USE OF LONG-ACTING FLUTICASONE PROPIONATE INJECTABLE SUSPENSIONS FOR TREATING AND PREVENTING INFLAMMATIONS OF THE GASTROINTESTINAL TRACT

BACKGROUND

Technical Field

This disclosure relates to the use of corticosteroids in the treatment and prevention of inflammation, and more specifically to methods for treating or preventing benign strictures of the gastrointestinal (GI) tract and eosinophilic esophagitis (EoE) using injectable compositions containing a sustained-release composition that is formulated for prolonged (or extended) release of a corticosteroid into esophageal tissue.

Description of Related Art

Eosinophilic esophagitis (EoE) is a rare, chronic, immune-mediated disease that is characterized by inflammation and the accumulation of large numbers of eosinophils within the epithelial lining of the esophagus. Eosinophils are recruited to the esophagus which leads to the eosinophilic release of inflammatory cytokines, resulting in inflammation. This inflammation is associated with pain, difficult swallowing, nausea/vomiting, abdominal/chest pain, and food impaction, possibly with a severity requiring medical attention.

As illustrated in Figure 1, in a human subject (2) the inflammation (12) caused by EoE is typically localized to portions of the esophagus (4) situated between the gastroesophageal (GE) junction (8) (above the stomach (10)) and the upper esophageal sphincter (UES) (6).

Current treatment of EoE includes non-pharmacological intervention such as dietary restrictions, mechanical intervention such as endoscopic dilation, and pharmacological intervention. Pharmacological intervention primarily consists of the use of swallowed topical corticosteroids (STCs). The United States Food and Drug Administration (FDA) has also approved Dupixent to treat humans aged 12 and older. Dupixent is a monoclonal antibody that is administered subcutaneously. Jorveza, an orodispersible tablet of budenoside, has been approved in Europe but not the US. The American Gastroenterological Association and the Joint Task Force on Allergy-Immunology Practice (AGA-JTF) advises using STCs such as budesonide or fluticasone. The AGA-JTF recommends topical corticosteroids over systemic corticosteroids for long-term therapy of EoE to prevent long-term complications.

Significant issues exist with the currently available methods for treating EoE. Dupixent is only effective in 60% of patients and is associated with upper respiratory tract infections in 18% of patients. Further, weekly dosing is recommended, meaning compliance and treatment costs are common obstacles. Similarly, Jorveza, is limited by recurrent disease in certain patients as well as a requirement of twice daily dosing, meaning compliance is also an issue here. Jorveza patients also suffer from side effects such as oropharyngeal candidiasis, which has been reported to occur in 64% of patients using higher doses and requiring them to discontinue its use. Other corticosteroid treatments such as inhalants or aqueous solutions are used, but also have many issues including multiple daily dosing requirements, low local absorption, and recurrence of disease upon halting treatment. The topical corticosteroids recommended by the AGA-JTF are efficacious, but are generally only useful for short-term treatment, and relapse occurs upon cessation.

A need exists for methods of treating EoE that reduce the side effects while improving efficacy and patient compliance.

Benign strictures of the gastrointestinal (GI) tract are a pathological condition characterized by the formation of a localized, luminal narrowing within the digestive tract that is non-neoplastic and non-malignant in nature. This narrowing typically results from the development of fibrous scar tissue or collagenous deposits within the mucosal and submucosal layers of the GI tract wall, leading to luminal constriction. Benign strictures within the GI tract can manifest in various anatomical segments, including but not limited to the esophagus, stomach, bile ducts, small intestine, or large intestine. Typical medical symptoms with benign strictures will depend on the location of the stricture and include dysphagia, odynophagia, regurgitation, heartbum or acid reflux, epigastric pain, nausea, vomiting, abdominal distension, altered bowel habits, and weight loss. Symptoms can range for mild to severe and serious, and in extreme cases can lead to death.

Current strategies for treating benign gastrointestinal strictures include endoscopic dilation, pharmacological therapy and surgical intervention. Endoscopic dilation involves controlled mechanical dilation via endoscopy to expand the narrowed segment and thereby enhance luminal patency. Pharmacological therapy generally involves the administration of antiinflammatory medications, particularly in cases related to inflammatory conditions like inflammatory bowel disease (IBD), and may mitigate inflammation and ameliorate stricture- related symptoms. In instances of severe strictures or complications, surgical resection or strictureplasty may be indicated to remove the affected segment or restore luminal continuity.

Despite the availability of different strategies to treat benign strictures, there remains a significant unmet need for stricture patients. BRIEF SUMMARY

Described herein are methods for treating or preventing inflammatory diseases in a subject by administering an extended-release composition to tissue of the gastrointestinal (GI) tract by injection, topical application, ingestion, or a combination thereof. Also disclosed are pharmaceutical compositions that enable the prolonged (or extended) release of corticosteroids into heathy or inflamed tissues of the GI tract.

One embodiment provides a method for treating eosinophilic esophagitis (EoE) in a subject in need thereof by locally administering a therapeutically effective amount of a pharmaceutical composition in the subject, wherein the pharmaceutical composition comprises an extended-release composition that is formulated for prolonged (or extended) release of a corticosteroid into esophageal tissue. In some embodiments the pharmaceutical composition is administered by injecting into the esophageal tissue. In some embodiments a plurality of injections of the pharmaceutical composition are carried out into the esophageal tissue, such that at least two of the injections occur at different injection sites in the esophageal tissue.

Another embodiment relates to methods for treating or preventing an inflammatory disease in the GI tract of a subject in need thereof by locally administering a therapeutically effective amount of a pharmaceutical composition in the subject, wherein the pharmaceutical composition comprises an extended-release composition that is formulated for prolonged release of the corticosteroid into tissue of the GI tract. 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 administering comprises injecting the pharmaceutical composition into a tissue of the GI tract (such as a benign stricture).

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

The following figures set forth embodiments in which like reference numerals denote like parts. Embodiments are illustrated by way of example and not by way of limitation in all of the accompanying figures, wherein:

Figure 1 shows a human subject suffering from eosinophilic esophagitis (EoE);

Figure 2 shows schematically a microparticle of core/shell morphology;

Figure 3 illustrates the esophagus of a patient with a circumferential ring (Ring 1) located at a distance (dl) above the gastroesophageal (GE) junction. Additional circumferential rings (Ring 2, Ring 3 and Ring 4) that are located at increasing distances (d2, d3 and d4) above the GE junction are also illustrated; Figure 4 illustrates a site of injection located along a first ring of the esophagus defined by a circumference of the esophagus at a distance dl above the gastroesophageal (GE) junction;

Figure 5 shows a flattened-out view of the esophagus of a subject in which a plurality of injections occur at injections sites located along a first ring of the esophagus defined by a circumference of the esophagus at a distance dl above the gastroesophageal (GE) junction;

Figure 6 illustrates a flattened-out view of the esophagus of a subject in which multiple injections occur at injection sites located along different rings of the esophagus such that injections into adjacent rings are offset relative to one another;

Figure 7 illustrates a flattened-out view of the esophagus of a subject in which multiple injections occur at injection sites located along different rings of the esophagus such that injections into adjacent rings are not offset relative to one another;

Figure 8 illustrates a flattened-out view of the esophagus of a subject in which multiple injections occur as both starting dose injections and subsequent dose injections;

Figure 9 illustrates a flattened-out view of the esophagus of a subject in which multiple injections occur in a spiral pattern with respect to a longitudinal axis of the esophagus;

Figure 10 illustrates the pathology of eosinophilic esophagitis (EoE) including the formation of localized strictures (narrower) of the esophagus.

DETAILED DESCRIPTION

Described herein are methods of treating or preventing inflammatory diseases of the GI tract (such as benign strictures and eosinophilic esophagitis) by administering an extended- release composition to GI tissue of a human subject. Pharmaceutical compositions containing an extended-release composition can be administered by injection, by topical administration, ingestion, or combinations thereof. Patterns of injecting the pharmaceutical compositions into esophageal tissue are described below, in which a plurality of injections may be carried out to administer the extended-release composition over a controlled area of the esophagus, which may or may not include areas of inflammation.

Definitions

The articles “a” and “an” are used herein to refer to one or to more than one (z.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.

As used herein, the term “about” means that the described parameter may include a deviation of ± 10 percent. As used herein, unless specifically indicated otherwise, the word “or” means “either/or,” but is not limited to “either/or.” Instead, “or” may also mean “and/or.”

As used herein, the term “active pharmaceutical ingredient,” “therapeutic agent,” or “drug”, means one or more corticosteroids.

As used herein, the term “benign stricture” means a narrowing of a portion of the gastrointestinal tract, such as a narrowing of the esophagus, which is not caused by cancer.

As used herein, the term “biodegradable” means capable of partially or completely dissolving or decomposing in living tissue, particularly human or other mammalian tissue. Biodegradable compounds can be degraded by any mechanism, including, without limitation, hydrolysis, catalysis and enzymatic action.

“Bleb” refers to a bladder-like structure (akin to a blister) with thin walls that may be full of a fluid.

“Body compartment” refers to a space or cavity within the body of a vertebrate (including human) that is accessible by injection. Typically, the body compartment is at least semi-enclosed or fully enclosed by hard or soft tissue (e.g., bones, membranes, ligamentous structure) that defines the space. Soft tissue is typically present and may have various degrees of vascularization. More specifically, the body compartment may be naturally occurring anatomical space such as esophageal tissue. In addition, the body compartment may also be a surgically created space (e.g., a pocket for inserting an implanted device, soft tissue implant such as breast implant, and the like) or any space near the implant that can be accessed through injection.

“Coating solution” refers to a solution of pre-formed polymers (e.g., commercially available polymers) and is suitable for coating the drug core according to known methods of the art, e.g., fluidized bed coating.

As used herein, the terms “crystalline drug core,” “core particle,” and “drug core” interchangeably refer to a pre-formed particle that includes a single crystal or multiple crystals of the drug. The drug core is encapsulated by a polymeric shell. The core particle can further comprise other compounds, including, without limitation, binders, buffers, antioxidants, excipients, and additional active pharmaceutical ingredients. The core particle can be a single large crystal, a multiplicity of crystals, or mixtures of the above. In a preferred embodiment, the drug core is substantially pure drug (i.e., at least 90%, or at least 95% or at least 98% of the entire weight of the drug core is the drug). In a preferred embodiment, the drug core is 100% crystalline drug.

“EC50” is the concentration of the therapeutic agent that provides 50% of the maximal effect, e.g., in reducing inflammation or pain. The term “esophageal tissue” refers to a tissue or body compartment related to the esophagus of a subject or patent.

“Local concentration” refers to the concentration of the corticosteroid drug within a body compartment (as defined herein), including the concentration in the tissue or fluid of the body compartment.

As used herein, the term “microparticle” means a particle having mean dimension less than 1 mm. The microparticles can be any solid geometric shape including, without limitation, spheres, needles, ellipsoids, cylinders, polyhedrons and irregular shapes.

Microparticles are coated crystalline drug particles. As used herein, a microparticle (14) has a “core/shell” morphology, shown schematically in Figure 2, in which the drug core (16) is encapsulated by a polymeric shell (18), the polymeric shell (18). In some embodiments, the polymeric shell is a homogeneous polymer coating formed by, e.g., a fluid bed method. See e.g., WO 2014/153541. In other embodiments, the polymeric shell (18) may include one or more discrete thin coatings of the same or different polymers (two coatings, 20 and 22, are shown) formed by, e.g., a dipping method. See e.g., WO 2014/153541. Importantly, the polymeric shell (18) is formed of polymer coatings that are not miscible with the drug core, thus, the interface (24) between the drug core and the polymeric shell is sharp with minimal amounts of drug or polymer (e.g., less than 5%, or less than 1% or less than 0.5% of the total weight of either the drug or polymer shall be mixed). Because the drug core contains a highly hydrophobic corticosteroid drug, the polymeric shell includes at least one hydrophilic polymer. In some embodiments the polymeric shell becomes hydrophobic after curing. Although the polymeric shell may be ultimately degraded, it should maintain its structural integrity throughout the sustained release period.

“Minimum therapeutically effective amount” is the least amount of the therapeutic agent that is capable of producing a therapeutic effect (e.g., pain reduction or anti-inflammation).

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 primates, mammals, and vertebrates.

“Plasma concentration” refers to the concentration of the corticosteroid drug in the plasma or serum. The injectable microparticles are capable of highly localized release during a prolonged period while maintaining a low plasma concentration, e.g., sufficiently low to minimize HPA axis suppression during the sustained release period. The term “plurality” means “two or more”, unless expressly specified otherwise. For example, “plurality” may simply refer to a multiple number of injections carried out into esophageal tissue.

As used in this disclosure, a “ring” of the esophagus is a ring-shaped area of the esophagus that is defined by a circumference of the esophagus at a certain distance above the gastroesophageal (GE) junction.

The term “subject at high risk for benign stricture formation” refers to subjects suffering from chronic inflammatory processes (such as inflammatory bowel disease), subjects having gastroesophageal pathologies (such as gastroesophageal disease or eosinophilic esophagitis), subjects that have been previous treated for benign gastrointestinal stricture(s), subjects suffering from Peptic Ulcer disease, subject suffering from a radiation injury, subjects suffering a chemical ingestion, subjects having post-surgical complications, subjects suffering from infectious diseases, and the like.

The term “submucosal” refers to the layer of tissue under the mucosa (e.g., inner lining of some organs and body cavities that makes mucus).

When used with respect to a therapeutic agent or a drug e.g., a corticosteroids), the terms “sustained release”, “extended release” or “prolonged release” are used interchangeably. Sustained release refers to continuously releasing the therapeutic agent over an extended period of time after administration of a single dose, thus providing a prolonged therapeutic effect throughout the release period.

“Sustained release” is in contrast to a bolus type administration in which the entire amount of the active agent/sub stance is made biologically available at one time. Nevertheless, “sustained release” may include an initial faster release followed by a longer, extended period of slower release. As discussed in further detail below, the construction of the microparticles makes it possible to minimize the initial faster release (e.g., a burst release) and prolong the extended- release period to achieve a profile of near constant release that is irrespective of the drug concentration. “Sustained release” should provide at least a minimum therapeutically effective amount (as defined herein) of the corticosteroids during the release period. It should be understood that the minimum therapeutically effective amount of corticosteroid depends on the severity of the inflammation and/or pain to be addressed.

Within the scope of the present disclosure, sustained release of the corticosteroid is achieved due to the unique structure of the microparticles, which are in core/shell morphology. In particular, a crystalline drug core of a corticosteroid is encapsulated by a polymeric shell composed of one or more polymeric coatings, each permeable to the corticosteroid. In a preferred embodiment, all layers comprise the same polymer. In other embodiments, two to four layers of the polymer are coated on the corticosteroid, with each layer incrementally slowing the release of the active ingredient and 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 the body compartment (e.g., esophageal tissue).

“Sustained release period” or “prolonged release period” refer to the entire period of release during which a local concentration of the corticosteroid drug is maintained at or above a minimum therapeutically effective amount. The desired sustained-release period can, of course, vary with the disease or condition being treated, the nature of the corticosteroid, and the condition of the particular patient being treated. Thus, the desired sustained-release period can be determined by the attending physician.

The phrase “therapeutically effective amount” refers to an amount of a therapeutic agent that, when delivered to a body compartment (e.g., submucosally) in the form of the coated microparticles as defined herein, produces a degree of reduced inflammation or pain in the body compartment (e.g., wall of esophagus) in a patient (at a reasonable benefit/risk ratio applicable to any medical treatment). The effective amount of the therapeutic agent may vary depending on such factors as the type and severity of inflammation being treated, its advancement, the degree of pain to which patient is subject, the particular microparticle being administered, the active agent and/or the size/age/gender of the subject. One of ordinary skill in the art may empirically determine the effective amount of a particular therapeutic agent according to known methods in the art. Unless specified otherwise, “therapeutically effective amount” refers to the amount of the therapeutic agent localized within the body compartment.

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

“Unit dosage form” refers to physically discrete units (e.g., loaded syringe cylinders) suitable as unitary dosages for human subjects, each unit containing a predetermined quantity of the therapeutic agent in association with a pharmaceutical acceptable vehicle. The quantity of the therapeutic agent is calculated to produce the desired therapeutic effect for a desired period of time.

“Vehicle” refers to a non-toxic carrier, adjuvant, or solvent into which the microparticles are suspended. The vehicle does not alter or destroy the pharmacological activity of the therapeutic agent with which it is formulated. Pharmaceutically acceptable carriers or vehicles that may be used in the compositions include, but are not limited to, water, physiological saline, hyaluronic acid, carboxymethylcellulose (CMC), and the like. As used herein, the term “biocompatible” means characterized by not causing a toxic, injurious or immunological response when brought into contact with living tissue, particularly human or other mammalian tissue.

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.

As used herein, the term “hydrophobic” means having lower affinity for an aqueous solvent than an organic solvent.

As used herein, the term “hydrophilic” means having lower affinity for an organic solvent than an aqueous solvent.

As used herein, the recitation of a numerical range for a variable is intended to convey that the disclosure may be practiced with the variable equal to any of the values within that range. Thus, for a variable which is inherently discrete, the variable can be equal to any integer value within the numerical range, including the end-points of the range. Similarly, for a variable which is inherently continuous, the variable can be equal to any real value within the numerical range, including the end-points of the range. As an example, and without limitation, a variable which is described as having values between 0 and 2 can take the values 0, 1 or 2 if the variable is inherently discrete, and can take the values 0.0, 0.1, 0.01, 0.001, or any other real values >0 and <2 if the variable is inherently continuous.

Methods for Treating or Preventing Gastrointestinal Inflammation

Methods of the present disclosure include treating or preventing an inflammatory disease in the gastrointestinal (GI) tract of a subject in need thereof by locally administering a therapeutically effective amount of a pharmaceutical composition in the subject, wherein the pharmaceutical composition comprises an extended-release composition that is formulated for prolonged release of the corticosteroid into tissue of the gastrointestinal tract. 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 comprises esophageal tissue. In some embodiments the administering comprises injecting the pharmaceutical composition into the tissue. For example, the administering may involve injecting the pharmaceutical composition into the esophageal tissue. In some embodiments the administering comprises at least one submucosal injection of the pharmaceutical composition into the tissue. In some embodiments the administering comprises at least one starting dose injection of the pharmaceutical composition into the tissue. The administering may include injecting at least two starting doses of the pharmaceutical composition into the tissue. In some embodiments the administering comprises a plurality of injections of the pharmaceutical composition into the tissue, such that at least two of the injections occur at different injection sites in the tissue. For example, in some embodiments the administering comprises at least one injection of the pharmaceutical composition into an area of inflammation in the gastrointestinal tract, at least one injection of the pharmaceutical composition into an injection site that is not located in an area of inflammation in the gastrointestinal tract, or a combination thereof.

In some embodiments the methods for treating or preventing inflammation further comprising locally administering by subsequent injection a therapeutically effective amount of the pharmaceutical composition to tissue of the gastrointestinal tract. For example, in some embodiment the method further comprises locally administering by subsequent injection a therapeutically effective amount of the pharmaceutical composition to the esophageal tissue.

Methods of treating an inflammatory disease of the GI tract include methods of treating benign GI strictures, wherein the administering comprises at least one injection of the pharmaceutical composition into at least one benign localized stricture in the GI tract of the subject. In some embodiments the administering comprises at least one injection of the pharmaceutical composition into the GI tissue (e.g., localized benign stricture) to form at least one bleb containing the extended-release composition.

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

In some embodiments the methods for treating or preventing inflammation (e.g., localized benign stricture(s)) can include an additional step of administering a topical agent to tissue of the gastrointestinal tract. For example, in some embodiments the method further comprises administering a topical agent to esophageal tissue. The topical agent may comprises an additional corticosteroid. In some embodiments the methods for treating or preventing inflammation (e.g., localized stricture(s)) are carried out on a subject that suffers from a chronic inflammatory disease. For example, in some embodiments the subject suffers from an inflammatory bowel disease, a gastroesophageal disease, a peptic ulcer disease, a radiation injury, a chemical ingestion injury, a post-surgical complication, an injection, or any combination thereof. As explained below, in some embodiments the subject may suffer from eosinophilic esophagitis (EoE).

In some embodiments methods of the present disclosure involve preventing or reducing the formation of benign GI strictures in a subject at high risk for benign stricture formation. For example, in some embodiments the subject was previously treated for at least one benign GI stricture but does not currently present any benign GI stricture.

In some embodiments methods of the present disclosure involve treating at least one benign GI stricture in the subject by injecting the pharmaceutical composition into the at least one benign GI stricture and optionally into tissue surrounding the at least one benign GI stricture. In some embodiments the subject was previously treated with dilation therapy.

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 or prevention of an inflammatory disease in the gastrointestinal tract (such as a benign GI stricture) of a subject, wherein a therapeutically effective amount of the pharmaceutical composition is locally administered in the subject, and wherein the pharmaceutical composition comprises an extended-release composition formulated for prolonged release of the corticosteroid into tissue 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 a benign GI stricture) of a subject, wherein a therapeutically effective amount of the pharmaceutical composition is locally administered in the subject, and wherein the pharmaceutical composition comprises an extended-release composition that is formulated for prolonged release of the corticosteroid into tissue of the gastrointestinal tract.

Methods of the present disclosure also include a method for treating eosinophilic esophagitis in a subject in need thereof by locally administering a therapeutically effective amount of a pharmaceutical composition in the subject, wherein the pharmaceutical composition comprises an extended-release composition formulated for prolonged release of a corticosteroid into esophageal tissue.

In some embodiments the administering comprises injecting the pharmaceutical composition into the esophageal tissue of the subject being treated. Injections may be performed subcutaneously or intradermally from inside the esophagus or from outside the esophagus (e.g., externally). For example, in some embodiments at least one submucosal injection of the pharmaceutical composition into the esophageal tissue is performed to administer the extended- release composition. In other embodiments the pharmaceutical composition may be administered topically to the esophagus of the subject, or may be administered both topically and by injection.

Injections of the pharmaceutical composition into the esophageal tissue may include at least one starting dose injection (for initiating the treatment), and may also include at least one secondary (or subsequent) dose injection.

The dosage of corticosteroid contained in each injection can be varied to accommodate different subjects, tissues and levels of inflammation. In some embodiments the administering comprises one or more injections of the pharmaceutical composition into the esophageal tissue, such that each injection independently contains from about 0.1 mg to about 20 mg of the corticosteroid. For example, the dosage 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.

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

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 locally administered in a subject, and wherein the pharmaceutical composition comprises an extended-release composition formulated for prolonged release of the corticosteroid into esophageal tissue. Some embodiments relate 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 in a subject, and wherein the pharmaceutical composition comprises an extended-release composition that is formulated for prolonged release of the corticosteroid into esophageal tissue. Esophageal Injections

As explained above, methods of the present disclosure may involve treating or preventing an inflammatory disease in the GI tract (such as benign GI strictures or eosinophilic esophagitis) by injecting a therapeutically effective amount of the extended-release corticosteroid into esophageal tissue.

In some embodiments the administering comprises a plurality of injections of the pharmaceutical composition into the esophageal tissue such that at least two of the injections occur at different injection sites in the esophageal tissue. For example, the administering may involve injecting at least two starting doses of the pharmaceutical composition into the esophageal tissue at different injection sites. Other embodiments may include multiple injections of the pharmaceutical composition into the same injection site (e.g., at different time periods). For example, in some embodiments the pharmaceutical composition may be injected into the same area of the esophagus by performing an injection from both inside the esophagus and from outside the esophagus (i.e., externally).

In some embodiments the injection sites are located on rings of the esophagus. In the context of this disclosure, a “ring” of the esophagus is a ring-shaped area of the esophagus that is defined by a circumference of the esophagus at a certain distance above the gastroesophageal (GE) junction. In general, points of injection along a ring of the esophagus all occur at about the same distance above the GE junction. Injections into a ring of the esophagus may occur at the same location along the ring circumference or may occur at different locations along the ring circumference.

Methods of the present disclose may be carried out such that the administering comprises a plurality of injections of the pharmaceutical composition into the esophageal tissue, wherein at least two of the injections occur at injection sites located along a first ring of the esophagus defined by a circumference of the esophagus at a distance dl above the gastroesophageal (GE) junction of the subject.

Figure 3 illustrates one such embodiment in which four rings of the esophagus (4) — a 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 dA (44) between adjacent rings may be the same or different for a particular injection pattern.

In some embodiments the distance dl (36) is at least 2 cm above the GE junction (8), while in other embodiments the distance dl (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 the GE junction (8). In some embodiments the distance d2 (38) is at least 1 cm greater than the distance dl (36), while in other embodiments the 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 the distance dl (36).

Figure 4 illustrates an embodiment in which a single injection of the pharmaceutical composition into the esophageal tissue occurs at a point of injection (44) located on a first ring (28) of the esophagus (4) defined by a circumference of the esophagus (4) at a distance dl (36) above the GE junction (8). In this illustration the injection of the pharmaceutical composition optionally forms a bleb (46) containing the extended-release composition. In other embodiments injection of the pharmaceutical composition does not form a bleb. In some embodiments the injection sites (44) located along the first ring (28) of the esophagus (4) are situated equidistant relative to one another along the circumference of the first ring (28). While in other embodiments injection sites (44) located along the first ring (28) of the esophagus (4) are not situated equidistant relative to one another along the circumference of the first ring (44).

In some embodiments, injections on a ring of the esophagus are not located at the exact same distance d above the GE junction as the ring. Injections may be situated above or below the distance d of a ring. For example, as illustrated in Figure 4, the injection (45) is located above the second ring (30), and in this embodiment the injection (45) does not form a bleb. Injections sites into a particular ring of the esophagus may vary as much as 1 cm above or below a particular ring. In some embodiments the injection site is located from about 0.1 cm to about 1.0 cm, or from about 0.2 cm to about 0.8 cm, or from about 0.3 cm to about 0.7 cm, or from about 0.4 cm to about 0.6 cm, or from about 0.1 cm to about 0.5 cm, or from about 0.3 cm to about 0.7 cm, or from about 0.5 cm to about 0.9 cm, above or below a particular ring. In some embodiment, multiple injections may occur onto the same ring of the esophagus in a manner such that the injections are located at different distances relative to the distance d of the ring above the GE junction.

Figure 5 shows a flattened-out view (5) of the esophagus (4) for an embodiment wherein four injections occur at different injections sites (44-1, 44-2, 44-3 and 44-4) located along a first ring (28) of the esophagus (4) defined by a circumference at a distance dl (36), in which the injections sites (44-1, 44-2, 44-3 and 44-4) are situated equidistant relative to one another along the circumference of the first ring (28). Consequently, the different injection sites (44-1, 44-2, 44-3 and 44-4) are located in different quadrants (48-1, 48-2, 48-3 and 48-4) of the esophagus (4), as illustrated in Figure 5. In some embodiments blebs (46-1, 46-2, 46-3 and 46-4) may be formed at one or more of the injection sites (44-1, 44-2, 44-3 and 44-4) as also illustrated in Figure 5.

In some embodiments at least three of the injections occur at injection sites located along a ring. In other embodiments the number of injections may range from two to ten at different injection sites located along a ring. Such multiple injections may be situated equidistant relative to one another or not equidistant relative to one another.

As illustrated in the flattened-out views of Figures 6A-6B, the pharmaceutical composition may be injected into a plurality of rings in the esophagus of a subject.

Figure 6 illustrates an embodiment wherein injections are carried out into four rings (28, 30, 32 and 34) of the esophagus such that injections into adjacent rings are offset relative to one another. Thus, whereas 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, 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.

Figure 7 illustrates an embodiment wherein injections are carried out into four rings (28, 30, 32 and 34) of the esophagus such that injections into adjacent rings are not offset relative to one another. Thus, all four of the injections into each of the first, second, third and fourth rings (28, 30, 32 and 34) are located within the first, second, third, or fourth quadrants (48-1, 48-2, 48- 3 and 48-4) of the esophagus.

Methods of the present disclosure may include administering one or more starting dose injections and one or more subsequent injections, each comprising a therapeutically effective amount of the pharmaceutical composition, to the esophageal tissue.

Figure 8 illustrates an embodiment wherein both starting dose injections (labelled as •) and subsequent dose injections (labelled as o) are carried out into four rings (28, 30, 32 and 34) of the esophagus such that injections (of each of the starting and subsequent doses) into adjacent rings are offset relative to one another. Thus, whereas the injection sites (54-1 and 54-2) for the starting doses (•) into the first ring (28) are located in the first and third quadrants (48-1 and 48- 3) of the esophagus, the injections sites (56-1 and 56-2) of the starting does (•) into the second ring (30) are located in the second and fourth quadrants (48-2 and 48-2) of the esophagus — and the subsequent dose injections (o) (55-1, 55-2, 57-1 and 57-2) into adjacent rings are similarly offset as illustrated in Figure 6C. In other embodiments, the starting dose injections and/or subsequent dose injections may or may not be offset relative to one another. Figure 9 illustrates an embodiment wherein a pattern of injection sites (58-1, 58-2, 58-3 and 58-4) within the esophagus is a spiral pattern with respect to a longitudinal axis of the esophagus.

A plurality of injections of the pharmaceutical composition may be carried out into a plurality of rings in the esophagus of a subject. For example, injections may occur at injection sites located along at least three rings, or at least four rings, or at least five rings, or at least six rings, or at least seven rings, or at least eight rings, of the esophagus defined by respective circumferences of the esophagus at respective distances of the rings above the gastroesophageal junction of the subject.

In some embodiments at least one injection of the pharmaceutical composition occurs into an area of esophageal inflammation, at least one injection of the pharmaceutical composition occurs into an injection site that is not located in an area of esophageal inflammation, or a combination thereof. For example, in some embodiments at least one injection of the pharmaceutical composition occurs into an area of esophageal inflammation, at least one injection of the pharmaceutical composition occurs into an area adjacent to the area of esophageal inflammation, or a combination thereof. With respect to injections occurring into an injection site that is located in an area of esophageal inflammation, at least one injection of the pharmaceutical composition may occur into a localized benign stricture in the esophagus of the subject. In some embodiments at least one injection of the pharmaceutical composition occurs into a localized benign stricture, at least one injection of the pharmaceutical composition occurs into an area adjacent to a localized benign stricture, or a combination thereof.

Figure 10 illustrates a localized stricture (60) in 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 circular rings (64) and narrowing (66) inside the esophagus. In extreme cases, this inflammation can lead to a localized benign stricture (60) having the potential to limit or block food and liquid that is traveling from the throat to the stomach (10). In some embodiments at least one injection of the pharmaceutical composition occur within a localized benign stricture (60).

Corticosteroid

As explained above, pharmaceutical compositions of the present disclosure comprise an extended-release composition formulated for prolonged release of a corticosteroid into esophageal tissue. In some embodiments the corticosteroid comprises a glucocorticoid agonist. For example, the corticosteroid may include at least one selected from desoxy corticosone, 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.

In some embodiments the corticosteroid comprises fluticasone or a pharmaceutically acceptable salt or ester thereof. For example, the corticosteroid may include fluticasone, fluticasone furoate, fluticasone propionate, or a combination thereof. In some embodiments the corticosteroid comprises fluticasone propionate, which is shown below.

(Fluticasone Propionate)

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

Microparticles

In some embodiments the extended-release composition comprises a corticosteroid and a hydrophilic polymer, which may be in the form of a microparticle having core/shell morphology. The microparticles of the core/shell morphology described herein are constructed to exhibit a sustained release profile uniquely suited for highly localized, extended delivery of a corticosteroid drug within a body compartment such as esophageal tissue.

In some embodiments the extended-release composition has a core-shell structure. For example, the extended-release composition may comprise microparticles including (1) a crystalline drug core comprising one or more crystals of the corticosteroid, and (2) a polymeric shell encapsulating the crystalline drug core, wherein the polymeric shell is in contact with but is immiscible with the crystalline drug core. The proportion of the crystalline drug core in the microparticles is more than 20%, or more than 30%, or more than 40%, or more than 50%, or more than 60%, or more than 70%, or more than 80%, or more than 90%, by weight relative to a total weight of the microparticles.

Microparticles of the present disclosure may have a mean diameter in the range of 50 pm to 800 pm and a standard deviation of less than 50% of the mean diameter. In some embodiments more than 90% of the microparticles have a mean diameter in the range of 50 pm to 800 pm, 50 pm to 700 pm, or 50 pm to 600 pm, or 50 pm to 500 pm, or 50 pm to 400 pm, or 50 pm to 300 pm, or 50 pm to 200 pm, or 50 pm to 100 pm.

In some embodiments the crystalline drug core comprises about 100% of the corticosteroid. The crystalline core is substantially pure drug as the crystalline core is prepared from recrystallized drug in the form of either a single large crystal or an aggregate of smaller crystals. Thus, “substantially pure” means at least about 90%, or at least about 95% or at least about 98%, or at least about 100% of the entire weight of the drug core is the drug in a crystalline form.

The polymeric shell comprises one or more concentrically or consecutively coated polymeric coatings of the same or different polymers. Standard biocompatible and biodegradable polymeric coatings known in the art can be employed to the extent that they meet the requirements described above with respect to retaining permeability and/or structural integrity during the desired sustained-release period. While the sustained release period is enhanced within the scope of the disclosure via higher drug loading and the beneficial and unexpected interaction of the body compartment (e.g., esophageal tissue) and the dissolutionbased delivery system described herein, there are additional factors at play supporting the superior efficacy of the method herein including, but not limited to:

• the degree of solubility of the corticosteroid

• the rate of clearance of the corticosteroid from the esophagus

• the size of the core particle and/or the amount of the corticosteroid initially present in the core particle

• the presence of other compounds within the core particle that affect the rate of release of the corticosteroid

• the permeability of the polymeric coating(s) to the corticosteroid

• the rate of degradation of the polymeric coating(s), as well as other factors.

As is known in the art, both the permeability and biodegradability of polymeric coatings can be affected by the choice of polymeric material (e.g., degree of hydrophobicity or hydrophilicity relative to the corticosteroid; degree of lability of bonds under physiological conditions), degree of cross-linking and thickness. For co-polymers, the ratio of the different monomers also can be varied to affect permeability and biodegradability.

In some embodiments the polymeric shell comprises a hydrophilic polymer. For example, the polymeric shell may include one or more biodegradable polymers selected from a polyvinyl alcohol (PVA), an ethylene vinyl acetate(EVA), a poly(p-xylylene) polymer, a poly(lactic acid) (PLA), a poly(glycolic acid) (PGA), a poly(lactic-co-glycolic acid) (PLGA), a poly(s-caprolactone) (PCL), a poly(valerolactone) (PVL), a poly(s-decalactone) (PDL), a poly(l,4-dioxane-2,3-dione), a poly(l,3-dioxane-2-one), poly(para-dioxanone) (PDS), a poly(hydroxybutyric acid) (PHB), a poly(hydroxyvaleric acid) (PHV), a poly(P-malic acid) (PMLA), and combinations thereof. In some embodiments the polymeric shell comprises a polyvinyl alcohol (PVA).

To modulate permeability and release rates, the polymeric shell may be covalently or ionically cross-linked. For example, monomers can be chosen which include chemical groups capable of forming additional bonds between monomers, or separate cross-linking agents can be included in the polymer-forming solutions in addition to the monomers. In some embodiments, the cross-linking groups are thermally activated, whereas in other embodiments they are photoactivated, including photoactivation by visible or ultraviolet radiation. Cross-linking groups include, without limitation, unsaturated groups such as vinyl, allyl, cinnamate, acrylate, diacrylate, oligoacrylate, methacrylate, dimethacrylate, and oligomethoacrylate groups.

As many corticosteroids are hydrophobic, and because it is desirable to reduce or avoid dissolution of the drug core into the polymeric shell in order to maintain a sharp interface between the core and shell, the polymeric shell may include a hydrophilic polymer, particularly in the coating that is most proximate to the crystalline core. Examples of hydrophilic polymeric coatings include, without limitation, poly(vinyl alcohol) (PVA), polyethylene glycol) (PEG), poly(ethylene oxide), poly(vinylpyrrolidone), poly(ethyloxazoline), or polysaccharides or carbohydrates such as alkylcelluloses, hydroxyalkylcelluloses, hyaluronic acid, dextran, heparan sulfate, chondroitin sulfate, heparin, or alginate, or proteins such as gelatin, collagen, albumin, ovalbumin, or poly amino acids.

Additional examples of suitable polymers can be prepared from monomers selected from the following group: sugar phosphates, alkylcellulose, hydroxyalkyl celluloses, lactic acid, glycolic acid, P-propiolactone, P-butyrolactone, y-butyrolactone, pivalolactone, a-hydroxy butyric acid, a-hydroxyethyl butyric acid, a-hydroxy isovaleric acid, a-hydroxy-P-methyl valeric acid, a-hydroxy caproic acid, a-hydroxy isocaproic acid, a-hydroxy heptanic acid, a-hydroxy octanic acid, a-hydroxy decanoic acid, a-hydroxy myristic acid, a-hydroxy stearic acid, a- hydroxy lignoceric acid and P-phenol lactic acid.

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

Because the crystalline drug core may contain at least 70% by weight of the microparticles, in some embodiments the overall size of the microparticle is largely determined by the size of the crystalline drug core. Typically, the polymeric shell has a thickness of about less than 12%, or less than 5% or less than 3% of the total diameter of the microparticle. Likewise, in some embodiments the weight of the microparticle is also correlated to the weight of the crystalline core, resulting in a high drug loading.

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

In some embodiments the in vivo sustained release profile of the corticosteroid correlates to the in vitro dissolution characteristics of the microparticles, which in turn are determined by, among others, the solubility and permeability of the drug core, the level of crosslinking of the polymeric shell, and the rate of degradation of the polymeric shell. In some embodiments microparticles have dissolution half-life of 12-20 hours, when tested using United States Pharmacopoeia Type II apparatus in which the dissolution conditions are 3 milligrams of microparticles in 200 milliliters of dissolution medium of 70% v/v methanol and 30% v/v of water at 25°C.

The injectable sustained-release compositions described in U.S. Patent No. 9,987,233 are incorporated herein by reference.

In some embodiments, use of the polymer-coated microsphere enables the extended- release composition to expose GI tissues to the corticosteroid over a prolonged period of time lasting as long as 6-12 months. Use of fluticasone as the corticosteroid can also enable the use of higher doses while limiting the systemic side effects — due to the high (-99%) first-pass metabolism of fluticasone. The high first pass metabolism of fluticasone thus enables high concentrations to be administered locally, because any drug that escapes the local mucosal tissue would be metabolized by the liver before it is able to have any systemic exposure. This advantage is not possible with steroids such as triamcinolone or beclomethasone where first pass metabolism is substantially lower.

Methods of Forming Microparticles

Methods of forming polymeric 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.

In some embodiments microparticles of the present disclosure are formed using the method of forming microparticles as described in U.S. Patent Publication 2007/003619, which is fully incorporated herein by reference. The crystalline drug core is coated with one or more layers of polymeric coatings, which together form the polymeric shell. For example, in one aspect, a PVA polymeric coating can be applied using a dip coating technique. In brief, a 1% coating solution of PVA in water can be formed by dissolving excess PVA in water at 60° C. for 2 h (see, e.g., Byron and Dalby (1987), J. Pharm. Sci. 76(l):65-67). Alternatively, a higher concentration PVA solution (e.g., 3-4%) can be prepared in a reflux with heating to approximately 90-100° C. After cooling, the microparticles can be added to the PVA solution and agitated by, for example, swirling or stirring. The microparticles are then removed from the solution by, for example, filtration on filter paper with a mesh size appropriate to the microparticles. Optionally, vacuum-filtration can be employed to assist in drying. Untreated, PVA polymeric coatings or films are readily permeable to water and hydrophilic drugs. Heating of PVA, however, causes an increase in crystallinity and decrease of permeability of up to 500- fold with increasing temperatures in the range of 100-250° C. for periods of 0-160 hours (Byron and Dalby (1987), supra).

Thus, in some embodiments, PVA polymeric coatings can be heated to temperatures between 100° C. and 250° C., between 125° C. and 175° C., or between 155° C. and 170° C. for periods between 1 sec. and 160 hours, between 1 min. and 10 hours, or between 5 minutes and 2 hours. For example, the heating may be carried out to 220°C for one hour. Optionally, the coating process can be repeated several times to prepare a thicker polymeric coating. In some embodiments from two to five coatings are applied to achieve a 5% w/w thickness of the coating.

In one embodiment, the microparticles undergo a heat treatment step at a temperature within the range of 210-230°C for at least one hour. By controlling the temperature of the heat treatment step, the level of crosslinking, and hence permeability, can be precision controlled.

Pharmaceutical Compositions

As explained above, methods described herein involve administering at least one pharmaceutical composition comprising an extended-release composition formulated for prolonged release of a corticosteroid into GI tissue (such as esophageal tissue). In addition to the extended-release compositions described above, pharmaceutical compositions of the present disclosure may include a pharmaceutically acceptable vehicle in which the extended-release composition is suspended. For example, in some embodiments the pharmaceutical composition is prepared in situ by combining the extended-release composition with a vehicle.

Treatment and prevention methods of the present disclosure may be carried out such that the pharmaceutical composition is prepared using a multi-vial system allowing components of the pharmaceutical composition to be formulated immediately prior to administration.

Such multi-vial systems can ensure adequate stability of the pharmaceutical composition even when the extended-release composition exhibits short-term stability in aqueous conditions. The multi-vial system includes at least one vial containing an extended-release composition (so- called corticosteroid vial) and at least one vial containing a liquid vehicle (so-called vehicle vial). In practice, the liquid contents of at least one vehicle vial are added to the solid contents of at least one corticosteroid viral and, upon agitation, the pharmaceutical composition is obtained in the corticosteroid vial as a suspension of the extended-release composition in the liquid vehicle.

In some embodiments the pharmaceutical composition is prepared using a 2-vial system including a corticosteroid vial comprising the extended-release composition, and a vehicle vial comprising a liquid vehicle. The extended-release composition may be in the form of a sterile powder comprising cured, PVA-coated crystals of the corticosteroid. In one embodiment, for example, the corticosteroid vial includes a sterile powder of an extended-release composition comprising cured, PVA-coated crystals of fluticasone propionate; and the separate vehicle vial contains sterile water and excipients necessary to prepare a uniform suspension of the extended- release composition. In some embodiments pharmaceutical compositions of the present disclosure, prepared from multi-vial systems or otherwise, are stable for periods ranging from 1 to 12 hours following combination of the extended-release composition with the liquid vehicle.

Pharmaceutically acceptable vehicles of the present disclosure may contain water and an excipient capable of suspending the extended-release composition in an aqueous medium. In some embodiments the excipient is selected from a binder, a suspending agent, a disintegration agent, a filling agent, a surfactant, a solubilizer, a stabilizer, a lubricant, a wetting agent, a diluent, and combinations thereof. For example, the excipient may be selected from a polysorbate, a polysaccharide, an acid salt, an alkali salt, a neutral salt and combinations thereof.

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

Table 1 below summarizes the compositions of two multi -vial systems of the present disclosure including the proportions of the individual components in the corticosteroid vial and in the vehicle vial.

Table 1: Compositions of 2-Vial Systems

The disclosure is illustrated by the following examples, which are not intended to be limiting. EXAMPLES

EXAMPLE 1

PROCEDURE FOR RECRYSTALLIZING FLUTICASONE PROPIONATE

Recrystallization of fluticasone propionate (FP) was carried out according to Example 1 of WO 2020/210720, the entire contents of which are incorporated herein by reference. Specifically, FP was recrystallized from 10-15mg/ml concentration in methanol in both small and large scales. During the slow evaporation e.g., for 72 hours, the temperature was held steadily at 45°C. The small scales were carried out in 20ml-2L solutions; whereas the large scales were carried out in 20-100L. Both the small and large scales produced thick elongated crystals that are suitable for further resizing. EXAMPLE 2

RESIZING THE 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 produced by Example 1 were milled in a rotor/ stator homogenizer. An exemplary set of operational parameters are as follows:

5-10% solid medium;

Carrier fluid: 0.1%-0.5% polysorbate 80 (a surfactant) in USP water

Rotor speed: 15000 - 20000 rpm (the mill is capable of going in range of 3000- 26000 rpm)

Rotor configuration comprising coarse, medium, or fine or combination of 2 or more rotors;

Number of runs through this cycle, up to 5 times

The milled crystals were then sieved through two separate sieves to eliminate fines or remnant large crystals. The drug crystal obtained had relatively narrow distribution and the minimal amount of fine material and absence of very fine material (no particles below 9 pm).

EXAMPLE 3

GENERAL PROCEDURE FOR COATING CRYSTALLINE DRUG CORE

The recrystallized FP crystals prepared according 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, 50-60 L min' ¹ ; nozzle air, 5.0-25 psi; pump speed, 10-35 rpm; inlet temperature, 99°C; exhaust temperature, 35-40°C; spray on/off cycle: 0.1/0.3 min.

The PVA content is periodically measured by quantitative ^T H nuclear magnetic resonance (NMR) spectroscopy by comparing the relative signal intensities of the FP and PVA resonances in the drug product to corresponding signals from calibration standards (See Example 4). A target final PVA concentration in the drug product is in the range of 0.1-20% w/w, or preferably 2-10% w/w. Coating of the particles is continued until the desired amount of PVA has been achieved. The coated particles are then dried in an oven at 40°C for 1 h. The dry, coated particles are sieved in a sieve stack defined by 150 pm mesh and 53 pm mesh sieves. EXAMPLE 4

NMR ANALYSIS FOR DETERMINING DRUG CONTENT IN MICROPARTICLES

NMR analysis was used to determine the amounts of the drug core and the polymeric shell in microparticles by calibrating with samples of known quantity of the pure drug.

The NMR system includes a Bruker Spectrospin 300 MHz magnet, Bruker B-ACS 120 autosampler, Bruker Avance II 300 console, and a Bruker BBO 300 MHz SI 5mm with Z gradient probe. A calibration curve was prepared using five samples of known fluticasone propionate, and PVA concentrations made in NMR grade d6-DMSO. Proton (1H) NMR was run on two samples: the first containing only pure fluticasone propionate and the second containing PVA-coated fluticasone. Each sample was loaded manually and spun at 20 Hz inside the magnet. The probe was tuned and matched for proton (1H) NMR. The magnet was shimmed manually with the first sample in the magnet. Each sample was integrated for 1.5 hours with 1024 scans. Fluticasone peaks were integrated from 5.5 to 6.35 ppm, and the PVA peak was integrated from 4.15 to 4.7 ppm. Using this method, the finished coated fluticasone particles were determined to contain 2.1% PVA total weight of coated particles. Assuming spherical particle shape and mean particle diameter of 100 pm, this represents a coating thickness of ca. 7 pm.

EXAMPLE 5

SUSTAINED RELEASE (SR) CORTICOSTEROID

The recrystallized FP crystals were prepared according to Example 2 and were 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 bench top fluidized bed coater system (Vector Corporation) using the following range of parameters: air flow, 50-60 L/min; nozzle air, 23 psi; pump speed, 15 rpm; inlet temperature, 99°C; exhaust temperature, 35-40°C; spray on/off cycle: 0.1/0.3 min. Coating of the particles was continued until the amount of PVA reached 6% (w/w) based on the NMR sampling (See Example 4).

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

The microparticles have mean diameters in the range of 60-150 pm. The PVA content of the resulting microparticles was 6% as analyzed by NMR analysis according to the method described in Example 4. Polymer-coated fluticasone particles were steam-sterilized (122°C, 16 psi, 30 min) in amber vials. The sterilization process did not affect the chemical composition of the formulation according to 1H NMR spectroscopy and HPLC analysis. EXAMPLE 6

PREPARATION OF 2-VIAL SYSTEM.

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

EXAMPLE 7 PREPARATION OF 2.5 MG/ML SUSPENSION.

Using a syringe and 18G needs, 6 mL of air is injected into the vehicle vial of Example 6, then 6 mL of vehicle from the vehicle vial is injected into the corticosteroid vial of Example 6 to rinse particles all the walls of the corticosteroid vial. The corticosteroid vial is then swirled to ensure uniform suspension of particles and to avoid clumping and aggregation. Two additional 6 mL vehicle injections are made into the corticosteroid vial to obtain a suspension having approximately 18 mL of volume with an SR concentration of approximately 2.5 mg/mL. The constituted SR suspension is temperature controlled to 20-25°C (68-77°F) prior to use and is used within 1 hours of constitution.

EXAMPLE 8

TREATMENT PROTOCOL (8 INJECTIONS AT 2.5 MG/ML).

Using the SR suspension of Example 7 (2.5 mg/mL), 8 esophageal injections are performed on an adult human patient suffering from eosinophilic esophagitis (EoE). 1.0 mL of the SR suspension (~ 2.5 mg per injection) is injected into 8 separate injection sites on four different rings of the esophagus as illustrated in Figure 6. All of the injections are submucosal injections into the esophageal tissue and are carried out inside the throat using a standard esophageal injection probe.

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

EXAMPLE 9 TREATMENT PROTOCOLS (ASCENDING TOTAL DOSAGES).

Using SR suspensions of the present disclosure, different treatment protocols can be carried out on one or more adult human patients suffering from eosinophilic esophagitis (EoE), such that the total dose of the sustained release (SR) corticosteroid can be varied from about 1 mg to about 100 mg. The total dose in these experiments equals the dose-per-inj ection-site multiplied by the number of injections carried out in a particular treatment. The concentration of the sustained release (SR) corticosteroid for each injection can vary from about 0.25 mg/mL to about 10 mg/mL, and the number of injections for each treatment protocol can vary from 1 injection to 20 injections. Examples 9-1 thru 9-8 below illustrate treatment protocols in which the total dose of the SR corticosteroid is increased from about 4 mg to about 40 mg.

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

A 1.0 mg/mL solution of the sustained release (SR) corticosteroid is prepared using the 2- vial system of Example 6. Four esophageal injections are performed on an adult human patient suffering from eosinophilic esophagitis (EoE). 1.0 mL of the SR suspension (~ 1.0 mg per injection) is injected into 4 separate injection sites on two different rings of the esophagus as illustrated in Figure 6 — delivering a total dose of about 4 mg to each of the one or more adult human patients. All of the injections are submucosal injections into the esophageal tissue and are carried out inside the throat using a standard esophageal injection probe.

Referring to Figure 6, two of the injections are carried out in the first and fourth quadrants (48-1 and 48-3) of the first ring (28) which is approximately 6 cm above the gastroesophageal (GE) junction (8) — such that the injection sites are situated equidistant relative to one another along the circumference of the first ring (28). The remaining two of the injections are carried out in the second and fourth quadrants (48-2 and 48-4) of the second ring (30) which is approximately 7 cm above the GE junction (8) — such that the injection sites are situated equidistant relative to one another along the circumference of the second ring (30). Example 9-2: (8 injections / 8 mg total dose)

A 1.0 mg/mL solution of the sustained release (SR) corticosteroid is prepared using the 2- vial system of Example 6. Eight esophageal injections are performed on an adult human patient suffering from eosinophilic esophagitis (EoE). 1.0 mL of the SR suspension (~ 1.0 mg per injection) is injected into 8 separate injection sites on four different rings of the esophagus as illustrated in Figure 6 — delivering a total dose of about 8 mg to each of the one or more adult human patients. All of the injections are submucosal injections into the esophageal tissue and are carried out inside the throat using a standard esophageal injection probe.

Referring to Figure 6, two of the injections are carried out in the first and fourth quadrants (48-1 and 48-3) of the first ring (28) which is approximately 6 cm above the gastroesophageal (GE) junction (8) — such that the injection sites are situated equidistant relative to one another along the circumference of the first ring (28). Two of the injections are carried out in the second and fourth quadrants (48-2 and 48-4) of the second ring (30) which is approximately 7 cm above the GE junction (8) — such that the injection sites are situated equidistant relative to one another along the circumference of the second ring (30). Two of the injections are carried out in the first and third quadrants (48-2 and 48-4) of the third ring (32) which is approximately 8 cm above the GE junction (8) — such that the injection sites are situated equidistant relative to one another along the circumference of the third ring (32). Two of the injections are carried out in the second and fourth quadrants (48-2 and 48-4) of the fourth ring (34) which is approximately 10 cm above the GE junction (8) — such that the injection sites are situated equidistant relative to one another along the circumference of the fourth ring (28).

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

A 1.0 mg/mL solution of the sustained release (SR) corticosteroid is prepared using the 2- vial system of Example 6. Twelve esophageal injections are performed on an adult human patient suffering from eosinophilic esophagitis (EoE). 1.0 mL of the SR suspension (~ 1.0 mg per injection) is injected into 12 separate injection sites on four different rings of the esophagus as illustrated in Figure 6 — delivering a total dose of about 12 mg to each of the one or more adult human patients. All of the injections are submucosal injections into the esophageal tissue and are carried out inside the throat using a standard esophageal injection probe.

Referring to Figure 6, three of the injections are carried out into the first ring (28) which is approximately 6 cm above the gastroesophageal (GE) junction (8) — such that the injection sites are situated equidistant relative to one another along the circumference of the first ring (28). Three of the injections are carried out into the second ring (30) which is approximately 7 cm above the GE junction (8) — such that the injection sites are situated equidistant relative to one another along the circumference of the second ring (30). Three of the injections are carried out into the third ring (32) which is approximately 8 cm above the GE junction (8) — such that the injection sites are situated equidistant relative to one another along the circumference of the third ring (32). Three of the injections are carried out into the fourth ring (34) which is approximately 10 cm above the GE junction (8) — such that the injection sites are situated equidistant relative to one another along the circumference of the fourth ring (34).

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

A 1.0 mg/mL solution of the sustained release (SR) corticosteroid is prepared using the 2- vial system of Example 6. Sixteen esophageal injections are performed on an adult human patient suffering from eosinophilic esophagitis (EoE). 1.0 mL of the SR suspension (~ 1.0 mg per injection) is injected into 16 separate injection sites on four different rings of the esophagus as illustrated in Figure 6 — delivering a total dose of about 16 mg to each of the one or more adult human patients. All of the injections are submucosal injections into the esophageal tissue and are carried out inside the throat using a standard esophageal injection probe.

Referring to Figure 6, four of the injections are carried out in the first, second, third and fourth quadrants of the first ring (28) which is approximately 6 cm above the gastroesophageal (GE) junction (8) — such that the injection sites are situated equidistant relative to one another along the circumference of the first ring (28). Four of the injections are carried out in the first, second, third and fourth quadrants of the second ring (30) which is approximately 7 cm above the GE junction (8) — such that the injection sites are situated equidistant relative to one another along the circumference of the second ring (30). Three of the injections are carried out in the first, second, third and fourth quadrants of the third ring (32) which is approximately 8 cm above the GE junction (8) — such that the injection sites are situated equidistant relative to one another along the circumference of the third ring (32). Three of the injections are carried out in the first, second, third and fourth quadrants of the fourth ring (34) which is approximately 10 cm above the GE junction (8) — such that the injection sites are situated equidistant relative to one another along the circumference of the fourth ring (34).

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

A 2.5 mg/mL solution of the sustained release (SR) corticosteroid is prepared using the 2- vial system of Example 6. Four esophageal injections are performed on an adult human patient suffering from eosinophilic esophagitis (EoE). 1.0 mL of the SR suspension (~ 2.5 mg per injection) is injected into 4 separate injection sites on two different rings of the esophagus as illustrated in Figure 6 — delivering a total dose of about 10 mg to each of the one or more adult human patients. All of the injections are submucosal injections into the esophageal tissue and are carried out inside the throat using a standard esophageal injection probe.

Referring to Figure 6, two of the injections are carried out in the first and fourth quadrants (48-1 and 48-3) of the first ring (28) which is approximately 6 cm above the gastroesophageal (GE) junction (8) — such that the injection sites are situated equidistant relative to one another along the circumference of the first ring (28). The remaining two of the injections are carried out in the second and fourth quadrants (48-2 and 48-4) of the second ring (30) which is approximately 7 cm above the GE junction (8) — such that the injection sites are situated equidistant relative to one another along the circumference of the second ring (30).

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

A 2.5 mg/mL solution of the sustained release (SR) corticosteroid is prepared using the 2- vial system of Example 6. Eight esophageal injections are performed on an adult human patient suffering from eosinophilic esophagitis (EoE). 1.0 mL of the SR suspension (~ 2.5 mg per injection) is injected into 8 separate injection sites on four different rings of the esophagus as illustrated in Figure 6 — delivering a total dose of about 20 mg to each of the one or more adult human patients. All of the injections are submucosal injections into the esophageal tissue and are carried out inside the throat using a standard esophageal injection probe.

Referring to Figure 6, two of the injections are carried out in the first and fourth quadrants (48-1 and 48-3) of the first ring (28) which is approximately 6 cm above the gastroesophageal (GE) junction (8) — such that the injection sites are situated equidistant relative to one another along the circumference of the first ring (28). Two of the injections are carried out in the second and fourth quadrants (48-2 and 48-4) of the second ring (30) which is approximately 7 cm above the GE junction (8) — such that the injection sites are situated equidistant relative to one another along the circumference of the second ring (30). Two of the injections are carried out in the first and third quadrants (48-2 and 48-4) of the third ring (32) which is approximately 8 cm above the GE junction (8) — such that the injection sites are situated equidistant relative to one another along the circumference of the third ring (32). Two of the injections are carried out in the second and fourth quadrants (48-2 and 48-4) of the fourth ring (34) which is approximately 10 cm above the GE junction (8) — such that the injection sites are situated equidistant relative to one another along the circumference of the fourth ring (28). Example 9-7: (12 injections / 30 mg total dose)

A 2.5 mg/mL solution of the sustained release (SR) corticosteroid is prepared using the 2- vial system of Example 6. Twelve esophageal injections are performed on an adult human patient suffering from eosinophilic esophagitis (EoE). 1.0 mL of the SR suspension (~ 2.5 mg per injection) is injected into 12 separate injection sites on four different rings of the esophagus as illustrated in Figure 6 — delivering a total dose of about 30 mg to each of the one or more adult human patients. All of the injections are submucosal injections into the esophageal tissue and are carried out inside the throat using a standard esophageal injection probe.

Referring to Figure 6, three of the injections are carried out into the first ring (28) which is approximately 6 cm above the gastroesophageal (GE) junction (8) — such that the injection sites are situated equidistant relative to one another along the circumference of the first ring (28). Three of the injections are carried out into the second ring (30) which is approximately 7 cm above the GE junction (8) — such that the injection sites are situated equidistant relative to one another along the circumference of the second ring (30). Three of the injections are carried out into the third ring (32) which is approximately 8 cm above the GE junction (8) — such that the injection sites are situated equidistant relative to one another along the circumference of the third ring (32). Three of the injections are carried out into the fourth ring (34) which is approximately 10 cm above the GE junction (8) — such that the injection sites are situated equidistant relative to one another along the circumference of the fourth ring (34).

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

A 2.5 mg/mL solution of the sustained release (SR) corticosteroid is prepared using the 2- vial system of Example 6. Sixteen esophageal injections are performed on an adult human patient suffering from eosinophilic esophagitis (EoE). 1.0 mL of the SR suspension (~ 2.5 mg per injection) is injected into 16 separate injection sites on four different rings of the esophagus as illustrated in Figure 6 — delivering a total dose of about 40 mg to each of the one or more adult human patients. All of the injections are submucosal injections into the esophageal tissue and are carried out inside the throat using a standard esophageal injection probe.

Referring to Figure 6, four of the injections are carried out in the first, second, third and fourth quadrants of the first ring (28) which is approximately 6 cm above the gastroesophageal (GE) junction (8) — such that the injection sites are situated equidistant relative to one another along the circumference of the first ring (28). Four of the injections are carried out in the first, second, third and fourth quadrants of the second ring (30) which is approximately 7 cm above the GE junction (8) — such that the injection sites are situated equidistant relative to one another along the circumference of the second ring (30). Three of the injections are carried out in the first, second, third and fourth quadrants of the third ring (32) which is approximately 8 cm above the GE junction (8) — such that the injection sites are situated equidistant relative to one another along the circumference of the third ring (32). Three of the injections are carried out in the first, second, third and fourth quadrants of the fourth ring (34) which is approximately 10 cm above the GE junction (8) — such that the injection sites are situated equidistant relative to one another along the circumference of the fourth ring (34).

Example 9-9: (alternative injection patterns)

Other treatment protocols are carried out using similar conditions to Examples 9-1 thru 9- 8 except that the injection pattern is not limited to equidistant injections, the number of injections is not limited to range from 4 to 16, and the protocol is not limited to the treatment of EoE. Some treatment protocols are carried out such that the injection pattern is irregular and may be based upon the position of inflammation in the gastrointestinal (GI) tract of the subject being treated. For example, some treatment protocols are carried out such that at least one injection occurs directly into a benign stricture of the GI tract, and at least one additional injection may occur into another area of the GI tract (such as an area adjacent to the benign stricture).

EMBODIMENTS

Embodiment [1] of the present disclosure relates to a method for treating or preventing an inflammatory disease in the gastrointestinal tract of a subject in need thereof, the method comprising locally administering a therapeutically effective amount of a pharmaceutical composition in the subject, wherein the pharmaceutical composition comprises an extended- release composition that is formulated for prolonged release of the corticosteroid into tissue of the gastrointestinal tract.

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

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

Embodiment [4] of the present disclosures relates to the method according to any one of Embodiments [1 ]-[3], wherein the administering comprises injecting the pharmaceutical composition into the tissue. Embodiment [5] of the present disclosures relates the method according to any of Embodiments [1 ]-[4], wherein the administering comprises injecting the pharmaceutical composition into the esophageal tissue.

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

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

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

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

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

Embodiment [11] of the present disclosure relates to the method according to any of Embodiments [1 ]-[ 10], wherein the administering comprises at least one injection of the pharmaceutical composition occurs into a localized benign stricture in the gastrointestinal tract of the subject.

Embodiment [12] of the present disclosure relates to the method according to any of Embodiments [1]-[11], wherein the administering comprises at least one injection of the pharmaceutical composition into the tissue to form at least one bleb containing the extended- release composition.

Embodiment [13] of the present disclosure relates to the method according to any of Embodiments [1 ]-[ 12], wherein the administering comprises one or more injections of the pharmaceutical composition into the tissue, such that each injection independently contains from about 0.1 mg to about 20 mg, or from about 0.5 mg to about 10 mg, or from about 1 mg to about 8 mg, or from about 1 mg to about 6 mg, or from about 2 mg to about 12 mg, or from about 3 mg to about 8 mg, or from about 5 mg to about 20 mg, or from about 5 mg to about 15 mg, or from about 6 mg to about 14 mg, or from about 7 mg to about 18 mg, or from about 7 mg to about 16 mg, or from about 8 mg to about 20 mg, or from about 8 mg to about 16 mg, or from about 9 mg to about 18 mg, or from about 9 mg to about 15 mg, or from about 10 mg to about 20 mg, or from about 10 mg to about 18 mg, or from about 10 mg to about 16 mg, of the corticosteroid.

Embodiment [14] of the present disclosure relates to a method for treating eosinophilic esophagitis in a subject in need thereof, the method comprising locally administering a therapeutically effective amount of a pharmaceutical composition in the subject, wherein the pharmaceutical composition comprises an extended-release composition that is formulated for prolonged release of the corticosteroid into esophageal tissue.

Embodiment [15] of the present disclosures relates the method according to Embodiment [14], wherein the administering comprises injecting the pharmaceutical composition into the esophageal tissue.

Embodiment [16] of the present disclosure relates to the method according to Embodiment [14] or [15], wherein the administering comprises at least one submucosal injection of the pharmaceutical composition into the esophageal tissue.

Embodiment [17] of the present disclosure relates to the method according to any of Embodiments [14]-[16], wherein the administering comprises at least one starting dose injection of the pharmaceutical composition into the esophageal tissue.

Embodiment [18] of the present disclosure relates to the method according to any of Embodiments [14]-[17], wherein the administering comprises a plurality of injections of the pharmaceutical composition into the esophageal tissue, such that at least two of the injections occur at different injection sites in the esophageal tissue.

Embodiment [19] of the present disclosure relates to the method according to any of Embodiments [14]-[18], wherein the administering comprises injecting at least two starting doses of the pharmaceutical composition into the esophageal tissue.

Embodiment [20] of the present disclosure relates to the method according to any of Embodiments [1]-[19], wherein the administering comprises a plurality of injections of the pharmaceutical composition into the esophageal tissue, such that at least two of the injections occur at injection sites located along a first ring of the esophagus defined by a circumference of the esophagus at a distance dl above the gastroesophageal junction of the subject.

Embodiment [21] of the present disclosure relates to the method according to

Embodiment [20], wherein the distance dl 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.

Embodiment [22] of the present disclosure relates to the method according to Embodiment [20] or [21], wherein the injection sites located along the first ring of the esophagus are situated equidistant relative to one another along the circumference of the first ring, or wherein the injection sites located along the first ring of the esophagus are not situated equidistant relative to one another along the circumference of the first ring.

Embodiment [23] of the present disclosure relates to the method according to any of Embodiments [20]-[22], wherein at least three of the injections occur at injection sites located along the first ring, or at least four of the injections occur at injection sites located along the first ring, or at least five of the injections occur at injection sites located along the first ring, or at least six of the injections occur at injection sites located along the first ring, or at least seven of the injections occur at injection sites located along the first ring, or at least eight of the injections occur at injection sites located along the first ring, or at least nine of the injections occur at injection sites located along the first ring, or at least ten of the injections occur at injection sites located along the first ring.

Embodiment [24] of the present disclosure relates to the method according to any of Embodiments [20]-[23 ], wherein at least two injections of the pharmaceutical composition into the esophageal tissue occur at injection sites located along a second ring of the esophagus defined by a circumference of the esophagus at a distance d2 above the gastroesophageal junction, wherein the distance d2 is greater than the distance dl.

Embodiment [25] of the present disclosure relates to the method according to 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 dl.

Embodiment [26] of the present disclosure relates to the method according to Embodiment [24] or [25], wherein the injection sites located along the second ring of the esophagus are situated equidistant relative to one another along the circumference of the second ring, or wherein the injection sites located along the second ring of the esophagus are not situated equidistant relative to one another along the circumference of the second ring.

Embodiment [27] of the present disclosure relates to the method according to any of Embodiments [24]-[26], wherein at least three of the injections occur at injection sites located along the second ring, or at least four of the injections occur at injection sites located along the second ring, or at least five of the injections occur at injection sites located along the second ring, or at least six of the injections occur at injection sites located along the second ring, or at least seven of the injections occur at injection sites located along the second ring, or at least eight of the injections occur at injection sites located along the second ring, or at least nine of the injections occur at injection sites located along the second ring, or at least ten of the injections occur at injection sites located along the second ring.

Embodiment [28] of the present disclosure relates to the method according to any of Embodiments [l]-[27], wherein the administering comprises a plurality of injections of the pharmaceutical composition into esophageal tissue, such that injections occur at injection sites located along a plurality of 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 wherein a pattern of injection sites within the esophagus is a spiral pattern with respect to a longitudinal axis of the esophagus.

Embodiment [29] of the present disclosure relates to the method according to any of Embodiments [l]-[28], wherein the administering comprises a plurality of injections of the pharmaceutical composition into esophageal tissue, such that injections occur at injection sites located along at least three rings, or at least four rings, or at least five rings, or at least six rings, or at least seven rings, or at least eight rings, of the esophagus defined by respective circumferences of the esophagus at respective distances of the rings above the gastroesophageal junction of the subject.

Embodiment [30] of the present disclosure relates to the method according to any of Embodiments [1 ]-[29], wherein the administering comprises at least one injection of the pharmaceutical composition occurs into an area of esophageal inflammation, at least one injection of the pharmaceutical composition into an injection site that is not located in an area of esophageal inflammation, or a combination thereof.

Embodiment [31] of the present disclosure relates to the method according to any of Embodiments [1 ]-[30], wherein the administering comprises at least one injection of the pharmaceutical composition occurs into a localized benign stricture in the esophagus of the subject.

Embodiment [32] of the present disclosure relates to the method according to any of Embodiments [l]-[31], wherein the pharmaceutical composition is injected into the esophageal tissue to form at least one bleb containing the extended-release composition.

Embodiment [33] of the present disclosure relates to the method according to any of Embodiments [1 ]-[32], wherein the administering comprises one or more injections of the pharmaceutical composition into the esophageal tissue, such that each injection independently contains from about 0.1 mg to about 20 mg, or from about 0.5 mg to about 10 mg, or from about 1 mg to about 8 mg, or from about 1 mg to about 6 mg, or from about 2 mg to about 12 mg, or from about 3 mg to about 8 mg, or from about 5 mg to about 20 mg, or from about 5 mg to about 15 mg, or from about 6 mg to about 14 mg, or from about 7 mg to about 18 mg, or from about 7 mg to about 16 mg, or from about 8 mg to about 20 mg, or from about 8 mg to about 16 mg, or from about 9 mg to about 18 mg, or from about 9 mg to about 15 mg, or from about 10 mg to about 20 mg, or from about 10 mg to about 18 mg, or from about 10 mg to about 16 mg, of the corticosteroid.

Embodiment [34] of the present disclosure relates to the method according to any of Embodiments [ 1 ]-[33], wherein the corticosteroid comprises a glucocorticoid agonist.

Embodiment [35] of the present disclosure relates to the method according to any of Embodiments [ 1 ]-[34], 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, fluoromethoIone, fluocinolone acetonide, diflucortolone valerate, paramethasone acetate, halcinonide, hydrocortisone phosphate, clobetasone butyrate, amcinonide, prednisolone succinate, and pharmaceutically acceptable salts and/or esters thereof.

Embodiment [36] of the present disclosure relates to the method according to any of Embodiments [ 1 ]-[35], wherein the corticosteroid comprises fluticasone or a pharmaceutically acceptable salt or ester thereof.

Embodiment [37] of the present disclosure relates to the method according to any of Embodiments [ 1 ]-[36], wherein the corticosteroid comprises fluticasone, fluticasone furoate, fluticasone propionate, or a combination thereof.

Embodiment [38] of the present disclosure relates to the method according to any of Embodiments [ 1 ]-[37], wherein the corticosteroid comprises fluticasone propionate.

Embodiment [39] of the present disclosure relates to the method according to any of Embodiments [ 1 ]-[38], wherein the corticosteroid is crystalline.

Embodiment [40] of the present disclosure relates to the method according to any of Embodiments [ 1 ]-[39], wherein the extended-release composition comprises the corticosteroid and a hydrophilic polymer.

Embodiment [41] of the present disclosure relates to the method according to any of Embodiments [l]-[40], wherein the extended-release composition has a core-shell structure. Embodiment [42] of the present disclosure relates to the method according to any of Embodiments [ 1 ]-[41 ], wherein the extended-release composition comprises microparticles including (1) a crystalline drug core comprising one or more crystals of the corticosteroid, and (2) a polymeric shell encapsulating the crystalline drug core, the polymeric shell being in contact but immiscible with the crystalline drug core, and wherein a proportion of the crystalline drug core in the microparticles is more than 20%, or more than 30%, or more than 40%, or more than 50%, or more than 60%, or more than 70%, or more than 80%, or more than 90%, by weight relative to a total weight of the microparticles.

Embodiment [43] of the present disclosure relates to the method according to Embodiment [42], wherein the microparticles have a mean diameter in the range of 50 pm to 800 pm and a standard deviation of less than 50% of the mean diameter.

Embodiment [44] of the present disclosure relates to the method according to Embodiment [42] or [43], wherein more than 90% of the microparticles have a mean diameter in the range of 50 pm to 800 pm, 50 pm to 700 pm, or 50 pm to 600 pm, or 50 pm to 500 pm, or 50 pm to 400 pm, or 50 pm to 300 pm, or 50 pm to 200 pm, or 50 pm to 100 pm.

Embodiment [45] of the present disclosure relates to the method according to 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.

Embodiment [46] of the present disclosure relates to the method according to any of Embodiments [42]-[45], wherein the polymeric shell comprises a hydrophilic polymer.

Embodiment [47] of the present disclosure relates to the method according to any of Embodiments [42]-[46], wherein the polymeric shell comprises one or more biodegradable polymers selected from the group consisting of a polyvinyl alcohol (PVA), an ethylene vinyl acetate(EVA), a poly(p-xylylene) polymer, a poly(lactic acid) (PLA), a poly(glycolic acid) (PGA), a poly(lactic-co-glycolic acid) (PLGA), a poly(s-caprolactone) (PCL), a poly(valerolactone) (PVL), a poly(s-decalactone) (PDL), a poly(l,4-dioxane-2,3-dione), a poly(l,3-dioxane-2-one), poly(para-dioxanone) (PDS), a poly(hydroxybutyric acid) (PHB), a poly(hydroxyvaleric acid) (PHV), and a poly(P-malic acid) (PMLA).

Embodiment [48] of the present disclosure relates to the method according to any of Embodiments [42]-[47], wherein the polymeric shell comprises a polyvinyl alcohol (PVA).

Embodiment [49] of the present disclosure relates to the method according to any of Embodiments [42]-[48], wherein the polymeric shell comprises a cross-linked polymer.

Embodiment [50] of the present disclosure relates to the method according to Embodiment [49], wherein the cross-linked polymer is covalently or ionically cross linked. Embodiment [51] of the present disclosure relates to the method according to any of Embodiments [42]-[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 polymeric shell.

Embodiment [52] of the present disclosure relates to the method according to any of Embodiments [42]-[51], wherein the microparticles have a mean diameter of between 50 pm and 800 pm, or between 60 pm and 250 pm, or between 80 pm and 150 pm.

Embodiment [53] of the present disclosure relates to the method according to any of Embodiments [ 1 ]-[52], wherein the pharmaceutical composition further comprises a pharmaceutically acceptable vehicle in which the extended-release composition is suspended.

Embodiment [54] of the present disclosure relates to the method according to any of Embodiments [ 1 ]-[53], wherein the pharmaceutical composition is prepared by combining the extended-release composition with a pharmaceutically acceptable vehicle.

Embodiment [55] of the present disclosure relates to the method according to any of Embodiments [ 1 ]-[54], wherein the pharmaceutical composition is stable for a period of up to one hour, or two hours, or three hours, or four hours, or five hours, or six hours, or seven hours, or eight hours, or nine hours, or ten hours, or eleven hours, or twelve hours, following combining of the extended-release composition with a pharmaceutically acceptable vehicle.

Embodiment [56] of the present disclosure relates to the method according to any of Embodiments [ 1 ]-[55], wherein the extended-release composition is in the form of a sterile powder comprising cured PVA-coated crystals of the corticosteroid.

Embodiment [57] of the present disclosure relates to the method according to any of Embodiments [ 1 ]-[56], wherein the pharmaceutical composition further comprises a pharmaceutically acceptable vehicle comprising water and an excipient capable of suspending the extended-release composition in an aqueous medium.

Embodiment [58] of the present disclosure relates to the method according to any of Embodiments [ 1 ]-[57], wherein the pharmaceutical composition further comprises a pharmaceutically acceptable vehicle containing water and an excipient capable of suspending the extended-release composition in an aqueous medium, and wherein the excipient is selected from the group consisting of a binder, a suspending agent, a disintegration agent, a filling agent, a surfactant, a solubilizer, a stabilizer, a lubricant, a wetting agent, a diluent, and combinations thereof.

Embodiment [59] of the present disclosure relates to the method according to any of Embodiments [ 1 ]-[58], wherein the pharmaceutical composition further comprises a pharmaceutically acceptable vehicle containing water and an excipient capable of suspending the extended-release composition in an aqueous medium, and wherein the excipient is selected from the group consisting of a polysorbate, a polysaccharide, an acid salt, an alkali salt, a neutral salt and combinations thereof.

Embodiment [60] of the present disclosure relates to the method according to any of Embodiments [ 1 ]-[59], wherein the pharmaceutical composition further comprises a pharmaceutically acceptable vehicle containing 0.05 to 0.1% by weight of Polysorbate 80, 0.1 to 2.0% by weight of carboxymethylcellulose (CMC), and 0.1 to 2.0% by weight of sodium chloride, in sterile water, relative to a total weight of the pharmaceutically acceptable vehicle.

Embodiment [61] of the present disclosure relates to the method according to any of Embodiments [l]-[60], wherein the pharmaceutical composition further comprises a pharmaceutically acceptable vehicle containing about 0.015% by weight of Polysorbate 80, about 0.5% by weight of carboxymethylcellulose (CMC), and about 0.9% by weight of sodium chloride, in sterile water, relative to a total weight of the pharmaceutically acceptable vehicle.

Embodiment [62] of the present disclosure relates to the method according to any of Embodiments [ 1 ]-[61 ], further comprising administering a topical agent to tissue of the gastrointestinal tract.

Embodiment [63] of the present disclosure relates to the method according to any of Embodiments [l]-[62], further comprising administering a topical agent to esophageal tissue.

Embodiment [64] of the present disclosure relates to the method according to Embodiment [62] or [63], wherein the topical agent comprises an additional corticosteroid.

Embodiment [65] of the present disclosure relates to the method according to any of Embodiments [l]-[64], further comprising locally administering by subsequent injection a therapeutically effective amount of the pharmaceutical composition to tissue of the gastrointestinal tract.

Embodiment [66] of the present disclosure relates to the method according to any of Embodiments [ 1 ]-[65], further comprising locally administering by subsequent injection a therapeutically effective amount of the pharmaceutical composition to the esophageal tissue.

Embodiment [67] of the present disclosure relates to the method according to any one of Embodiments [ 1 ]-[66], wherein the subject suffers from a chronic inflammatory disease.

Embodiment [68] of the present disclosure relates to the method according to any one of Embodiments [ 1 ]-[67] , wherein the subject suffers from an inflammatory bowel disease, a gastroesophageal disease, a peptic ulcer disease, a radiation injury, a chemical ingestion injury, a post-surgical complication, an injection, or any combination thereof. Embodiment [69] of the present disclosure relates to the method according to any one of Embodiments [ 1 ]-[68], wherein the subject suffers from eosinophilic esophagitis.

Embodiment [70] of the present disclosure relates to the method according to any of Embodiments [ 1 ]-[69], comprising preventing or reducing the formation of benign gastrointestinal strictures in a subject at high risk for benign stricture formation.

Embodiment [ 1] of the present disclosure relates to the method according to Embodiment [70], wherein the subject was previously treated for at least one benign gastrointestinal stricture.

Embodiment [72] of the present disclosure relates to the method according to any of Embodiments [ 1 ]-[69], comprising treating at least one benign gastrointestinal stricture in the subject, such that 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.

Embodiment [73] of the present disclosure relates to the method according to any of Embodiments [ 1 ]-[72], wherein the subject was previously treated with dilation therapy.

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 in the gastrointestinal tract of a subject, wherein a therapeutically effective amount of the pharmaceutical composition is locally administered in the subject, and wherein the pharmaceutical composition comprises an extended- release composition formulated for prolonged release of the corticosteroid into tissue of the gastrointestinal tract.

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

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 locally administered in a subject, and wherein the pharmaceutical composition comprises an extended-release composition formulated for prolonged release of the corticosteroid into esophageal tissue. 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 in a subject, and wherein the pharmaceutical composition comprises an extended-release composition that is formulated for prolonged release of the corticosteroid into esophageal tissue.

The various embodiments described above can be combined to provide further embodiments. All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet, including U.S. Patent Application No. 63/413,167, filed October 4, 2022, are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications and publications to provide yet further embodiments.

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 disclosure