or from about 10 mg to about 16 mg.

[0076] In some embodiments, the method further comprises administering a topical agent to the esophageal tissue. For example, the method can include an additional step or a simultaneous step of administering a topical agent to the esophageal tissue, wherein the topical agent comprises an additional corticosteroid.

[0077] Some embodiments relate to the use of an effective amount of a pharmaceutical composition of the present disclosure in the preparation of a medicament for treating eosinophilic esophagitis, wherein the therapeutically effective amount of the pharmaceutical composition is administered topically in a subject, and wherein the pharmaceutical composition comprises a delayed-release composition formulated for prolonged release of the corticosteroid into esophageal tissue. Some embodiments relate to a pharmaceutical composition of the present disclosure for treating eosinophilic esophagitis, wherein the therapeutically effective amount of the pharmaceutical composition is administered topically in a subject, and wherein the pharmaceutical composition comprises a delayed-release composition formulated for prolonged release of the corticosteroid into esophageal tissue.

[0078] Esophageal injection

[0079] As noted above, the methods of the present disclosure may involve treating or preventing inflammatory diseases in the GI tract (such as benign GI stricture or eosinophilic esophagitis) by injecting a therapeutically effective amount of a delayed-release corticosteroid into esophageal tissue.

[0080] In some embodiments, administration includes multiple injections of the pharmaceutical composition into the esophageal tissue such that at least two injections occur at different injection sites in the esophageal tissue. For example, administration may involve injecting at least two starting doses of the pharmaceutical composition into the esophageal tissue at different injection sites. Other embodiments may include multiple injections of the pharmaceutical composition into the same injection site (e.g., at different time periods). For example, in some embodiments, the pharmaceutical composition may be injected into the same area of ​​the esophagus by injecting from the inside of the esophagus and the outside of the esophagus (i.e., outside).

[0081] In some embodiments, the injection site is located on the esophageal ring. In the context of this disclosure, the "ring" of the esophagus is the annular region of the esophagus defined by the circumference of the esophagus located a distance above the gastroesophageal (GE) junction. Generally speaking, the injection points along the esophageal ring are all located approximately the same distance above the GE junction. Injection into the esophageal ring may occur at the same location along the circumference of the ring, or may occur at different locations along the circumference of the ring.

[0082] The methods of the present disclosure can be performed such that administration comprises multiple injections of the pharmaceutical composition into esophageal tissue, wherein at least two injections occur at injection sites located along a first esophageal ring defined by the circumference of the esophagus at a distance d1 above the gastroesophageal (GE) junction of the subject.

[0083] Figure 3 One such embodiment is illustrated wherein four rings (a first ring (28), a second ring (30), a third ring (32), and a fourth ring (34)) of the esophagus (4) are defined based on their respective distances (d1 (36), d2 (38), d3 (40), and d4 (42)) above the GE junction (8). The distance dΔ (44) between adjacent rings may be the same or different for a particular injection pattern.

[0084] In some embodiments, distance d1 (36) is at least 2 cm higher than the GE junction (8), while in other embodiments, distance d1 (36) is at least 3 cm, or at least 4 cm, or at least 5 cm, or at least 6 cm, or at least 7 cm, or at least 8 cm, or at least 10 cm higher than the GE junction (8). In some embodiments, distance d2 (38) is at least 1 cm higher than distance d1 (36), while in other embodiments, distance d2 (38) is at least 2 cm, or at least 3 cm, or at least 4 cm, or at least 5 cm, or at least 6 cm, or at least 7 cm, or at least 8 cm, or at least 9 cm, or at least 10 cm higher than distance d1 (36).

[0085] Figure 4An embodiment is illustrated in which a single injection of a pharmaceutical composition is administered into esophageal tissue at a first injection site (44) located on a first ring (28) of the esophagus (4), the first ring being defined by the circumference of the esophagus (4) at a distance d1 (36) above the GE junction (8). In this illustration, the injection of the pharmaceutical composition optionally forms a blister (46) containing the delayed-release composition. In other embodiments, the injection of the pharmaceutical composition does not form a blister. In some embodiments, the injection sites (44) located along the first ring (28) of the esophagus (4) are equidistant from one another along the circumference of the first ring (28). In other embodiments, the injection sites (44) located along the first ring (28) of the esophagus (4) are not equidistant from one another along the circumference of the first ring (44).

[0086] In some embodiments, the injection location on the esophageal ring is not exactly the same as the distance d above the GE junction. The injection can be distributed above or below the ring distance d. For example, Figure 4 As illustrated, the injection (45) is located above the second ring (30), and in this embodiment, the injection (45) does not form a blister. The site of injection into a particular esophageal ring may vary by up to 1 cm above or below the particular ring. In some embodiments, the injection site is located from about 0.1 cm to about 1.0 cm, or from about 0.2 cm to about 0.8 cm, or from about 0.3 cm to about 0.7 cm, or from about 0.4 cm to about 0.6 cm, or from about 0.1 cm to about 0.5 cm, or from about 0.3 cm to about 0.7 cm, or from about 0.5 cm to about 0.9 cm above or below the particular ring. In some embodiments, multiple injections can be made in the same esophageal ring in such a way that the injections are located at different distances relative to the distance d of the ring above the GE junction.

[0087] Figure 5 A plan view (5) of an esophagus (4) is shown in accordance with an embodiment wherein four injections are performed at different injection sites (44-1, 44-2, 44-3, and 44-4) along a first ring (28) of the esophagus (4), the first ring being defined by a circumference at a distance d1 (36), wherein the injection sites (44-1, 44-2, 44-3, and 44-4) are equidistant from one another along the circumference of the first ring (28). Thus, the different injection sites (44-1, 44-2, 44-3, and 44-4) are located in different quadrants (48-1, 48-2, 48-3, and 48-4) of the esophagus (4), as shown. Figure 5 In some embodiments, blisters (46-1, 46-2, 46-3, and 46-4) may be formed at one or more injection sites (44-1, 44-2, 44-3, and 44-4), as also shown in FIG. Figure 5 exemplified.

[0088] In some embodiments, at least three injections occur at injection sites located along the ring. In other embodiments, the number of injections at different injection sites along the ring can range from two to ten. Such multiple injection points can be located equidistant from one another or unequally spaced from one another.

[0089] like Figure 6 A- Figure 6 As illustrated in plan view in FIG. 2B , the pharmaceutical composition can be injected into a plurality of loops in the esophagus of a subject.

[0090] Figure 6 An embodiment is illustrated in which injections are made into four rings (28, 30, 32, and 34) of the esophagus such that injections in adjacent rings are offset relative to one another. Thus, the injection sites (50-1 and 50-2) in the first ring (28) are located in the first and third quadrants (48-1 and 48-3) of the esophagus, while the injection sites (52-1 and 52-2) in the second ring (30) are located in the second and fourth quadrants (48-2 and 48-4) of the esophagus.

[0091] Figure 7 An embodiment is illustrated in which injections are made into four rings (28, 30, 32, and 34) of the esophagus such that injections in adjacent rings are not offset relative to one another. Thus, all four injections in each of the first, second, third, and fourth rings (28, 30, 32, and 34) are located within the first, second, third, or fourth quadrant (48-1, 48-2, 48-3, and 48-4) of the esophagus.

[0092] The methods of the present disclosure may comprise administering to the esophageal tissue one or more initial dose injections and one or more subsequent injections, each injection comprising a therapeutically effective amount of the pharmaceutical composition.

[0093] Figure 8 An embodiment is illustrated in which the initial dose injection (marked as ●) and subsequent dose injections (marked as o) are injected into four rings (28, 30, 32, and 34) of the esophagus such that the injections in adjacent rings (injections of each initial dose and subsequent dose) are offset relative to each other. Thus, the injection sites (54-1 and 54-2) of the initial dose (●) in the first ring (28) are located in the first and third quadrants (48-1 and 48-3) of the esophagus, the injection sites (56-1 and 56-2) of the initial dose (●) in the second ring (30) are located in the second and fourth quadrants (48-2 and 48-2) of the esophagus, and the subsequent doses (o) (55-1, 55-2, 57-1, and 57-2) in adjacent rings are similarly offset, as shown in FIG. Figure 6 C. In other embodiments, the initial dose injection and / or subsequent dose injections may or may not be offset relative to each other.

[0094] Figure 9 An embodiment is illustrated wherein the pattern of injection sites (58-1, 58-2, 58-3, and 58-4) within the esophagus is in a spiral pattern relative to the longitudinal axis of the esophagus.

[0095] The pharmaceutical composition can be injected multiple times into multiple rings in the esophagus of the subject. For example, injections can occur at injection sites located along at least three rings, or at least four rings, or at least five rings, or at least six rings, or at least seven rings, or at least eight rings of the esophagus, the rings being defined by corresponding circumferences of the esophagus at corresponding distances of the rings above the subject's gastroesophageal junction.

[0096] In some embodiments, the pharmaceutical composition is injected at least once into the area of ​​esophagitis, injected at least once into an injection site that is not located in the area of ​​esophagitis, or a combination thereof. For example, in some embodiments, the pharmaceutical composition is injected at least once into the area of ​​esophagitis, injected at least once into an area adjacent to the area of ​​esophagitis, or a combination thereof. For injections into injection sites located in the area of ​​esophagitis, the pharmaceutical composition may be injected at least once into a localized benign stricture in the subject's esophagus. In some embodiments, the pharmaceutical composition is injected at least once into a localized benign stricture, injected at least once into an area adjacent to a localized benign stricture, or a combination thereof.

[0097] Figure 10 A localized stricture (60) in the esophagus (4) of a human subject suffering from EoE is illustrated. Unlike the normal portion (62) of the esophagus (4), inflammation caused by EoE can cause a ring (64) and stricture (66) to form on the inside of the esophagus. In extreme cases, this inflammation can lead to a localized benign stricture (60) that can restrict or block the flow of food and liquids from the throat to the stomach (10). In some embodiments, a pharmaceutical composition is injected at least once into the localized benign stricture (60).

[0098] corticosteroids

[0099] As described above, the pharmaceutical composition of the present disclosure comprises a delayed-release composition, which is formulated for prolonged release of a corticosteroid into esophageal tissue. In some embodiments, the corticosteroid comprises a glucocorticoid agonist. For example, the corticosteroid may comprise at least one selected from the group consisting of deoxycorticosterone, hydrocortisone, cortisone, methylprednisolone, prednisone, prednisolone, triamcinolone, dexamethasone, betamethasone, beclomethasone, 17,21-dipropionate beclomethasone, budesonide, flunisolide, fludrocortisone, mometasone, dapoxetine ... metasone, fluticasone, alclometasone, clocortolone, flurandrenolide, fluocinonide, hydrocortisone acetate, fluorometholone, fluocinolone acetonide, diflucortolone valerate, paramethasone acetate, halcinonide, hydrocortisone phosphate, clobetasone butyrate, amcinonide, prednisolone succinate, and pharmaceutically acceptable salts and / or esters thereof.

[0100] In some embodiments, the corticosteroid comprises fluticasone or a pharmaceutically acceptable salt or ester thereof. For example, the corticosteroid can comprise fluticasone, fluticasone furoate, fluticasone propionate, or a combination thereof. In some embodiments, the corticosteroid comprises fluticasone propionate, which is described below.

[0101]

[0102] The corticosteroids of the present disclosure may include crystalline corticosteroids.Crystalline corticosteroids are described in US 9,987,233, the entire contents of which are incorporated herein by reference.

[0103] particle

[0104] In some embodiments, the delayed-release composition comprises a corticosteroid and a hydrophilic polymer, which can be in the form of microparticles having a core / shell morphology. The core / shell morphology microparticles described herein are configured to exhibit a sustained-release profile uniquely suited for highly localized, delayed delivery of corticosteroid drugs within body cavities (such as esophageal tissue).

[0105] In some embodiments, the delayed-release composition has a core-shell structure. For example, the delayed-release composition may comprise microparticles comprising (1) a crystalline drug core comprising one or more corticosteroid crystals, and (2) a polymer shell encapsulating the crystalline drug core, wherein the polymer shell is in contact with but not miscible with the crystalline drug core. The proportion of the crystalline drug core in the microparticles is greater than 20%, or greater than 30%, or greater than 40%, or greater than 50%, or greater than 60%, or greater than 70%, or greater than 80%, or greater than 90% by weight relative to the total weight of the microparticles.

[0106] The microparticles of the present disclosure may have an average diameter in the range of 50 μm to 800 μm and a standard deviation of less than 50% of the average diameter. In some embodiments, more than 90% of the microparticles have an average diameter in the range of 50 μm to 800 μm, 50 μm to 700 μm, or 50 μm to 600 μm, or 50 μm to 500 μm, or 50 μm to 400 μm, or 50 μm to 300 μm, or 50 μm to 200 μm, or 50 μm to 100 μm.

[0107] In some embodiments, the crystalline drug core comprises about 100% corticosteroid. The crystalline core is substantially pure drug because it is prepared from recrystallized drug in the form of a single large crystal or an aggregate of smaller crystals. Thus, "substantially pure" means that at least about 90%, or at least about 95%, or at least about 98%, or at least about 100% of the total weight of the drug core is drug in crystalline form.

[0108] The polymer shell comprises one or more concentrically or continuously applied polymer coatings of the same or different polymers. Standard biocompatible and biodegradable polymer coatings known in the art can be used, as long as they meet the above-mentioned requirements for maintaining permeability and / or structural integrity during the desired sustained release period. Although the sustained release period is extended within the scope of the present disclosure via higher drug loads and the beneficial and unexpected interaction of body cavities (e.g., esophageal tissue) and the dissolution-based delivery system described herein, there are other factors that play a role in supporting the superior efficacy of the methods herein, including but not limited to:

[0109] Solubility of corticosteroids

[0110] The rate of clearance of corticosteroids from the esophagus

[0111] The size of the core particle and / or the amount of corticosteroid initially present in the core particle

[0112] The presence of other compounds in the core particle that affect the release rate of the corticosteroid

[0113] Permeability of polymer coatings to corticosteroids

[0114] • Degradation rate of the polymer coating and other factors.

[0115] As is known in the art, the permeability and biodegradability of a polymer coating can be influenced by the choice of polymer material (e.g., the degree of hydrophobicity or hydrophilicity relative to the corticosteroid; the degree of instability of the bond under physiological conditions), the degree of cross-linking, and the thickness. For copolymers, the ratio of the different monomers can also be varied to affect permeability and biodegradability.

[0116] In some embodiments, the polymer shell comprises a hydrophilic polymer. For example, the polymer shell may comprise one or more biodegradable polymers selected from the group consisting of polyvinyl alcohol (PVA), ethylene vinyl acetate (EVA), polyparaxylene polymers, polylactic acid (PLA), polyglycolic acid (PGA), polylactic-co-glycolic acid (PLGA), poly ε-caprolactone (PCL), polyvalerolactone (PVL), poly ε-decalactone (PDL), poly 1,4-dioxane-2,3-dione, poly 1,3-dioxane-2-one, polydioxanone (PDS), polyhydroxybutyric acid (PHB), polyhydroxyvaleric acid (PHV), poly β-malic acid (PMLA), and combinations thereof. In some embodiments, the polymer shell comprises polyvinyl alcohol (PVA).

[0117] In order to adjust permeability and release rate, the polymer shell can be covalently or ionically crosslinked. For example, monomers comprising chemical groups capable of forming additional bonds between monomers can be selected, or in addition to the monomers, a separate crosslinking agent can be included in the polymer formation solution. In some embodiments, the crosslinking groups are heat-activated, while in other embodiments, they are photoactivated, including photoactivation by visible light or ultraviolet radiation. Crosslinking groups include, but are not limited to, unsaturated groups, such as vinyl, allyl, cinnamate, acrylate, diacrylate, oligoacrylate, methacrylate, dimethacrylate, and oligomeric methacrylate groups.

[0118] Since many corticosteroids are hydrophobic, and because it is desirable to reduce or avoid dissolution of the drug core into the polymer shell to maintain a clear interface between the core and the shell, the polymer shell may comprise a hydrophilic polymer, particularly in the coating closest to the crystalline core. Examples of hydrophilic polymer coatings include, but are not limited to, polyvinyl alcohol (PVA), polyethylene glycol (PEG), polyethylene oxide, polyvinyl pyrrolidone, polyethyloxazoline, or a polysaccharide or carbohydrate such as an alkylcellulose, hydroxyalkylcellulose, hyaluronic acid, dextran, heparin sulfate, chondroitin sulfate, heparin or alginate, or a protein such as gelatin, collagen, albumin, ovalbumin or polyamino acids.

[0119] Additional examples of suitable polymers can be prepared from monomers selected from the group consisting of sugar phosphates, alkyl celluloses, hydroxyalkyl celluloses, lactic acid, glycolic acid, β-propiolactone, β-butyrolactone, γ-butyrolactone, pivalolactone, α-hydroxybutyric acid, α-hydroxyethylbutyric acid, α-hydroxyisovaleric acid, α-hydroxy-β-methylvaleric acid, α-hydroxyhexanoic acid, α-hydroxyisocaproic acid, α-hydroxyheptanoic acid, α-hydroxyoctanoic acid, α-hydroxydecanoic acid, α-hydroxymyristic acid, α-hydroxystearic acid, α-hydroxylignoceric acid, and β-phenol lactic acid.

[0120] In various embodiments, in each microparticle, 70-97% of the total weight of the microparticle is corticosteroid and 3-30% is polymer. In one embodiment, the drug core comprises more than 70% of the total weight of the microparticle and the polymer shell comprises less than 30% of the total weight of the microparticle. In other embodiments, the drug core comprises more than 75%, more than 80%, more than 85%, more than 90%, or more than 95% of the total weight of the microparticle, with the remainder of the microparticle being the polymer shell. In some embodiments, the microparticle comprises 90-98% weight / weight crystalline drug core and 2-10% weight / weight polymer shell.

[0121] Because the crystalline drug core can comprise at least 70% of the microparticles by weight, in some embodiments, the overall size of the microparticles is largely determined by the size of the crystalline drug core. Typically, the thickness of the polymer shell is less than 12%, or less than 5%, or less than 3% of the total diameter of the microparticles. Similarly, in some embodiments, the weight of the microparticles is also related to the weight of the crystalline core, resulting in a higher drug loading.

[0122] In various embodiments, the microparticles have an average diameter between 50 μm and 800 μm, or an average diameter between 60 μm and 250 μm, or an average diameter between 80 μm and 150 μm. In a preferred embodiment, the average diameter is about 150 μm with a standard deviation of less than 50% of the average diameter. In another preferred embodiment, the average diameter is about 75 μm with a standard deviation of less than 50% of the average diameter.

[0123] In some embodiments, the in vivo sustained-release profile of the corticosteroid is correlated with the in vitro dissolution characteristics of the microparticles, which in turn are determined by the solubility and permeability of the drug core, the level of cross-linking of the polymer shell, and the degradation rate of the polymer shell. In some embodiments, the microparticles have a dissolution half-life of 12-20 hours when tested in a USP Type II apparatus using 3 mg of microparticles in 200 mL of a dissolution medium of 70% v / v methanol and 30% v / v water at 25°C.

[0124] The injectable sustained-release compositions described in US Patent No. 9,987,233 are incorporated herein by reference.

[0125] In some embodiments, the use of polymer-coated microspheres enables delayed-release compositions that expose GI tissues to the corticosteroid over an extended period of up to 6-12 months. The use of fluticasone as a corticosteroid also allows for higher doses to be used while limiting systemic side effects—this is because fluticasone has a high first-pass metabolism (approximately 99%). Thus, fluticasone's high first-pass metabolism enables the local administration of high concentrations, as any drug that escapes the local mucosal tissues will be metabolized by the liver before any systemic exposure occurs. Steroids such as triamcinolone acetonide or beclomethasone do not have this advantage because their first-pass metabolism is much lower.

[0126] Method of forming microparticles

[0127] Methods for forming polymer coatings on particles are well known in the art. For example, standard techniques include solvent evaporation / extraction techniques, water drying techniques (see, e.g., U.S. Patent No. 4,994,281), organic phase separation techniques (see, e.g., U.S. Patent No. 5,639,480), spray drying techniques (see, e.g., U.S. Patent No. 5,651,990), air suspension techniques, and dip coating techniques—the entire contents of which are incorporated herein by reference.

[0128] In some embodiments, the microparticles of the present disclosure are formed using a method for forming microparticles as described in U.S. Patent Publication No. 2007 / 003619, which is incorporated herein by reference in its entirety. The crystalline drug core is coated with one or more layers of polymer coating that together form a polymer shell. For example, in one aspect, a PVA polymer coating can be applied using a dip coating technique. Briefly, a 1% aqueous solution of a PVA coating solution is formed by dissolving excess PVA in water at 60° C. for 2 h (see, e.g., Byron and Dalby (1987), J. Pharm. Sci. 76(1):65-67). Alternatively, a higher concentration of PVA solution (e.g., 3-4%) can be prepared by a reflux process heated to about 90-100° C. After cooling, the microparticles can be added to the PVA solution and agitated by, for example, rotation or stirring. The microparticles are then removed from the solution by filtering through, for example, filter paper having a mesh size appropriate for the microparticles. Optionally, vacuum filtration can be used to assist in drying. Untreated PVA polymer coatings or films are readily permeable to water and hydrophilic drugs. However, heating PVA at increasing temperatures in the range of 100-250° C. for periods of 0-160 hours results in increased crystallinity and a decrease in permeability by up to 500-fold (Byron and Dalby (1987), supra).

[0129] Thus, in some embodiments, the PVA polymer coating can be heated to a temperature between 100°C and 250°C, between 125°C and 175°C, or between 155°C and 170°C for a period of between 1 second and 160 hours, between 1 minute and 10 hours, or between 5 minutes and 2 hours. For example, heating to 220°C can be performed within one hour. Optionally, the coating process can be repeated several times to prepare a thicker polymer coating. In some embodiments, two to five layers of coating are applied to achieve a coating thickness of 5% weight / weight.

[0130] In one embodiment, the microparticles undergo a heat treatment step for at least one hour at a temperature in the range of 210-230° C. By controlling the temperature of the heat treatment step, the level of cross-linking, and thus the permeability, can be precisely controlled.

[0131] Pharmaceutical composition

[0132] As described above, the methods described herein relate to administering at least one pharmaceutical composition comprising a delayed-release composition formulated for prolonged release of a corticosteroid into GI tissue (such as esophageal tissue). In addition to the above-mentioned delayed-release composition, the pharmaceutical composition of the present disclosure may further comprise a pharmaceutically acceptable vehicle in which the delayed-release composition is suspended. For example, in some embodiments, the pharmaceutical composition is prepared in situ by combining the delayed-release composition with a vehicle.

[0133] The therapeutic and prophylactic methods of the present disclosure can be carried out by preparing the pharmaceutical compositions using a multi-vial system, thereby allowing for reconstitution of the components of the pharmaceutical composition immediately prior to administration.

[0134] Even if the delayed-release composition exhibits short-term stability under aqueous conditions, such a multi-vial system can ensure sufficient stability of the pharmaceutical composition. The multi-vial system comprises at least one vial containing the delayed-release composition (the so-called corticosteroid vial) and at least one vial containing a liquid vehicle (the so-called vehicle vial). In practice, the liquid contents of the at least one vehicle vial are added to the solid contents of the at least one corticosteroid vial, and after agitation, the pharmaceutical composition is obtained in the corticosteroid vial as a suspension of the delayed-release composition in the liquid vehicle.

[0135] In some embodiments, a two-vial system is used to prepare the pharmaceutical composition, comprising a corticosteroid vial containing a delayed-release composition and a vehicle vial containing a liquid vehicle. The delayed-release composition can be in the form of a sterile powder comprising solidified, PVA-coated corticosteroid crystals. In one embodiment, for example, the corticosteroid vial contains a sterile powder of a delayed-release composition comprising solidified, PVA-coated fluticasone propionate crystals; and a separate vehicle vial contains sterile water and excipients required to prepare a uniform suspension of the delayed-release composition.

[0136] In some embodiments, the pharmaceutical compositions of the present disclosure, prepared from a multi-vial system or otherwise, remain stable for a period of 1 to 12 hours after the delayed-release composition is combined with the liquid vehicle.

[0137] The pharmaceutically acceptable vehicle of the present disclosure may contain water and an excipient capable of suspending the delayed-release composition in an aqueous medium. In some embodiments, the excipient is selected from a binder, a suspending agent, a disintegrant, a filler, a surfactant, a solubilizer, a stabilizer, a lubricant, a wetting agent, a diluent, and a combination thereof. For example, the excipient may be selected from polysorbates, polysaccharides, acidic salts, alkaline salts, neutral salts, and combinations thereof.

[0138] In some embodiments, the pharmaceutically acceptable vehicle contains 0.05 to 0.1% by weight of polysorbate, 0.1 to 2.0% by weight of cellulose, and 0.1 to 2.0% by weight of an inorganic salt, relative to the total weight of the pharmaceutically acceptable vehicle, dissolved in sterile water. For example, in some embodiments, the pharmaceutically acceptable vehicle contains one or more of the following components: 0.05 to 0.1% by weight of polysorbate 80, 0.1 to 3.5% by weight of carboxymethyl cellulose (CMC), 0.5 to 2.0% by weight of sodium hyaluronate (HA), and 0.1 to 2.0% by weight of sodium chloride, relative to the total weight of the pharmaceutically acceptable vehicle, dissolved in sterile water. In other embodiments, the pharmaceutically acceptable vehicle may contain about 0.015% by weight of polysorbate 80, about 0.75% by weight of carboxymethyl cellulose (CMC), and about 0.9% by weight of sodium chloride, relative to the total weight of the pharmaceutically acceptable vehicle, dissolved in sterile water.

[0139] Table 1 below summarizes the composition of two multi-vial systems of the present disclosure, including the proportions of the individual components in the corticosteroid vials and the vehicle vials.

[0140] Table 1 : Composition of 2 vials system

[0141]

[0142] The present disclosure is illustrated by the following examples, which are not intended to be limiting.

[0143] Example

[0144] Example 1

[0145] Fluticasone Propionate Recrystallization Procedure

[0146] Fluticasone propionate (FP) was recrystallized according to Example 1 of WO 2020 / 210720, the entire contents of which are incorporated herein by reference. Specifically, FP was recrystallized in methanol at a concentration of 10-15 mg / ml on both small and large scales. The temperature was maintained at 45°C during slow evaporation (e.g., 72 hours). Small-scale operations were performed in 20 ml to 2 L of solution, while large-scale operations were performed in 20 to 100 L of solution. Both small and large-scale operations produced thick, elongated crystals suitable for further sizing.

[0147] Example 2

[0148] Adjusting the size of recrystallized fluticasone propionate

[0149] Fluticasone propionate (FP) was recrystallized according to Example 3 of WO 2020 / 210720. Specifically, the recrystallized fluticasone propionate crystals produced in Example 1 were ground in a rotor / stator homogenizer. An exemplary set of operating parameters is as follows:

[0150] 5-10% solid culture medium;

[0151] Vehicle liquid: 0.1%-0.5% polysorbate 80 (a surfactant) in USP in water

[0152] Rotor speed: 15000-20000rpm (mill speed range is 3000-26000rpm)

[0153] Rotor configurations include coarse, medium, fine, or a combination of 2 or more rotors;

[0154] The maximum number of times this loop will run is 5

[0155] The ground crystals are then screened through two separate sieves to eliminate fines or residual large crystals. The resulting drug crystals have a narrow distribution, minimal fine matter content, and no ultrafine matter (no particles below 9 μm).

[0156] Example 3

[0157] General procedure for coating crystalline drug cores

[0158] Recrystallized FP crystals prepared according to Example 2 were coated with polyvinyl alcohol (PVA, 2% w / v in DI-H2O containing 25% v / v isopropyl alcohol) in a Model VFC-LAB Micro benchtop fluid bed coater system (Vector Corporation) using the following parameter ranges:

[0159] Air flow, 50-60L min -1 ;

[0160] Nozzle air, 5.0-25 psi;

[0161] Pump speed, 10-35 rpm;

[0162] inlet temperature, 99°C;

[0163] Exhaust temperature, 35-40°C;

[0164] Spray on / off cycle: 0.1 / 0.3min.

[0165] The relative signal intensities of the FP and PVA resonances in the drug product were compared with the corresponding signals from the calibration standards. 1The PVA content is measured periodically by H nuclear magnetic resonance (NMR) spectroscopy (see Example 4). The target final PVA concentration in the drug product is in the range of 0.1-20% weight / weight, or preferably in the range of 2-10% weight / weight. The granules are continuously coated until the desired amount of PVA is reached. The coated granules are then dried in an oven at 40°C for 1 hour. The dried coated granules are sieved through a sieve set consisting of a 150 μm mesh sieve and a 53 μm mesh sieve.

[0166] Example 4

[0167] NMR analysis for determining drug content in microparticles

[0168] The amount of drug core and polymer shell in the microparticles was determined using NMR analysis by calibration with samples of known amounts of pure drug.

[0169] The NMR system consisted of a Bruker Spectrospin 300 MHz magnet, a Bruker B-ACS 120 autosampler, a Bruker Avance II 300 console, and a Bruker BBO 300 MHz S15 mm with a Z-gradient probe. A calibration curve was prepared using five known samples of fluticasone propionate and PVA prepared in NMR-grade d6-DMSO. Proton (1H) NMR was performed on two samples: the first sample contained pure fluticasone propionate alone, and the second sample contained PVA-coated fluticasone. Each sample was manually loaded and spun within the magnet at 20 Hz. The probe was adjusted and matched for proton (1H) NMR. The magnet was manually shimmed using the first sample in the magnet. Integration for each sample took 1.5 hours, with 1024 scans performed. The integration range for the fluticasone peak was 5.5 to 6.35 ppm, and the integration range for the PVA peak was 4.15 to 4.7 ppm. Using this method, the final coated fluticasone particles were determined to contain 2.1% PVA based on the total weight of the coated particles. Assuming a spherical particle shape and an average particle size of 100 μm, this represents a coating thickness of approximately 7 μm.

[0170] Example 5

[0171] sustained-release (SR) corticosteroids

[0172] Recrystallized FP crystals were prepared according to Example 2 and coated with polyvinyl alcohol (PVA, 2% weight / volume in DI-H2O containing 25% volume / volume isopropyl alcohol) according to Example 3 in a Model VFC-LAB Micro benchtop fluid bed coater system (Vector Corporation) using the following parameter ranges: air flow, 50-60 L / min; nozzle air, 23 psi; pump speed, 15 rpm; inlet temperature, 99°C; exhaust temperature, 35-40°C; spray on / off cycle: 0.1 / 0.3 min. Coating of the particles continued until the amount of PVA reached 6% (weight / weight) based on NMR sampling (see Example 4).

[0173] The resulting microparticles were then heat-treated at 130°C for 3 hours.

[0174] The average diameter of the microparticles ranged from 60 to 150 μm. The PVA content of the resulting microparticles was determined to be 6% by NMR analysis according to the method described in Example 4. The polymer-coated fluticasone particles were steam sterilized in amber vials (122° C., 16 psi, 30 min). The sterilization process did not affect the chemical composition of the formulation, as indicated by H NMR spectroscopy and HPLC analysis.

[0175] Example 6

[0176] Preparation of a 2-vial system.

[0177] A 2-vial system was prepared, comprising a corticosteroid vial and a vehicle vial. The corticosteroid vial contained approximately 44 mg of the sustained-release (SR) corticosteroid of Example 5 (94% (w / w) FP crystals coated with 6% (w / w) PVA). The vehicle vial contained the excipients described in "System B" of Table 1 (0.74% (w / w) sodium carboxymethylcellulose, 0.015% (w / w) polysorbate 80, 0.813% (w / w) sodium chloride, 0.216% (w / w) sodium dihydrogen phosphate heptahydrate, 0.026% (w / w) sodium dihydrogen phosphate, the balance being sterile water) and was agitated by shaking until homogenized. Prior to use, the corticosteroid vial and the vehicle vial were stored at a controlled temperature of 20-25°C (68-77°F).

[0178] Example 7

[0179] Preparation of 2.5mg / ml suspension.

[0180] Using a syringe and an 18G needle, inject 6 mL of air into the vehicle vial of Example 6. Then, inject 6 mL of vehicle from the vehicle vial into the corticosteroid vial of Example 6 to flush any particles from the walls of the corticosteroid vial. The corticosteroid vial is then swirled to ensure uniform suspension of particles and to avoid clumping and aggregation. Two additional 6 mL injections of vehicle are injected into the corticosteroid vial to obtain a suspension with a volume of approximately 18 mL and an SR concentration of approximately 2.5 mg / mL. The resulting SR suspension is temperature-controlled at 20-25°C (68-77°F) prior to use and used within 1 hour of composition.

[0181] Example 8

[0182] Treatment regimen (2.5MG / ML, 8 injections).

[0183] The SR suspension of Example 7 (2.5 mg / mL) was administered 8 times to adult patients with eosinophilic esophagitis (EoE). Figure 6 As exemplified, 1.0 mL of SR suspension (approximately 2.5 mg per injection) was injected into 8 separate injection sites on four different rings of the esophagus. All injections were submucosal into the esophageal tissue and performed inside the throat using a standard esophageal injection probe.

[0184] refer to Figure 6 , two injections were made in the first and fourth quadrants (48-1 and 48-3) of the first ring (28), which was located approximately 6 cm above the gastroesophageal (GE) junction (8). Two injections were made in the second and fourth quadrants (48-2 and 48-4) of the second ring (30), which was located approximately 7 cm above the GE junction (8). Two injections were made in the first and third quadrants (48-2 and 48-4) of the third ring (32), which was located approximately 8 cm above the GE junction (8). Two injections were made in the second and fourth quadrants (48-2 and 48-4) of the fourth ring (34), which was located approximately 10 cm above the GE junction (8).

[0185] Example 9

[0186] Treatment regimen (total dose escalation).

[0187] Using the SR suspension of the present disclosure, one or more adult patients suffering from eosinophilic esophagitis (EoE) can be subjected to different treatment regimens such that the total dose of sustained-release (SR) corticosteroid can vary from about 1 mg to about 100 mg. The total dose in these experiments is equal to the dose per injection site multiplied by the number of injections performed in a particular treatment. The concentration of sustained-release (SR) corticosteroid per injection can vary from about 0.25 mg / mL to about 10 mg / mL, and the number of injections per treatment regimen can vary from 1 injection to 20 injections. Examples 9-1 to 9-8 below illustrate treatment regimens in which the total dose of SR corticosteroid is increased from about 4 mg to about 40 mg.

[0188] Example 9-1 : (4 injections / 4mg total dose)

[0189] A 1.0 mg / mL sustained-release (SR) corticosteroid solution was prepared using the 2-vial system of Example 6. Four esophageal injections were administered to adult patients with eosinophilic esophagitis (EoE). Figure 6 As exemplified, 1.0 mL of SR suspension (approximately 1.0 mg per injection) is injected into four separate injection sites on two different rings of the esophagus, providing a total dose of approximately 4 mg to each of one or more adult patients. All injections are submucosal into the esophageal tissue and are performed inside the throat using a standard esophageal injection probe.

[0190] refer to Figure 6 Two injections were performed in the first and fourth quadrants (48-1 and 48-3) of a first ring (28) located approximately 6 cm above the gastroesophageal (GE) junction (8), such that the injection sites were equidistant from one another along the circumference of the first ring (28). The remaining two injections were performed in the second and fourth quadrants (48-2 and 48-4) of a second ring (30) located approximately 7 cm above the GE junction (8), such that the injection sites were equidistant from one another along the circumference of the second ring (30).

[0191] Example 9-2: (8 injections / 8 mg total dose)

[0192] A 1.0 mg / mL sustained-release (SR) corticosteroid solution was prepared using the 2-vial system of Example 6. Eight esophageal injections were administered to adult patients with eosinophilic esophagitis (EoE). Figure 6 As exemplified, 1.0 mL of SR suspension (approximately 1.0 mg per injection) is injected into 8 separate injection sites on four different rings of the esophagus, delivering a total dose of approximately 8 mg to each of one or more adult patients. All injections are submucosal into the esophageal tissue and are performed inside the throat using a standard esophageal injection probe.

[0193] refer to Figure 6 , two injections were made in the first and fourth quadrants (48-1 and 48-3) of a first ring (28), which was located approximately 6 cm above the gastroesophageal (GE) junction (8), such that the injection sites were equidistant from one another along the circumference of the first ring (28). Two injections were made in the second and fourth quadrants (48-2 and 48-4) of a second ring (30), which was located approximately 7 cm above the GE junction (8), such that the injection sites were equidistant from one another along the circumference of the second ring (30). Two injections were made in the first and third quadrants (48-2 and 48-4) of a third ring (32), which was located approximately 8 cm above the GE junction (8), such that the injection sites were equidistant from one another along the circumference of the third ring (32). Two injections were made in the second and fourth quadrants (48-2 and 48-4) of the fourth ring (34), which was located approximately 10 cm above the GE junction (8), such that the injection sites were equidistant from each other along the circumference of the fourth ring (34).

[0194] Example 9-3 : (12 injections / 12 mg total dose)

[0195] A 1.0 mg / mL sustained-release (SR) corticosteroid solution was prepared using the 2-vial system of Example 6. Twelve esophageal injections were administered to adult patients with eosinophilic esophagitis (EoE). Figure 6 As exemplified, 1.0 mL of SR suspension (approximately 1.0 mg per injection) is injected into 12 separate injection sites on four different rings of the esophagus, delivering a total dose of approximately 12 mg to each of one or more adult patients. All injections are submucosal into the esophageal tissue and are performed inside the throat using a standard esophageal injection probe.

[0196] refer to Figure 6 , three injections are performed in a first ring (28), which is located approximately 6 cm above the gastrointestinal (GE) junction (8), such that the injection sites are equidistant from one another along the circumference of the first ring (28). Three injections are performed in a second ring (30), which is located approximately 7 cm above the GE junction (8), such that the injection sites are equidistant from one another along the circumference of the second ring (30). Three injections are performed in a third ring (32), which is located approximately 8 cm above the GE junction (8), such that the injection sites are equidistant from one another along the circumference of the third ring (32). Three injections are performed in a fourth ring (34), which is located approximately 10 cm above the GE junction (8), such that the injection sites are equidistant from one another along the circumference of the fourth ring (34).

[0197] Example 9-4 : (16 injections / 16 mg total dose)

[0198] A 1.0 mg / mL sustained-release (SR) corticosteroid solution was prepared using the 2-vial system of Example 6. Sixteen esophageal injections were administered to adult patients with eosinophilic esophagitis (EoE). Figure 6 As exemplified, 1.0 mL of SR suspension (approximately 1.0 mg per injection) is injected into 16 separate injection sites on four different rings of the esophagus, delivering a total dose of approximately 16 mg to each of one or more adult patients. All injections are submucosal into the esophageal tissue and are performed inside the throat using a standard esophageal injection probe.

[0199] refer to Figure 6 Four injections were administered in the first, second, third, and fourth quadrants of a first ring (28) located approximately 6 cm above the gastrointestinal (GE) junction (8) such that the injection sites were equidistant from one another along the circumference of the first ring (28). Four injections were administered in the first, second, third, and fourth quadrants of a second ring (30) located approximately 7 cm above the GE junction (8) such that the injection sites were equidistant from one another along the circumference of the second ring (30). Three injections were administered in the first, second, third, and fourth quadrants of a third ring (32) located approximately 8 cm above the GE junction (8) such that the injection sites were equidistant from one another along the circumference of the third ring (32). Three injections were administered in the first, second, third, and fourth quadrants of a fourth ring (34) located approximately 10 cm above the GE junction (8) such that the injection sites were equidistant from one another along the circumference of the fourth ring (34).

[0200] Example 9-5 : (4 injections / 10 mg total dose)

[0201] A 2.5 mg / mL sustained-release (SR) corticosteroid solution was prepared using the 2-vial system of Example 6. Four esophageal injections were administered to adult patients with eosinophilic esophagitis (EoE). Figure 6 As exemplified, 1.0 mL of SR suspension (approximately 2.5 mg per injection) is injected into four separate injection sites on two different rings of the esophagus, delivering a total dose of approximately 10 mg to each of one or more adult patients. All injections are submucosal into the esophageal tissue and are performed inside the throat using a standard esophageal injection probe.

[0202] refer to Figure 6Two injections were performed in the first and fourth quadrants (48-1 and 48-3) of a first ring (28) located approximately 6 cm above the gastroesophageal (GE) junction (8), such that the injection sites were equidistant from one another along the circumference of the first ring (28). The remaining two injections were performed in the second and fourth quadrants (48-2 and 48-4) of a second ring (30) located approximately 7 cm above the GE junction (8), such that the injection sites were equidistant from one another along the circumference of the second ring (30).

[0203] Example 9-6 : (8 injections / 20mg total dose)

[0204] A 2.5 mg / mL sustained-release (SR) corticosteroid solution was prepared using the 2-vial system of Example 6. Eight esophageal injections were administered to adult patients with eosinophilic esophagitis (EoE). Figure 6 As exemplified, 1.0 mL of SR suspension (approximately 2.5 mg per injection) is injected into eight separate injection sites on four different rings of the esophagus, delivering a total dose of approximately 20 mg to each of one or more adult patients. All injections are submucosal into the esophageal tissue and are performed inside the throat using a standard esophageal injection probe.

[0205] refer to Figure 6 , two injections were made in the first and fourth quadrants (48-1 and 48-3) of a first ring (28), which was located approximately 6 cm above the gastroesophageal (GE) junction (8), such that the injection sites were equidistant from one another along the circumference of the first ring (28). Two injections were made in the second and fourth quadrants (48-2 and 48-4) of a second ring (30), which was located approximately 7 cm above the GE junction (8), such that the injection sites were equidistant from one another along the circumference of the second ring (30). Two injections were made in the first and third quadrants (48-2 and 48-4) of a third ring (32), which was located approximately 8 cm above the GE junction (8), such that the injection sites were equidistant from one another along the circumference of the third ring (32). Two injections were made in the second and fourth quadrants (48-2 and 48-4) of the fourth ring (34), which was located approximately 10 cm above the GE junction (8), such that the injection sites were equidistant from each other along the circumference of the fourth ring (34).

[0206] Example 9-7 : (12 injections / 30 mg total dose)

[0207] A 2.5 mg / mL sustained-release (SR) corticosteroid solution was prepared using the 2-vial system of Example 6. Twelve esophageal injections were administered to adult patients with eosinophilic esophagitis (EoE). Figure 6 As exemplified, 1.0 mL of SR suspension (approximately 2.5 mg per injection) is injected into 12 separate injection sites on four different rings of the esophagus, delivering a total dose of approximately 30 mg to each of one or more adult patients. All injections are submucosal into the esophageal tissue and are performed inside the throat using a standard esophageal injection probe.

[0208] refer to Figure 6 , three injections are performed in a first ring (28), which is located approximately 6 cm above the gastrointestinal (GE) junction (8), such that the injection sites are equidistant from one another along the circumference of the first ring (28). Three injections are performed in a second ring (30), which is located approximately 7 cm above the GE junction (8), such that the injection sites are equidistant from one another along the circumference of the second ring (30). Three injections are performed in a third ring (32), which is located approximately 8 cm above the GE junction (8), such that the injection sites are equidistant from one another along the circumference of the third ring (32). Three injections are performed in a fourth ring (34), which is located approximately 10 cm above the GE junction (8), such that the injection sites are equidistant from one another along the circumference of the fourth ring (34).

[0209] Example 9-8 : (16 injections / 40 mg total dose)

[0210] A 2.5 mg / mL sustained-release (SR) corticosteroid solution was prepared using the 2-vial system of Example 6. Sixteen esophageal injections were administered to adult patients with eosinophilic esophagitis (EoE). Figure 6 As exemplified, 1.0 mL of SR suspension (approximately 2.5 mg per injection) is injected into 16 separate injection sites on four different rings of the esophagus, delivering a total dose of approximately 40 mg to each of one or more adult patients. All injections are submucosal into the esophageal tissue and are performed inside the throat using a standard esophageal injection probe.

[0211] refer to Figure 6Four injections were administered in the first, second, third, and fourth quadrants of a first ring (28) located approximately 6 cm above the gastrointestinal (GE) junction (8) such that the injection sites were equidistant from one another along the circumference of the first ring (28). Four injections were administered in the first, second, third, and fourth quadrants of a second ring (30) located approximately 7 cm above the GE junction (8) such that the injection sites were equidistant from one another along the circumference of the second ring (30). Three injections were administered in the first, second, third, and fourth quadrants of a third ring (32) located approximately 8 cm above the GE junction (8) such that the injection sites were equidistant from one another along the circumference of the third ring (32). Three injections were administered in the first, second, third, and fourth quadrants of a fourth ring (34) located approximately 10 cm above the GE junction (8) such that the injection sites were equidistant from one another along the circumference of the fourth ring (34).

[0212] Example 9-9 :(Alternative injection mode)

[0213] Other treatment protocols were performed using conditions similar to those of Examples 9-1 to 9-8, except that the injection pattern was not limited to isometric injections, the number of injections was not limited to 4 to 16, and the protocol was not limited to EoE treatment. Some treatment protocols were performed so that the injection pattern was irregular and could be based on the location of inflammation in the gastrointestinal (GI) tract of the subject being treated. For example, some treatment protocols were performed so that at least one injection was directly injected into a benign stricture of the GI tract, and at least one additional injection could be injected into another area of ​​the GI tract (such as an area adjacent to the benign stricture).

[0214] Implementation Plan

[0215] Embodiments of the present disclosure [1] relate to a method for treating or preventing an inflammatory disease in the gastrointestinal tract of a subject in need thereof, the method comprising topically administering to the subject a therapeutically effective amount of a pharmaceutical composition, wherein the pharmaceutical composition comprises a delayed-release composition formulated for prolonged release of a corticosteroid into the gastrointestinal tissue.

[0216] Embodiment [2] of the present disclosure relates to the method according to embodiment [1], wherein the tissue comprises esophageal tissue, stomach tissue, bile duct tissue, small intestine tissue, large intestine tissue, or any combination thereof.

[0217] Embodiment [3] of the present disclosure relates to the method according to embodiment [1] or [2], wherein the tissue comprises esophageal tissue.

[0218] Embodiment [4] of the present disclosure relates to the method according to any one of embodiments [1]-[3], wherein the administering comprises injecting the pharmaceutical composition into the tissue.

[0219] Embodiment [5] of the present disclosure relates to the method according to any one of embodiments [1]-[4], wherein the administering comprises injecting the pharmaceutical composition into the esophageal tissue.

[0220] Embodiment [6] of the present disclosure relates to the method according to any one of embodiments [1]-[5], wherein the administering comprises at least one submucosal injection of the pharmaceutical composition into the tissue.

[0221] Embodiment [7] of the present disclosure relates to the method according to any one of embodiments [1]-[6], wherein the administering comprises injecting at least one initial dose of the pharmaceutical composition into the tissue.

[0222] Embodiment [8] of the present disclosure relates to a method according to any one of embodiments [1]-[7], wherein the administering comprises multiple injections of the pharmaceutical composition into the tissue such that at least two of the injections occur at different injection sites in the tissue.

[0223] Embodiment [9] of the present disclosure relates to the method according to any one of embodiments [1]-[8], wherein the administering comprises injecting at least two initial doses of the pharmaceutical composition into the tissue.

[0224] Embodiment

[10] of the present disclosure relates to a method according to any one of embodiments [1]-[9], wherein the administration comprises injecting the pharmaceutical composition at least once into an inflamed area in the gastrointestinal tract, injecting the pharmaceutical composition at least once into an injection site that is not located in an inflamed area in the gastrointestinal tract, or a combination thereof.

[0225] Embodiment

[11] of the present disclosure relates to the method according to any one of embodiments [1]-

[10] , wherein the administering comprises injecting the pharmaceutical composition at least once into a localized benign stricture in the gastrointestinal tract of the subject.

[0226] Embodiment

[12] of the present disclosure relates to a method according to any one of embodiments [1]-

[11] , wherein the administering comprises injecting the pharmaceutical composition into the tissue at least once to form at least one blister containing the delayed-release composition.

[0227] Embodiment

[13] of the present disclosure relates to a method according to any one of embodiments [1]-

[12] , wherein the administration comprises one or more injections of the pharmaceutical composition into the tissue such that each injection independently contains from about 0.1 mg to about 20 mg, or from about 0.5 mg to about 10 mg, or from about 1 mg to about 8 mg, or from about 1 mg to about 6 mg, or from about 2 mg to about 12 mg, or from about 3 mg to about 8 mg, or from about 5 mg to about 20 mg, or from about 5 mg to about 15 mg, or from about 6 mg to about 14 mg, or from about 7 mg to about 18 mg, or from about 7 mg to about 16 mg, or from about 8 mg to about 20 mg, or from about 8 mg to about 16 mg, or from about 9 mg to about 18 mg, or from about 9 mg to about 15 mg, or from about 10 mg to about 20 mg, or from about 10 mg to about 18 mg, or from about 10 mg to about 16 mg of corticosteroid.

[0228] Embodiments of the present disclosure

[14] relate to a method for treating eosinophilic esophagitis in a subject in need thereof, the method comprising topically administering to the subject a therapeutically effective amount of a pharmaceutical composition, wherein the pharmaceutical composition comprises a delayed-release composition formulated for extended release of a corticosteroid into esophageal tissue.

[0229] Embodiment

[15] of the present disclosure relates to the method according to embodiment

[14] , wherein the administering comprises injecting the pharmaceutical composition into the esophageal tissue.

[0230] Embodiment

[16] of the present disclosure relates to the method according to embodiment

[14] or

[15] , wherein the administering comprises at least one submucosal injection of the pharmaceutical composition into the esophageal tissue.

[0231] Embodiment

[17] of the present disclosure relates to the method according to any one of embodiments

[14] -

[16] , wherein the administering comprises injecting at least one initial dose of the pharmaceutical composition into the esophageal tissue.

[0232] Embodiment

[18] of the present disclosure relates to a method according to any one of embodiments

[14] -

[17] , wherein the administering comprises multiple injections of the pharmaceutical composition into the esophageal tissue such that at least two of the injections occur at different injection sites in the esophageal tissue.

[0233] Embodiment

[19] of the present disclosure relates to the method according to any one of embodiments

[14] -

[18] , wherein the administering comprises injecting at least two starting doses of the pharmaceutical composition into the esophageal tissue.

[0234] Embodiment

[20] of the present disclosure relates to a method according to any one of embodiments [1]-

[19] , wherein the administering comprises multiple injections of the pharmaceutical composition into the esophageal tissue such that at least two of the injections occur at injection sites located on a first ring of the esophagus, the first ring being defined by the circumference of the esophagus at a distance d1 above the gastroesophageal junction of the subject.

[0235] Embodiment

[21] of the present disclosure relates to a method according to embodiment

[20] , wherein the distance d1 is at least 2 cm, or at least 3 cm, or at least 4 cm, or at least 5 cm, or at least 6 cm, or at least 7 cm, or at least 8 cm, or at least 10 cm above the gastroesophageal junction.

[0236] Embodiment

[22] of the present disclosure relates to a method according to embodiment

[20] or

[21] , wherein the injection sites located on the first ring of the esophagus are equidistantly distributed relative to each other along the circumference of the first ring, or wherein the injection sites positioned along the first ring of the esophagus are not equidistantly distributed relative to each other along the circumference of the first ring.

[0237] Embodiment

[23] of the present disclosure relates to a method according to any one of embodiments

[20] -

[22] , wherein at least three of the injections occur at injection sites located along the first ring, at least four of the injections occur at injection sites located along the first ring, at least five of the injections occur at injection sites located along the first ring, at least six of the injections occur at injection sites located along the first ring, at least seven of the injections occur at injection sites located along the first ring, at least eight of the injections occur at injection sites located along the first ring, at least nine of the injections occur at injection sites located along the first ring, or at least ten of the injections occur at injection sites located along the first ring.

[0238] Embodiment

[24] of the present disclosure relates to a method according to any one of embodiments

[20] -

[23] , wherein at least two injections of the pharmaceutical composition into the esophageal tissue occur at injection sites located along a second ring of the esophagus, the second ring being defined by the circumference of the esophagus at a distance d2 above the gastroesophageal junction, wherein the distance d2 is greater than the distance d1.

[0239] Embodiment

[25] of the present disclosure relates to a method according to embodiment

[24] , wherein the distance d2 is greater than the distance d1 by at least 1 cm, or at least 2 cm, or at least 3 cm, or at least 4 cm, or at least 5 cm, or at least 6 cm, or at least 7 cm, or at least 8 cm, or at least 9 cm, or at least 10 cm.

[0240] Embodiment

[26] of the present disclosure relates to a method according to embodiment

[24] or

[25] , wherein the injection sites positioned along the second ring of the esophagus are equidistantly distributed relative to each other along the circumference of the second ring, or wherein the injection sites positioned along the second ring of the esophagus are not equidistantly distributed relative to each other along the circumference of the second ring.

[0241] Embodiment

[27] of the present disclosure relates to a method according to any one of embodiments

[24] -

[26] , wherein at least three of the injections occur at injection sites located along the second ring, at least four of the injections occur at injection sites located along the second ring, at least five of the injections occur at injection sites located along the second ring, at least six of the injections occur at injection sites located along the second ring, at least seven of the injections occur at injection sites located along the second ring, at least eight of the injections occur at injection sites located along the second ring, at least nine of the injections occur at injection sites located along the second ring, or at least ten of the injections occur at injection sites located along the second ring.

[0242] Embodiment

[28] of the present disclosure relates to a method according to any one of embodiments [1]-

[27] , wherein the administering comprises multiple injections of the pharmaceutical composition into esophageal tissue such that the injections occur at injection sites positioned along a plurality of rings of the esophagus, the plurality of rings being defined by respective circumferences of the esophagus at respective distances above the gastroesophageal junction of the subject, and wherein the pattern of injection sites within the esophagus is a spiral pattern relative to the longitudinal axis of the esophagus.

[0243] Embodiment

[29] of the present disclosure relates to a method according to any one of embodiments [1]-

[28] , wherein the administering comprises multiple injections of the pharmaceutical composition into esophageal tissue such that injections occur at injection sites located along at least three rings, or at least four rings, or at least five rings, or at least six rings, or at least seven rings, or at least eight rings of the esophagus, the rings being defined by corresponding circumferences of the esophagus at corresponding distances of the rings above the gastroesophageal junction of the subject.

[0244] Embodiment

[30] of the present disclosure relates to a method according to any one of embodiments [1]-

[29] , wherein the administering comprises injecting the pharmaceutical composition at least once into an area of ​​esophagitis, injecting the pharmaceutical composition at least once into an injection site that is not located in the area of ​​esophagitis, or a combination thereof.

[0245] Embodiment

[31] of the present disclosure relates to the method according to any one of embodiments [1]-

[30] , wherein the administering comprises injecting the pharmaceutical composition at least once into a localized benign stricture in the esophagus of the subject.

[0246] Embodiment

[32] of the present disclosure relates to the method according to any one of embodiments [1]-

[31] , wherein the pharmaceutical composition is injected into the esophageal tissue to form at least one blister containing the delayed-release composition.

[0247] Embodiment

[33] of the present disclosure relates to a method according to any one of embodiments [1]-

[32] , wherein the administration comprises one or more injections of the pharmaceutical composition into the esophageal tissue such that each injection independently contains from about 0.1 mg to about 20 mg, or from about 0.5 mg to about 10 mg, or from about 1 mg to about 8 mg, or from about 1 mg to about 6 mg, or from about 2 mg to about 12 mg, or from about 3 mg to about 8 mg, or from about 5 mg to about 20 mg, or from about 5 mg to about 15 mg, or from about 6 mg to about 14 mg, or from about 7 mg to about 18 mg, or from about 7 mg to about 16 mg, or from about 8 mg to about 20 mg, or from about 8 mg to about 16 mg, or from about 9 mg to about 18 mg, or from about 9 mg to about 15 mg, or from about 10 mg to about 20 mg, or from about 10 mg to about 18 mg, or from about 10 mg to about 16 mg of corticosteroid.

[0248] Embodiment

[34] of the present disclosure relates to the method according to any one of embodiments [1]-

[33] , wherein the corticosteroid comprises a glucocorticoid agonist.

[0249] Embodiment

[35] of the present disclosure relates to a method according to any one of embodiments [1] to

[34] , wherein the corticosteroid comprises at least one selected from the group consisting of deoxycorticosterone, hydrocortisone, cortisone, methylprednisolone, prednisone, prednisolone, triamcinolone, dexamethasone, betamethasone, beclomethasone, beclomethasone 17,21-dipropionate, budesonide, flunisolide, fludrocortisone, mometasone, fluticasone, alclomethasone, clocortolone, flurandrenolide, fluocinolone acetonide, hydrocortisone acetate, fluorometholone, fluocinolone acetonide, diflucortolone valerate, paramethasone acetate, halcinonide, hydrocortisone phosphate, clobetasone butyrate, amcinonide, prednisolone succinate, and pharmaceutically acceptable salts and / or esters thereof.

[0250] Embodiment

[36] of the present disclosure relates to the method according to any one of embodiments [1]-

[35] , wherein the corticosteroid comprises fluticasone or a pharmaceutically acceptable salt or ester thereof.

[0251] Embodiment

[37] of the present disclosure relates to the method according to any one of embodiments [1]-

[36] , wherein the corticosteroid comprises fluticasone, fluticasone furoate, fluticasone propionate, or a combination thereof.

[0252] Embodiment

[38] of the present disclosure relates to the method according to any one of embodiments [1]-

[37] , wherein the corticosteroid comprises fluticasone propionate.

[0253] Embodiment

[39] of the present disclosure relates to the method according to any one of embodiments [1]-

[38] , wherein the corticosteroid is crystalline.

[0254] Embodiment

[40] of the present disclosure relates to the method according to any one of embodiments [1]-

[39] , wherein the delayed-release composition comprises the corticosteroid and a hydrophilic polymer.

[0255] Embodiment

[41] of the present disclosure relates to the method according to any one of embodiments [1] to

[40] , wherein the delayed-release composition has a core-shell structure.

[0256] Embodiment

[42] of the present disclosure relates to a method according to any one of embodiments [1]-

[41] , wherein the delayed-release composition comprises microparticles comprising (1) a crystalline drug core comprising one or more of the corticosteroid crystals, and (2) a polymer shell encapsulating the crystalline drug core, the polymer shell being in contact with but not miscible with the crystalline drug core, and wherein the proportion of the crystalline drug core in the microparticles is greater than 20%, or greater than 30%, or greater than 40%, or greater than 50%, or greater than 60%, or greater than 70%, or greater than 80%, or greater than 90% by weight relative to the total weight of the microparticles.

[0257] Embodiment

[43] of the present disclosure relates to the method according to embodiment

[42] , wherein the average diameter of the microparticles is in the range of 50 μm to 800 μm, and the standard deviation is less than 50% of the average diameter.

[0258] Embodiment

[44] of the present disclosure relates to a method according to embodiment

[42] or

[43] , wherein more than 90% of the microparticles have an average diameter in the range of 50 μm to 800 μm, 50 μm to 700 μm, or 50 μm to 600 μm, or 50 μm to 500 μm, or 50 μm to 400 μm, or 50 μm to 300 μm, or 50 μm to 200 μm, or 50 μm to 100 μm.

[0259] Embodiment

[45] of the present disclosure relates to a method according to any one of embodiments

[42] -

[44] , wherein the crystalline drug core comprises at least about 90%, or at least about 95%, or at least about 98%, or at least about 100% of the corticosteroid.

[0260] Embodiment

[46] of the present disclosure relates to a method according to any one of embodiments

[42] -

[45] , wherein the polymer shell comprises a hydrophilic polymer.

[0261] Embodiment

[47] of the present disclosure relates to a method according to any one of embodiments

[42] -

[46] , wherein the polymer shell comprises one or more biodegradable polymers selected from the group consisting of: polyvinyl alcohol (PVA), ethylene vinyl acetate (EVA), polyparaxylene polymer, polylactic acid (PLA), polyglycolic acid (PGA), polylactic-co-glycolic acid (PLGA), polyε-caprolactone (PCL), polyvalerolactone (PVL), polyε-decalactone (PDL), poly 1,4-dioxane-2,3-dione, poly 1,3-dioxane-2-one, polydioxanone (PDS), polyhydroxybutyric acid (PHB), polyhydroxyvaleric acid (PHV) and polyβ-malic acid (PMLA).

[0262] Embodiment

[48] of the present disclosure relates to a method according to any one of embodiments

[42] -

[47] , wherein the polymer shell comprises polyvinyl alcohol (PVA).

[0263] Embodiment

[49] of the present disclosure relates to a method according to any one of embodiments

[42] -

[48] , wherein the polymer shell comprises a cross-linked polymer.

[0264] Embodiment

[50] of the present disclosure relates to the method according to embodiment

[49] , wherein the cross-linked polymer is covalently or ionically cross-linked.

[0265] Embodiment

[51] of the present disclosure relates to a method according to any one of embodiments

[42] -

[50] , wherein the microparticles comprise 60-99%, or 70-99%, or 80-98%, or 90-98% weight / weight of the crystalline drug core and 1-30%, or 1-20%, or 1-10%, or 2-10% weight / weight of the polymer shell.

[0266] Embodiment

[52] of the present disclosure relates to a method according to any one of embodiments

[42] -

[51] , wherein the average diameter of the microparticles is between 50 μm and 800 μm, or between 60 μm and 250 μm, or between 80 μm and 150 μm.

[0267] Embodiment

[53] of the present disclosure relates to the method according to any one of embodiments [1]-

[52] , wherein the pharmaceutical composition further comprises a pharmaceutically acceptable vehicle, and the delayed-release composition is suspended in the vehicle.

[0268] Embodiment

[54] of the present disclosure relates to the method according to any one of embodiments [1]-

[53] , wherein the pharmaceutical composition is prepared by combining the delayed-release composition with a pharmaceutically acceptable vehicle.

[0269] Embodiment

[55] of the present disclosure relates to a method according to any one of embodiments [1]-

[54] , wherein after the delayed-release composition is combined with a pharmaceutically acceptable vehicle, the pharmaceutical composition is stable for a period of up to one hour, or two hours, or three hours, or four hours, or five hours, or six hours, or seven hours, or eight hours, or nine hours, or ten hours, or eleven hours, or twelve hours.

[0270] Embodiment

[56] of the present disclosure relates to a method according to any one of embodiments [1]-

[55] , wherein the delayed-release composition is in the form of a sterile powder comprising solidified PVA-coated crystals of the corticosteroid.

[0271] Embodiment

[57] of the present disclosure relates to a method according to any one of embodiments [1]-

[56] , wherein the pharmaceutical composition further comprises a pharmaceutically acceptable vehicle comprising water and an excipient capable of suspending the delayed-release composition in an aqueous medium.

[0272] Embodiment

[58] of the present disclosure relates to a method according to any one of embodiments [1]-

[57] , wherein the pharmaceutical composition further comprises a pharmaceutically acceptable vehicle comprising water and an excipient capable of suspending the delayed-release composition in an aqueous medium, wherein the excipient is selected from the group consisting of a binder, a suspending agent, a disintegrant, a filler, a surfactant, a solubilizer, a stabilizer, a lubricant, a wetting agent, a diluent, and combinations thereof.

[0273] Embodiment

[59] of the present disclosure relates to a method according to any one of embodiments [1]-

[58] , wherein the pharmaceutical composition further comprises a pharmaceutically acceptable vehicle comprising water and an excipient capable of suspending the delayed-release composition in an aqueous medium, wherein the excipient is selected from the group consisting of: polysorbates, polysaccharides, acidic salts, basic salts, neutral salts, and combinations thereof.

[0274] Embodiment

[60] of the present disclosure relates to a method according to any one of embodiments [1]-

[59] , wherein the pharmaceutical composition further comprises a pharmaceutically acceptable vehicle containing 0.05 to 0.1 weight % of polysorbate 80, 0.1 to 2.0 weight % of carboxymethyl cellulose (CMC) and 0.1 to 2.0 weight % of sodium chloride relative to the total weight of the pharmaceutically acceptable vehicle, and the vehicle is dissolved in sterile water.

[0275] Embodiment

[61] of the present disclosure relates to a method according to any one of embodiments [1]-

[60] , wherein the pharmaceutical composition further comprises a pharmaceutically acceptable vehicle containing approximately 0.015 weight % polysorbate 80, approximately 0.5 weight % carboxymethyl cellulose (CMC) and approximately 0.9 weight % sodium chloride, relative to the total weight of the pharmaceutically acceptable vehicle, the vehicle being dissolved in sterile water.

[0276] Embodiment

[62] of the present disclosure relates to the method according to any one of embodiments [1]-

[61] , further comprising administering a topical agent to the gastrointestinal tissue.

[0277] Embodiment

[63] of the present disclosure relates to the method according to any one of embodiments [1]-

[62] , further comprising administering a topical agent to the esophageal tissue.

[0278] Embodiment

[64] of the present disclosure relates to the method according to embodiment

[62] or

[63] , wherein the topical medicament comprises an additional corticosteroid.

[0279] Embodiment

[65] of the present disclosure relates to the method according to any one of embodiments [1]-

[64] , further comprising locally administering a therapeutically effective amount of the pharmaceutical composition to the gastrointestinal tissue by subsequent injection.

[0280] Embodiment

[66] of the present disclosure relates to the method according to any one of embodiments [1]-

[65] , further comprising locally administering a therapeutically effective amount of the pharmaceutical composition to the esophageal tissue by subsequent injection.

[0281] Embodiment

[67] of the present disclosure relates to the method according to any one of embodiments [1]-

[66] , wherein the subject suffers from a chronic inflammatory disease.

[0282] Embodiment

[68] of the present disclosure relates to a method according to any one of embodiments [1]-

[67] , wherein the subject suffers from inflammatory bowel disease, gastroesophageal disease, peptic ulcer disease, radiation injury, chemical ingestion injury, postoperative complications, infection, or any combination thereof.

[0283] Embodiment

[69] of the present disclosure relates to the method according to any one of embodiments [1]-

[68] , wherein the subject suffers from eosinophilic esophagitis.

[0284] Embodiment

[70] of the present disclosure relates to a method according to any one of embodiments [1]-

[69] , comprising preventing or reducing the formation of benign gastrointestinal strictures in a subject at high risk of developing benign strictures.

[0285] Embodiment

[71] of the present disclosure relates to the method according to embodiment

[70] , wherein the subject has been previously treated for at least one benign gastrointestinal stricture.

[0286] Embodiment

[72] of the present disclosure relates to a method according to any one of embodiments [1]-

[69] , comprising treating at least one benign gastrointestinal stenosis in the subject, such that the administration comprises injecting the pharmaceutical composition into the at least one benign gastrointestinal stenosis, and optionally into tissue surrounding the at least one benign gastrointestinal stenosis.

[0287] Embodiment

[73] of the present disclosure relates to the method according to any one of embodiments [1]-

[72] , wherein the subject has been previously treated with dilation therapy.

[0288] Embodiment

[74] of the present disclosure relates to the use of an effective amount of a pharmaceutical composition of the present disclosure in the preparation of a medicament for treating or preventing a gastrointestinal inflammatory disease in a subject, wherein a therapeutically effective amount of the pharmaceutical composition is locally administered to the subject, and wherein the pharmaceutical composition comprises a delayed-release composition formulated for prolonged release of a corticosteroid into the gastrointestinal tissue.

[0289] Embodiment

[75] of the present disclosure relates to a pharmaceutical composition of the present disclosure for treating or preventing a gastrointestinal inflammatory disease in a subject, wherein a therapeutically effective amount of the pharmaceutical composition is locally administered to the subject, and wherein the pharmaceutical composition comprises a delayed-release composition formulated for prolonged release of a corticosteroid into the gastrointestinal tissue.

[0290] Embodiments of the present disclosure

[76] relate to the use of an effective amount of a pharmaceutical composition of the present disclosure in the preparation of a medicament for treating eosinophilic esophagitis, wherein a therapeutically effective amount of the pharmaceutical composition is locally administered to a subject, and wherein the pharmaceutical composition comprises a delayed-release composition formulated for prolonged release of a corticosteroid into the esophageal tissue.

[0291] Embodiment

[77] of the present disclosure relates to a pharmaceutical composition of the present disclosure for use in treating eosinophilic esophagitis, wherein a therapeutically effective amount of the pharmaceutical composition is administered topically in a subject, and wherein the pharmaceutical composition comprises a delayed-release composition formulated for prolonged release of a corticosteroid into esophageal tissue.

[0292] The various embodiments described above can be combined to provide further embodiments. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned in this specification and / or listed in the application data sheet, including U.S. patent application No. 63 / 413,167 filed on October 4, 2022, are incorporated herein by reference in their entirety. If necessary, aspects of the embodiments can be modified to adopt concepts from the various patents, applications, and publications to provide further embodiments.

[0293] These and other changes can be made to the embodiments in light of the above detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and claims, but should be construed to include all possible embodiments and the full scope of equivalents to which such claims are entitled. Therefore, the claims are not limited by this disclosure.

Claims

1. A method for treating eosinophilic esophagitis in a subject in need thereof, the method comprising topically administering to the subject a therapeutically effective amount of a pharmaceutical composition, wherein the pharmaceutical composition comprises a delayed release composition formulated for prolonged release of a corticosteroid into esophageal tissue.

2. The method of claim 1, wherein said administering comprises injecting said pharmaceutical composition into said esophageal tissue.

3. The method of claim 1, wherein said administering comprises multiple injections of said pharmaceutical composition into said esophageal tissue such that at least two of said injections occur at different injection sites in said esophageal tissue.

4. The method of any one of claims 1-3, wherein the administering comprises multiple injections of the pharmaceutical composition into the esophageal tissue such that at least two of the injections occur at injection sites located along a first ring of the esophagus, the first ring being defined by the circumference of the esophagus at a distance d1 above the gastroesophageal junction of the subject. The method of claim 4 , wherein the distance d1 is at least 2 cm above the gastroesophageal junction.

6. The method of claim 4 or 5, wherein the injection sites located along the first ring of the esophagus are equidistantly distributed relative to each other along the circumference of the first ring.

7. The method of any one of claims 4-6, wherein the pharmaceutical composition is injected at least twice into injection sites located along a second ring of the esophagus, the second ring being defined by the circumference of the esophagus at a distance d2 above the gastroesophageal junction, wherein the distance d2 is greater than the distance d1. The method of claim 7 , wherein the distance d2 is at least 1 cm greater than the distance d1 .

9. The method of claim 7 or 8, wherein the injection sites located along the second ring of the esophagus are equidistantly distributed relative to each other along the circumference of the second ring.

10. The method of any one of claims 1-9, wherein the administering comprises multiple injections of the pharmaceutical composition into the esophageal tissue such that injections occur at injection sites located along a plurality of rings of the esophagus, the plurality of rings being defined by respective circumferences of the esophagus at respective distances above the gastroesophageal junction of the subject, and wherein the pattern of injection sites within the esophagus is a spiral pattern relative to the longitudinal axis of the esophagus.

11. The method of any one of claims 1-10, wherein the pharmaceutical composition is injected at least once into an area of ​​esophageal inflammation.

12. The method of any one of claims 1-11, wherein the administering comprises one or more injections of the pharmaceutical composition into the esophageal tissue such that each injection independently contains 0.1 to 20 mg of the corticosteroid.

13. The method of any one of claims 1-12, wherein the corticosteroid comprises a glucocorticoid agonist.

14. The method according to any one of claims 1 to 13, wherein the corticosteroid comprises at least one selected from the group consisting of deoxycorticosterone, hydrocortisone, cortisone, methylprednisolone, prednisone, prednisolone, triamcinolone, dexamethasone, betamethasone, beclomethasone, beclomethasone-17,21-dipropionate, budesonide, flunisolide, fludrocortisone, mometasone, fluticasone, alclomethasone, clocortolone, flurandrenolide, fluocinolone acetate, hydrocortisone acetate, fluorometholone, fluocinolone acetonide, diflucortolone valerate, paramethasone acetate, halcinonide, hydrocortisone phosphate, clobetasone butyrate, amcinonide, prednisolone succinate, and pharmaceutically acceptable salts and / or esters thereof.

15. The method of any one of claims 1-14, wherein the corticosteroid comprises fluticasone or a pharmaceutically acceptable salt or ester thereof.

16. The method of any one of claims 1-15, wherein the corticosteroid comprises fluticasone propionate.

17. The method of any one of claims 1-16, wherein the corticosteroid is crystalline.

18. The method of any one of claims 1-17, wherein the delayed release composition comprises the corticosteroid and a hydrophilic polymer.

19. The method according to any one of claims 1 to 18, wherein the delayed release composition comprises core-shell microparticles comprising: (1) a crystalline drug core comprising one or more of said corticosteroid crystals; and (2) a polymer shell encapsulating the crystalline drug core, the polymer shell being in contact with but not miscible with the crystalline drug core, And wherein the proportion of the crystalline drug core in the microparticles is more than 70 weight % relative to the total weight of the microparticles.

20. The method of claim 18, wherein the crystalline drug core comprises 100% of the corticosteroid.

21. The method of claim 19 or 20, wherein the polymer shell comprises a hydrophilic polymer.

22. The method of any one of claims 19-21, wherein the polymer shell comprises one or more biodegradable polymers selected from the group consisting of polyvinyl alcohol (PVA), ethylene vinyl acetate (EVA), polyparaxylene polymers, polylactic acid (PLA), polyglycolic acid (PGA), polylactic-co-glycolic acid (PLGA), poly-ε-caprolactone (PCL), polyvalerolactone (PVL), poly-ε-decanolactone (PDL), poly-1,4-dioxane-2,3-dione, poly-1,3-dioxane-2-one, poly-p-dioxanone (PDS), polyhydroxybutyric acid (PHB), polyhydroxyvaleric acid (PHV), and poly-β-malic acid (PMLA).

23. The method of any one of claims 19-22, wherein the polymer shell comprises polyvinyl alcohol (PVA).

24. The method of any one of claims 19-23, wherein the microparticles comprise 90-98% w / w of the crystalline drug core and 2-10% w / w of the polymer shell.

25. The method of any one of claims 1-24, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable vehicle comprising water and an excipient capable of suspending the delayed release composition in an aqueous medium.

26. The method of claim 25, wherein the excipient is selected from the group consisting of a binder, a suspending agent, a disintegrant, a filler, a surfactant, a solubilizer, a stabilizer, a lubricant, a wetting agent, a diluent, and combinations thereof.

27. The method of claim 25 or 26, wherein the excipient is selected from the group consisting of polysorbates, polysaccharides, acidic salts, basic salts, neutral salts, and combinations thereof.

28. The method according to any one of claims 1-27, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable vehicle containing: 0.05 to 0.1 weight % of polysorbate 80 relative to the total weight of the pharmaceutically acceptable vehicle; 0.1 to 2.0 wt % carboxymethyl cellulose (CMC); and 0.1 to 2.0 wt% sodium chloride, the vehicle is dissolved in sterile water.

29. The method of any one of claims 1-27, further comprising administering a topical agent to the esophageal tissue, wherein the topical agent comprises an additional corticosteroid.

30. The method of any one of claims 1-29, further comprising locally administering a therapeutically effective amount of the pharmaceutical composition to the esophageal tissue by subsequent injection.

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