Use of long-acting fluticasone propionate injectable suspension for the treatment and prevention of gastrointestinal inflammation

Abstract

Disclosed herein are methods for treating or preventing inflammatory disorders of the gastrointestinal (GI) tract by topically administering a pharmaceutical composition comprising a sustained release composition formulated for extended release of a corticosteroid to GI tissue.

Description

[Technical Field]

[0001] The present disclosure relates to the use of corticosteroids in the treatment and prevention of inflammation, and more particularly to methods of treating or preventing benign strictures of the gastrointestinal (GI) tract and eosinophilic esophagitis (EoE) using injectable compositions comprising sustained-release compositions formulated for the long-term (or extended) release of corticosteroids to esophageal tissue. [Background technology]

[0002] 2. Description of Related Art Eosinophilic esophagitis (EoE) is a rare, chronic, immune-mediated disease characterized by inflammation and the accumulation of large numbers of eosinophils within the esophageal epithelial lining. Eosinophils accumulate in the esophagus, triggering the release of eosinophilic inflammatory cytokines, resulting in inflammation. This inflammation can be accompanied by pain, difficulty swallowing, nausea / vomiting, abdominal / chest pain, and food obstruction, and severe cases may require medical treatment.

[0003] As shown in Figure 1, in human subjects (2), inflammation caused by EoE (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).

[0004] Current treatments for EoE include non-pharmacological interventions such as dietary restriction, mechanical interventions such as endoscopic dilation, and pharmacological interventions. Pharmacological interventions primarily consist of the use of orally administered topical corticosteroids (STCs). The U.S. Food and Drug Administration (FDA) has also approved Dupixent for the treatment of people aged 12 years and older. Dupixent is a subcutaneously administered monoclonal antibody. Jorvezza, an orally disintegrating tablet of budenoside, is approved in Europe but not in the United States. The American Gastroenterological Association and the Allergy and Immunology Joint Task Force (AGA-JTF) recommend the use of STCs such as budesonide and fluticasone. The AGA-JTF recommends topical corticosteroids over systemic corticosteroids for the long-term treatment of EoE to prevent long-term complications.

[0005] Currently available treatments for EoE present significant challenges. Dupixent is effective in only 60% of patients, with 18% experiencing upper respiratory tract infections. Furthermore, adherence and cost are common barriers due to the recommended weekly dosing regimen. Similarly, adherence to Jorveza is also problematic due to the potential for disease recurrence in certain patients and the requirement for twice-daily dosing. Patients taking Jorveza also suffer from side effects, such as oropharyngeal candidiasis, which reportedly occurred in 64% of patients taking high doses, necessitating discontinuation of the drug. Other corticosteroid treatments, such as inhaled or aqueous solutions, are also used, but suffer from numerous issues, including the need for multiple daily doses, poor topical absorption, and disease recurrence upon discontinuation. While topical corticosteroids recommended by the AGA-JTF are effective, they are generally only useful for short-term treatment and are prone to recurrence upon discontinuation.

[0006] There is a need for treatments for EoE that improve efficacy and patient compliance while reducing side effects.

[0007] Benign GI strictures are pathological conditions characterized by the formation of localized luminal narrowing within the gastrointestinal (GI) tract and are non-neoplastic and non-malignant in nature. These strictures typically result from the development of fibrous scar tissue or collagen deposits within the mucosal and submucosal layers of the GI tract wall, leading to luminal narrowing. Benign GI strictures can occur in various anatomical segments, including the esophagus, stomach, bile duct, small intestine, and large intestine. Typical medical symptoms associated with benign strictures vary depending on the location of the stricture and include dysphagia, odynophagia, reflux, heartburn or acid reflux, epigastric pain, nausea, vomiting, abdominal distension, changes in bowel habits, and weight loss. Symptoms range from mild to severe to critical, and in extreme cases, can be fatal.

[0008] Current strategies for treating benign gastrointestinal strictures include endoscopic dilation, medical therapy, and surgical intervention. Endoscopic dilation involves mechanically controlling dilation using an endoscope to expand the stricture and improve luminal patency. Medical therapy, particularly in cases associated with inflammatory diseases such as inflammatory bowel disease (IBD), typically involves the administration of anti-inflammatory medications, which may reduce inflammation and improve stricture-related symptoms. In cases of severe strictures or complications, surgical resection or strictureplasty may be required to remove the affected segment or restore luminal continuity. Summary of the Invention [Problem to be solved by the invention]

[0009] Despite the availability of various strategies to treat benign strictures, there remains a significant unmet need for patients with strictures. [Means for solving the problem]

[0010] Described herein are methods for treating or preventing inflammatory disorders in a subject by administering sustained-release compositions to tissues of the gastrointestinal (GI) tract by injection, topical application, ingestion, or a combination thereof. Also disclosed are pharmaceutical compositions that allow for the long-term (or extended) release of corticosteroids to healthy or inflamed tissues of the GI tract.

[0011] One embodiment provides a method of treating eosinophilic esophagitis (EoE) in a subject in need thereof by locally administering to the subject a therapeutically effective amount of a pharmaceutical composition, wherein the pharmaceutical composition comprises a sustained-release composition formulated for extended (or prolonged) release of a corticosteroid to the esophageal tissue. In some embodiments, the pharmaceutical composition is administered by injection into the esophageal tissue. In some embodiments, the esophageal tissue is injected with the pharmaceutical composition multiple times, with at least two of the injections occurring at different injection sites within the esophageal tissue.

[0012] Another embodiment relates to a method of treating or preventing an inflammatory disease in the GI tract in a subject in need thereof by locally administering to the subject a therapeutically effective amount of a pharmaceutical composition, wherein the pharmaceutical composition comprises a sustained release composition formulated for sustained release of a corticosteroid to tissue of the GI tract. In some embodiments, the tissue comprises esophageal tissue, stomach tissue, bile duct tissue, small intestinal tissue, large intestinal tissue, or any combination thereof. In some embodiments, administering comprises injecting the pharmaceutical composition into tissue of the GI tract (such as a benign stricture).

[0013] The following figures illustrate embodiments in which like reference numerals refer to like parts: Embodiments are illustrated by way of example, and not by way of limitation, in all accompanying figures. [Brief explanation of the drawings]

[0014] [Figure 1] 1 shows a human subject suffering from eosinophilic esophagitis (EoE). [Figure 2] Schematic representation of a core / shell morphology of microparticles. [Figure 3] The patient's esophagus is shown with a circumferential ring (ring 1) at a fixed distance (d1) above the gastroesophageal (GE) junction. Additional circumferential rings (ring 2, ring 3, ring 4) are also shown at increasing distances (d2, d3, d4) above the GE junction. [Figure 4] The injection site is shown located along the first ring of the esophagus, defined by the circumference of the esophagus at a distance d1 from above the gastroesophageal (GE) junction. [Figure 5] A flattened view of a subject's esophagus is shown, with multiple injections occurring at injection sites located along the first ring of the esophagus, defined by the circumference of the esophagus at a distance d1 above the gastroesophageal (GE) junction. [Figure 6] 1 shows a flattened view of a subject's esophagus with multiple injections at injection sites along different rings of the esophagus, with injections into adjacent rings offset from each other. [Figure 7]1 shows a flattened view of a subject's esophagus with multiple injections at injection sites along different rings of the esophagus, with injections into adjacent rings offset from each other. [Figure 8] 1 shows a flattened view of the esophagus of a subject receiving multiple injections, both the initial and subsequent dose injections. [Figure 9] 1 shows a flattened view of a subject's esophagus in which multiple injections are performed in a spiral pattern relative to the longitudinal axis of the esophagus. [Figure 10] Demonstrates the pathology of eosinophilic esophagitis (EoE), which includes the formation of focal strictures (narrowing) of the esophagus. DETAILED DESCRIPTION OF THE INVENTION

[0015] Described herein are methods for treating or preventing inflammatory diseases of the GI tract (such as benign strictures and eosinophilic esophagitis) by administering a sustained-release composition to the GI tissue of a human subject. The pharmaceutical composition, including the sustained-release composition, can be administered by injection, topical administration, oral ingestion, or a combination thereof. A pattern for injecting the pharmaceutical composition into esophageal tissue is described below, which may involve multiple injections to administer the sustained-release composition to controlled regions of the esophagus, which may or may not include inflamed areas.

[0016] definition The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0017] As used herein, the term "about" means that the parameter being described may include a deviation of ±10 percent.

[0018] As used herein, unless expressly stated otherwise, the word "or" means "either / or" but is not limited to "either / or." Alternatively, "or" may mean "and / or."

[0019] As used herein, the terms "active pharmaceutical ingredient," "therapeutic agent," or "drug" refer to one or more corticosteroids.

[0020] As used herein, the term "benign stricture" means a narrowing of a portion of the digestive tract, such as a narrowing of the esophagus, that is not caused by cancer.

[0021] As used herein, the term "biodegradable" means capable of being partially or completely dissolved or broken down in living tissue, particularly the tissue of a human or other mammal. A biodegradable compound may be broken down by any mechanism, including, but not limited to, hydrolysis, catalytic action, enzymatic action, etc.

[0022] "Blebs" refer to thin-walled, bladder-like structures (similar to blisters) that may be filled with fluid.

[0023] "Body compartment" refers to a space or cavity within a vertebrate (including a human) that can be accessed by injection. Typically, a body compartment is at least semi-enclosed or completely surrounded by hard or soft tissues (such as bone, membranes, and ligamentous structures) that define the space. Soft tissue is typically present and may have varying degrees of vascularization. More specifically, a body compartment may be a naturally occurring anatomical space, such as esophageal tissue. Additionally, a body compartment may be a surgically created space (e.g., a pocket for inserting an implant device, a soft tissue implant such as a breast implant, etc.) or any space near an implant that can be accessed by injection.

[0024] "Coating solution" refers to a solution of a preformed polymer (e.g., a commercially available polymer) suitable for coating a drug core according to methods known in the art, such as fluidized bed coating.

[0025] As used herein, the terms "crystalline drug core," "core particle," and "drug core" refer interchangeably to a preformed particle containing a single crystal or multiple crystals of a drug. The drug core is encapsulated in a polymer shell. The core particle may further contain 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 thereof. In preferred embodiments, the drug core is substantially pure drug (i.e., at least 90%, or at least 95%, or at least 98% of the total weight of the drug core is drug). In preferred embodiments, the drug core is 100% crystalline drug.

[0026] "EC50" is the concentration of a therapeutic drug that produces 50% of its maximum effect, such as reducing inflammation or pain.

[0027] The term "esophageal tissue" refers to tissue or body compartments associated with the esophagus of a subject or patient.

[0028] "Local concentration" refers to the concentration of a corticosteroid drug within a body compartment (as defined herein), including the concentration in a tissue or body compartment within the body.

[0029] As used herein, the term "microparticle" refers to a particle having an average dimension of less than 1 mm. Microparticles can have any three-dimensional geometric shape, including but not limited to, spherical, acicular, ellipsoidal, cylindrical, polyhedral, and irregular shapes.

[0030] Microparticles are coated crystalline drug particles. As used herein, microparticles (14) have a "core / shell" morphology, as shown schematically in FIG. 2, in which a drug core (16) is encapsulated by a polymer shell (18). In some embodiments, the polymer shell is a homogeneous polymer coating formed, for example, by a fluidized bed process. See, e.g., WO 2014 / 153541. In other embodiments, the polymer shell (18) can comprise one or more individual thin coatings of the same or different polymers (two coatings, 20 and 22, are shown), formed, for example, by a dipping process. See, e.g., WO 2014 / 153541. Importantly, because the polymer shell (18) is formed from a polymer coating that is immiscible with the drug core, the interface (24) between the drug core and the polymer shell is sharp with minimal amounts of drug or polymer (e.g., less than 5%, less than 1%, or less than 0.5% of the total weight of the drug or polymer is mixed). Because the drug core contains a highly hydrophobic corticosteroid drug, the polymer shell contains 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 during the sustained-release period.

[0031] A "minimum therapeutically effective amount" is the smallest amount of a therapeutic agent that can produce a therapeutic effect (eg, pain relief or anti-inflammatory).

[0032] As used herein, a "patient" or "subject" to be treated by the methods according to various embodiments may mean either a human or a non-human animal, such as a primate, mammal, or vertebrate.

[0033] "Plasma concentration" refers to the concentration of a corticosteroid drug in plasma or serum. Injectable microparticles, for example, are capable of highly localized release over an extended period of time while maintaining plasma concentrations low enough to minimize HPA axis suppression during the sustained release period.

[0034] The term "multiple" means "two or more" unless expressly specified otherwise. For example, "multiple" may simply refer to multiple injections into esophageal tissue.

[0035] As used in this disclosure, the "ring" of the esophagus is the ring-shaped region of the esophagus defined by the circumference of the esophagus a certain distance above the gastroesophageal (GE) junction.

[0036] The term "subjects at high risk of benign stricture formation" refers to subjects suffering from a chronic inflammatory process (such as inflammatory bowel disease), subjects with gastroesophageal pathology (such as gastroesophageal disease or eosinophilic esophagitis), subjects who have previously been treated for benign gastrointestinal stricture, subjects suffering from peptic ulcer disease, subjects suffering from radiation injury, subjects suffering from chemical ingestion, subjects suffering from post-surgical complications, subjects suffering from an infection, etc.

[0037] The term "submucosa" refers to the layer of tissue below the mucosa (eg, the lining of some organs and body cavities that produces mucus).

[0038] When used in reference to a therapeutic agent or drug (e.g., a corticosteroid), the terms "sustained release," "extended release," or "long-term release" are used interchangeably. Sustained release refers to the continuous release of a therapeutic agent over an extended period of time following a single dose, with the therapeutic effect being sustained throughout the entire release period.

[0039] "Sustained release" is in contrast to bolus administration, in which the entire amount of active agent / substance is bioavailable at once. However, "sustained release" may include an initial rapid release followed by a longer, prolonged period of slower release. As explained in more detail below, the microparticle structure minimizes the initial rapid release (e.g., burst release) and allows for an extended period of sustained release, achieving a nearly constant release profile regardless of drug concentration. "Sustained release" should provide at least a minimum therapeutically effective amount (as defined herein) of corticosteroid during the release period. It should be understood that the minimum therapeutically effective amount of corticosteroid will vary depending on the severity of the inflammation and / or pain being addressed.

[0040] Within the scope of the present disclosure, sustained release of the corticosteroid is achieved through the unique structure of core / shell microparticles. Specifically, a crystalline corticosteroid drug core is encapsulated by a polymer shell composed of one or more polymer coatings, each of which is permeable to the corticosteroid. In preferred embodiments, all layers comprise the same polymer. In other embodiments, two to four layers of polymer are coated onto the corticosteroid, with each layer progressively slowing the release of the active ingredient, collectively providing the desired sustained release. Furthermore, sustained release of the corticosteroid is achieved by tailoring this delivery platform to the aqueous or sink environment of a body compartment (e.g., esophageal tissue).

[0041] "Sustained-release period" or "extended-release period" refers to the entire 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 will 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 will be determined by the attending physician.

[0042] The phrase "therapeutically effective amount" refers to an amount of therapeutic agent that, when delivered to a body compartment (e.g., submucosally) in the form of coated microparticles as defined herein, results in a degree of reduction in inflammation or pain in a patient's body compartment (e.g., the esophageal wall) (at a reasonable benefit / risk ratio applicable to any medical procedure). The effective amount of therapeutic agent can vary depending on factors such as the type and severity of inflammation being treated, the progression of the inflammation, the level of pain experienced by the patient, the particular microparticles administered, the active agent, and / or the size, age, and 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 specified, "therapeutically effective amount" refers to the amount of therapeutic agent that is localized within a body compartment.

[0043] The term "treating" is art-recognized and includes treating a disease or condition by ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected.

[0044] "Unit dosage form" refers to a physically discrete unit (e.g., a filled syringe cylinder) suitable as a unitary dosage for a human subject, each unit containing a predetermined amount of a therapeutic agent associated with a pharmaceutically acceptable vehicle, the amount of therapeutic agent being calculated to produce a desired therapeutic effect over a desired period of time.

[0045] "Vehicle" refers to a non-toxic carrier, adjuvant, or solvent in which microparticles are suspended. This vehicle does not alter or destroy the pharmacological activity of the therapeutic agent incorporated therein. Pharmaceutically acceptable carriers or vehicles that can be used in the composition include, but are not limited to, water, saline, hyaluronic acid, carboxymethylcellulose (CMC), and the like. As used herein, the term "biocompatible" means characterized by not eliciting a toxic, harmful, or immunological response upon contact with living tissue, particularly the tissue of humans or other mammals.

[0046] As used herein, the term "substantially insoluble" means having a solubility of less than 1 part solute per 1000 parts solvent or vehicle by weight.

[0047] As used herein, the term "hydrophobic" means having a lower affinity for aqueous solvents than for organic solvents.

[0048] As used herein, the term "hydrophilic" means having a lower affinity for organic solvents than for aqueous solvents.

[0049] The recitation herein of a numerical range for a variable is intended to convey that the disclosure can be practiced with the variable equal to any value within that range. Thus, for a variable that is discrete in nature, the variable can be equal to any integer value within that numerical range, including the end-points of the range. Similarly, for a variable that is continuous in nature, the variable can be equal to any integer value within that numerical range, including the end-points of the range. By way of example, and without limitation, a variable described as having a value between 0 and 2 can take on values ​​of 0, 1, or 2 if the variable is discrete in nature, or 0.0, 0.1, 0.01, 0.001, or any other real value between 0 and 2 if the variable is continuous in nature.

[0050] Methods for treating or preventing gastroenteritis The disclosed methods include treating or preventing inflammatory disorders of the gastrointestinal (GI) tract in a subject in need thereof by locally administering to the subject a therapeutically effective amount of a pharmaceutical composition, wherein the pharmaceutical composition comprises a sustained-release composition formulated for extended release of a corticosteroid to gastrointestinal tissue. In some embodiments, the tissue comprises esophageal tissue, stomach tissue, bile duct tissue, small intestine tissue, large intestine tissue, or any combination thereof. In some embodiments, the tissue is esophageal tissue. In some embodiments, administering comprises injecting the pharmaceutical composition into the tissue. For example, administering may include injecting the pharmaceutical composition into esophageal tissue. In some embodiments, administering comprises at least one submucosal injection of the pharmaceutical composition into the tissue.

[0051] In some embodiments, administering comprises injecting at least one initial dose of the pharmaceutical composition into the tissue. Administering may comprise injecting at least two initial doses of the pharmaceutical composition into the tissue. In some embodiments, administering comprises multiple injections of the pharmaceutical composition into the tissue, with at least two of the injections occurring at different injection sites within the tissue. For example, in some embodiments, administering comprises at least one injection of the pharmaceutical composition into an inflamed area of ​​the gastrointestinal tract, at least one injection of the pharmaceutical composition into an injection site not located in an inflamed area of ​​the gastrointestinal tract, or a combination thereof.

[0052] In some embodiments, the method of treating or preventing inflammation further comprises locally administering a therapeutically effective amount of the pharmaceutical composition to tissue of the gastrointestinal tract by subsequent injection, for example, in some embodiments, the method further comprises locally administering a therapeutically effective amount of the pharmaceutical composition to tissue of the esophagus by subsequent injection.

[0053] Methods for treating inflammatory diseases of the GI tract include methods for treating benign GI strictures, wherein administering comprises injecting the pharmaceutical composition at least once into at least one benign focal stricture in the GI tract of a subject. In some embodiments, administering comprises injecting the pharmaceutical composition at least once into the GI tissue (e.g., the focal benign stricture) to form at least one bleb comprising the sustained-release composition.

[0054] In some embodiments, the administration comprises one or more injections of the pharmaceutical composition into the tissue, each injection independently comprising about 0.1 mg to about 20 mg, or about 0.5 mg to about 10 mg, or about 1 mg to about 8 mg, or about 1 mg to about 6 mg, or about 2 mg to about 12 mg, or about 3 mg to about 8 mg, or about 5 mg to about 20 mg, or about 5 mg to about 15 mg, or about 6 mg to about 14 mg, or about 7 mg to about 18 mg, or about 7 mg to about 16 mg, or about 8 mg to about 20 mg, or about 8 mg to about 16 mg, or about 9 mg to about 18 mg, or about 9 mg to about 15 mg, or about 10 mg to about 20 mg, or about 10 mg to about 18 mg, or about 10 mg to about 16 mg of the corticosteroid.

[0055] In some embodiments, the method of treating or preventing inflammation (e.g., localized benign stricture(s)) may include the additional step of administering a topical agent to tissue of the gastrointestinal tract. For example, in some embodiments, the method further includes administering a topical agent to esophageal tissue. The topical agent may include an additional corticosteroid.

[0056] In some embodiments, the method of treating or preventing inflammation (e.g., focal stricture(s)) 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 uptake disorder, post-operative complications, infusion, or any combination thereof. As described below, in some embodiments, the subject may suffer from eosinophilic esophagitis (EoE).

[0057] In some embodiments, the disclosed methods include preventing or reducing the formation of benign GI strictures in subjects at high risk for benign stricture formation. For example, in some embodiments, the subject has previously been treated for at least one benign GI stricture but does not currently exhibit a benign GI stricture.

[0058] In some embodiments, the methods of the present disclosure include treating at least one benign GI stricture in a subject by injecting a pharmaceutical composition into the at least one benign GI stricture and, optionally, into tissue surrounding the at least one benign GI stricture, hi some embodiments, the subject has previously been treated with dilation therapy.

[0059] Some embodiments relate to the use of an effective amount of a pharmaceutical composition of the present disclosure for the preparation of a medicament for treating or preventing an inflammatory disease in the gastrointestinal tract (such as benign GI stricture) in a subject, wherein a therapeutically effective amount of the pharmaceutical composition is topically administered to the subject, and the pharmaceutical composition comprises a sustained release composition formulated for extended release of a corticosteroid to the tissues of the gastrointestinal tract. Some embodiments relate to a pharmaceutical composition of the present disclosure for use in treating or preventing an inflammatory disease in the gastrointestinal tract (such as benign GI stricture) in a subject, wherein a therapeutically effective amount of the pharmaceutical composition is topically administered to the subject, and the pharmaceutical composition comprises a sustained release composition formulated for extended release of a corticosteroid to the tissues of the gastrointestinal tract.

[0060] Methods of the present disclosure also include a method of treating eosinophilic esophagitis in a subject in need thereof by locally administering to the subject a therapeutically effective amount of a pharmaceutical composition, the pharmaceutical composition comprising a sustained release composition formulated for extended release of a corticosteroid to esophageal tissue.

[0061] In some embodiments, administering comprises injecting the pharmaceutical composition into the esophageal tissue of the subject to be treated. The injection can be subcutaneous or intradermal, from inside the esophagus, or from outside (e.g., externally) the esophagus. For example, in some embodiments, at least one submucosal injection of the pharmaceutical composition into the esophageal tissue is performed to administer the sustained-release composition. In other embodiments, the pharmaceutical composition can be administered locally to the subject's esophagus, or both locally and by injection.

[0062] Injection of the pharmaceutical composition into the esophageal tissue includes injection of at least one initial dose (to initiate treatment) and may also include injection of at least one secondary (or subsequent) dose.

[0063] The dose of corticosteroid contained in each injection can be varied to suit different subjects, tissues, and levels of inflammation. In some embodiments, administration comprises one or more injections of the pharmaceutical composition into the esophageal tissue, each injection independently comprising from about 0.1 mg to about 20 mg of corticosteroid. For example, the dose of corticosteroid contained in each injection may 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.

[0064] In some embodiments, the method further comprises administering a topical agent to the esophageal tissue. For example, the method can include the additional or simultaneous step of administering a topical agent to the esophageal tissue, where the topical agent comprises an additional corticosteroid.

[0065] Some embodiments relate to the use of an effective amount of a pharmaceutical composition of the present disclosure for the preparation of a medicament for the treatment of eosinophilic esophagitis, wherein a therapeutically effective amount of the pharmaceutical composition is topically administered to a subject, and the pharmaceutical composition comprises a sustained release composition formulated for extended release of a corticosteroid to esophageal tissue. Some embodiments relate to a pharmaceutical composition of the present disclosure for use in the treatment of eosinophilic esophagitis, wherein a therapeutically effective amount of the pharmaceutical composition is topically administered to a subject, and the pharmaceutical composition comprises a sustained release composition formulated for extended release of a corticosteroid to esophageal tissue.

[0066] Esophageal injection As explained above, the methods of the present disclosure can include treating or preventing inflammatory diseases of the GI tract (such as benign GI strictures or eosinophilic esophagitis) by injecting a therapeutically effective amount of a sustained-release corticosteroid into esophageal tissue.

[0067] In some embodiments, administering comprises multiple injections of the pharmaceutical composition into the esophageal tissue, with at least two of the injections occurring at different injection sites within the esophageal tissue. For example, administering may comprise injecting at least two initial 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 region of the esophagus by performing injections both inside and outside the esophagus (i.e., externally).

[0068] In some embodiments, the injection site is located on the esophageal ring. As used in the context of this disclosure, the "esophageal ring" is a ring-shaped region of the esophagus defined by the circumference of the esophagus at a fixed distance above the gastroesophageal (GE) junction. Generally, all injection points along the esophageal ring occur at approximately the same distance above the GE junction. Injections into the esophageal ring may occur at the same location along the circumference of the ring or at different locations along the circumference of the ring.

[0069] The methods of the present invention may be practiced such that the administration comprises multiple injections of the pharmaceutical composition into esophageal tissue, with at least two of the injections occurring at injection sites located along a first ring of the esophagus, defined by the circumference of the esophagus at a distance d1 above the gastroesophageal (GE) junction of the subject.

[0070] Figure 3 illustrates one such embodiment in which four rings of the esophagus (4), namely, first ring (28), second ring (30), third ring (32), and fourth ring (34), are defined based on their respective distances dl (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.

[0071] In some embodiments, distance d1 (36) is at least 2 cm above 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 above GE junction (8). In some embodiments, distance d2 (38) is at least 1 cm greater 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 greater than distance d1 (36).

[0072] FIG. 4 illustrates an embodiment in which a single injection of a pharmaceutical composition into esophageal tissue occurs at an injection point (44) located on the first ring (28) of the esophagus (4), defined by the circumference of the esophagus (4) located a distance d1 (36) from the GE junction (8). In this illustration, injection of the pharmaceutical composition optionally forms a bleb (46) containing the sustained release composition. In other embodiments, injection of the pharmaceutical composition does not form a bleb. In some embodiments, injection sites (44) located along the first ring (28) of the esophagus (4) are equidistant from one another around the circumference of the first ring (28). However, in other embodiments, injection sites located along the first ring (28) of the esophagus (4) are not equidistant from one another around the circumference of the first ring (44).

[0073] In some embodiments, the injection into the esophageal ring is not placed exactly at the distance d from the ring above the GE junction. The injection can be placed above or below the distance d from the ring. For example, as shown in FIG. 4, injection (45) is placed above the second ring (30); in this embodiment, injection (45) does not form a bleb. The injection site into a particular ring of the esophagus can vary by as much as 1 cm above or below the particular ring. In some embodiments, the injection site is located about 0.1 cm to about 1.0 cm, or about 0.2 cm to about 0.8 cm, or about 0.3 cm to about 0.7 cm, or about 0.4 cm to about 0.6 cm, or about 0.1 cm to about 0.5 cm, or about 0.3 cm to about 0.7 cm, or about 0.5 cm to about 0.9 cm above or below the particular ring. In some embodiments, multiple injections into the same ring of the esophagus can be performed in such a way that the injections are placed at different distances from the distance d from the ring above the GE junction.

[0074] Figure 5 shows a flattened view 5 of the esophagus 4 for an embodiment in which four injections are performed at different injection sites 44-1, 44-2, 44-3, and 44-4 located along a first ring 28 of the esophagus 4, defined by a circumference of distance d1 36, where 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. As a result, as shown in Figure 5, 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. In some embodiments, as also shown in FIG. 5, blebs (46-1, 46-2, 46-3, and 46-4) may form at one or more of the injection sites (44-1, 44-2, 44-3, and 44-4).

[0075] In some embodiments, at least three injections are performed at injection sites located along the ring. In other embodiments, the number of injections at different injection sites located along the ring may range from 2 to 10. Such multiple injections may be equidistant from one another or may not be equidistant from one another.

[0076] As shown in the flattened views of Figures 6A-6B, the pharmaceutical composition can be injected into multiple rings within the subject's esophagus.

[0077] 6 illustrates an embodiment in which four rings of the esophagus (28, 30, 32, and 34) are injected, with injections into adjacent rings offset from one another. Thus, the injection sites (50-1 and 50-2) into 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) into the second ring (30) are located in the second and fourth quadrants (48-2 and 48-4) of the esophagus.

[0078] 7 illustrates an embodiment in which injections are made into four rings of the esophagus (28, 30, 32, 34) and injections into adjacent rings are not offset from one another, so that all four injections into each of the first, second, third, and fourth rings (28, 30, 32, and 34) are within the first, second, third, or fourth quadrant (48-1, 48-2, 48-3, and 48-4) of the esophagus.

[0079] The methods of the present disclosure can include administering to esophageal tissue one or more initial dose injections and one or more subsequent injections, each containing a therapeutically effective amount of a pharmaceutical composition.

[0080] 8 illustrates an embodiment in which both the initial dose injection (denoted by ●) and subsequent dose injections (denoted by ○) are performed into four esophageal rings (28, 30, 32, and 34), with the injections (initial dose and subsequent doses, respectively) into adjacent rings being offset from one another. Thus, the injection sites (54-1 and 54-2) for the initial dose (●) into the first ring (28) are located in the first and third quadrants (48-1 and 48-3) of the esophagus, while the injection sites (56-1 and 56-2) for the initial dose (●) into the second ring (30) are located in the second and fourth quadrants (48-2 and 48-2) of the esophagus, with the subsequent dose injections (○) into adjacent rings (55-1, 55-2, 57-1, and 57-2) similarly offset as shown in FIG. 6C. In other embodiments, the injection of the initial dose and / or the injection of the subsequent doses may or may not be offset from one another.

[0081] FIG. 9 illustrates an embodiment in which the pattern of injection sites (58-1, 58-2, 58-3, and 58-4) within the esophagus is a spiral pattern relative to the longitudinal axis of the esophagus.

[0082] Multiple injections of the pharmaceutical composition may be performed within multiple rings within the subject's esophagus. For example, injections may be performed at injection sites along at least three, four, five, six, seven, or eight rings of the esophagus, as defined by the respective circumferences of the esophagus at the respective distances of the rings above the gastroesophageal junction of the subject.

[0083] In some embodiments, at least one injection of the pharmaceutical composition is administered into the area of ​​esophageal inflammation, at least one injection of the pharmaceutical composition is administered into an injection site not located in the area of ​​esophageal inflammation, or a combination thereof. For example, in some embodiments, at least one injection of the pharmaceutical composition is administered into the area of ​​esophageal inflammation, at least one injection of the pharmaceutical composition is administered into an area adjacent to the area of ​​esophageal inflammation, or a combination thereof. With regard to injections administered into an injection site located in the area of ​​esophageal inflammation, at least one injection of the pharmaceutical composition may be administered into a localized benign stricture in the subject's esophagus. In some embodiments, at least one injection of the pharmaceutical composition is administered into the localized benign stricture, at least one injection of the pharmaceutical composition is administered into an area adjacent to the localized benign stricture, or a combination thereof.

[0084] Figure 10 shows a localized narrowing (60) of the esophagus (4) of a human subject suffering from EoE. Unlike the normal portion (62) of the esophagus (4), inflammation caused by EoE can lead to the formation of a circular ring (64) within the esophagus and a narrowing (66). In extreme cases, this inflammation can result in a localized benign narrowing (60), restricting or obstructing the flow of food and fluids from the throat to the stomach (10). In some embodiments, at least one injection of a pharmaceutical composition is administered within the localized benign narrowing (60).

[0085] Corticosteroids As explained above, the pharmaceutical compositions of the present disclosure include sustained release compositions formulated for extended release of a corticosteroid to esophageal tissue, hi some embodiments, the corticosteroid comprises a glucocorticoid agonist. For example, the corticosteroid can include at least one selected from desoxycorticosone, hydrocortisone, cortisone, methylprednisolone, prednisone, prednisolone, triamcinolone, dexamethasone, betamethasone, beclomethasone, beclomethasone-17,21-dipropionate, budesonide, flunisolide, fludrocortisone, mometasone, 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.

[0086] 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, as shown below. [ka]

[0087] Corticosteroids of the present disclosure may include crystalline corticosteroids, which are described in U.S. Patent No. 9,987,233, the entire contents of which are incorporated herein by reference.

[0088] fine particles In some embodiments, the sustained release composition comprises a corticosteroid and a hydrophilic polymer, which may be in the form of microparticles having a core / shell morphology. The core / shell microparticles described herein are constructed to exhibit a sustained release profile that is particularly suitable for highly localized, long-term delivery of corticosteroid drugs in body compartments such as esophageal tissue.

[0089] In some embodiments, the sustained-release composition has a core-shell structure. For example, the sustained-release composition can include microparticles comprising: (1) a crystalline drug core comprising one or more crystals of a corticosteroid; and (2) a polymer shell encapsulating the crystalline drug core, wherein the polymer shell is in contact with but immiscible 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, based on the total weight of the microparticles.

[0090] The microparticles of the present disclosure may have an average diameter in the range of 50 μm to 800 μm, with a standard deviation of less than 50% of the average diameter. In some embodiments, greater 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.

[0091] In some embodiments, the crystalline drug core comprises about 100% corticosteroid. The crystalline core is prepared from recrystallized drug in the form of a single large crystal or aggregates of smaller crystals, and is therefore substantially pure drug. 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.

[0092] The polymer shell is composed of one or more concentric or sequential 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 requirements of maintaining permeability and / or structural integrity during the desired sustained-release period. While sustained-release periods are enhanced within the scope of the present disclosure by higher drug loadings and beneficial and unexpected interactions between body compartments (e.g., esophageal tissue) and the dissolution-based delivery systems described herein, there are additional factors that support the superior efficacy of the methods described herein, including, but not limited to: Corticosteroid solubility Esophageal excretion rate of corticosteroids The size of the core particle and / or the amount of corticosteroid initially contained in the core particle. The presence of other compounds within the core particles that affect the release rate of the corticosteroid Permeability of the polymer coating(s) to corticosteroids The rate of degradation of the polymer coating(s) and other factors

[0093] As is known in the art, the permeability and biodegradability of polymeric coatings can be influenced by the choice of polymer material (e.g., the degree of hydrophobicity or hydrophilicity toward the corticosteroid, the degree of bond lability under physiological conditions), the degree of crosslinking, and the thickness. In the case of copolymers, varying the ratio of different monomers can also affect permeability and biodegradability.

[0094] In some embodiments, the polymer shell comprises a hydrophilic polymer. For example, the polymer shell can comprise one or more biodegradable polymers selected from polyvinyl alcohol (PVA), ethylene vinyl acetate (EVA), poly(p-xylylene) polymer, poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(lactic-co-glycolic acid) (PLGA), poly(ε-caprolactone) (PCL), poly(valerolactone) (PVL), poly(ε-decalactone) (PDL), poly(1,4-dioxane-2,3-dione), poly(1,3-dioxane-2-one), poly(paradioxanone) (PDS), poly(hydroxybutyric acid) (PHB), poly(hydroxyvaleric acid) (PHV), poly(β-malic acid) (PMLA), and combinations thereof. In some embodiments, the polymer shell comprises polyvinyl alcohol (PVA).

[0095] To control permeability and release rate, the polymer shell can be crosslinked covalently or ionically. For example, monomers containing chemical groups capable of forming additional bonds between monomers can be selected, or a separate crosslinking agent can be included in the polymer-forming solution in addition to the monomers. In some embodiments, the crosslinking groups are thermally activated, while in other embodiments, the crosslinking groups are photoactivated, including photoactivation with visible or ultraviolet light. Crosslinking groups include, but are not limited to, unsaturated groups such as vinyl, allyl, cinnamate, acrylate, diacrylate, oligoacrylate, methacrylate, dimethacrylate, and oligomethacrylate groups.

[0096] Because many corticosteroids are hydrophobic and it is desirable to reduce or prevent dissolution of the drug core into the polymer shell in order to maintain a sharp interface between the core and shell, the polymer shell can include a hydrophilic polymer, particularly in the coating closest to the crystalline core. Examples of hydrophilic polymer coatings include, but are not limited to, poly(vinyl alcohol) (PVA), poly(ethylene glycol) (PEG), poly(ethylene oxide), poly(vinylpyrrolidone), poly(ethyloxazoline), or polysaccharides or carbohydrates such as alkylcellulose, hydroxyalkylcellulose, hyaluronic acid, dextran, heparan sulfate, chondroitin sulfate, heparin, or alginate, or proteins such as gelatin, collagen, albumin, ovalbumin, or polyamino acids.

[0097] Further examples of suitable polymers can be prepared from monomers selected from the following group: sugar phosphates, alkyl celluloses, hydroxyalkyl celluloses, lactic acid, glycolic acid, β-propiolactone, β-butyrolactone, γ-butyrolactone, pivalolactone, α-hydroxybutyric acid, α-hydroxyethyl butyric acid, α-hydroxyisovaleric acid, α-hydroxy-β-methylvaleric acid, α-hydroxycaproic acid, α-hydroxyisocaproic acid, α-hydroxyheptanoic acid, α-hydroxyoctanoic acid, α-hydroxydecanoic acid, α-hydroxymyristic acid, α-hydroxystearic acid, α-hydroxylignoceric acid, and β-phenollactic acid.

[0098] In various embodiments, for each microparticle, 70-97% of the total weight of the microparticle is corticosteroid and 3-30% is polymer. In one embodiment, the drug core is greater than 70% of the total weight of the microparticle, and the polymer shell is less than 30% of the total weight of the microparticle. In other embodiments, the drug core is greater than 75%, greater than 80%, greater than 85%, greater than 90%, or greater than 95% of the total weight of the microparticle, with the remainder of the microparticle being the polymer shell. In some embodiments, the microparticles comprise 90-98% w / w crystalline drug core and 2-10% w / w polymer shell.

[0099] Because the crystalline drug core may comprise at least 70% by weight of the microparticles, in some embodiments, the overall size of the microparticles is primarily determined by the size of the crystalline drug core. Typically, the thickness of the polymer shell is less than about 12%, or less than 5%, or less than 3% of the overall diameter of the microparticle. Similarly, in some embodiments, the weight of the microparticles is also correlated with the weight of the crystalline core, resulting in a high drug loading.

[0100] In various embodiments, the microparticles have an average diameter of 50 μm to 800 μm, or an average diameter of 60 μm to 250 μm, or an average diameter of 80 μm to 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.

[0101] In some embodiments, the in vivo sustained release profile of the corticosteroid correlates with the in vitro dissolution characteristics of the microparticles, which are determined by, among other things, the solubility and permeability of the drug core, the level of crosslinking of the polymer shell, and the degradation rate of the polymer shell. In some embodiments, the microparticles have a dissolution half-life of 12 to 20 hours when tested using a U.S. Pharmacopeia Type II apparatus, dissolving 3 milligrams of microparticles in 200 milliliters of a dissolution medium of 70% v / v methanol and 30% v / v water at 25°C.

[0102] The injectable sustained release compositions described in US Pat. No. 9,987,233 are incorporated herein by reference.

[0103] In some embodiments, the use of polymer-coated microspheres allows sustained-release compositions to expose GI tissues to corticosteroids for periods as long as 6-12 months. Fluticasone, when used as a corticosteroid, allows for the use of high doses while minimizing systemic side effects due to its high first-pass metabolism (approximately 99%). Fluticasone's high first-pass metabolism allows for the administration of high concentrations locally, as any drug that leaks from local mucosal tissues is metabolized in the liver before systemic exposure. This advantage cannot be achieved with steroids such as triamcinolone or beclomethasone, which have significantly lower first-pass metabolism.

[0104] Method for forming fine particles Methods for forming polymer coatings on particles are well known in the art. For example, standard techniques include solvent evaporation / extraction techniques, in-water drying techniques (see, e.g., U.S. Pat. No. 4,994,281), organic phase separation techniques (see, e.g., U.S. Pat. No. 5,639,480), spray drying techniques (see, e.g., U.S. Pat. No. 5,651,990), air suspension techniques, and dip coating techniques, the entire contents of which are incorporated herein by reference.

[0105] In some embodiments, the microparticles of the present disclosure are formed using the microparticle formation method 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 polymer coating layers, which 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 coating solution of PVA can be formed by dissolving excess PVA in water at 60°C for 2 hours (see, e.g., Byron and Dalby (1987), J. Pharm. Sci. 76(1):65-67). Alternatively, a more concentrated PVA solution (e.g., 3-4%) can be prepared by heating to approximately 90-100°C under reflux. After cooling, the microparticles are added to the PVA solution and agitated, e.g., by swirling or stirring. The microparticles are then removed from the solution, e.g., by filtration through filter paper with a mesh size appropriate for the microparticles. Vacuum filtration can also be used to aid drying, if necessary. Untreated PVA polymer coatings or films are readily permeable to water and hydrophilic drugs, but heating PVA increases the crystallinity and decreases the permeability by up to 500-fold as the temperature increases over the range of 100-250°C over a period of 0-160 hours (Byron and Dalby (1987), supra).

[0106] Thus, in some embodiments, the PVA polymer coating can be heated to temperatures between 100°C and 250°C, 125°C and 175°C, or 155°C and 170°C for 1 second to 160 hours, 1 minute to 10 hours, or 5 minutes to 2 hours. For example, it can be heated to 220°C for 1 hour. If necessary, the coating process can be repeated several times to prepare thicker polymer coatings. In some embodiments, 2 to 5 coats are applied to achieve a coating thickness of 5% w / w.

[0107] In one embodiment, the microparticles are subjected to a heat treatment step for at least 1 hour at a temperature in the range of 210-230° C. By controlling the temperature of the heat treatment step, the level of crosslinking, and therefore the permeability, can be precisely controlled.

[0108] Pharmaceutical Composition As explained above, the methods described herein include administering at least one pharmaceutical composition comprising a sustained-release composition formulated to release a corticosteroid to GI tissue (such as esophageal tissue) over an extended period of time. In addition to the sustained-release composition described above, the pharmaceutical compositions of the present disclosure may also include a pharmaceutically acceptable vehicle in which the sustained-release composition is suspended. For example, in some embodiments, the pharmaceutical composition is prepared extemporaneously by combining the sustained-release composition with the vehicle.

[0109] The therapeutic and prophylactic methods of the present disclosure can be practiced such that the pharmaceutical compositions are prepared using a multi-vial system that allows the components of the pharmaceutical composition to be combined just prior to administration.

[0110] Such a multi-vial system can ensure sufficient stability of the pharmaceutical composition even when the sustained-release composition exhibits short-term stability under aqueous conditions. The multi-vial system includes at least one vial containing a sustained-release composition (a so-called corticosteroid vial) and at least one vial containing a liquid vehicle (a 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 upon stirring, the pharmaceutical composition is obtained within the corticosteroid vial as a suspension of the sustained-release composition in the liquid vehicle.

[0111] In some embodiments, the pharmaceutical composition is prepared using a two-vial system comprising a corticosteroid vial containing a sustained-release composition and a vehicle vial containing a liquid vehicle. The sustained-release composition may be in the form of a sterile powder containing hardened PVA-coated crystals of a corticosteroid. For example, in one embodiment, a corticosteroid vial contains a sterile powder of a sustained-release composition containing hardened PVA-coated crystals of fluticasone propionate, and a separate vehicle vial contains sterile water and excipients necessary to prepare a uniform suspension of the sustained-release composition.

[0112] In some embodiments, pharmaceutical compositions of the present disclosure prepared in a multi-vial system or otherwise are stable for a period ranging from 1 to 12 hours after combination of the sustained release composition with the liquid vehicle.

[0113] The pharmaceutically acceptable vehicle of the present disclosure may include an excipient that can suspend the sustained-release composition in water or an aqueous medium. In some embodiments, the excipient is selected from binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and combinations thereof. For example, the excipient may be selected from polysorbates, polysaccharides, acid salts, alkali salts, neutral salts, and combinations thereof.

[0114] In some embodiments, the pharmaceutically acceptable vehicle comprises, based on the total weight of the pharmaceutically acceptable vehicle, 0.05-0.1 wt. % polysorbate, 0.1-2.0 wt. % cellulose, and 0.1-2.0 wt. % inorganic salt in sterile water. For example, in some embodiments, the pharmaceutically acceptable vehicle comprises, based on the total weight of the pharmaceutically acceptable vehicle, one or more of 0.05-0.1 wt. % polysorbate 80, 0.1-3.5 wt. % carboxymethylcellulose (CMC), 0.5-2.0 wt. % sodium hyaluronate (HA), and 0.1-2.0 wt. % sodium chloride in sterile water. In other embodiments, the pharmaceutically acceptable vehicle may contain about 0.015% by weight polysorbate 80, about 0.75% by weight carboxymethylcellulose (CMC), and about 0.9% by weight sodium chloride in sterile water, based on the total weight of the pharmaceutically acceptable vehicle.

[0115] Table 1 below summarizes the compositions of the two multi-vial systems of the present disclosure, including the percentage of each component in the corticosteroid vial and the vehicle vial. [Table 1]

[0116] The present disclosure is illustrated by the following non-limiting examples. [Example]

[0117] Example 1 Fluticasone propionate recrystallization procedure Fluticasone propionate (FP) recrystallization was performed according to Example 1 of WO 2020 / 210720, the entire contents of which are incorporated herein by reference. Specifically, FP was recrystallized from concentrations of 10-15 mg / mL in methanol on both a small-scale and a large-scale. The temperature was maintained stable at 45°C during slow evaporation, e.g., over a period of 72 hours. Small-scale runs were performed with 20 mL to 2 L of solution, and large-scale runs were performed with 20-100 L. Both small-scale and large-scale runs produced thick, elongated crystals suitable for further sizing.

[0118] Example 2 Sizing of recrystallized fluticasone propionate Recrystallization of fluticasone propionate (FP) was carried out according to Example 3 of WO 2020 / 210720. Specifically, the recrystallized fluticasone propionate crystals prepared in Example 1 were milled in a rotor / stator homogenizer. Exemplary operating parameters are as follows: 5-10% solid medium; Carrier fluid: 0.1% to 0.5% polysorbate 80 (surfactant) in USP water Rotor speed: 15,000-20,000 rpm (mill can rotate in the range of 3,000-26,000 rpm) Rotor configurations include coarse, medium, fine, or a combination of two or more rotors. This cycle can be performed up to 5 times.

[0119] The crushed crystals were then passed through two separate sieves to remove fine particles and any remaining large crystals. The resulting drug crystals had a relatively narrow distribution, with minimal amounts of fine material and no very fine material (no particles smaller than 9 μm).

[0120] Example 3 General Procedure for Coating Crystalline Drug Cores Recrystallized FP crystals prepared according to Example 2 are coated with polyvinyl alcohol (PVA, 2% w / v in 25% v / v isopropyl alcohol in DI-H2O) in a Model VFC-LAB Micro benchtop fluidized bed coater system (Vector Corporation) using the following range of parameters: Air flow rate: 50-60L / min Nozzle air, 5.0~25psi Pump speed: 10-35 rpm Inlet temperature, 99℃ Exhaust temperature: 35-40°C Spray on / off cycle: 0.1 / 0.3 min.

[0121] PVA content was quantitatively determined by comparing the relative signal intensities of FP and PVA resonances in drug products with the corresponding signals from calibration standards. 1 The PVA content is measured periodically by H nuclear magnetic resonance (NMR) spectroscopy (see Example 4). The target final PVA concentration in the drug product ranges from 0.1 to 20% w / w, preferably 2 to 10% w / w. Coating of the particles continues until the desired amount of PVA is achieved. The coated particles are then dried in an oven at 40°C for 1 hour. The dried, coated particles are sieved through a sieve stack containing 150 μm and 53 μm mesh sieves.

[0122] Example 4 NMR analysis to determine drug content in microparticles NMR analysis was used to determine the amount of drug core and polymer shell in the microparticles by calibrating with samples of known amounts of pure drug.

[0123] The NMR system included a Bruker Spectrospin 300 MHz magnet, a Bruker B-ACS120 autosampler, a Bruker Avance II 300 console, and a Bruker BBO 300 MHz S1 5mm with a Z-gradient probe. A calibration curve was generated using five samples of known fluticasone propionate and PVA concentrations 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 in the magnet at 20 Hz. The probe was adjusted and matched for proton (1H) NMR. The first sample was placed in the magnet and the magnet was manually shimmed. Each sample was integrated for 1.5 hours with 1024 scans. The fluticasone peak integrated between 5.5 and 6.35 ppm, and the PVA peak integrated between 4.15 and 4.7 ppm. Using this method, the finished coated fluticasone particles were found to contain 2.1% PVA by weight of the total coated particle. Assuming the particles are spherical and have an average particle size of 100 μm, the coating thickness would be approximately 7 μm.

[0124] Example 5 Sustained-release (SR) corticosteroids Recrystallized FP crystals were prepared according to Example 2 and coated with polyvinyl alcohol (PVA, 2% w / v in 25% v / v isopropyl alcohol in DI-H2O) according to Example 3 in a Model VFC-LAB Micro benchtop fluidized bed coater system (Vector Corporation) using the following range of parameters: air flow rate, 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% (w / w) based on NMR sampling (see Example 4).

[0125] The resulting particles were heat treated at 130°C for 3 hours.

[0126] The mean 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 (122°C, 16 psi, 30 minutes) in amber vials. 1H NMR spectroscopy and HPLC analysis indicated that the sterilization process did not affect the chemical composition of the formulation.

[0127] Example 6 Preparation of a two-vial system. A two-vial system was prepared, containing a corticosteroid vial and a vehicle vial. The corticosteroid vial contained approximately 44 mg of the sustained-release (SR) corticosteroid (94% (w / w) FP crystals coated with 6% (w / w) PVA) from Example 5. The vehicle vial contained the excipients listed under "System B" in Table 1 (0.74% (w / w) carboxymethylcellulose sodium, 0.015% (w / w) polysorbate 80, 0.813% (w / w) sodium chloride, 0.216% (w / w) dibasic sodium phosphate heptahydrate, 0.026% (w / w) monobasic sodium phosphate, balance sterile water) and was agitated by shaking until homogeneous. The corticosteroid and vehicle vials were stored at a controlled temperature of 20-25°C (68-77°F) prior to use.

[0128] Example 7 Preparation of a 2.5 mg / mL suspension. Using a syringe and 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 particles from the entire wall of the corticosteroid vial. Next, swirl the corticosteroid vial to ensure uniform suspension of particles and avoid clumping or aggregation. Inject two additional 6 mL of solvent 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 constituted SR suspension should be temperature-controlled at 20-25°C (68-77°F) prior to use and used within 1 hour of constitution.

[0129] Example 8 Treatment protocol (8 infusions at 2.5 mg / mL). Eight esophageal injections were performed in adult patients with eosinophilic esophagitis (EoE) using the SR suspension (2.5 mg / mL) of Example 7. As shown in Figure 6, 1.0 mL of the SR suspension (approximately 2.5 mg per injection) was injected into eight separate injection sites in four different rings of the esophagus. All injections were submucosal into the esophageal tissue and were performed inside the throat using a standard esophageal injection probe.

[0130] Referring to Figure 6, two of the injections are performed in the first and fourth quadrants (48-1 and 48-3) of the first ring (28), located approximately 6 cm above the gastroesophageal (GE) junction (8). Two of the injections are performed in the second and fourth quadrants (48-2 and 48-4) of the second ring (30), located approximately 7 cm above the GE junction (8). Two of the injections are performed in the first and third quadrants (48-2 and 48-4) of the third ring (32), located approximately 8 cm above the GE junction (8). Two of the injections are performed in the second and fourth quadrants (48-2 and 48-4) of the fourth ring (34), located approximately 10 cm above the GE junction (8).

[0131] Example 9 Treatment protocol (order of increasing total dose). Using the SR suspension of the present disclosure, various treatment protocols can be implemented in one or more adult patients suffering from eosinophilic esophagitis (EoE) in which 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 in each injection can vary from about 0.25 mg / mL to about 10 mg / mL, and the number of injections in each treatment protocol can vary from 1 to 20. Examples 9-1 through 9-8 below demonstrate treatment protocols in which the total dose of SR corticosteroid increases from about 4 mg to about 40 mg.

[0132] Example 9-1: (4 injections / total dose of 4 mg) A 1.0 mg / mL solution of sustained-release (SR) corticosteroid is prepared using the two-vial system of Example 6. Four esophageal injections are administered to adult patients suffering from eosinophilic esophagitis (EoE). As shown in Figure 6, 1.0 mL of the SR suspension (approximately 1.0 mg per injection) is injected into four separate injection sites in two different rings of the esophagus, for a total dose of approximately 4 mg administered to each of one or more adult patients. All injections are submucosal into the esophageal tissue and are administered in the throat using a standard esophageal injection probe.

[0133] Referring to Figure 6, two of the injections are made in the first and fourth quadrants (48-1 and 48-3) of the first ring (28) approximately 6 cm above the gastroesophageal (GE) junction (8), with the injection sites spaced equidistant from each other around the circumference of the first ring (28). The remaining two injections are made in the second and fourth quadrants (48-2 and 48-4) of the second ring (30) approximately 7 cm above the GE junction (8), with the injection sites spaced equidistant from each other around the circumference of the second ring (30).

[0134] Example 9-2: (8 injections / total dose of 8 mg) A 1.0 mg / mL solution of sustained-release (SR) corticosteroid is prepared using the two-vial system of Example 6. Eight esophageal injections are administered to adult patients suffering from eosinophilic esophagitis (EoE). As shown in Figure 6, 1.0 mL of SR suspension (approximately 1.0 mg per injection) is injected into eight separate injection sites in four different rings of the esophagus, for a total dose of approximately 8 mg administered to each of one or more adult patients. All injections are submucosal into the esophageal tissue and are administered in the throat using a standard esophageal injection probe.

[0135] Referring to Figure 6, two of the injections are performed in the first and fourth quadrants (48-1 and 48-3) of the first ring (28), approximately 6 cm above the gastroesophageal (GE) junction (8), with the injection sites spaced equidistant from each other around the circumference of the first ring (28). Two of the injections are performed in the second and fourth quadrants (48-2 and 48-4) of the second ring (30), approximately 7 cm above the GE junction (8), with the injection sites spaced equidistant from each other around the circumference of the second ring (30). Two of the injections are performed in the first and third quadrants (48-2 and 48-4) of the third ring (32), approximately 8 cm above the GE junction (8), with the injection sites spaced equidistant from each other around the circumference of the third ring (32). Two of the injections are made in the second and fourth quadrants (48-2 and 48-4) of the fourth ring (34), approximately 10 cm above the GE junction (8), with the injection sites spaced equidistant from each other along the circumference of the fourth ring (28).

[0136] Example 9-3: (12 injections / total dose of 12 mg) A 1.0 mg / mL solution of sustained-release (SR) corticosteroid is prepared using the two-vial system of Example 6. Twelve esophageal injections are administered to adult patients suffering from eosinophilic esophagitis (EoE). As shown in Figure 6, 1.0 mL of SR suspension (approximately 1.0 mg per injection) is injected into 12 separate injection sites in four different rings of the esophagus, for a total dose of approximately 12 mg administered to each of one or more adult patients. All injections are submucosal into the esophageal tissue and are administered in the throat using a standard esophageal injection probe.

[0137] Referring to Figure 6, three of the injections are made in a first ring (28) approximately 6 cm above the gastroesophageal (GE) junction (8), with injection sites spaced equidistant from one another around the circumference of the first ring (28). Three of the injections are made in a second ring (30) approximately 7 cm above the GE junction (8), with injection sites spaced equidistant from one another around the circumference of the second ring (30). Three of the injections are made in a third ring (32) approximately 8 cm above the GE junction (8), with injection sites spaced equidistant from one another around the circumference of the third ring (32). Three of the injections are made in a fourth ring (34) approximately 10 cm above the GE junction (8), with injection sites spaced equidistant from one another around the circumference of the fourth ring (34).

[0138] Example 9-4: (16 injections / total dose of 16 mg) A 1.0 mg / mL solution of sustained-release (SR) corticosteroid is prepared using the two-vial system of Example 6. Sixteen esophageal injections are administered to adult patients suffering from eosinophilic esophagitis (EoE). As shown in Figure 6, 1.0 mL of SR suspension (approximately 1.0 mg per injection) is injected into 16 separate injection sites in four different rings of the esophagus, for a total dose of approximately 16 mg administered to each of one or more adult patients. All injections are submucosal into the esophageal tissue and are administered in the throat using a standard esophageal injection probe.

[0139] Referring to Figure 6, four of the injections were made in the first, second, third, and fourth quadrants of the first ring (28), located approximately 6 cm above the gastroesophageal (GE) junction (8), with the injection sites spaced equidistant from one another around the circumference of the first ring (28). Four of the injections were made in the first, second, third, and fourth quadrants of the second ring (30), located approximately 7 cm above the GE junction (8), with the injection sites spaced equidistant from one another around the circumference of the second ring (30). Three of the injections were made in the first, second, third, and fourth quadrants of the third ring (32), located approximately 8 cm above the GE junction (8), with the injection sites spaced equidistant from one another around the circumference of the third ring (32). Three of the injections are made in the first, second, third and fourth quadrants of the fourth ring (34) approximately 10 cm above the GE junction (8), with the injection sites spaced equidistant from one another around the circumference of the fourth ring (34).

[0140] Example 9-5: (4 injections / total dose of 10 mg) A 2.5 mg / mL solution of sustained-release (SR) corticosteroid is prepared using the two-vial system of Example 6. Four esophageal injections are administered to adult patients suffering from eosinophilic esophagitis (EoE). As shown in Figure 6, 1.0 mL of SR suspension (approximately 2.5 mg per injection) is injected into four separate injection sites in two different rings of the esophagus, for a total dose of approximately 10 mg administered to each of one or more adult patients. All injections are submucosal into the esophageal tissue and are administered in the throat using a standard esophageal injection probe.

[0141] Referring to Figure 6, two of the injections are made in the first and fourth quadrants (48-1 and 48-3) of the first ring (28) approximately 6 cm above the gastroesophageal (GE) junction (8), with the injection sites spaced equidistant from each other around the circumference of the first ring (28). The remaining two injections are made in the second and fourth quadrants (48-2 and 48-4) of the second ring (30) approximately 7 cm above the GE junction (8), with the injection sites spaced equidistant from each other around the circumference of the second ring (30).

[0142] Example 9-6: (8 injections / total dose of 20 mg) A 2.5 mg / mL solution of sustained-release (SR) corticosteroid is prepared using the two-vial system of Example 6. Eight esophageal injections are administered to adult patients suffering from eosinophilic esophagitis (EoE). As shown in Figure 6, 1.0 mL of SR suspension (approximately 2.5 mg per injection) is injected into eight separate injection sites in four different rings of the esophagus, for a total dose of approximately 20 mg administered to each of one or more adult patients. All injections are submucosal into the esophageal tissue and are administered in the throat using a standard esophageal injection probe.

[0143] Referring to Figure 6, two of the injections are performed in the first and fourth quadrants (48-1 and 48-3) of the first ring (28), approximately 6 cm above the gastroesophageal (GE) junction (8), with the injection sites spaced equidistant from each other around the circumference of the first ring (28). Two of the injections are performed in the second and fourth quadrants (48-2 and 48-4) of the second ring (30), approximately 7 cm above the GE junction (8), with the injection sites spaced equidistant from each other around the circumference of the second ring (30). Two of the injections are performed in the first and third quadrants (48-2 and 48-4) of the third ring (32), approximately 8 cm above the GE junction (8), with the injection sites spaced equidistant from each other around the circumference of the third ring (32). Two of the injections are made in the second and fourth quadrants (48-2 and 48-4) of the fourth ring (34), approximately 10 cm above the GE junction (8), with the injection sites spaced equidistant from each other along the circumference of the fourth ring (28).

[0144] Example 9-7: (12 injections / total dose of 30 mg) A 2.5 mg / mL solution of sustained-release (SR) corticosteroid is prepared using the two-vial system of Example 6. Twelve esophageal injections are administered to adult patients suffering from eosinophilic esophagitis (EoE). As shown in Figure 6, 1.0 mL of SR suspension (approximately 2.5 mg per injection) is injected into 12 separate injection sites in four different rings of the esophagus, for a total dose of approximately 30 mg administered to each of one or more adult patients. All injections are submucosal into the esophageal tissue and are administered in the throat using a standard esophageal injection probe.

[0145] Referring to Figure 6, three of the injections were made in a first ring (28) approximately 6 cm above the gastroesophageal (GE) junction (8), with injection sites equidistant from one another along the circumference of the first ring (28). Three of the injections were made in a second ring (30) approximately 7 cm above the GE junction (8), with injection sites equidistant from one another along the circumference of the second ring (30). Three of the injections were made in a third ring (32) approximately 8 cm above the GE junction (8), with injection sites equidistant from one another along the circumference of the third ring (32). Three of the injections were made in a fourth ring (34) approximately 10 cm above the GE junction (8), with injection sites equidistant from one another along the circumference of the fourth ring (34).

[0146] Example 9-8: (16 injections / total dose of 40 mg) A 2.5 mg / mL solution of sustained-release (SR) corticosteroid is prepared using the two-vial system of Example 6. Sixteen esophageal injections are administered to adult patients suffering from eosinophilic esophagitis (EoE). As shown in Figure 6, 1.0 mL of SR suspension (approximately 2.5 mg per injection) is injected into 16 separate injection sites in four different rings of the esophagus, for a total dose of approximately 40 mg administered to each of one or more adult patients. All injections are submucosal into the esophageal tissue and are administered in the throat using a standard esophageal injection probe.

[0147] Referring to Figure 6, four of the injections were made in the first, second, third, and fourth quadrants of the first ring (28), located approximately 6 cm above the gastroesophageal (GE) junction (8), with the injection sites spaced equidistant from one another around the circumference of the first ring (28). Four of the injections were made in the first, second, third, and fourth quadrants of the second ring (30), located approximately 7 cm above the GE junction (8), with the injection sites spaced equidistant from one another around the circumference of the second ring (30). Three of the injections were made in the first, second, third, and fourth quadrants of the third ring (32), located approximately 8 cm above the GE junction (8), with the injection sites spaced equidistant from one another around the circumference of the third ring (32). Three of the injections are made in the first, second, third and fourth quadrants of the fourth ring (34) approximately 10 cm above the GE junction (8), with the injection sites spaced equidistant from one another around the circumference of the fourth ring (34).

[0148] Example 9-9: (Alternative Infusion Pattern) Other treatment protocols are performed using conditions similar to those of Examples 9-1 through 9-8, except that the injection pattern is not limited to evenly spaced injections, the number of injections is not limited to a range of 4 to 16, and the protocol is not limited to the treatment of EoE. Some treatment protocols may be performed with an irregular injection pattern based on the location of inflammation within the gastrointestinal (GI) tract being treated. For example, some treatment protocols may involve at least one injection directly into a benign stricture in the GI tract and at least one injection into another region of the GI tract (e.g., an area adjacent to the benign stricture).

[0149] Embodiment Embodiment [1] of the present disclosure is a method for treating or preventing an inflammatory disease of the gastrointestinal tract in a subject in need thereof, the method comprising topically administering to the subject a therapeutically effective amount of a pharmaceutical composition, the pharmaceutical composition comprising a sustained release composition formulated for extended release of a corticosteroid to gastrointestinal tissue.

[0150] Embodiment [2] of the present disclosure relates to the method of embodiment [1], wherein the tissue comprises esophageal tissue, stomach tissue, bile duct tissue, small intestine tissue, large intestine tissue, or any combination thereof.

[0151] An embodiment [3] of the present disclosure relates to the method according to embodiment [1] or [2], wherein the tissue comprises esophageal tissue.

[0152] An embodiment [4] of the present disclosure relates to the method according to any one of embodiments [1] to [3], wherein the administering comprises injecting the pharmaceutical composition into the tissue.

[0153] An embodiment [5] of the present disclosure relates to the method according to any one of embodiments [1] to [4], wherein the administering comprises injecting the pharmaceutical composition into the esophageal tissue.

[0154] Embodiment [6] of the present disclosure relates to a method according to any one of embodiments [1] to [5], wherein the administering comprises submucosally injecting the pharmaceutical composition into the tissue at least once.

[0155] Embodiment [7] of the present disclosure relates to a method according to any one of embodiments [1] to [6], wherein the administering comprises injecting at least one initial dose of the pharmaceutical composition into the tissue.

[0156] Embodiment [8] of the present disclosure relates to the method according to any one of embodiments [1] to [7], wherein the administration comprises multiple injections of the pharmaceutical composition into the tissue, with at least two of the injections being at different injection sites within the tissue.

[0157] Embodiment [9] of the present disclosure relates to a method according to any one of embodiments [1] to [8], wherein the administering comprises injecting at least two initial doses of the pharmaceutical composition into the tissue.

[0158] Embodiment

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

[0159] Embodiment

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

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

[0160] Embodiment

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

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

[0161] Embodiment

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

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

[0162]

[0013] Embodiment

[14] of the present disclosure relates to a method of treating eosinophilic esophagitis in a subject in need thereof, the method comprising locally administering to the subject a therapeutically effective amount of a pharmaceutical composition, the pharmaceutical composition comprising a sustained release composition formulated for extended release of the corticosteroid to esophageal tissue.

[0163] Embodiment

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

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

[0164] Embodiment

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

[14] or

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

[0165] Embodiment

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

[14] to

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

[0166] Embodiment

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

[14] to

[17] , wherein the administering comprises multiple injections of the pharmaceutical composition into the esophageal tissue, with at least two of the injections being at different injection sites within the esophageal tissue.

[0167] Embodiment

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

[14] to

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

[0168] Embodiment

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

[19] , wherein the administration comprises multiple injections of the pharmaceutical composition into the esophageal tissue, with at least two of the injections occurring at injection sites located along a first esophageal ring defined by the circumference of the esophagus a distance d1 above the gastrointestinal junction of the subject.

[0169] An embodiment

[21] of the present disclosure relates to the method of 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.

[0170] Embodiment

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

[20] or

[21] , wherein the injection sites located along the first ring of the esophagus are spaced equidistant from one another around the circumference of the first ring, or the injection sites located along the first ring of the esophagus are not spaced equidistant from one another around the circumference of the first ring.

[0171] Embodiment

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

[20] to

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

[0172] Embodiment

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

[20] to

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

[0173] An embodiment

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

[24] , wherein the distance d2 is 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 greater than the distance d1.

[0174] Embodiment

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

[24] or

[25] , wherein the injection sites located along the second ring of the esophagus are spaced equidistant from one another around the circumference of the second ring, or the injection sites located along the second ring of the esophagus are not spaced equidistant from one another around the circumference of the second ring.

[0175] Embodiment

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

[24] to

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

[0176] Embodiment

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

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

[0177] Embodiment

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

[28] , wherein the administration comprises multiple injections of the pharmaceutical composition into esophageal tissue, the injections being performed at injection sites located along at least three, or at least four, or at least five, or at least six, or at least seven, or at least eight rings of the esophagus, defined by the circumference of the esophagus at each distance of the rings above the gastroesophageal junction of the subject.

[0178] Embodiment

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

[29] , wherein the administering comprises at least one injection of the pharmaceutical composition into an inflamed area of ​​the esophagus, at least one injection of the pharmaceutical composition into an injection site not located in an inflamed area of ​​the esophagus, or a combination thereof.

[0179] Embodiment

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

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

[0180] Embodiment

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

[31] , comprising injecting the pharmaceutical composition into the esophageal tissue to form at least one bleb containing the sustained-release composition.

[0181] Embodiment

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

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

[0182] Embodiment

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

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

[0183] Embodiment

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

[34] , wherein the corticosteroid is selected from the group consisting of desoxycorticosone, hydrocortisone, cortisone, methylprednisolone, prednisone, prednisolone, triamcinolone, dexamethasone, betamethasone, beclomethasone, beclomethasone-17,21-dipropionate, budesonide, flunisolide, fludrocortisone, mometasone, fluticasone, The composition comprises at least one selected from the group consisting of 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.

[0184] Embodiment

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

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

[0185] Embodiment

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

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

[0186] Embodiment

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

[37] , wherein the corticosteroid comprises fluticasone propionate.

[0187] Embodiment

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

[38] , wherein the corticosteroid is crystalline.

[0188] Embodiment

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

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

[0189] An embodiment

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

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

[0190] Embodiment

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

[41] , wherein the sustained-release composition comprises microparticles comprising (1) a crystalline drug core comprising one or more crystals of the corticosteroid, and (2) a polymer shell encapsulating the crystalline drug core, wherein the polymer shell is in contact with but immiscible with the crystalline drug core, and 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, based on the total weight of the microparticles.

[0191] An embodiment

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

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

[0192] Embodiment

[44] of the present disclosure relates to the method of 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.

[0193] Embodiment

[45] of the present disclosure relates to the method of any 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.

[0194] Embodiment

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

[42] to

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

[0195] Embodiment

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

[42] to

[46] , wherein the polymer shell comprises one or more biodegradable polymers selected from the group consisting of polyvinyl alcohol (PVA), ethylene vinyl acetate (EVA), poly(p-xylylene) polymer, poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(lactic-co-glycolic acid) (PLGA), poly(ε-caprolactone) (PCL), poly(valerolactone) (PVL), poly(ε-decalactone) (PDL), poly(1,4-dioxane-2,3-dione), poly(1,3-dioxane-2-one), poly(paradioxanone) (PDS), poly(hydroxybutyric acid) (PHB), poly(hydroxyvaleric acid) (PHV), and poly(β-malic acid) (PMLA).

[0196] Embodiment

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

[42] to

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

[0197] Embodiment

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

[42] to

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

[0198] An embodiment

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

[49] , wherein the crosslinked polymer is crosslinked by covalent or ionic bonds.

[0199] Embodiment

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

[42] to

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

[0200] An embodiment

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

[42] to

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

[0201] Embodiment

[53] of the present disclosure relates to the method described in any one of embodiments [1] to

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

[0202] Embodiment

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

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

[0203] Embodiment

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

[54] , wherein the pharmaceutical composition is stable for up to 1 hour, or 2 hours, or 3 hours, or 4 hours, or 5 hours, or 6 hours, or 7 hours, or 8 hours, or 9 hours, or 10 hours, or 11 hours, or 12 hours after combining the sustained-release composition with a pharmaceutically acceptable vehicle.

[0204] Embodiment

[56] of the present disclosure relates to the method of any of embodiments [1] to

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

[0205] Embodiment

[57] of the present disclosure relates to the method described in any one of embodiments [1] to

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

[0206] Embodiment

[58] of the present disclosure relates to the method described in any one of embodiments [1] to

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

[0207] Embodiment

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

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

[0208] Embodiment

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

[59] , wherein the pharmaceutical composition further comprises a pharmaceutically acceptable vehicle comprising 0.05 to 0.1 wt% polysorbate 80, 0.1 to 2.0 wt% carboxymethylcellulose (CMC), and 0.1 to 2.0 wt% sodium chloride in sterile water, based on the total weight of the pharmaceutically acceptable vehicle.

[0209] Embodiment

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

[60] , wherein the pharmaceutical composition further comprises a pharmaceutically acceptable vehicle comprising about 0.015 wt% polysorbate 80, about 0.5 wt% carboxymethylcellulose (CMC), and about 0.9 wt% sodium chloride in sterile water, based on the total weight of the pharmaceutically acceptable vehicle.

[0210] Embodiment

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

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

[0211] An embodiment

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

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

[0212] Embodiment

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

[62] or

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

[0213] Embodiment

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

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

[0214] Embodiment

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

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

[0215] Embodiment

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

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

[0216] Embodiment

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

[67] , wherein the subject is suffering from inflammatory bowel disease, gastroesophageal disease, peptic ulcer disease, radiation injury, chemical uptake disorder, post-operative complications, infusion, or any combination thereof.

[0217] Embodiment

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

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

[0218] Embodiment

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

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

[0219] An embodiment

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

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

[0220] Embodiment

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

[69] , comprising treating at least one benign gastrointestinal stricture in the subject, wherein the administering comprises injecting the pharmaceutical composition into the at least one benign gastrointestinal stricture, and optionally into tissue surrounding the at least one benign gastrointestinal stricture.

[0221] Embodiment

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

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

[0222]

[0013] Embodiment

[74] of the present disclosure relates to the use of an effective amount of a pharmaceutical composition of the present disclosure for the preparation of a medicament for the treatment or prevention of an inflammatory disease of the gastrointestinal tract in a subject, wherein a therapeutically effective amount of the pharmaceutical composition is topically administered to the subject, and the pharmaceutical composition comprises a sustained release composition formulated for extended release of the corticosteroid to tissues of the gastrointestinal tract.

[0223] Embodiment

[75] of the present disclosure relates to a pharmaceutical composition of the present disclosure for use in treating or preventing an inflammatory disease of the gastrointestinal tract in a subject, wherein a therapeutically effective amount of the pharmaceutical composition is topically administered to the subject, and the pharmaceutical composition comprises a sustained release composition formulated for extended release of the corticosteroid to the gastrointestinal tissue.

[0224]

[0013] Embodiment

[76] of the present disclosure relates to the use of an effective amount of a pharmaceutical composition of the present disclosure for the preparation of a medicament for the treatment of eosinophilic esophagitis, wherein a therapeutically effective amount of the pharmaceutical composition is administered locally to a subject, and the pharmaceutical composition comprises a sustained release composition formulated for extended release of the corticosteroid to esophageal tissue.

[0225] 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 locally administered to a subject, and the pharmaceutical composition comprises a sustained release composition formulated for extended release of the corticosteroid to esophageal tissue.

[0226] 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 referred to herein and / or listed in the Application Data Sheet, including U.S. patent application Ser. No. 63 / 413,167, filed October 4, 2022, are incorporated herein by reference in their entirety. Aspects of the embodiments can be modified, as needed, to employ concepts from the various patents, applications, and publications to provide further embodiments.

[0227] 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 the claims, but should be construed to include all possible embodiments, along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the foregoing disclosure.

Claims

1. 1. A method of treating eosinophilic esophagitis in a subject in need thereof, the method comprising locally administering to the subject a therapeutically effective amount of a pharmaceutical composition, the pharmaceutical composition comprising a sustained release composition formulated for extended release of a corticosteroid to esophageal tissue.

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

3. 10. 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 are at different injection sites within said esophageal tissue.

4. 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 are made at injection sites located along a first ring of the esophagus, defined by the circumference of the esophagus a distance d1 above the gastroesophageal junction of the subject.

5. 5. The method of claim 4, wherein the distance d1 is at least 2 cm above the gastroesophageal junction.

6. 6. The method of claim 4 or 5, wherein the injection sites located along the first ring of the esophagus are located equidistant from one another along the circumference of the first ring.

7. 7. The method of any one of claims 4 to 6, wherein at least two injections of the pharmaceutical composition into the esophageal tissue are performed at injection sites located along a second ring of the esophagus defined by the circumference of the esophagus a distance d2 above the gastroesophageal junction, wherein the distance d2 is greater than the distance d1.

8. The method of claim 7 , wherein the distance d2 is at least 1 cm greater than the distance d1.

9. 9. The method of claim 7 or 8, wherein the injection sites located along the second ring of the esophagus are located equidistant from one another along the circumference of the second ring.

10. 10. The method of any one of claims 1 to 9, wherein the administering comprises multiple injections of the pharmaceutical composition into the esophageal tissue, the injections occurring at injection sites located along multiple rings of the esophagus defined by the circumference of the esophagus at respective distances of the rings 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 according to any one of claims 1 to 10, wherein at least one injection of the pharmaceutical composition is administered into the area of ​​esophageal inflammation.

12. 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, each injection independently comprising 0.1 to 20 mg of the corticosteroid.

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

14. 14. The method of any one of claims 1 to 13, wherein the corticosteroid comprises at least one selected from the group consisting of desoxycorticosone, hydrocortisone, cortisone, methylprednisolone, prednisone, prednisolone, triamcinolone, dexamethasone, betamethasone, beclomethasone, beclomethasone-17,21-dipropionate, budesonide, flunisolide, fludrocortisone, mometasone, 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.

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

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

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

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

19. The sustained release composition comprises: (1) a crystalline drug core comprising one or more crystals of said corticosteroid; and (2) a polymer shell encasing the crystalline drug core, the polymer shell being in contact with but immiscible with the crystalline drug core; The core-shell microparticles include 19. The method of any one of claims 1 to 18, wherein the proportion of the crystalline drug core in the microparticles is greater than 70% by weight, based on the total weight of the microparticles.

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

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

22. 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), poly(p-xylylene) polymer, poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(lactic-co-glycolic acid) (PLGA), poly(ε-caprolactone) (PCL), poly(valerolactone) (PVL), poly(ε-decalactone) (PDL), poly(1,4-dioxane-2,3-dione), poly(1,3-dioxan-2-one), poly(para-dioxanone) (PDS), poly(hydroxybutyric acid) (PHB), poly(hydroxyvaleric acid) (PHV), and poly(β-malic acid) (PMLA).

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

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

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

26. 26. The method of claim 25, wherein the excipient is selected from the group consisting of binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and combinations thereof.

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

28. The pharmaceutical composition comprises, by weight of the total pharmaceutically acceptable vehicle, in sterile water: 0.05 to 0.1% by weight of polysorbate 80, 0.1 to 2.0% by weight of carboxymethyl cellulose (CMC), and 0.1 to 2.0% by weight of sodium chloride 28. The method of any one of claims 1 to 27, further comprising the pharmaceutically acceptable vehicle comprising:

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

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

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