WO2023102491A1 - Methods for treating gastrointestinal inflammatory disease - Google Patents

Abstract

The present disclosure relates to a method for treating or preventing GI inflammatory disease, preferably ulcerative colitis, in a subject, comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and /or hydrate thereof, wherein the pharmaceutical formulation releases ondansetron or the pharmaceutically acceptable salt and/ or hydrate thereof in the colon.

Description

METHODS FOR TREATING GASTROINTESTINAL INFLAMMATORY DISEASE

CROSS-REFERENCE TO RELA TED APPLICA TIONS

[0001] This application claims priority to U.S. Provisional No. 63/284,970, filed December 1, 2021, and U.S. Provisional No. 63/343,871, filed May 19, 2022, each of which is incorporated herein by reference in its entirety.

FIELD

[0002] The present disclosure encompasses pharmaceutical formulations including ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof and methods of treating or preventing gastrointestinal (GI) inflammatory diseases in a human subject by administering the pharmaceutical formulations.

BACKGROUND

[0003] Gastrointestinal (GI) inflammatory diseases are diseases that affect the GI tract from mouth to anus, namely the esophagus, stomach, small intestine, large intestine, and rectum. It also includes the diseases related to accessory organs of digestion i.e., liver, gallbladder, and pancreas. There are many gastrointestinal diseases including celiac disease, diverticulitis, duodenal ulcer, intestinal polyps, irritable bowel syndrome, proctitis, protein-losing enteropathy, hemorrhoids, postoperative ileus, pouchitis, stress ulcer, ileitis, lactose intolerance, antibiotic enterocolitis, autoimmune enteropathy, dyspepsia, non-infectious gastroenteritis, eosinophilic duodenitis, peptic ulcers, appendicitis, atrophic gastritis, gastric ulcer, NSAID-induced ulcer, acute pancreatitis, gallstones, gallstone pancreatitis, alcoholic pancreatitis, eosinophilic gastritis, peritonitis, bile acid diarrhea, Inflammatory Bowel disease (IBD). IBD is the most common disease diagnosed by gastroenterologist. Ulcerative colitis (UC) and Crohn’s disease (CD) are the types of IBD.

[0004] UC is a major type of IBD. UC is a chronic, relapsing inflammatory disease of the colon, characterized by inflammation and ulceration of the mucosal layer of the rectum and the large intestine. Common symptoms include mucosal ulcerations, bloody diarrhea, and abdominal pain. Patients with UC are at an increased risk of developing colorectal cancer, (e.g. Danese et al. N Eng. J Med, 2011, 365, 1713-1725). Approximately one-third of UC patients do not have an adequate response to treatment or will lose response to therapy at a rate of 10- 20% per year. Many patients with moderate-to-severe UC report that their disease is not well

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277902726 controlled by their current treatment and continue to be burdened by physical and psychological symptoms. Approximately one-fourth report that the disease seriously impairs the quality of life and work productivity. Currently approved oral treatments such as tofacitinib and ozanimod are associated with safety concerns and limited long-term efficacy.

[0005] Crohn’s Disease (CD) causes chronic inflammation that can occur in any part of the GI tract beginning from stomach to anus but most commonly affects the distal ileum or colon. The disease is characterized by pain, diarrhea, fever and weight loss which may be complicated by intestinal fistulation, obstruction or both (Friedman et al. Inflammatory Bowel Dis. 2001; Wu et al. Inflammatory Bowel Dis., 2007).

[0006] Although there exist several therapeutic approaches to treat GI inflammatory disease, yet there is no cure to the same. Current treatment strategies include changes in your diet to remove common trigger foods (e.g., dairy, caffeine, alcohol, spices, whole grains, beans, lentils, and artificial colors, flavors, and sweeteners), anti-inflammatory drugs (aminosalicylates, corticosteroids), immunomodulators (azathioprine, mercaptopurine, cyclosporine, tofacitinib), biologies (infliximab, adalimumab, and golimumab), and others (vedolizumab, ustekinumab). Immunomodulators can be given alone or in combination with biologies. Biologies require infusion, are often cost-prohibitive, and are associated with the risk of severe adverse effects and development of resistance upon chronic use.

[0007] GI inflammatory disease possess risk of developing cancerous lesions from the inflamed tissue, particularly colon. There is thus a widely recognized need for new methods and formulation for treating GI inflammatory disease, that are safe, effective, economical, and have long term efficacy.

SUMMARY

[0008] The present disclosure focuses on alleviating or ameliorating the problems associated with the administration of ondansetron. Particularly, systemic exposure of ondansetron results in commonly reported adverse effects including headaches, fatigue, dry mouth, malaise, and constipation. In embodiments, the methods and compositions of the disclosure alleviate or ameliorate less common adverse effects including central nervous systems (CNS) manifestations such as, for example, drowsiness and sedation.

[0009] The inventors have surprisingly found that targeted release of ondansetron in the colon not only reduces the systemic and/or CNS adverse effects but also increases the efficacy of

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277902726 ondansetron in treating GI inflammatory disease. Accordingly, the disclosure also encompasses colonic release of ondansetron by administration of the formulation, and the methods of the disclosure result in treatment or reduction of adverse histopathological condition in colon including crypt damage, oedema, infiltration of leukocytes, and extent of infiltration of leukocytes (inflammatory markers of severity of disease).

[0010] The present disclosure encompasses a method for treating or preventing GI inflammatory disease in a subject in need thereof, comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides targeted release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon.

[0011] In embodiments, the disclosure encompasses a method of treating or reducing adverse histopathological condition in colon of a subject in need thereof, including administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides targeted release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon. In embodiments, the adverse histopathological condition in colon comprises at least one of crypt damage, oedema, infiltration of leukocytes and extent of infiltration of leukocytes. In embodiments, adverse histopathological condition is associated with GI inflammatory disease.

[0012] In embodiments, the disclosure encompasses a method of treating or reducing adverse histopathological condition in colon associated with GI inflammatory disease of a subject comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides targeted release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon. In embodiments, the adverse histopathological condition includes crypt damage, oedema, infiltration of leukocytes, extent of infiltration of leukocytes or combination thereof.

[0013] In embodiments, the disclosure encompasses a method of treating GI inflammatory diseases in a subject, wherein the administration of pharmaceutical formulation comprising ondansetron, or a pharmaceutically acceptable salt and/or hydrate thereof inhibits or reduces the activity of one or more proinflammatory cytokines (e.g., IL-ip, IL-18, TNFa and IL-6). [0014] In embodiments, the invention further encompasses a method of treating or reducing GI symptoms in a subject, comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides targeted release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon. In embodiments, the GI symptoms comprising at least one of abdominal pain, diarrhea, , weight loss, occult bleeding and bile acid diarrhea.

[0015] In embodiments, the disclosure encompasses a method of treating or preventing behavioral symptoms associated with GI inflammatory disease in a subject, comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides targeted release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon. In embodiments, behavioral symptoms include neuropsychological symptoms such as, for example, anxiety, stress reactivity, visceral hypersensitivity, insomnia and depression.

[0016] In embodiments, the GI inflammatory disease is selected from the group consisting of celiac disease, diverticulitis, duodenal ulcer, intestinal polyps, irritable bowel syndrome, proctitis, protein-losing enteropathy, hemorrhoids, postoperative ileus, pouchitis, stress ulcer, ileitis, lactose intolerance, antibiotic enterocolitis, autoimmune enteropathy, dyspepsia, non- infectious gastroenteritis, eosinophilic duodenitis, peptic ulcers, appendicitis, atrophic gastritis, gastric ulcer, NSAID-induced ulcer, acute pancreatitis, gallstones, gallstone pancreatitis, alcoholic pancreatitis, eosinophilic gastritis, peritonitis, bile acid diarrhea and IBD.

[0017] In embodiments, the GI inflammatory disease is IBD. In embodiments, the IBD includes UC and CD. In preferred embodiments, the GI inflammatory disease is UC.

[0018] In embodiments, the disclosure encompasses a method of treating or preventing UC in a subject, comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides targeted release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon. In embodiments, UC is in active or remission stage. [0019] In embodiments, the disclosure encompasses a method of treating or reducing adverse histopathological condition associated with UC in colon of a subject, comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides targeted release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon. In embodiments, adverse histopathological condition comprising at least one of crypt damage, oedema, infiltration of leukocytes, and extent of infiltration of leukocytes.

[0020] In embodiments, the targeted release includes delayed release, sustained release, delayed release followed by sustained release, delayed release followed by immediate release, pulsatile release or combination thereof.

[0021] In embodiments, the pharmaceutical formulation herein is adapted to minimize the side effects of the ondansetron e.g., reduce relative plasma concentration of ondansetron compared to the conventional non-targeted oral immediate release (IR) delivery having the same amount of the ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof.

[0022] In embodiments, the pharmaceutical formulation provides about 70%, 60%, 50%, 40%, 30%, 20% or 10% reduced relative plasma concentration of ondansetron compared to the conventional non-targeted oral (IR) delivery having the same amount of the ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof.

[0023] In embodiments, the pharmaceutical formulation provides about 70%, 60%, 50%, 40%, 30%, 20% or 10% better efficacy of ondansetron compared to the conventional non-targeted oral (IR)delivery having the same amount of the ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof.

[0024] In embodiments, the administration of the pharmaceutical formulations is once daily (“OD”), twice daily, three-times daily, four-times daily, once every two days, once every three days, once a week, once every two weeks, once every three weeks or once a month. In embodiments, the administration of formulation is once daily.

[0025] In embodiments, the ondansetron is included in a pharmaceutical formulation and administered at a daily dose in range of about 2 mg to about 32 mg, Examples of suitable dosages include: about 2 mg to about 32 mg, about 2 mg to about 28 mg, about 2 mg to about 24 mg, about 2 mg to about 20 mg, about 2 mg to about 16 mg, about 2 mg to about 12 mg, about 2 mg to about 8 mg, about 2 mg, about 3 mg about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, or about 32 mg.

[0026] In embodiments, the pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof can be administered to colon via any known method including oral or rectal.

[0027] In embodiments, the pharmaceutical formulation comprises an enteric coating formulated to release ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof at about pH 5.0 or above, about 5.5, about 6.0, about 6.5, or about 7.0. In embodiments, the pharmaceutical formulation comprises a polysaccharide coating susceptible to attack by colonic bacteria.

[0028] In embodiments, the pharmaceutical formulation releases ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof at an onset of about pH 5.0, about pH 5.5, about pH 6.0, about pH 6.5, about pH 7.0, or combination thereof following oral administration to a subject.

[0029] In embodiments, the pharmaceutical formulation further comprises one or more second therapeutic agent.

[0030] In embodiments, the disclosure encompasses a method for treating or preventing GI inflammatory disease in a subject comprising administering to the subject a pharmaceutical formulation orally comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation releases ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof in the colon, and wherein the formulation is a tablet, capsule, caplet, suspension, pellet, granule, gel. In embodiments, the pellets can be suspended, compressed or filled in capsules.

[0031] The disclosure further encompasses a pharmaceutical formulation comprising ondansetron or pharmaceutically acceptable salt and/or hydrate thereof, wherein the formulation provides target release in the colon. In embodiments, the target release includes delayed release, sustained release, delayed release followed by sustained release, delayed release followed by immediate release, pulsatile release or combinations thereof. In embodiments, the pharmaceutical formulation for targeted release in the colon comprises ondansetron and a two-component coating, wherein the first component is a pH trigger, and wherein the second component is a microbiota trigger.

[0032] In embodiments, the pharmaceutical formulation is for use in treating or preventing GI inflammatory disease in a subject in need thereof, wherein the pharmaceutical formulation comprises an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides target release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon.

[0033] In embodiments, the pharmaceutical formulation is for use in treating or reducing adverse histopathological condition in colon of a subject in need thereof, wherein the pharmaceutical formulation comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides target release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon.

[0034] In embodiments, the pharmaceutical formulation is for use in treating or preventing UC in a subject in need thereof, wherein the pharmaceutical formulation comprises an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides target release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon.

[0035] In embodiments, the pharmaceutical formulation is for use in treating or reducing adverse histopathological condition in colon of a subject associated with UC, wherein the pharmaceutical formulation comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides target release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon.

BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1A shows the effect of ondansetron in limiting the generation of IL- 1 [3 cytokines in a NLRP3 inflammasome activation model of Example 2 [0037] Figure IB shows the effect of ondansetron in limiting the generation of IL- 18 cytokines in a NLRP3 inflammasome activation model of Example 2

[0038] Figure 1C shows the effect of ondansetron in limiting the generation of TNF a cytokines in aNLRP3 inflammasome activation model of Example 2

[0039] Figure ID shows the effect of ondansetron in limiting the generation of IL-6 cytokines in a NLRP3 inflammasome activation model of Example 2

[0040] Figure 2A shows the effect of intracolonic (targeted) delivery of ondansetron on body weight score in a prophylactic TNBS mouse colitis model of Example 3

[0041] Figure 2B shows the effect of intracolonic (targeted) delivery of ondansetron on stool consistency score in a prophylactic TNBS mouse colitis model of Example 3

[0042] Figure 2C shows the effect of intracolonic (targeted) delivery of ondansetron on occult blood score in a prophylactic TNBS mouse colitis model of Example 3.

[0043] Figure 2D shows the effect of intracolonic (targeted) delivery of ondansetron on DAI score in a prophylactic TNBS mouse colitis model of Example 3.

[0044] Figure 2E shows the effect of intracolonic (targeted) delivery of ondansetron on crypt damage score in a prophylactic TNBS mouse colitis model of Example 3.

[0045] Figure 2F shows the histopathological observation of distal colon from sham control group animal stained with hematoxylin and eosin under different magnifications of Example 3, which reveals normal architecture.

[0046] Figure 2G shows the histopathological observation of distal colon from pathological control group animal stained with hematoxylin and eosin under different magnifications of Example 3, which reveals marked loss of cryptic architecture with mixed infiltration and submucosal oedema of Example 3.

[0047] Figure 2H shows the histopathological observation of distal colon from Infliximab (5 mg/kg) i.p. group animal stained with hematoxylin and eosin under different magnifications of Example 3 [0048] Figure 21 shows the histopathological observation of distal colon from ondansetron (1 mg/kg) intracolonic group animal stained with hematoxylin and eosin under different magnifications of Example 3

[0049] Figure 2J shows the histopathological observation of distal colon from ondansetron (2 mg/kg) intracolonic group animal stained with hematoxylin and eosin under different magnifications of Example 3, which reveals reduced loss of cryptic architecture.

[0050] Figure 3A shows the effect of oral (conventional-non-targeted) and intracolonic (targeted) delivery of ondansetron on body weight score in a prophylactic TNBS mouse colitis model of Example 4.

[0051] Figure 3B shows the effect of oral (conventional-non-targeted) and intracolonic (targeted) delivery of ondansetron on stool consistency score in a prophylactic TNBS mouse colitis model of Example 4.

[0052] Figure 3C shows the effect of oral (conventional-non-targeted) and intracolonic (targeted) delivery of ondansetron on occult blood score in a prophylactic TNBS mouse colitis model of Example 4.

[0053] Figure 3D shows the effect of oral (conventional-non-targeted) and intracolonic (targeted) delivery of ondansetron on DAI in a prophylactic TNBS mouse colitis model of Example 4.

[0054] Figure 3E shows the effect of oral (conventional-non-targeted) and intracolonic (targeted) delivery of ondansetron on infiltration of leukocyte score in a prophylactic TNBS mouse colitis model of Example 4.

[0055] Figure 3F shows the effect of oral (conventional-non-targeted) and intracolonic (targeted) delivery of ondansetron on extent of infiltration of leukocyte score in a prophylactic TNBS mouse colitis model of Example 4.

[0056] Figure 3G shows the effect of oral (conventional-non-targeted) and intracolonic (targeted) delivery of ondansetron on crypt damage score in a prophylactic TNBS mouse colitis model of Example 4. [0057] Figure 3H shows the effect of oral (conventional-non-targeted) and intracolonic (targeted) delivery of ondansetron on oedema score in a prophylactic TNBS mouse colitis model of Example 4.

[0058] Figure 31 shows the effect of oral (conventional-non-targeted) and intracolonic (targeted) delivery of ondansetron on cumulative histopathological score in a prophylactic TNBS mouse colitis model of Example 4.

[0059] Figure 3J shows the histopathological observation of distal colon from sham control group animal stained with hematoxylin and eosin under different magnifications Example 4, which reveals normal architecture.

[0060] Figure 3K shows the histopathological observation of distal colon from pathological control group animal stained with hematoxylin and eosin under different magnifications of Example 4.

[0061] Figure 3L shows the histopathological observation of distal colon from infliximab (5mg/kg) i.p. group animal stained with hematoxylin and eosin under different magnifications of Example 4.

[0062] Figure 3M shows the histopathological observation of distal colon from ondansetron (1 mg/kg) intracolonic group animal stained with hematoxylin and eosin under different magnifications of Example 4.

[0063] Figure 3N shows the histopathological observation of distal colon from ondansetron (2 mg/kg) intracolonic group animal stained with hematoxylin and eosin under different magnifications of Example 4.

[0064] Figure 30 shows the histopathological observation of distal colon from ondansetron (2 mg/kg) oral group animal stained with hematoxylin and eosin under different magnifications of Example 4

[0065] Figure 3P shows the drug plasma concentration after oral (conventional-non-targeted) and intracolonic (targeted) delivery of ondansetron of Example 4. DETAILED DESCRIPTION

[0066] In the following passages, different embodiments of the disclosure are defined in more detail. Each embodiment so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

Abbreviations

[0067] As used herein, the following abbreviations have the following meanings:

[0068] AE: adverse events

[0069] UC: Ulcerative colitis

[0070] CD: Crohn’s disease

[0071] TNBS: 2,4,6-Trinitrobenzene sulfonic acid

[0072] AUC: Area under the curve

[0073] mg: milligram

[0074] IR: immediate release

[0075] IL-1[3: Interleukin 1|3

[0076] IL-18: Interleukin 18

[0077] TNF a: Tumor Necrosis Factor a

[0078] IL-6: Interleukin 6

[0079] i.p.: intraperitoneal

[0080] IBD: Inflammatory Bowel Disease

[0081] OD: Once Daily

[0082] CNS: Central Nervous System [0083] IHC: ImmunoHistoChemistry

[0084] DAI: Disease Activity Andex

[0085] API: Active Pharmaceutical Ingredient.

[0086] NLRP3: Nod Like Receptor family Pyrin domain containing 3

[0087] LPS: Lipopolysaccharide

[0088] ATP: Adenosine triphosphate

[0089] ANNOVA: Analysis of variance

[0090] ELISA: Enzyme-Linked Immunoassay

[0091] IBS: Irritable Bowel Syndrome

Definitions

[0092] It will be understood that the terminology used herein is for the purpose of describing embodiments only and is not intended to be limiting. As used in this specification, the singular forms “a”, “an” and “the” include plural referents and vice versa unless the context clearly dictates otherwise.

[0093] As used herein, the term “about” refers to ±10% of the indicated numerical value unless otherwise stated or otherwise evident by the context, and except where such a range would exceed 100 % of a possible value, or fall below 0 % of a possible value, such as less than 0 % content of an ingredient, or more than 100 % of the total contents of a composition.

[0094] As used herein, the term “appropriate period of time” refers to a time period from about

1 hour to about 30 days. In exemplary embodiments, an agent can be administered within about Ihour to about 30 days from the administration of the other active agent, e.g. about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 1 day, about

2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, or about 30 days, including all values and ranges in between from the administration of the other active agent. In embodiments, an agent can be administered within about 1 hour to about 10 days from the administration of the other active agent, e.g. 1 hour to about 30 days from the administration of the other active agent, e.g. about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, including all values and ranges in between.

[0095] As used herein, the term “active agent” or “therapeutic agent” refers to a chemical agent capable of activity.

[0096] As used herein, the term “relative plasma concentration” refers to plasma concentration of ondansetron when compared with the plasma concentration after immediate release formulation

[0097] As used herein, the term “colon” refers to longest part of large intestine connected to small intestine at one end and the anus at the other.

[0098] As used herein, the terms “comprises”, “comprising”, “includes”, “including”, “having” means “including but not limited to”.

[0099] As used herein, the term “effective amount” refers to an amount sufficient to produce the desired effect or cause an improvement in a clinically significant condition of the subject.

[0100] As used herein, the terms “formulation” and “composition” are used interchangeably, except where otherwise clearly intended to have different meanings.

[0101] As used herein, the terms “GI inflammatory disease”, “GI disease” or “GBA disease” refer to a medical condition wherein there is chronic inflammation in any part of the GI tract GI inflammatory disease is usually diagnosed following recurrent symptoms of constant diarrhea mixed with blood, of gradual onset. GI inflammatory disease according to the present teachings refers to any stage or severity of GI inflammatory disease (e.g., disease remission or acute disease).

[0102] As used herein the term “immediate-release dosage form” refers to a formulation which rapidly disintegrates upon oral administration to a human or other animal releasing an active pharmaceutical ingredient (API) from the formulation. In embodiments the T80% of the immediate-release dosage form is less than 3 hours. In embodiments the T80% of the immediate-release dosage form is less than 1 hour. In embodiments the T80% of the immediate-release dosage form is less than 30 minutes. In embodiments the T80% of the immediate-release dosage form is less than 10 minutes.

[0103] As used herein, the term “inhibit,” refers to the ability of a compound or any agent to reduce or impede a described function, level, activity, synthesis, release, binding, etc., based on the context in which the term “inhibit” is used. The term “inhibit” is used interchangeably with “reduce,” “block,” and “decrease.”

[0104] As used herein, the term “delayed-release dosage form” refers to any formulation that, upon oral administration to a human or other animal, releases an API at a slower rate over an extended period of time when compared to an immediate-release dosage-form of the API.

[0105] As used herein, the terms “patient” or “subject” refer to a living organism suffering from or prone to a condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals and other non-mammalian animals.

[0106] As used herein, the term “pharmaceutically acceptable salt” refers to a salt known to be non-toxic and commonly used in pharmaceutical literature. Typical inorganic acids used to form such salts include, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, or hypophosphoric acid. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxy alkanoic and hydroxyl alkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids may also be used.

[0107] As used herein, the terms “pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject. It also refers to an excipient that can be included in the compositions of the disclosure and that causes no significant adverse toxicological conditionon the subject.

[0108] As used herein, the term “preventing”, “prevention” means preventing the occurrence of a disease, condition, or associated symptoms or preventing the recurrence of the same, for example after a period of improvement.

[0109] As used herein, the term “resistant starch” or “modified starch” refers to starch that resists digestion in the upper GI tract by amylolytic enzymes and becomes available to colonic bacteria as an energy substrate. Resistant starch needs to be processed in order for it to be digested. It requires a high temperature and moisture in order to allow for gelatinization, granule rupture and leakage of amylose into solution to occur. The morphological and physical changes of starch during heat treatment were investigated. Gelatinization of starches is an important property that varies significantly amongst starch species. During gelatinization, the starch granules swell to many times their original size, starch solubilization increases, amylose leaches out, granule optical birefringence is lost, native crystallites melt and eventually the entire starch granule collapses.

[0110] As used herein, the term, “simultaneous administration” means at the same time or within a short period of time, usually less than 1 hour, for example, 10, 20, 30, 40, or 50 minutes.

[oni] As used herein, the term “targeted release” refers to delivery of composition to a patient in a manner that increases the concentration of the active agent in certain parts of the body relative to others. The compositions and methods disclosed herein achieve “colon target release,” which refers to a method of delivering active agent to a patient in a manner that increases the delivery of the active agent in the colon with reduced or no release elsewhere in the GI tract. The goal of a targeted drug delivery system is to prolong, localize, and target a specific tissue/organ of the body for metabolism of the active agent. The conventional drug delivery system is the absorption of the drug across a biological membrane, whereas the targeted release system releases the drug in a dosage form. In embodiments, the advantages to the targeted release system are the reduction in the frequency of the dosages taken by the patient, having a more uniform effect of the drug, reduction of drug side-effects, and reduced fluctuation in circulating drug levels. [0112] As used herein, the term “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician or caregiver or by an individual, which includes one or more of the following:

(1) Preventing the disease, for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the histopathology or symptomatology of the disease;

(2) Inhibiting the disease, for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the histopathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology); and

(3) Ameliorating the disease, for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the histopathology or symptomatology of the disease, condition or disorder (i.e., reversing the histopathology and/or symptomatology).

[0113] As used herein, the term “treatment” refers to one or more of the following:

(1) prevention of a disease, for example, prevention of a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the histopathology or symptomatology of the disease;

(2) inhibition of a disease, for example, inhibition of a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the histopathology and/or symptomatology); and

(3) amelioration of a disease, for example, amelioration of a disease, condition or disorder in an individual that is experiencing or displaying the histopathology or symptomatology of the disease, condition or disorder (i.e., reversing the histopathology and/or symptomatology).

[0114] Whether an individual is in need of treatment is a judgment made by a caregiver (e.g. nurse practitioner, physician, physician assistant, nurse, etc. in the case of humans; veterinarian in the case of animals, including non-human mammals) that an individual or animal requires or will benefit from treatment.

[0115] As used herein, the term “behavioral symptoms” refers to repetitive or persistent behaviors that are inappropriate, disruptive or cause problem. Herein the behavioral symptoms include neuropsychological symptoms

[0116] As used herein, the term “neuropsychological symptoms” refers to cognitive or emotional impairment in humans. Herein neuropsychological symptoms may include anxiety, stress reactivity, visceral hypersensitivity, insomnia, or depression.

[0117] As used herein, the term “unit dosage form” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals (e.g., dogs), each unit containing a predetermined quantity of active material calculated to produce the desired onset, tolerability, and/or therapeutic effects, in association with a suitable pharmaceutical excipient (e.g., an ampoule).

[0118] As used herein, the term “drug plasma concentration” refers to amount of drug in blood plasma after a specified time of drug administration.

[0119] As used herein, the term “adverse histopathological condition” refers to change in the tissue appearance in colon due to GI inflammatory diseases.

[0120] As used herein, the term “pathological” refers to progression of disease with time.

[0121] As used herein, the term “infiltration of leukocyte” refers to the movement of leukocytes towards the inflamed mucosa in colon due to GI inflammatory disease.

[0122] As used herein, the term “extent of infiltration of leukocyte” refers to the marker of severity of disease.

[0123] As used herein, the term “oedema” refers to the swelling caused due to accumulation of water inside tissue. Herein the oedema is of colon due to GI inflammatory diseases.

[0124] As used herein, the term “crypt damage” refers to the damage in the crypt glands present in the epithelial lining of colon. Herein, the crypt damage is caused due to GI inflammatory diseases. [0125] As used herein, the term “mucosal damage” refers to the damage in the mucosa of GI tract.

[0126] As used herein, the term “GI symptom” refers to a physical or mental condition that is indicative of GI inflammatory disease. The symptoms of GI inflammatory disease are not limited to abdominal pain, diarrhea, , weight loss, and occult bleeding

Active Agents: Ondansetron and Pharmaceutically Acceptable Salts and/or Hydrates Thereof

[0127] The disclosure provides compositions and methods for administering and treating various GI inflammatory disorders. In embodiments, the composition comprises ondansetron, which is (±) l,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-lH-imidazol-l-yl)methyl]-4H- carbazol-4-one and has the following structural formula:

[0128] The empirical formula of ondansetron is C18H19N3O, representing a molecular weight of 293.4. In embodiments, ondansetron is administered as one of its salts and/or hydrates or a combination thereof. In embodiments, ondansetron is administered as ondansetron hydrochloride (HC1) dihydrate (which is synonymous and sometime referred to as “hydrate,” which has the empirical formula CisHwNsChHCWTbO, representing a molecular weight of 365.9. In embodiments, ondansetron HC1 dihydrate is a white to off-white powder that is soluble in water and normal saline.

[0129] Ondansetron is a weak base (pKa =7.4) and is soluble under acidic conditions. The solubility is markedly reduced in solutions for which pH is greater than or equal to 6. Precipitation of ondansetron (as free base) occurs in solutions with a pH 5.7 or more (Salem er al, “Ondansetron hydrochloride” Analytical Profiles of Drug Substances and Excipients Volume 27, 2001, Pages 301-338). Therefore, ondansetron is weakly soluble at colonic pH.

Methods of Treatment [0130] In embodiments, the disclosure encompasses methods for treating or preventing a GI inflammatory disease in a subject in need thereof comprising administering to the subject a pharmaceutical formulation including ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof. In embodiments, the pharmaceutical formulation provides targeted release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon.

[0131] In embodiments, the disclosure encompasses a method of treating or reducing adverse histopathological condition in colon of a subject in need thereof including administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides targeted release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon. In embodiments, adverse histopathological condition comprising any one of crypt damage, oedema, infiltration of leukocytes, extent of infiltration of leukocytes. In embodiments, adverse histopathological condition is associated with GI inflammatory disease.

[0132] In embodiments, the disclosure encompasses a method for treating or preventing GI symptom in a subject in need thereof comprising administering to the subject a pharmaceutical formulation including ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof. In embodiments, the pharmaceutical formulation provides targeted release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon. In embodiments, the GI symptom comprising at least one of abdominal pain, diarrhea, , weight loss, and occult bleeding.

[0133] In embodiments, the GI inflammatory disease is selected from the group consisting of celiac disease, diverticulitis, duodenal ulcer, intestinal polyps, irritable bowel syndrome, proctitis, protein-losing enteropathy, hemorrhoids, postoperative ileus, pouchitis, stress ulcer, ileitis, lactose intolerance, antibiotic enterocolitis, autoimmune enteropathy, dyspepsia, noninfectious gastroenteritis, eosinophilic duodenitis, peptic ulcers, appendicitis, atrophic gastritis, gastric ulcer, NSAID-induced ulcer, acute pancreatitis, gallstones, gallstone pancreatitis, alcoholic pancreatitis, eosinophilic gastritis, peritonitis, bile acid diarrhea and IBD. In embodiments IBD is UC or CD. In embodiments, the GI inflammatory disease is UC. In embodiments, the GI inflammatory disease is CD.

[0134] In embodiments, the disclosure encompasses methods of treating or preventing GI inflammatory disease in a subject in need thereof comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/ or hydrate thereof, wherein the pharmaceutical formulation provides targeted release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon. In embodiments, the targeted release includes immediate release, delayed release, sustained release, delayed release followed by sustained release, delayed release followed by immediate release, pulsatile release or a combination thereof.

[0135] In embodiments, the disclosure encompasses a pharmaceutical formulation including about 70%, about 60%, about 50%, about 40%, about 30%, about 20% or about 10% reduced relative plasma concentration of ondansetron compared to the conventional non-targeted oral (IR) delivery having the same amount of the ondansetron.

[0136] In embodiments, the pharmaceutical formulation for colonic release of the active agent includes about 70%, about 60%, about 50%, about 40%, about 30%, about 20% or about 10% better efficacy of ondansetron compared to the conventional non-targeted oral (IR) delivery having the same amount of ondansetron.

[0137] In embodiments, the GI inflammatory disease is effectively treated using relatively low dose of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof via colonic release of an orally administered formulation. Consequently, the treatment is effective with reduced or no adverse effects.

[0138] In embodiments, the disclosure encompasses a method of treating GI inflammatory disease in a subject in need thereof, wherein the administration of pharmaceutical formulation comprising ondansetron, or a pharmaceutically acceptable salt and/or hydrate thereof inhibits or reduces the activity of proinflammatory cytokines (e.g., IL-ip, IL-18, TNF and IL-6).

[0139] In embodiments, the disclosure encompasses a method for treating or preventing a GI inflammatory disease in a subject in need thereof including orally administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides targeted release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon, wherein the pharmaceutical formulation is a tablet, capsule, caplets, suspension, pellets, granules or gels. In embodiments, pellets can be suspended, compressed as tablet or filled in capsules. [0140] In embodiments, the disclosure encompasses a treatment regimen, which involves administration of pharmaceutical formulation to a subject in need thereof once daily, twice daily, three-times daily, four-times daily, once every two days, once every three days, once a week, once every two weeks, once every three weeks or once a month. The administration is preferably oral, but other routes are also contemplated, including for example, rectal administration, or intracolonic administration. In embodiments, the administration of pharmaceutical formulation to a subject in need thereof is once daily.

[0141] In embodiments, the disclosure encompasses methods of treating a disorder, wherein the pharmaceutical formulation releases ondansetron or pharmaceutically acceptable salt and/or hydrate thereof in the colon via pH-dependent release, via microbially-triggered delivery, via time-controlled delivery, via osmotically regulated delivery, via pressure- controlled delivery, via bioadhesion delivery, or via combination thereof. In embodiments, the pharmaceutical formulation releases ondansetron or pharmaceutically acceptable salt and/or hydrate thereof in the colon via the combination of pH-dependent release and microbially triggered delivery.

[0142] In embodiments, the pharmaceutical formulation provides pH dependent release. In embodiments, the formulation comprise an enteric coating formulated to release ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof at about pH 5.0 or above. In embodiments, the release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof occurs at about pH 5.0 to about pH 6.0. In embodiments, release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof occurs at about pH 6.0 to about pH 7.0. In embodiments, release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof occurs at about pH 7.0 to about pH 8.0. In embodiments, release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof occurs at about pH 6.0. In embodiments, release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof occurs at about pH 6.5. In embodiments, release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof occurs at about pH 7.0.

[0143] In embodiments, the pharmaceutical formulation includes microbially triggered delivery. In embodiments, the formulation comprises a polysaccharide coating susceptible to metabolism by colonic bacteria. [0144] In embodiments, administration of the pharmaceutical formulation is once daily, twice daily, once in two days, once in three days, once a week, once in two weeks, once in three weeks or once in a month.

[0145] In embodiments, administration of the pharmaceutical formulation is once daily.

[0146] In embodiments, the pharmaceutical formulation including ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof are administered daily at a per unit dose in range of about 2 mg to about 32 mg. In embodiments, the pharmaceutical compositions including ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof are administered daily at a per unit dose in range of between about 2 mg to about 28 mg, about 2 mg to about 24 mg, or about 2 mg to about 20 mg, about 2 mg to about 16 mg, about 2 mg to about 12 mg, or about 2 mg to about 8 mg. In embodiments, for example, the pharmaceutical compositions including ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof are administered daily at a per unit dose of about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31mg, about 32 mg including all values and ranges in between.

[0147] In embodiments, the present disclosure provides the dose of ondansetron (in milligrams per kg body weight of the subject) is in the range of from about 0.02 mg/kg to about 0.50 mg/kg, 0.02 mg/kg to about 0.40 mg/kg, 0.02 mg/kg to about 0.30 mg/kg, 0.02 mg/kg to about 0.20 mg/kg, or 0.02 mg/kg to about 0.10 mg/kg.

[0148] In embodiments, the pharmaceutical formulation comprises one or more second therapeutic agents.

[0149] In embodiments, the method comprises administering one or more second formulations comprising one or more second therapeutic agents to the subject as an adjuvant therapy. In embodiments, the second formulation may be administered either simultaneously or sequentially separated by an appropriate period of time. In embodiments, the second formulation may be administered by the same route of administration as the first formulation or a different route of administration as the first formulation. In embodiments, the second formulation is an immediate-release formulation, extended release formulation or delayed- release formulation.

[0150] In embodiments, the one or more second therapeutic agents is balsalazide, mesalamine, olsalazine, sulfasalazine, infliximab, vedolizumab, tofacitinib, or ozanimod.

[0151] In embodiments, the disclosure encompasses a method for treating or reducing adverse histopathological condition in colon of a subject in need thereof, comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides targeted release of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof in the colon. In embodiments, the adverse histopathological condition is associated with GI inflammatory disease. In embodiments, adverse histopathological condition in colon comprises at least one of crypt damage, infiltration of leukocytes, extent of infiltration of leukocytes, oedema, or combination thereof. In embodiments, the GI inflammatory disease is selected from the group consisting of celiac disease, diverticulitis, duodenal ulcer, intestinal polyps, irritable bowel syndrome, proctitis, protein-losing enteropathy, hemorrhoids, postoperative ileus, pouchitis, stress ulcer, ileitis, lactose intolerance, antibiotic enterocolitis, autoimmune enteropathy, dyspepsia, noninfectious gastroenteritis, eosinophilic duodenitis, peptic ulcers, appendicitis, atrophic gastritis, gastric ulcer, NSAID-induced ulcer, acute pancreatitis, gallstones, gallstone pancreatitis, alcoholic pancreatitis, eosinophilic gastritis, peritonitis, bile acid diarrhea and IBD. In embodiments, the IBD is UC or CD.

[0152] In embodiments, the disclosure encompasses a method for treating or preventing crypt damage in a subject, comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides targeted release of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof in the colon. In embodiments, crypt damage is associated with GI inflammatory disease.

[0153] In embodiments, the disclosure encompasses a method for treating or preventing oedema in colon in a subject, comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides targeted release of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof in the colon. In embodiments, oedema is associated with GI inflammatory disease.

[0154] In embodiments, the disclosure encompasses a method for reducing infiltration of leukocyte associated with GI inflammatory disease in a subject, comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides targeted release of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof in the colon.

[0155] In embodiments, the disclosure encompasses a method for reducing extent of infiltration of leukocytes associated with GI inflammatory disease in a subject, comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides targeted release of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof in the colon.

[0156] In embodiments, the disclosure encompasses a method for treating or preventing behavioral symptoms associated with GI inflammatory disease in a subject, comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation releases ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon. In embodiments, behavioral symptoms include neuropsychological symptoms selected from the group consisting of anxiety, stress reactivity, visceral hypersensitivity, insomnia, depression or combination thereof.

[0157] In embodiments, the disclosure encompasses a method of treating or preventing UC in a subject in need thereof comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation includes targeted release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon. In embodiments, UC is in an active state or in remission.

[0158] In embodiments, the disclosure encompasses a method of treating or preventing adverse histopathological condition in colon associated with UC in a subject comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides targeted release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon. In embodiments, adverse histopathological condition comprising at least one crypt damage, infiltration of leukocytes, extent of infiltration of leukocytes, and oedema.

[0159] In embodiments, the disclosure encompasses a method of treating or preventing UC in a subject in need thereof comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof once daily, twice daily, thrice daily or once a week, wherein the pharmaceutical formulation includes targeted release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon. In embodiments, UC is in active or in remission stage.

[0160] In embodiments, the disclosure encompasses a method of treating or preventing UC in a subject in need thereof comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides targeted release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon. In embodiments, UC is in active or in remission stage. In embodiments, a second therapeutic agent is sequentially administered. In embodiments, the second therapeutic agent is concomitantly administered.

[0161] In embodiments, the disclosure encompasses a method of treating or preventing UC in a subject in need thereof comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides targeted release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon. In embodiments, the targeted release includes immediate release, delayed release, sustained release, delayed release followed by sustained release, delayed release followed by immediate release, pulsatile release or a combination thereof.

[0162] In embodiments, the disclosure encompasses a method of treating or preventing UC in active stage in a subject in need thereof comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation includes targeted release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon. [0163] In embodiments, the disclosure encompasses a method of treating or preventing UC in remission stage in a subject in need thereof comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation includes targeted release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon.

[0164] In embodiments, the disclosure encompasses a method of treating or preventing CD in a subject in need thereof comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation includes targeted release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon.

Dosage and Administration:

[0165] In embodiments, the disclosure encompasses a method of treating or preventing GI inflammatory disease in a subject in need thereof comprising administering to the subject a pharmaceutical formulation comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation releases ondansetron in the colon.

[0166] In embodiments, the disclosure encompasses a method of treating or preventing adverse histopathological condition in colon in a subject in need thereof comprising administering to the subject a pharmaceutical formulation comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation releases ondansetron in the colon. In embodiments, adverse histopathological condition is associated with GI inflammatory disease.

[0167] In embodiments, the GI inflammatory disease is selected from the group consisting of celiac disease, diverticulitis, duodenal ulcer, intestinal polyps, irritable bowel syndrome, proctitis, protein-losing enteropathy, hemorrhoids, postoperative ileus, pouchitis, stress ulcer, ileitis, lactose intolerance, antibiotic enterocolitis, autoimmune enteropathy, dyspepsia, noninfectious gastroenteritis, eosinophilic duodenitis, peptic ulcers, appendicitis, atrophic gastritis, gastric ulcer, NSAID-induced ulcer, acute pancreatitis, gallstones, gallstone pancreatitis, alcoholic pancreatitis, eosinophilic gastritis, peritonitis, bile acid diarrhea and IBD. In embodiments, the GI inflammatory disease is IBD. In embodiments, IBD is UC or CD. [0168] Generally, an effective amount of the ondansetron in the pharmaceutical formulation is in the range of 0.02 mg/kg to about 0.30 mg/kg.

[0169] In embodiments, the total dose of ondansetron, or a pharmaceutically acceptable salt and/or hydrate thereof (based on the amount of active ingredient) (in milligrams per kg body weight of the subject) is about 0.02 mg/kg to about 1 mg/kg, e.g., about 0.02 mg/kg, about 0.04 mg/kg, about 0.06 mg/kg, about 0.08 mg/kg, about 0.10 mg/kg, about 0.12 mg/kg, about 0.14 mg/kg, about 0.16 mg/kg, about 0.18 mg/kg, about 0.20 mg/kg, about 0.22 mg/kg, about 0.24 mg/kg, about 0.26 mg/kg, about 0.28 mg/kg, about 0.30 mg/kg, about 0.32 mg/kg, about 0.34 mg/kg, about 0.36 mg/kg, about 0.38 mg/kg, about 0.40 mg/kg, about 0.42 mg/kg, about 0.44 mg/kg, about 0.46 mg/kg, about 0.48 mg/kg, about 0.50 mg/kg, about 0.52 mg/kg, about 0.54 mg/kg, about 0.56 mg/kg, about 0.58 mg/kg, about 0.60 mg/kg, about 0.62 mg/kg, about 0.64 mg/kg, about 0.66 mg/kg, about 0.68 mg/kg, about 0.70 mg/kg, about 0.72 mg/kg, about 0.74 mg/kg, about 0.76 mg/kg, about 0.78 mg/kg, about 0.80 mg/kg, about 0.82 mg/kg, about 0.84 mg/kg, about 0.86 mg/kg, about 0.88 mg/kg, about 0.90 mg/kg, about 0.92 mg/kg, about 0.94 mg/kg, about 0.96 mg/kg, about 0.98 mg/kg, or about 1.00 mg/kg, including all values and ranges in between.

[0170] In embodiments, the dose of ondansetron (in milligrams per kg body weight of the subject) is in the range of from about 0.02 mg/kg to about 1 mg/kg, 0.02 mg/kg to about 0.50 mg/kg, 0.02 mg/kg to about 0.40 mg/kg, 0.02 mg/kg to about 0.30 mg/kg, 0.02 mg/kg to about 0.20 mg/kg, 0.02 mg/kg to about 0.10 mg/kg to be administered once daily.

[0171] The unit dose of ondansetron (total unit dose), or a pharmaceutically acceptable salt and/or hydrate thereof, is about 2 mg to about 32 mg, e.g., about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg including all values and ranges in between. In embodiments, the unit dose of ondansetron in a pharmaceutical formulation is administered, once daily, twice daily, once in two days, once in three days, once a week, once in two weeks, once in three weeks or once a month. In embodiments, the unit dose of ondansetron is administered once daily. In embodiments, the unit dose of ondansetron is administered twice daily. In embodiments, the pharmaceutical compositions, formulations, and dosage forms can be administered one or more times per day for a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days and can be extended for 1 or more month or administered at various intervals in the above time frame.

[0172] In embodiments, a range of unit doses of ondansetron used in the pharmaceutical formulation in the present disclosure includes about 2 mg to about 32 mg, about 2 mg to about 28 mg, about 2 mg to about 24 mg, about 2 mg to about 20 mg, about 2 mg to about 16 mg, about 2 mg to about 12 mg, about 2 mg to about 8 mg. In embodiments, the dose is administered once daily, twice daily, once in atwo-day period, once in three-days period, once a week, once in two weeks, once in three weeks or once a month.

[0173] In various embodiments, the unit dose of ondansetron included in the present disclosure is about 2 mg, about 3 mg about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about

16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg. The dose may be administered once daily, twice daily, once in two days, once in three days, once a week, once in two weeks, once in three weeks or once a month.

[0174] In embodiments, the dose of ondansetron is about 2 mg, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about

17 mg, about 18 mg, about 19 mg or about 20 mg. The dose may be administrated once daily, twice daily, once in two days, once in three days, once a week, once in two weeks, once in three weeks or once a month.

Pharmaceutical Compositions

[0175] In embodiments, the pharmaceutical formulation comprises an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the formulation releases ondansetron, the active agent, in the colon.

[0176] In embodiments, the pharmaceutical formulation includes an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the formulation releases ondansetron in the colon and not in the small intestine. [0177] In embodiments, the pharmaceutical formulation includes targeted release of ondansetron or pharmaceutically acceptable salt and/or hydrate thereof in the colon via pH- dependent release delivery, microbially-triggered delivery, time-controlled delivery, osmotically-regulated delivery, pressure-controlled delivery, bioadhesion delivery, or a combination thereof. In embodiments, the pharmaceutical formulation releases ondansetron or pharmaceutically acceptable salt and/or hydrate thereof in the colon via a combination of pH- dependent release and microbially-triggered release in the colon.

[0178] In embodiments, the pharmaceutical formulation includes a pH dependent release. In embodiments, the formulation comprises an enteric coating formulated to release ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof at about pH 5.0 or above. In embodiments, the pharmaceutical formulation releases ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof at of about pH 5.0 to about pH 8.0, e.g., about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, about 8.0, including all values and ranges in between.

[0179] In embodiments, the pharmaceutical formulation releases ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof at about pH 5.0 to about pH 6.0. In embodiments, the pharmaceutical formulation releases ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof at about pH 6.0 to about pH 7.0. In embodiments, the pharmaceutical formulation releases ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof at about pH 7.0 to about pH 8.0. In embodiments, the pharmaceutical formulation releases ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof at about pH 6.0. In embodiments, the pharmaceutical formulation releases ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof at about pH 6.5. In embodiments, the pharmaceutical formulation releases ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof at about pH 7.0.

[0180] In embodiments, the pharmaceutical formulation provides microbially-triggered delivery. In embodiments, the pharmaceutical formulation comprise polysaccharide coating susceptible to attack by colonic bacteria.

[0181] In embodiments, the pharmaceutical formulation is adapted to reduce or minimize plasma concentration of the active agent, e.g., minimize the circulating plasma concentration of ondansetron in the subject when compared to an oral immediate release formulation having an equivalent amount of the ondansetron.

[0182] In embodiments, the pharmaceutical formulation comprising ondansetron has a reduced relative plasma concentration of about 70%, about 60%, about 50%, about 40%, about 30%, about 20% or about 10% compared to a conventional non-targeted oral (IR) delivery having the same amount of the ondansetron. To achieve these effects, the pharmaceutical formulation is designed to target the release of ondansetron in the colon, and/or release ondansetron in amounts that minimize plasma absorption. In embodiments, the pharmaceutical formulation is administered by known methods, e.g., orally or intrarectally, to release ondansetron to the colon. In embodiments, the pharmaceutical formulation is administered orally.

[0183] In embodiments, the pharmaceutical formulation for colon release is a tablet, capsule, caplets, suspension, pellet granule, or gel. In embodiments, pellets are suspended, compressed or filled in capsules. In embodiments, the pharmaceutical formulation is a tablet or capsule.

[0184] In embodiments, the pharmaceutical formulation for colon targeted release is in a liquid dosage form (e.g., suspension). In embodiments, suspensions comprise ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, and one or more pharmaceutically acceptable excipients including sodium methyl parahydroxybenzoate, sodium propyl parahydroxybenzoate, sodium dihydrogen phosphate dihydrate, di-sodium hydrogen phosphate anhydrous, liquid maltitol, acesulfame potassium, ammonia caramel, flavor, purified water and combinations thereof.

[0185] In embodiments, the pharmaceutical formulation for targeted-release in the colon is a solid unit dosage form including a film forming enteric coating and other pH-sensitive polymers having a pH threshold at about pH 5 or above including, but not limited to polyacrylamides, phthalate derivatives comprising acid phthalates of carbohydrates, amylose acetate phthalate, cellulose acetate phthalate, other cellulose ester phthalates, cellulose ether phthalates, hydroxypropyl cellulose phthalate, hydroxypropyl ethylcellulose phthalate, hydroxypropyl methylcellulose phthalate, methylcellulose phthalate, polyvinyl acetate phthalate, polyvinyl acetate hydrogen phthalate, sodium cellulose acetate phthalate, starch acid phthalate, styrene-maleic acid dibutyl phthalate copolymer, styrene-maleic acid polyvinylacetate phthalate copolymer, styrene and malice acid copolymers, polyacrylic acid derivatives includes but not limited to acrylic acid and acrylic ester copolymers, polymethacrylic acid and esters thereof, poly acrylic methacrylic acid copolymers, shellac, and vinyl acetate and crotonic acid copolymers.

[0186] Preferred pH sensitive polymers also include but not limited to acrylate polymer, a cellulose polymer or a polyvinyl-based polymer. Examples of suitable cellulose polymers include cellulose acetate phthalate (“CAP”); cellulose acetate trimellitate (“CAT”); and hydropropyl methylcellulose acetate succinate. Examples of suitable polyvinyl-based polymers include polyvinyl acetate phthalate (“PVAP”). preferably a co-polymer of a (meth)acrylic acid and a (meth)acrylic acid Cl -4 alkyl ester, for instance, a copolymer of methacrylic acid and methacrylic acid methyl ester. Such a polymer is known as a poly (methacrylic acid/methyl methacrylate) co-polymer. In embodiments, the solid dosage form comprises polysaccharides coating susceptible to metabolism by colonic bacteria.

[0187] Standard ingredients and methods of preparation of tablets, including pharmaceutical tablets are described in “Remington: The science and practice of pharmacy,” (1995), which is herein incorporated by reference for all purposes.

[0188] In embodiments, the solid dosage form such as tablets the active agent is mixed with a pharmaceutical carrier. In embodiments, the pharmaceutical carrier incorporated into the tablets include one or more of the following: diluents, waxes flavoring agents, binders, preservatives, tablet disintegrating agents, polymers, an encapsulating material, a coating material (e.g., enteric coating material) or combinations thereof.

[0189] In embodiments, the tablet comprises a binder, e.g. starch, com starch, polyvinylpyrrolidone, gums, gum acacia, gelatin, cellulose derivatives or combinations thereof; a diluent, e.g. microcrystalline cellulose, lactose, dibasic ortribasic calcium phosphate, saccharides confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose, starch xylitol, sorbitol, talc, calcium carbonate, calcium sulphate or combinations thereof; a lubricant, e.g. magnesium stearate, aluminum stearate or calcium stearate or zinc stearate, polyethylene glycol, glyceryl behenate, glyceryl monostearate, mineral oil sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil, talc, hydrogenated soybean oil, stearyl alcohol or combinations thereof; a glidant, e.g. magnesium trisilicate, powdered cellulose, starch, talc, tribasic calcium phosphate, calcium silicate, magnesium stearate, magnesium silicate, colloidal silicon dioxide, or silicon hydrogel or combinations thereof; a surface active agent; a wax; a disintegrating agent; a bioadhesive polymer, e.g. proteins (e.g. pectin or zein), polysaccharides (e.g. cellulose, or dextrans), polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes, polystyrene, polymers of acrylic esters and polymers of methacrylic esters, polylactides, polyanhydrides, polyorthoesters or combination thereof; a controlled release polymer, e.g. ethyl acrylate copolymer dispersion, methyl methacrylate copolymer dispersion or combinations thereof; a modified release polymer, e.g. cellulose derivatives (e.g. vinyl pyrrolidone polymers and copolymers); alkylene oxide and water, these can be used to form a solid preformulation containing a homogeneous mixture of a compound of the present disclosure, or a non-toxic pharmaceutically acceptable salt and/or hydrate thereof. The solid preformulation composition is then subdivided into unit dosage forms of a type described above.

[0190] In embodiments, the pharmaceutical formulation or composition can be coated or otherwise compounded to provide a dosage form for targeted drug delivery in the colon affording the advantage of prolonged action, better efficacy and reduced adverse effects. For example, the tablet or pill can comprise an inner composition covered by an outer component. Furthermore, the two components can be separated by an enteric layer that serves to resist disintegration and permits the inner component to pass intact through the stomach or to be delayed in release. In embodiments, the pharmaceutical formulation is a suspension.

[0191] Preferred coatings used in the formulations employ two independent mechanisms to facilitate targeting the ileo-colonic region of the gastrointestinal (GI) tract. The first is a pH trigger that dissolves about pH 7, and the second is a microbiota-trigger (e.g., resistant starch) that is digestible by bacterial enzymes found in the colon. A mixture of two suitable polymers at an appropriate ratio, applied as a film coating on to a core, minimizes, and can substantially eliminate, drug release in the stomach and small intestine. Subsequent targeted drug release in the colon is believed to occur by the combined active physiological triggers: i.e. by dissolution of a second material, for example EUDRAGIT® S, and digestion of a first material, e.g. starch or amylose.

[0192] In embodiments, the component inducing a microbiota trigger is modified starch. In order to make the starch more digestible by bacterial enzymes, heat treatment of the starch in the presence of butanol allows disruption of the crystalline structure of the starch granules. Under conditions of limited exposure to high pH in the distal small intestine fluid and rapid transit through the colon, often observed in patients with inflammatory bowel disease, particularly in ulcerative colitis, this dual-trigger pH-enzymatic coating offers an approach for site specific drug delivery to the large intestine. Starches are usually extracted from natural sources such as cereals; pulses; and tubers. Suitable starches for use in the present disclosure are typically food grade starches and include rice starch; wheat starch; com (or maize) starch; pea starch; potato starch; sweet potato starch; tapioca starch; sorghum starch; sago starch; and arrow root starch. The use of maize starch is exemplified below.

[0193] Starch is actually a mixture of two different polysaccharides, namely amylose and amylopectin. Different starches may have different proportions of these two polysaccharides. Most natural (unmodified) maize starches have from about 20 wt % to about 30 wt % amylose with the remainder being at least substantially made up of amylopectin. Starches suitable for use in the present disclosure typically have at least 0.1 wt %, e.g. at least 10% or 15%, preferably at least 35 wt %, amylose. “High amylase” starches are starches having at least 50 wt % amylose. Particularly suitable starches have from about 65 wt % to about 75 wt %, e.g. about 70 wt % amylose.

[0194] Starches suitable for use in the present disclosure may have up to 100% amylopectin, more typically from about 0.1 wt % to about 99.9 wt % amylopectin. “Low amylose” starches, i.e. starches having no more than 50 wt % amylose and at least 50 wt % amylopectin, e.g. up to 75 wt % amylopectin and even as much as up to 99 wt % amylopectin, are suitable. The starch may be, for instance, unmodified waxy com starch. This typically comprises about 100% amylopectin. “Low amylose” starch was not expected to be suitable, since low amylose starch is typically degraded by pancreatic enzymes in the small intestine. Preferred starches have no more than 50 wt % amylopectin. Particularly suitable starches have from about 25 wt % to about 35 wt % amylopectin, e.g. about 30 wt % amylopectin.

[0195] The person skilled in the art is capable of determining the relative proportions of amylose and amylopectin in any given starch. For example, near-infrared (“NIR”) spectroscopy could be used to determine the amylose and amylopectin content of a starch using calibration curves obtained by NIR using laboratory -produced mixtures of known amounts of these two components. Further, starch could be hydrolyzed to glucose using amyloglucosidase. A series of phosphorylation and oxidation reactions catalyzed by enzymes result in the formation of reduced nicotinamide adenine dinucleotide phosphate (“NADPH”). The quantity of NADPH formed is stochiometric with the original glucose content. Suitable test kits for this procedure are available (e.g., R-Biopharm GmbH, Germany). Another method that could be used involves subjecting the coating to digestion by bacterial enzymes, e.g. a-amylase, to produce short chain fatty acids (“SCFA”) which can be quantified by gas-liquid chromatography using a capillary column.

[0196] Preferred starches have amylose in its glassy form although amylose in its amorphous form may also be used in conjunction with the present disclosure.

[0197] Preferred starches are “off-the-shelf’ starches, i.e. starches which require no processing prior to use in the context of the present disclosure. Examples of particularly suitable “high amylose” starches include HYLON™ VII (National Starch, Germany) or EURYLON™ 7 (Roquette, Lestrem, France) or Amylogel 03003 (Cargill, Minneapolis, USA) all of which are examples of a maize starch having about 70 wt % amylose.

[0198] The present disclosure involves the use of a second material which dissolves in a pH dependent manner. The second material has a “pH threshold” which is the pH below which it is insoluble and at or above which it is soluble. The pH of the surrounding medium triggers dissolution of the second material. Thus, none (or essentially none) of the second material dissolves below the pH threshold. Once the pH of the surrounding medium reaches (or exceeds) the pH threshold, the second material becomes soluble. By “insoluble” we mean that 1 g of the second material requires more than 10,000 ml of solvent (surrounding medium) to dissolve at a given pH. By “soluble”, we mean that 1 g of the second material requires less than 10,000 ml, preferably less than 5,000 ml, more preferably less than 1000 ml, even more preferably less than 100 ml or 10 ml of solvent to dissolve at a given pH. Surrounding medium preferably means the medium in the gastrointestinal tract, such as the gastric juice or intestinal juice. Alternatively, the surrounding medium may be in the vitro equivalent of the medium in the gastrointestinal tract.

[0199] The normal pH of gastric juice is usually in the range of 1 to 3. The second material is insoluble below pH 5 and soluble at about pH 5 or above and soluble at about pH 5 or above and, thus, is usually insoluble in gastric juice. Such a material may be referred to as an “enteric” material.

[0200] The second material is soluble at pH 5 or above, e.g., in intestinal juice. The pH of intestinal juice gradually increases from about 6 in the duodenum to about 7 to 8 in the colon. The second material is preferably insoluble below pH 6.5 (and soluble at about pH 6.5 or above) and, more preferably, is insoluble below pH 7 (and soluble at about pH 7 or above).

[0201] The pH threshold at which a material becomes soluble may be determined by a simple titration technique which would be part of the common general knowledge to the person skilled in the art.

[0202] The second material is typically a film-forming polymeric material such as an acrylate polymer, a cellulose polymer or a polyvinyl-based polymer. Examples of suitable cellulose polymers include cellulose acetate phthalate (“CAP”); cellulose acetate trimellitate (“CAT”); and hydropropylmethylcellulose acetate succinate. Examples of suitable polyvinyl-based polymers include polyvinyl acetate phthalate (“PVAP”).

[0203] The second material is preferably a co-polymer of a (meth)acrylic acid and a (meth)acrylic acid Cl -4 alkyl ester, for instance, a copolymer of methacrylic acid and methacrylic acid methyl ester. Such a polymer is known as a poly (methacrylic acid/methyl methacrylate) co-polymer. Suitable examples of such co-polymers are usually anionic and not sustained release polymethacrylates. The ratio of carboxylic acid groups to methyl ester groups (the “acid: ester ratio”) in these co-polymers determines the pH at which the co-polymer is soluble. The acid:ester ratio may be from about 2:1 to about 1:3, e.g. about 1:1 or, preferably, about 1:2. The molecular weight (“MW”) of preferred anionic co-polymers is usually from about 120,000 to 150,000, preferably about 135,000.

[0204] Preferred anionic poly(methacrylic acid/methyl methacrylate) co-polymers include EUDRAGIT® L (acid:ester ratio about 1:1; MW about 135,000; pH threshold of about 6.0); EUDRAGIT® S (acid:ester ratio about 1 :2; MW about 135,000; pH threshold of about 7); and EUDRAGIT® FS (a poly(methyl acrylate/methyl methacryl ate/methacry lie acid; acid:ester ratio of about 1:10; MW about 220,000; pH threshold of about 7.)

[0205] The second material may be a copolymer of methacrylic acid and ethyl acrylate. EUDRAGIT® L100-55 (a poly(methacrylic acid/ethyl acrylate); acid:ester ratio of about 1:1; MW about 250,000; pH threshold of about 5.5) is suitable. The EUDRAGIT® co-polymers are manufactured and/or distributed by Degussa AG, Darmstadt, Germany.

[0206] Mixtures of film forming polymer materials may be used as appropriate. An example of a suitable mixture would include a mixture, e.g. a 1: 1 mixture, of EUDRAGIT® L and EUDRAGIT® S. However, the use of a particular film forming polymer material, e.g. a poly (methacrylic acid/methyl methacrylate) co-polymer, alone is preferred.

[0207] The use of EUDRAGIT® S alone as the second material is particularly preferred.

[0208] In embodiments, it has been found that a mixture of two suitable polymers at an appropriate ratio, applied as a film coating on to a core, at least minimizes, and can substantially eliminate, drug release in the stomach and small intestine. Subsequent drug release in the colon is believed to occur by the combined active physiological triggers: i.e., by dissolution of the second material, particularly EUDRAGIT® S, and digestion of the first material, e.g. starch or amylose.

[0209] The proportion of the first material to the second material is typically less than 99: 1 and may in some circumstances be up to 50:50. The proportion is usually up to 35:65 and is preferably from 15:85 to 35:65, e.g. 15:85 to 30:70. The Inventor has discovered that a ratio of first material to second material from about 25:75 to about 35:65, e.g. about 30:70, is particularly suitable for targeting release of the drug to the colon, particularly if the first material is starch and the second material is EUDRAGIT® S. The mixture of first and second materials is preferably substantially homogenous.

[0210] The proportion of the first material to the second material is typically less than 99: 1 and may in some circumstances be up to 50:50. The proportion is usually up to 35:65 and is preferably from 15:85 to 35:65, e.g. 15:85 to 30:70. The Inventor has discovered that a ratio of first material to second material from about 25:75 to about 35:65, e.g. about 30:70, is particularly suitable for targeting release of the drug to the colon, particularly if the first material is starch and the second material is EUDRAGIT® S. The mixture of first and second materials is preferably substantially homogenous.

[0211] In embodiments, the dosage form comprises an enteric coating. In embodiments, the enteric coating comprises a first material which is susceptible to attack by colonic bacteria and a second material which is a film-forming acrylate polymer. In embodiments, the first material is the inner layer and the second material is the outer layer. In embodiments, the first material is selected from the group consisting of amylopectin and starch. In embodiments, the first material is starch having no more than 50 wt % amylose and at least 50 wt % amylopectin. In embodiments, the first material is amylopectin. In embodiments, the release of the drug is delayed until the dosage form reaches colon of the subject. In embodiments, the second material is EUDRAGIT® SI 00. In embodiments, the second material is a film-forming acrylate polymer with a pH threshold at about pH 5 or above. In embodiments, the pH threshold is about 7. In embodiments, the second material is an anionic co-polymer of methacrylic acid and methacrylic acid methyl ester. In embodiments, the anionic co-polymer has a ratio of methacrylic acid to methacrylic acid methyl ester of about 1:2. In embodiments, the coating has a thickness as measured by theoretical weight gain of from about 0.1% to about 99%.

[0212] In embodiments, the pharmaceutical formulation for colon release may be conveniently prepared using PHLORAL® technology. In embodiments, the coating comprises of an inner coating and outer coating. In embodiments, the inner coating comprises a film forming polymeric material having a pH threshold at about pH 6.5 or above. In embodiments, the inner coating comprises EUDRAGIT® S (acid: ester ratio about 1:2; MW about 135,000; pH threshold of about 7). In embodiments, the outer coating comprises a polysaccharide selected from the group consisting of starch, amylose, amylopectin, chitosan, chondroitin sulfate, cyclodextrin, dextran, pullulan, carrageenan, scleroglucan, chitin, curdulan, and levan. In embodiments, the outer coating is digestible by bacterial enzymes. Various patents and patent applications related to this technology are incorporated herein in their entirety including US Patent No. 10,369,112.

[0213] In embodiments, the pharmaceutical formulation for colon release may be conveniently prepared using DUOCOAT ® technology. In embodiments, the coating comprises of an inner coating and outer coating. In embodiments, the inner coating comprises a partially neutralized anionic methacrylate copolymeric material and the outer coating comprises the same partially neutralized anionic methacrylate copolymeric material of the inner coating, with the proviso that the partially neutralized anionic methacrylate copolymeric material of the outer coating is less neutralized than the partially neutralized anionic methacrylate copolymeric material of the inner coating. In embodiments, the inner coating further comprises at least one water soluble inorganic salt. In embodiments, the cation of the inorganic salt is selected from the group consisting of alkali metal, alkaline earth metal, ammonium, manganese, iron, copper, zinc, and molybdenum cations, and the anion of the inorganic salt is selected from the group consisting of chloride, fluoride, bromide, iodide, nitrate, nitrite, and sulphate anions, with the proviso that carbonates and bicarbonates are excluded. Additional information related to this technology is described in US Patent Nos. 10,537,530 and 9,597,293, which are incorporated herein in its entirety for all purposes. [0214] Optionally, conventional excipients such as plasticizers for film formation (for example, triethyl citrate) and anti-tack agents (such as glyceryl monostearate) may be included in amounts up to 30% by weight of the final composition of the polymer coating preparation.

[0215] The thickness of the coating of the particle is typically from about 10 pm to about 150 pm. The thickness of a specific coating will, however, depend on the composition of the coating. For example, coating thickness is directly proportional to the amount of polysaccharide in the coating. Thus, In embodiments where the coating comprises high amylose starch and EUDRAGIT™ S at a ratio of about 30:70, the coating thickness may be from about 70 pm to about 130 pm, and preferably from about 90 pm to about 110 pm. The thickness (in pm) for a given coating composition is independent of core size.

[0216] The thickness of the coating may also be measured by the “theoretical weight gain” (“TWG”) of the coated formulation. The TWG for the present formulation will depend on a number of factors including the composition of the coating and the size of the core to be coated. For example, In embodiments where the core is a small tablet (e.g. having a diameter of about 8 mm) and the coating comprises high amylose starch and EUDRAGIT™ S (e.g. in a ratio of about 30:70), the TWG is typically from about 4% to about 12%, e.g. from about 5% to about 10%, preferably from about 8% to about 9%. In embodiments where the core is a pellet (e.g. having a diameter of about 1 mm) having the same coating, the TWG may be from about 15% to about 35%, e.g. from about 20% to about 30%, preferably about 25%.

[0217] By saying that the coating comprises a mixture of the first and second materials, it is intended to exclude the known multi-layer dosage form in which an active core is coated first with an inner coating of amylose and then with an outer coating of EUDRAGIT® LI 00. In the context of the present disclosure, such a multi-layer dosage form does not comprise a mixture of starch and EUDRAGIT® LI 00. The coating is preferably a single layer of a mixture of the first and second materials, preferably a homogenous mixture.

[0218] The formulation of the present disclosure may further comprise an additional coating layer. For example, if the delayed release composition layer comprises a mixture of EUDRAGIT® L and starch, the addition of an outer layer of a pH dependent release coating material having a pH threshold of about 7, e.g. EUDRAGIT® S, may be preferable. In embodiments, the delayed release coating of the present disclosure is applied directly to the active core, i.e., there is no additional layer between this coating and the active core. The delayed release coating is preferably the outer coating of the formulation. Advantageously, it has been found that no additional outer layer is required to ensure that the composition is a delayed release composition.

[0219] The composition preferably forms a coating around the bioactive which is most preferably mixture of starch and EUDRAGIT® S. The “bioactive” is usually the core comprising the active ingredient.

[0220] In embodiments, the dosage form comprises at least one particle with a core and a coating for the core. The formulation may comprise any suitable coated oral dosage form including capsules; tablets; mini-tablets; pellets; granules; and crystals.

Gastro-Intestinal Diseases

[0221] In embodiments, the method of the present disclosure is useful for the treatment of various GI inflammatory diseases. In embodiments, the pharmaceutical formulation is administered orally for the targeted release of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof in the colon. Targeted release of ondansetron in the colon not only reduces adverse effects but also increases the efficacy of the active ingredient.

[0222] In embodiments, the GI inflammatory disease is selected from the group consisting of celiac disease, diverticulitis, duodenal ulcer, intestinal polyps, irritable bowel syndrome, proctitis, protein-losing enteropathy, hemorrhoids, postoperative ileus, pouchitis, stress ulcer, ileitis, lactose intolerance, antibiotic enterocolitis, autoimmune enteropathy, dyspepsia, noninfectious gastroenteritis, eosinophilic duodenitis, peptic ulcers, appendicitis, atrophic gastritis, gastric ulcer, NSAID-induced ulcer, acute pancreatitis, gallstones, gallstone pancreatitis, alcoholic pancreatitis, eosinophilic gastritis, peritonitis, bile acid diarrhea and IBD. In embodiments, the GI inflammatory disease is IBD. In embodiments, IBD is UC and CD. In embodiments, the IBD is UC.

[0223] In embodiments, the pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in treating IBD. In embodiments, the pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in treating UC. In embodiments, pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in treating CD. In embodiments, the pharmaceutical formulation including ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof are administered daily at a per unit dose in range of about 2 mg to about 32 mg. In embodiments, the administration of formulations is once daily (“OD”), twice daily, three-times daily, four-times daily, once every two days, once every three days, once a week, once every two weeks, once every three weeks or once a month. In embodiments, the administration of formulation is once daily.

[0224] In embodiments, the pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in treating celiac disease. In embodiments, the pharmaceutical formulation including ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof are administered daily at a per unit dose in range of about 2 mg to about 32 mg. In embodiments, the administration of formulations is once daily (“OD”), twice daily, three-times daily, four- times daily, once every two days, once every three days, once a week, once every two weeks, once every three weeks or once a month. In embodiments, the administration of formulation is once daily.

[0225] In embodiments, the pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in treating diverticulitis. In embodiments, the pharmaceutical formulation including ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof are administered daily at a per unit dose in range of about 2 mg to about 32 mg. In embodiments, the administration of formulations is once daily (“OD”), twice daily, three-times daily, four- times daily, once every two days, once every three days, once a week, once every two weeks, once every three weeks or once a month. In embodiments, the administration of formulation is once daily.

[0226] In embodiments, the pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in treating duodenal ulcer. In embodiments, the pharmaceutical formulation including ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof are administered daily at a per unit dose in range of about 2 mg to about 32 mg. In embodiments, the administration of formulations is once daily (“OD”), twice daily, three-times daily, four- times daily, once every two days, once every three days, once a week, once every two weeks, once every three weeks or once a month. In embodiments, the administration of formulation is once daily.

[0227] In embodiments, the pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in treating intestinal polyps. In embodiments, the pharmaceutical formulation including ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof are administered daily at a per unit dose in range of about 2 mg to about 32 mg. In embodiments, the administration of formulations is once daily (“OD”), twice daily, three-times daily, four- times daily, once every two days, once every three days, once a week, once every two weeks, once every three weeks or once a month. In embodiments, the administration of formulation is once daily.

[0228] In embodiments, the pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in treating irritable bowel syndrome. In embodiments, the pharmaceutical formulation including ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof are administered daily at a per unit dose in range of about 2 mg to about 32 mg. In embodiments, the administration of formulations is once daily (“OD”), twice daily, three-times daily, four-times daily, once every two days, once every three days, once a week, once every two weeks, once every three weeks or once a month. In embodiments, the administration of formulation is once daily.

[0229] In embodiments, the pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in treating proctitis. In embodiments, the pharmaceutical formulation including ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof are administered daily at a per unit dose in range of about 2 mg to about 32 mg. In embodiments, the administration of formulations is once daily (“OD”), twice daily, three-times daily, four- times daily, once every two days, once every three days, once a week, once every two weeks, once every three weeks or once a month. In embodiments, the administration of formulation is once daily.

[0230] In embodiments, the pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in treating protein-losing enteropathy. In embodiments, the pharmaceutical formulation including ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof are administered daily at a per unit dose in range of about 2 mg to about 32 mg. In embodiments, the administration of formulations is once daily (“OD”), twice daily, three-times daily, four-times daily, once every two days, once every three days, once a week, once every two weeks, once every three weeks or once a month. In embodiments, the administration of formulation is once daily.

[0231] In embodiments, the pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in treating hemorrhoids. In embodiments, the pharmaceutical formulation including ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof are administered daily at a per unit dose in range of about 2 mg to about 32 mg. In embodiments, the administration of formulations is once daily (“OD”), twice daily, three-times daily, four- times daily, once every two days, once every three days, once a week, once every two weeks, once every three weeks or once a month. In embodiments, the administration of formulation is once daily.

[0232] In embodiments, the pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in treating postoperative ileus. In embodiments, the pharmaceutical formulation including ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof are administered daily at a per unit dose in range of about 2 mg to about 32 mg. In embodiments, the administration of formulations is once daily (“OD”), twice daily, three-times daily, four-times daily, once every two days, once every three days, once a week, once every two weeks, once every three weeks or once a month. In embodiments, the administration of formulation is once daily.

[0233] In embodiments, the pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in treating stress ulcer. In embodiments, the pharmaceutical formulation including ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof are administered daily at a per unit dose in range of about 2 mg to about 32 mg. In embodiments, the administration of formulations is once daily (“OD”), twice daily, three-times daily, four- times daily, once every two days, once every three days, once a week, once every two weeks, once every three weeks or once a month. In embodiments, the administration of formulation is once daily.

[0234] In embodiments, the pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in treating ileitis. In embodiments, the pharmaceutical formulation including ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof are administered daily at a per unit dose in range of about 2 mg to about 32 mg. In embodiments, the administration of formulations is once daily (“OD”), twice daily, three-times daily, four-times daily, once every two days, once every three days, once a week, once every two weeks, once every three weeks or once a month. In embodiments, the administration of formulation is once daily.

[0235] In embodiments, the pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in treating lactose intolerance. In embodiments, the pharmaceutical formulation including ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof are administered daily at a per unit dose in range of about 2 mg to about 32 mg. In embodiments, the administration of formulations is once daily (“OD”), twice daily, three-times daily, four-times daily, once every two days, once every three days, once a week, once every two weeks, once every three weeks or once a month. In embodiments, the administration of formulation is once daily.

[0236] In embodiments, the pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in treating antibiotic enterocolitis. In embodiments, the pharmaceutical formulation including ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof are administered daily at a per unit dose in range of about 2 mg to about 32 mg. In embodiments, the administration of formulations is once daily (“OD”), twice daily, three-times daily, four-times daily, once every two days, once every three days, once a week, once every two weeks, once every three weeks or once a month. In embodiments, the administration of formulation is once daily.

[0237] In embodiments, the pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in treating autoimmune enteropathy. In embodiments, the pharmaceutical formulation including ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof are administered daily at a per unit dose in range of about 2 mg to about 32 mg. In embodiments, the administration of formulations is once daily (“OD”), twice daily, three-times daily, four-times daily, once every two days, once every three days, once a week, once every two weeks, once every three weeks or once a month. In embodiments, the administration of formulation is once daily.

[0238] In embodiments, the pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in treating dyspepsia. In embodiments, the pharmaceutical formulation including ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof are administered daily at a per unit dose in range of about 2 mg to about 32 mg. In embodiments, the administration of formulations is once daily (“OD”), twice daily, three-times daily, four- times daily, once every two days, once every three days, once a week, once every two weeks, once every three weeks or once a month. In embodiments, the administration of formulation is once daily.

[0239] In embodiments, the pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in treating noninfectious gastroenteritis. In embodiments, the pharmaceutical formulation including ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof are administered daily at a per unit dose in range of about 2 mg to about 32 mg. In embodiments, the administration of formulations is once daily (“OD”), twice daily, three-times daily, four-times daily, once every two days, once every three days, once a week, once every two weeks, once every three weeks or once a month. In embodiments, the administration of formulation is once daily.

[0240] In embodiments, the pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in treating eosinophilic duodenitis. In embodiments, the pharmaceutical formulation including ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof are administered daily at a per unit dose in range of about 2 mg to about 32 mg. In embodiments, the administration of formulations is once daily (“OD”), twice daily, three-times daily, four-times daily, once every two days, once every three days, once a week, once every two weeks, once every three weeks or once a month. In embodiments, the administration of formulation is once daily.

[0241] In embodiments, the pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in treating peptic ulcers. In embodiments, the pharmaceutical formulation including ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof are administered daily at a per unit dose in range of about 2 mg to about 32 mg. In embodiments, the administration of formulations is once daily (“OD”), twice daily, three-times daily, four- times daily, once every two days, once every three days, once a week, once every two weeks, once every three weeks or once a month. In embodiments, the administration of formulation is once daily.

[0242] In embodiments, the pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in treating appendicitis. In embodiments, the pharmaceutical formulation including ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof are administered daily at a per unit dose in range of about 2 mg to about 32 mg. In embodiments, the administration of formulations is once daily (“OD”), twice daily, three-times daily, four- times daily, once every two days, once every three days, once a week, once every two weeks, once every three weeks or once a month. In embodiments, the administration of formulation is once daily.

[0243] In embodiments, the pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in treating atrophic gastritis. In embodiments, the pharmaceutical formulation including ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof are administered daily at a per unit dose in range of about 2 mg to about 32 mg. In embodiments, the administration of formulations is once daily (“OD”), twice daily, three-times daily, four- times daily, once every two days, once every three days, once a week, once every two weeks, once every three weeks or once a month. In embodiments, the administration of formulation is once daily.

[0244] In embodiments, the pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in treating gastric ulcer. In embodiments, the pharmaceutical formulation including ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof are administered daily at a per unit dose in range of about 2 mg to about 32 mg. In embodiments, the administration of formulations is once daily (“OD”), twice daily, three-times daily, four- times daily, once every two days, once every three days, once a week, once every two weeks, once every three weeks or once a month. In embodiments, the administration of formulation is once daily.

[0245] In embodiments, the pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in treating NSAID-induced ulcer. In embodiments, the pharmaceutical formulation including ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof are administered daily at a per unit dose in range of about 2 mg to about 32 mg. In embodiments, the administration of formulations is once daily (“OD”), twice daily, three-times daily, four-times daily, once every two days, once every three days, once a week, once every two weeks, once every three weeks or once a month. In embodiments, the administration of formulation is once daily.

[0246] In embodiments, the pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in treating acute pancreatitis. In embodiments, the pharmaceutical formulation including ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof are administered daily at a per unit dose in range of about 2 mg to about 32 mg. In embodiments, the administration of formulations is once daily (“OD”), twice daily, three-times daily, four- times daily, once every two days, once every three days, once a week, once every two weeks, once every three weeks or once a month. In embodiments, the administration of formulation is once daily.

[0247] In embodiments, the pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in treating gallstones. In embodiments, the pharmaceutical formulation including ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof are administered daily at a per unit dose in range of about 2 mg to about 32 mg. In embodiments, the administration of formulations is once daily (“OD”), twice daily, three-times daily, four- times daily, once every two days, once every three days, once a week, once every two weeks, once every three weeks or once a month. In embodiments, the administration of formulation is once daily.

[0248] In embodiments, the pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in treating gallstone pancreatitis. In embodiments, the pharmaceutical formulation including ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof are administered daily at a per unit dose in range of about 2 mg to about 32 mg. In embodiments, the administration of formulations is once daily (“OD”), twice daily, three-times daily, four-times daily, once every two days, once every three days, once a week, once every two weeks, once every three weeks or once a month. In embodiments, the administration of formulation is once daily.

[0249] In embodiments, the pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in treating alcoholic pancreatitis. In embodiments, the pharmaceutical formulation including ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof are administered daily at a per unit dose in range of about 2 mg to about 32 mg. In embodiments, the administration of formulations is once daily (“OD”), twice daily, three-times daily, four-times daily, once every two days, once every three days, once a week, once every two weeks, once every three weeks or once a month. In embodiments, the administration of formulation is once daily.

[0250] In embodiments, the pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in treating eosinophilic gastritis. In embodiments, the pharmaceutical formulation including ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof are administered daily at a per unit dose in range of about 2 mg to about 32 mg. In embodiments, the administration of formulations is once daily (“OD”), twice daily, three-times daily, four-times daily, once every two days, once every three days, once a week, once every two weeks, once every three weeks or once a month. In embodiments, the administration of formulation is once daily.

[0251] In embodiments, the pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in treating peritonitis. In embodiments, the pharmaceutical formulation including ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof are administered daily at a per unit dose in range of about 2 mg to about 32 mg. In embodiments, the administration of formulations is once daily (“OD”), twice daily, three-times daily, four- times daily, once every two days, once every three days, once a week, once every two weeks, once every three weeks or once a month. In embodiments, the administration of formulation is once daily.

[0252] In embodiments, pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in treating or reducing adverse histopathological condition in colon. In embodiments, adverse histopathological condition comprising at least one of crypt damage, oedema, infiltration of leukocytes, and extent of infiltration of leukocytes. In embodiments, adverse histopathological condition is selected from the group consisting of crypt damage, oedema, infiltration of leukocytes, extent of infiltration of leukocytes or combination thereof. In embodiments adverse histopathological condition includes crypt damage, oedema, infiltration of leukocytes, extent of infiltration of leukocytes or combination thereof.

[0253] In embodiments, pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in treating or reducing crypt damage. In embodiments, pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron and/or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in treating or reducing oedema of colon. In embodiments, pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron and/or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in reducing infiltration of leukocytes. In embodiments, pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron and/or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in reducing extent of infiltration of leukocytes.

[0254] In embodiments, the pharmaceutical formulation for colon targeted release comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, is useful in treating behavioral symptoms associated with GI inflammatory disease. In embodiments, the behavioral symptoms include neuropsychological symptoms, e.g. anxiety, stress reactivity, visceral hypersensitivity, insomnia or depression. Treatment Outcomes

[0255] Patients treated according to the methods and formulations disclosed herein preferably experience an improvement in the prognosis of GI inflammatory disease. In embodiments, an improvement is a reduction in symptomatology of GI inflammatory disease such as body weight loss, diarrhea and rectal bleeding. In embodiments, compared to pathological control, the use of ondansetron significantly (compared to pathological control) reduced the generation of pro-inflammatory cytokine IL-ip, IL-18, TNFa, and IL-6 by 66%, 64%, 66% and 47%, respectively.

[0256] In embodiments, an improvement in GI inflammatory disease prognosis is measured by body weight score, stool consistency score, occult blood score and DAI score. In embodiments, an improvement in GI inflammatory disease prognosis measured as significant reduction in infiltration of leukocytes, extent of infiltration of leukocyte, oedema and crypt damage score. Intracolonic administration of ondansetron showed lower plasma concentration of ondansetron and higher efficacy than conventional non-targeted oral (IR) delivery compared to colonic targeted delivery.

[0257] In embodiments, the methods and formulation provided herein result in a 10% to 80% reduction in body weight score. For example, In embodiments, the methods and compositions provided herein result in a 10% to 80%, 10% to 75%, 10% to 70%, 10% to 65%, 10% to 60%, 10% to 55%, 10% to 50%, 10% to 45%, 10% to 40%, 10% to 35%, 10% to 30%, 10% to 25%, 10% to 20%, 15% to 80%, 15% to 75%, 15% to 70%, 15% to 65%, 15% to 60%, 15% to 55%, 15% to 50%, 15% to 45%, 15% to 40%, 15% to 35%, 15% to 30%, 15% to 25%, 20% to 80%, 20% to 75%, 20% to 70%, 20% to 65%, 20% to 60%, 20% to 55%, 20% to 50%, 20% to 45%, 20% to 40%, 20% to 35%, 20% to 30%, 25% to 80%, 25% to 75%, 25% to 70%, 25% to 65%, 25% to 60%, 25% to 55%, 25% to 50%, 25% to 45%, 25% to 40%, 25% to 35%, 30% to 80%, 30% to 75%, 30% to 70%, 30% to 65%, 30% to 60%, 30% to 55%, 30% to 50%, 30% to 45%, 30% to 40%, 40% to 80%, 40% to 75%, 40% to 70%, 40% to 65%, 40% to 60%, 40% to 55%, 40% to 50%, 50% to 80%, 50% to 75%, 50% to 70%, 50% to 65%, 50% to 60%, 60% to 80%, 60% to 75%, 60% to 70%.

[0258] In embodiments, the methods and formulation provided herein result in a 10% to 80% reduction in oedema. For example, In embodiments, the methods and compositions provided herein result in a 10% to 80%, 10% to 75%, 10% to 70%, 10% to 65%, 10% to 60%, 10% to 55%, 10% to 50%, 10% to 45%, 10% to 40%, 10% to 35%, 10% to 30%, 10% to 25%, 10% to 20%, 15% to 80%, 15% to 75%, 15% to 70%, 15% to 65%, 15% to 60%, 15% to 55%, 15% to 50%, 15% to 45%, 15% to 40%, 15% to 35%, 15% to 30%, 15% to 25%, 20% to 80%, 20% to 75%, 20% to 70%, 20% to 65%, 20% to 60%, 20% to 55%, 20% to 50%, 20% to 45%, 20% to 40%, 20% to 35%, 20% to 30%, 25% to 80%, 25% to 75%, 25% to 70%, 25% to 65%, 25% to 60%, 25% to 55%, 25% to 50%, 25% to 45%, 25% to 40%, 25% to 35%, 30% to 80%, 30% to 75%, 30% to 70%, 30% to 65%, 30% to 60%, 30% to 55%, 30% to 50%, 30% to 45%, 30% to 40%, 40% to 80%, 40% to 75%, 40% to 70%, 40% to 65%, 40% to 60%, 40% to 55%, 40% to 50%, 50% to 80%, 50% to 75%, 50% to 70%, 50% to 65%, 50% to 60%, 60% to 80%, 60% to 75%, 60% to 70%.

[0259] In embodiments, the methods and formulation provided herein result in a 10% to 80% reduction in DAI score. For example, In embodiments, the methods and compositions provided herein result in a 10% to 80%, 10% to 75%, 10% to 70%, 10% to 65%, 10% to 60%, 10% to 55%, 10% to 50%, 10% to 45%, 10% to 40%, 10% to 35%, 10% to 30%, 10% to 25%, 10% to 20%, 15% to 80%, 15% to 75%, 15% to 70%, 15% to 65%, 15% to 60%, 15% to 55%, 15% to 50%, 15% to 45%, 15% to 40%, 15% to 35%, 15% to 30%, 15% to 25%, 20% to 80%, 20% to 75%, 20% to 70%, 20% to 65%, 20% to 60%, 20% to 55%, 20% to 50%, 20% to 45%, 20% to 40%, 20% to 35%, 20% to 30%, 25% to 80%, 25% to 75%, 25% to 70%, 25% to 65%, 25% to 60%, 25% to 55%, 25% to 50%, 25% to 45%, 25% to 40%, 25% to 35%, 30% to 80%, 30% to 75%, 30% to 70%, 30% to 65%, 30% to 60%, 30% to 55%, 30% to 50%, 30% to 45%, 30% to 40%, 40% to 80%, 40% to 75%, 40% to 70%, 40% to 65%, 40% to 60%, 40% to 55%, 40% to 50%, 50% to 80%, 50% to 75%, 50% to 70%, 50% to 65%, 50% to 60%, 60% to 80%, 60% to 75%, 60% to 70%.

[0260] In embodiments, the methods and formulation provided herein result in a 10% to 80% reduction in occult blood score. For example, In embodiments, the methods and compositions provided herein result in a 10% to 80%, 10% to 75%, 10% to 70%, 10% to 65%, 10% to 60%, 10% to 55%, 10% to 50%, 10% to 45%, 10% to 40%, 10% to 35%, 10% to 30%, 10% to 25%, 10% to 20%, 15% to 80%, 15% to 75%, 15% to 70%, 15% to 65%, 15% to 60%, 15% to 55%, 15% to 50%, 15% to 45%, 15% to 40%, 15% to 35%, 15% to 30%, 15% to 25%, 20% to 80%, 20% to 75%, 20% to 70%, 20% to 65%, 20% to 60%, 20% to 55%, 20% to 50%, 20% to 45%, 20% to 40%, 20% to 35%, 20% to 30%, 25% to 80%, 25% to 75%, 25% to 70%, 25% to 65%, 25% to 60%, 25% to 55%, 25% to 50%, 25% to 45%, 25% to 40%, 25% to 35%, 30% to 80%, 30% to 75%, 30% to 70%, 30% to 65%, 30% to 60%, 30% to 55%, 30% to 50%, 30% to 45%, 30% to 40%, 40% to 80%, 40% to 75%, 40% to 70%, 40% to 65%, 40% to 60%, 40% to 55%, 40% to 50%, 50% to 80%, 50% to 75%, 50% to 70%, 50% to 65%, 50% to 60%, 60% to 80%, 60% to 75%, 60% to 70%.

[0261] In embodiments, the methods and formulation provided herein result in a 10% to 80% reduction in stool consistency score. For example, In embodiments, the methods and compositions provided herein result in a 10% to 80%, 10% to 75%, 10% to 70%, 10% to 65%, 10% to 60%, 10% to 55%, 10% to 50%, 10% to 45%, 10% to 40%, 10% to 35%, 10% to 30%, 10% to 25%, 10% to 20%, 15% to 80%, 15% to 75%, 15% to 70%, 15% to 65%, 15% to 60%, 15% to 55%, 15% to 50%, 15% to 45%, 15% to 40%, 15% to 35%, 15% to 30%, 15% to 25%, 20% to 80%, 20% to 75%, 20% to 70%, 20% to 65%, 20% to 60%, 20% to 55%, 20% to 50%, 20% to 45%, 20% to 40%, 20% to 35%, 20% to 30%, 25% to 80%, 25% to 75%, 25% to 70%, 25% to 65%, 25% to 60%, 25% to 55%, 25% to 50%, 25% to 45%, 25% to 40%, 25% to 35%, 30% to 80%, 30% to 75%, 30% to 70%, 30% to 65%, 30% to 60%, 30% to 55%, 30% to 50%, 30% to 45%, 30% to 40%, 40% to 80%, 40% to 75%, 40% to 70%, 40% to 65%, 40% to 60%, 40% to 55%, 40% to 50%, 50% to 80%, 50% to 75%, 50% to 70%, 50% to 65%, 50% to 60%, 60% to 80%, 60% to 75%, 60% to 70%.

[0262] In embodiments, the methods and formulation provided herein result in a 10% to 80% reduction in infiltration of leukocytes. For example, In embodiments, the methods and compositions provided herein result in a 10% to 80%, 10% to 75%, 10% to 70%, 10% to 65%, 10% to 60%, 10% to 55%, 10% to 50%, 10% to 45%, 10% to 40%, 10% to 35%, 10% to 30%, 10% to 25%, 10% to 20%, 15% to 80%, 15% to 75%, 15% to 70%, 15% to 65%, 15% to 60%, 15% to 55%, 15% to 50%, 15% to 45%, 15% to 40%, 15% to 35%, 15% to 30%, 15% to 25%, 20% to 80%, 20% to 75%, 20% to 70%, 20% to 65%, 20% to 60%, 20% to 55%, 20% to 50%, 20% to 45%, 20% to 40%, 20% to 35%, 20% to 30%, 25% to 80%, 25% to 75%, 25% to 70%, 25% to 65%, 25% to 60%, 25% to 55%, 25% to 50%, 25% to 45%, 25% to 40%, 25% to 35%, 30% to 80%, 30% to 75%, 30% to 70%, 30% to 65%, 30% to 60%, 30% to 55%, 30% to 50%, 30% to 45%, 30% to 40%, 40% to 80%, 40% to 75%, 40% to 70%, 40% to 65%, 40% to 60%, 40% to 55%, 40% to 50%, 50% to 80%, 50% to 75%, 50% to 70%, 50% to 65%, 50% to 60%, 60% to 80%, 60% to 75%, 60% to 70%.

[0263] In embodiments, the methods and formulation provided herein result in a 10% to 80% reduction in extent in infiltration of leukocytes. For example, In embodiments, the methods and compositions provided herein result in a 10% to 80%, 10% to 75%, 10% to 70%, 10% to 65%, 10% to 60%, 10% to 55%, 10% to 50%, 10% to 45%, 10% to 40%, 10% to 35%, 10% to 30%, 10% to 25%, 10% to 20%, 15% to 80%, 15% to 75%, 15% to 70%, 15% to 65%, 15% to 60%, 15% to 55%, 15% to 50%, 15% to 45%, 15% to 40%, 15% to 35%, 15% to 30%, 15% to 25%, 20% to 80%, 20% to 75%, 20% to 70%, 20% to 65%, 20% to 60%, 20% to 55%, 20% to 50%, 20% to 45%, 20% to 40%, 20% to 35%, 20% to 30%, 25% to 80%, 25% to 75%, 25% to 70%, 25% to 65%, 25% to 60%, 25% to 55%, 25% to 50%, 25% to 45%, 25% to 40%, 25% to 35%, 30% to 80%, 30% to 75%, 30% to 70%, 30% to 65%, 30% to 60%, 30% to 55%, 30% to 50%, 30% to 45%, 30% to 40%, 40% to 80%, 40% to 75%, 40% to 70%, 40% to 65%, 40% to 60%, 40% to 55%, 40% to 50%, 50% to 80%, 50% to 75%, 50% to 70%, 50% to 65%, 50% to 60%, 60% to 80%, 60% to 75%, 60% to 70%.

[0264] In embodiments, the methods and formulation provided herein result in a 10% to 80% reduction in crypt damage. For example, In embodiments, the methods and compositions provided herein result in a 10% to 80%, 10% to 75%, 10% to 70%, 10% to 65%, 10% to 60%, 10% to 55%, 10% to 50%, 10% to 45%, 10% to 40%, 10% to 35%, 10% to 30%, 10% to 25%, 10% to 20%, 15% to 80%, 15% to 75%, 15% to 70%, 15% to 65%, 15% to 60%, 15% to 55%, 15% to 50%, 15% to 45%, 15% to 40%, 15% to 35%, 15% to 30%, 15% to 25%, 20% to 80%, 20% to 75%, 20% to 70%, 20% to 65%, 20% to 60%, 20% to 55%, 20% to 50%, 20% to 45%, 20% to 40%, 20% to 35%, 20% to 30%, 25% to 80%, 25% to 75%, 25% to 70%, 25% to 65%, 25% to 60%, 25% to 55%, 25% to 50%, 25% to 45%, 25% to 40%, 25% to 35%, 30% to 80%, 30% to 75%, 30% to 70%, 30% to 65%, 30% to 60%, 30% to 55%, 30% to 50%, 30% to 45%, 30% to 40%, 40% to 80%, 40% to 75%, 40% to 70%, 40% to 65%, 40% to 60%, 40% to 55%, 40% to 50%, 50% to 80%, 50% to 75%, 50% to 70%, 50% to 65%, 50% to 60%, 60% to 80%, 60% to 75%, 60% to 70%.

[0265] In embodiments, the methods and formulation provided herein result in a 10% to 80% reduction in cumulative score. For example, In embodiments, the methods and compositions provided herein result in a 10% to 80%, 10% to 75%, 10% to 70%, 10% to 65%, 10% to 60%, 10% to 55%, 10% to 50%, 10% to 45%, 10% to 40%, 10% to 35%, 10% to 30%, 10% to 25%, 10% to 20%, 15% to 80%, 15% to 75%, 15% to 70%, 15% to 65%, 15% to 60%, 15% to 55%, 15% to 50%, 15% to 45%, 15% to 40%, 15% to 35%, 15% to 30%, 15% to 25%, 20% to 80%, 20% to 75%, 20% to 70%, 20% to 65%, 20% to 60%, 20% to 55%, 20% to 50%, 20% to 45%, 20% to 40%, 20% to 35%, 20% to 30%, 25% to 80%, 25% to 75%, 25% to 70%, 25% to 65%, 25% to 60%, 25% to 55%, 25% to 50%, 25% to 45%, 25% to 40%, 25% to 35%, 30% to 80%,

30% to 75%, 30% to 70%, 30% to 65%, 30% to 60%, 30% to 55%, 30% to 50%, 30% to 45%,

30% to 40%, 40% to 80%, 40% to 75%, 40% to 70%, 40% to 65%, 40% to 60%, 40% to 55%,

40% to 50%, 50% to 80%, 50% to 75%, 50% to 70%, 50% to 65%, 50% to 60%, 60% to 80%,

60% to 75%, 60% to 70%.

[0266] In embodiments, targeted intracolonic delivery of ondansetron is more efficient than conventional non-targeted oral (IR) delivery. In embodiments pharmaceutical formulation comprising ondansetron for targeted intracolonic delivery provides about 70%, about 60%, about 50%, about 40%, about 30%, about 20% or about 10% reduced relative plasma concentration of ondansetron compared to conventional non-targeted oral(IR) delivery having an equivalent amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof.

[0267] In embodiments targeted intracolonic delivery of ondansetron showed better efficacy than conventional non-targeted oral (IR) delivery. In embodiments, the pharmaceutical formulation comprising ondansetron for targeted intracolonic delivery provides about 70%, about 60%, about 50%, about 40%, about 30%, about 20% or about 10% better efficacy of ondansetron compared to a conventional non-targeted oral IR delivery having an equivalent amount of ondansetron or a pharmaceutically acceptable salt and/ or hydrate thereof.

Specific Embodiments of The Present Disclosure

[0268] Embodiment 1. A method for treating or preventing a GI inflammatory disease in a subject in need thereof, comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides targeted release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon.

[0269] Embodiment 2. A method for treating or preventing GI inflammatory disease in a subject in need thereof, comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides targeted release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon and not in small intestine. [0270] Embodiment 3. A method for treating or preventing GI inflammatory disease in a subject in need thereof, comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation releases ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon, and wherein the method treats or prevents the GI inflammatory disease while reducing adverse effects associated with delivery of ondansetron to the stomach or small intestine.

[0271] Embodiment 4. A method for treating or reducing adverse histopathological condition in colon of a subject in need thereof, comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides targeted release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon.

[0272] Embodiment 5. A method for treating or reducing adverse histopathological condition in colon of a subject in need thereof, comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides targeted release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon and not in small intestine.

[0273] Embodiment 6. A method for treating or reducing adverse histopathological condition in colon of a subject in need thereof, comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation releases ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon, and wherein the method treats or prevents the adverse histopathological condition while reducing adverse effects associated with delivery of ondansetron to the stomach or small intestine.

[0274] Embodiment 7. The method according to any one of the embodiments 4-6, wherein the adverse histopathological condition in colon comprises at least one of crypt damage, oedema, infiltration of leukocytes, and extent of infiltration of leukocyte.

[0275] Embodiment 8. The method according to any one of the embodiments 4-7, wherein the adverse histopathological condition in colon is associated with GI inflammatory disease. [0276] Embodiment 9. A method for treating or preventing GI symptoms, comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation releases ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon.

[0277] Embodiment 10. The method according to embodiment 9, wherein the GI symptom comprising at least one of abdominal pain, diarrhea, , weight loss, and occult bleeding.

[0278] Embodiment 11. The method according to any one of embodiments 1-10, wherein the pharmaceutical formulation comprises ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof is in range of from about 2 mg to about 32 mg, about 2 mg to about 28 mg, about 2 mg to about 24 mg, about 2 mg to about 20 mg, about 2 mg to about 16 mg, about 2 mg to about 12 mg, or about 2 mg to about 8 mg.

[0279] Embodiment 12. The method according to embodiment 11 , wherein the pharmaceutical formulation comprises ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof at a unit dose of about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, or about 32 mg.

[0280] Embodiment 13. The method according to any one of embodiments 1-12, wherein the pharmaceutical formulation provides about 70%, about 60%, about 50%, about 40%, about 30%, about 20% or about 10% reduced relative plasma concentration of ondansetron compared to the conventional non-targeted oral (IR) delivery having the same amount of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof.

[0281] Embodiment 14. The method according to embodiment 13, wherein the pharmaceutical formulation provides at least 20% reduced relative plasma concentration of ondansetron compared to the conventional non-targeted oral (IR) delivery having an equivalent amount of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof.

[0282] Embodiment 15. The method according to embodiment 13, wherein the pharmaceutical formulation provides at least 30% reduced relative plasma concentration of ondansetron compared to the conventional non-targeted oral (IR) delivery having an equivalent amount of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof.

[0283] Embodiment 16. The method according to embodiment 13, wherein the pharmaceutical formulation provides at least 50% reduced relative plasma concentration of ondansetron compared to the conventional non-targeted oral (IR) delivery having an equivalent amount of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof.

[0284] Embodiment 17. The method according to any one of the embodiments 1-12, wherein the pharmaceutical formulation provides about 70%, about 60%, about 50%, about 40%, about 30%, about 20% or about 10% better efficacy of ondansetron compared to the conventional non-targeted oral (IR) delivery formulation having the same amount of said ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof.

[0285] Embodiment 18. The method according to embodiment 17, wherein the pharmaceutical formulation provides at least about 20% better efficacy of ondansetron compared to the conventional non-targeted oral (IR) delivery having the same amount of said ondansetron or a salt and/or hydrate thereof.

[0286] Embodiment 19. The method according to embodiment 17, wherein the pharmaceutical formulation provides at least about 30% better efficacy of ondansetron compared to the conventional non-targeted oral (IR) delivery having the same amount of said ondansetron or a salt and/or hydrate thereof.

[0287] Embodiment 20. The method according to embodiment 17, wherein the pharmaceutical formulation provides at least about 50% better efficacy of ondansetron compared to the conventional non-targeted oral (IR) delivery having the same amount of said ondansetron or a salt and/or hydrate thereof.

[0288] Embodiment 21. The method according to any one of the embodiments 1-20, wherein said subject is mammal, preferably human.

[0289] Embodiment 22. The method according to any one of the embodiments 1-21, wherein ondansetron is ondansetron hydrochloride.

[0290] Embodiment 23. The method according to embodiment 22, wherein ondansetron is ondansetron hydrochloride hydrate. [0291] Embodiment 24. The method according to any one of the embodiments 1-23, wherein the pharmaceutical formulation comprise an enteric coating formulated to release ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof at about pH 5.0 or above.

[0292] Embodiment 25. The method according to any one of the embodiments 1-23, wherein the pharmaceutical formulation comprise an enteric coating formulated to release ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof at about pH 6.

[0293] Embodiment 26. The method according to any one of the embodiments 1-23, wherein the pharmaceutical formulation comprise an enteric coating formulated to release ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof at about pH 6.5.

[0294] Embodiment 27. The method according to any one of the embodiments 1-23, wherein the pharmaceutical formulation comprise an enteric coating formulated to release ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof at about pH 7.0.

[0295] Embodiment 28. The method according to any one of the embodiments 1-23, wherein the pharmaceutical formulation comprise an enteric coating formulated to release ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof at about pH 5.0 to about pH 6.0.

[0296] Embodiment 29. The method according to any one of the embodiments 1-23, wherein the pharmaceutical formulation comprise an enteric coating formulated to release ondansetron or the pharmaceutically acceptable salt and/ or hydrate thereof from about pH 6.0 to about pH 7.0.

[0297] Embodiment 30. The method according to any one of the embodiments 1-23, wherein the pharmaceutical formulation comprise an enteric coating formulated to release ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof from about pH 7.0 to about pH 8.0.

[0298] Embodiment 31. The method according to any one of the embodiments 1-30, wherein the formulation comprises polysaccharide coating susceptible to attack by colonic bacteria.

[0299] Embodiment 32. The method according to any one of the embodiments 1-23, wherein the formulation is administered once daily, twice daily, once in a two day, once in three days, once a week, once in two weeks, once in three weeks or once a month. [0300] Embodiment 33. The method according to embodiment 32, wherein the formulation is administered once daily.

[0301] Embodiment 34. The method according to any one of the embodiments 1-33, wherein the formulation is administered orally.

[0302] Embodiment 35. The method according to any one of the embodiments 1-34, wherein the method comprising administering to the subject a pharmaceutical formulation orally comprising ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides target release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon, wherein the pharmaceutical formulation is a tablet, capsule, caplets, suspension, pellets, granules, gels, and optionally wherein the pellets can be suspended, compressed as tablet or filled in capsules.

[0303] Embodiment 36. The method according to embodiment 35, wherein GI inflammatory disease is treated effectively without causing significant adverse effects.

[0304] Embodiment 37. The method according to embodiment 35, wherein GI inflammatory disease is treated effectively with no CNS adverse effect.

[0305] Embodiment 38. The method according to any one of embodiment 1-37, wherein the GI inflammatory disease is selected from the group consisting of celiac disease, diverticulitis, duodenal ulcer, intestinal polyps, IBS, proctitis, protein-losing enteropathy, hemorrhoids, postoperative ileus, pouchitis, stress ulcer, ileitis, lactose intolerance, antibiotic enterocolitis, autoimmune enteropathy, dyspepsia, non-infectious gastroenteritis, eosinophilic duodenitis, peptic ulcers, appendicitis, atrophic gastritis, gastric ulcer, NSAID-induced ulcer, acute pancreatitis, gallstones, gallstone pancreatitis, alcoholic pancreatitis, eosinophilic gastritis, peritonitis, bile acid diarrhea and IBD.

[0306] Embodiment 39. The method according to any one of the embodiments 1-38, wherein GI inflammatory disease is IBD.

[0307] Embodiment 40. The method according to embodiment 39, wherein IBD is UC or CD.

[0308] Embodiment 41. The method according to any one of the embodiments 1-40, wherein the targeted release includes delayed release, sustained release, delayed release followed by sustained release, delayed release followed by immediate release, pulsatile release or combination thereof.

[0309] Embodiment 42. The method according to any one of the embodiments 1-41, wherein the pharmaceutical formulation is selected from the group consisting of a tablet, capsule, caplets, suspension, pellets, granules, gels, and optionally wherein pellets are suspended, compressed as tablet or filled in capsules.

[0310] Embodiment 43. The method according to any one of the embodiments 1-42, wherein the pharmaceutical composition comprises one or more second therapeutic agent.

[0311] Embodiment 44. The method according to any one of the embodiments 1-43, further comprise administering a second formulation comprising one or more second therapeutic agent to the subject as an adjuvant therapy.

[0312] Embodiment 45. The method according to embodiment 44, wherein the pharmaceutical formulation comprising ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof and second formulation may be administered either simultaneously or sequentially separated by a specific period of time.

[0313] Embodiment 46. The method according to embodiment 43 or 44, wherein the pharmaceutical formulation comprising ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof and second formulation may be administered by the same route of administration or a different route of administration.

[0314] Embodiment 47. The method according to embodiment 43 or 44 wherein the one or more second therapeutic agent is balsalazide, mesalamine, olsalazine, sulfasalazine, infliximab, vedolizumab, tofacitinib, ozanimod or a combination thereof.

[0315] Embodiment 48. The method according to any of the embodiment 43-46, wherein the second formulation is immediate-release, extended release or delay ed-release formulation.

[0316] Embodiment 49. A method for treating or preventing IBD in a subject, comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides targeted release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon. [0317] Embodiment 50. A method for treating or preventing CD in a subject, comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides targeted release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon.

[0318] Embodiment 51. A method for treating or preventing crypt damage in a subject, comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides targeted release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon.

[0319] Embodiment 52. The method according to claim 51, wherein the crypt damage is associated with GI inflammatory disease.

[0320] Embodiment 53. A method for treating or preventing oedema in colon in a subject, comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides targeted release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon.

[0321] Embodiment 54. The method according to claim 53, wherein the oedema is associated with GI inflammatory disease.

[0322] Embodiment 55. A method for reducing infiltration of leukocyte associated with GI inflammatory disease in a subject, comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides targeted release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon.

[0323] Embodiment 56. A method for reducing extent of infiltration of leukocyte associated with GI inflammatory disease in a subject, comprising administering to the subject a pharmaceutical formulation comprising ondansetron and/or a pharmaceutically acceptable salt and/ or hydrate thereof, wherein the pharmaceutical formulation provides targeted release of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof in the colon. [0324] Embodiment 57. A method for improving stool consistency associated with GI inflammatory disease, comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides target release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon.

[0325] Embodiment 58. A method for improving occult bleeding associated with GI inflammatory disease, comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides target release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon.

[0326] Embodiment 59. A method for treating behavioral symptom associated with GI inflammatory disease in a subject, comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides target release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon.

[0327] Embodiment 60. A method according to embodiment 59, wherein the behavioral symptom includes neuropsychological symptoms comprising at least one of anxiety, stress reactivity, visceral hypersensitivity, insomnia and depression.

[0328] Embodiment 61. The method according to any one of the preceding claims, wherein GI inflammatory disease is IBD.

[0329] Embodiment 62. The method according to any one of the embodiments 49-61, wherein the pharmaceutical formulation comprises ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof is from about 2 mg to about 32 mg, about 2 mg to about 28 mg, about 2 mg to about 24 mg, about 2 mg to about 20 mg, about 2 mg to about 16 mg, about 2 mg to about 12 mg, about 2 mg to about 8 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, and about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, or about 32 mg. [0330] Embodiment 63. The method according to any one of the embodiments 49 -62, wherein the formulation comprises enteric coating formulated to release ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof at about pH 5.0 or above.

[0331] Embodiment 64. The method according to any one of the embodiments 49-62, wherein the formulation comprises enteric coating formulated to release ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof at about pH 6.

[0332] Embodiment 65. The method according to any one of the embodiments 49-62, wherein the formulation comprises enteric coating formulated to release ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof at about pH 6.5.

[0333] Embodiment 66. The method according to any one of the embodiments 49-62, wherein the formulation comprises enteric coating formulated to release ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof at about pH 7.0.

[0334] Embodiment 67. The method according to any one of the embodiments 49-62, wherein the formulation comprises enteric coating formulated to releases ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof at about pH 5.0 to about pH 6.0.

[0335] Embodiment 68. The method according to any one of the embodiments 49-62, wherein the formulation comprises enteric coating formulated to release the ondansetron or a salt and/or hydrate thereof from about pH 6.0 to about pH 7.0.

[0336] Embodiment 69. The method according to any one of the embodiments 49-62, wherein the formulation comprises enteric coating formulated to release ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof from about pH 7.0 to about pH 8.0.

[0337] Embodiment 70. The method according to any one of the embodiments 49-69, wherein the formulation comprises polysaccharide coating susceptible to attack by colonic bacteria.

[0338] Embodiment 71. The method according to any one of the embodiments 49-70, wherein the formulation is administered once daily, twice daily, once in a two day, once in three days, once a week, once in two weeks, once in three weeks or once a month.

[0339] Embodiment 72. The method according to any one of the embodiments 49-71, wherein the method comprising administering to the subject a pharmaceutical formulation orally comprising ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation releases ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon, wherein the formulation is a tablet, capsule, caplets, suspension, pellets, granules, or gels.

[0340] Embodiment 73. The method according to embodiment 72, wherein the pellets may be suspended, compressed in tablet or filled in capsule.

[0341] Embodiment 74. A method for treating or preventing UC in a subject, comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides targeted release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon.

[0342] Embodiment 75. A method for treating or preventing UC in a subject, comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation releases ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon that treats GI inflammatory disease by reducing CNS adverse effects, e.g., dizziness and headache

[0343] Embodiment 76. The method according to embodiment 74 or 75, wherein the pharmaceutical formulation comprises ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof is from about 2 mg to about 32 mg, about 2 mg to about 28 mg, about 2 mg to about 24 mg, about 2 mg to about 20 mg, about 2 mg to about 16 mg, about 2 mg to about 12 mg, about 2 mg to about 8 mg, about 2 mg, about 3 mg about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, or about 32mg.

[0344] Embodiment 77. The method according to any one of the embodiments 74-76, wherein the pharmaceutical formulation provides about 70%, about 60%, about 50%, about 40%, about 30%, about 20% or about 10% reduced relative plasma concentration of ondansetron compared to the conventional non-targeted oral (IR) delivery having the same amount of the ondansetron. [0345] Embodiment 78 The method according to any one of embodiments 74-76, wherein the pharmaceutical formulation provides about 70%, about 60%, about 50%, about 40%, about 30%, about 20% or about 10% better efficacy of ondansetron compared to the conventional non-targeted oral (IR) delivery having the same amount of said ondansetron or a salt and/or hydrate thereof.

[0346] Embodiment 79. The method according to any one of the embodiments 74-77, wherein the formulation comprises enteric coating formulated to release ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof at about pH 5.0 or above.

[0347] Embodiment 80. The method according to any one of the embodiments 74-77, wherein the formulation comprises enteric coating formulated to release ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof at about pH 6.

[0348] Embodiment 81. The method according to any one of the embodiments 74-77, wherein the formulation comprises enteric coating formulated to release ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof at about pH 6.5.

[0349] Embodiment 82. The method according to any one of the embodiments 74-77, wherein the formulation comprises enteric coating formulated to release ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof at about pH 7.0.

[0350] Embodiment 83. The method according to any one of the embodiments 74-77 wherein the formulation comprises enteric coating formulated to releases ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof at about pH 5.0 to about pH 6.0.

[0351] Embodiment 84. The method according to any one of the embodiments 74-77, wherein the formulation comprises enteric coating formulated to release the ondansetron or a salt and/or hydrate thereof from about pH 6.0 to about pH 7.0.

[0352] Embodiment 85. The method according to any one of the embodiments 74-77, wherein the formulation comprises enteric coating formulated to release ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof from about pH 7.0 to about pH 8.0.

[0353] Embodiment 86. The method according to any one of the embodiments 74-85, wherein the formulation comprises polysaccharide coating susceptible to attack by colonic bacteria. [0354] Embodiment 87. A pharmaceutical formulation for use in treatment of adverse histopathological condition in colon in a subject, wherein the pharmaceutical formulation comprises an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides target release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon.

[0355] Embodiment 88. The pharmaceutical formulation according to embodiment 87, wherein the adverse histopathological condition comprises at least one of crypt damage, oedema, infiltration of leukocytes, extent of infiltration of leukocyte or a combination thereof.

[0356] Embodiment 89. The pharmaceutical formulation according to embodiment 87 or 88, wherein the adverse histopathological condition in colon is associated with GI inflammatory disease.

[0357] Embodiment 90. A pharmaceutical formulation for use in treatment of GI inflammatory disease in a subject in need thereof, wherein the pharmaceutical formulation comprises an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides target release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon.

[0358] Embodiment 91. The pharmaceutical formulation according to any one of the embodiments 87-90, wherein the formulation is a tablet, capsule, caplet, suspension, pellets, granules or gels.

[0359] Embodiment 92. The pharmaceutical formulation according to embodiment 91, wherein the pellets can be suspended, compressed as tablet or filled in capsule.

[0360] Embodiment 93. The pharmaceutical formulation according to embodiment 87-92, wherein ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof is administered at a dosage that treats GI disease with reduced or no adverse effects.

[0361] Embodiment 94. The pharmaceutical formulation according to any one of the embodiments 87-92, wherein ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof is administered to said subject (e.g. human) at a dosage from about 2 mg to about 32 mg, about 2 mg to about 28 mg, about 2 mg to about 24 mg, about 2 mg to about 20 mg, about 2 mg to about 16 mg, 2 mg to about 12 mg, 2 mg to about 8 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, or about 32 mg.

[0362] Embodiment 95. The pharmaceutical formulation according to embodiment 94, wherein ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof is administered to said subject (e.g., human) at a dosage in the range of from about 2 mg to about 20 mg.

[0363] Embodiment 96. The pharmaceutical formulation according to any one of the embodiments 87-95, wherein the pharmaceutical formulation provides about 70%, about 60%, about 50%, about 40%, about 30%, about 20% or about 10% reduced relative plasma concentration of ondansetron compared to the conventional non-targeted oral (IR) delivery having an equivalent amount of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof.

[0364] Embodiment 97. The pharmaceutical formulation according to embodiment 87-95, wherein the pharmaceutical formulation provides at least about 20% reduced relative plasma concentration of ondansetron compared to the conventional non-targeted oral (IR) delivery having an equivalent amount of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof.

[0365] Embodiment 98. The pharmaceutical formulation according to embodiment 97, wherein the pharmaceutical formulation provides at least 30% reduced relative plasma concentration of ondansetron compared to the conventional non-targeted oral (IR) delivery having an equivalent amount of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof.

[0366] Embodiment 99. The pharmaceutical formulation according to embodiment 97, wherein the pharmaceutical formulation provides at least 50% reduced relative plasma concentration of ondansetron compared to the conventional non-targeted oral (IR) delivery having an equivalent amount of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof. [0367] Embodiment 100. The pharmaceutical formulation according to any one of the embodiments 87-95, wherein the pharmaceutical formulation provides about 70%, about 60%, about 50%, about 40%, about 30%, about 20% or about 10% better efficacy of ondansetron in treating or preventing GI inflammatory disease compared to the conventional non-targeted oral (IR) delivery having the same amount of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof.

[0368] Embodiment 101. The pharmaceutical formulation according to embodiment 100, wherein the pharmaceutical formulation provides at least 20% better efficacy of ondansetron in treating or preventing GI inflammatory disease compared to the conventional non-targeted oral (IR) delivery having the same amount of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof.

[0369] Embodiment 102. The pharmaceutical formulation according to embodiment 100, wherein the pharmaceutical formulation provides at least 30% better efficacy of ondansetron in treating or preventing GI inflammatory disease compared to the conventional non-targeted oral (IR) delivery having the same amount of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof.

[0370] Embodiment 103. The pharmaceutical formulation according to embodiment 100, wherein the pharmaceutical formulation provides at least 50% better efficacy of ondansetron in treating or preventing GI inflammatory disease compared to the conventional non-targeted oral (IR) delivery having the same amount of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof.

[0371] Embodiment 104. The pharmaceutical formulation according to embodiment 87-95, wherein the pharmaceutical formulation comprises an enteric coating formulated to release ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof at about pH 5.0 or above.

[0372] Embodiment 105. The pharmaceutical formulation according to embodiment 87-95, wherein the pharmaceutical formulation comprises an enteric coating formulated to release ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof at about pH 6. [0373] Embodiment 106. The pharmaceutical formulation according to embodiment 87-95, wherein the pharmaceutical formulation comprises an enteric coating formulated to release ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof at about pH 6.5.

[0374] Embodiment 107. The pharmaceutical formulation according to embodiment 87-95, wherein the pharmaceutical formulation comprises an enteric coating formulated to release ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof at about pH 7.0.

[0375] Embodiment 108. The pharmaceutical formulation according to embodiment 87-95, wherein the pharmaceutical formulation comprises a polysaccharide coating susceptible to attack by colonic bacteria.

[0376] Embodiment 109. An individual unit dosage form provided as a kit, comprising the pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof of any of the preceding embodiments in a container with or without instructions for administration to a subject in need thereof.

[0377] Embodiment 110. The kit according to embodiment 109, comprises a package insert comprising instructions for using the stable formulation comprising ondansetron or pharmaceutically acceptable salt and/or hydrate thereof described herein for treatment of GI inflammatory disease in a subject.

[0378] Embodiment 111. A formulation for targeted release in the colon, comprising ondansetron and a two-component coating, wherein the first component is a pH trigger and wherein the second component is a microbiota trigger.

[0379] Embodiment 112. The formulation according to embodiment 114, wherein the pH trigger is triggered at a pH between 6.8 and 7.2.

[0380] Embodiment 113. The formulation according to embodiment 114 wherein the microbiota trigger comprises modified starch.

[0381] Embodiment 114. The formulation, method or kit of any one of the preceding embodiments, wherein the subject is human.

[0382] Embodiment 115. The formulation, method or kit of any one of the preceding embodiments, wherein the ondansetron is ondansetron hydrochloride. EXAMPLES

Example 1: Exemplary oral formulation of ondansetron for colon targeted delivery

TABLE 1: Components of Oral Formulation for Colonic Delivery

[0383] A single oral solid dosage form (e.g. tablet, pill, capsule and the like) based on osmotic drug delivery system includes the listed components in Table 1 for delivering Ondansetron HC1 to colon. Preparation of Base Tablet

[0384] Ondansetron HC1 is milled and mixed with the screened polyethylene oxide, sodium chloride, hypromellose, methacrylic acid and ethyl acrylate copolymer. Further, molten stearic acid and povidone are added and blended, to produce tablet bulk blend which is compressed into tablet.

Coating of Base Tablet

[0385] Base tablets are coated with coating dispersion containing cellulose acetate, ethylene glycol, vinyl alcohol copolymer, poloxamer, isopropyl alcohol and water. The coating dispersion is sprayed on base tablet until the desired coating level is achieved.

Example 2: Evaluation of efficacy of Ondansetron in LPS+ATP-induced model of NLRP3 Inflammasome activation

Aim:

[0386] To evaluate the efficacy of ondansetron in treating GI inflammatory disease.

Materials and Methods:

Animals:

[0387] 7-10 weeks old female 129sl/SvlmJ mice were used for the study. Animals were numbered and kept in acclimatization for a period of 5-7 days before the initiation of experiments. All experiments were conducted in accordance with the guidelines of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), Government of India Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). Animals were housed group wise (5-6 animals per cage) in controlled environmental conditions at a temperature of 22 ± 30°C, 50 ±20 % humidity, in 12-hour light -dark cycle and 15-20 fresh air changes per hour. Animals were maintained on normal rodent chow ad libitum and given free access to fresh autoclaved potable drinking water.

Generation of NLRP3 inflammasome activation model:

[0388] 7-10 weeks old female 129sl/SvlmJ mice were challenged by intraperitoneal (i.p.) injection of 200 pg/Kg (0.2 pg/g) LPS at t = 0 hr., followed by i.p. injection of 5 mM solution of ATP at t = 2 hr. (2 h after LPS challenge). Blood was collected at t = 2.5 hr. (30 minutes after ATP administration). IL-1J3, IL- 18, TNFa, and IL-6 levels were quantified in plasma by using ELISA method.

Test compound:

[0389] Ondansetron HC1 i.p.

Animal groups:

[0390] Mice were randomly divided into 5 groups as given in Table 2

TABLE 2: Animal Dosing Groups.

Dose & Dosing schedule:

[0391] 2mg/kg once a day for ondansetron

[0392] 20mg/kg once a day for MCC950, a specific small molecule inhibitor of NLRP3

Route of dosing:

[0393] Both ondansetron and MCC950 were administered by i.p. injection.

Experimental Plan:

[0394] 7-10 weeks old female 129sl/SvlmJ mice were administered with ondansetron HC1 or vehicle intraperitoneally at t = -Ihr and then challenged by i.p. injection of 200 pg/Kg (0.2 pg/g) LPS at t = 0 hr, followed by i.p. injection of 5 mM solution of ATP at t = 2 hr (2 h after LPS challenge). Blood was collected at t = 2.5hr LPS+ATP induced NLRP3 activation model (30 minutes after ATP administration) and IL-ip, IL-18, TNFa, and IL-6 levels were quantified.

Statistical analysis:

[0395] Statistical analysis was performed using validated statistical software (GraphPad Prism 5. Data is represented as individual data, line at Mean with standard error of the mean (SEM). Number of animals in each group is represented as n. Statistical comparisons among different groups were assessed using a one-way ANOVA followed by a Dunnett’s post hoc test at 95% confidence interval (p<0.05 was considered to be statistically significant). Two sided Grubbs’s test was used to identify an outlier by using GraphPad Prism 5.

Results:

[0396] Compared to pathological control, the use of ondansetron significantly reduced the generation of pro-inflammatory cytokine IL-1 P, IL-18, TNFa, and IL-6 in the treatment regime as shown in figure 1A-1D respectively. The Table 3 below shows that the plasma IL-ip, IL- 18, TNFa, and IL-6 levels were reduced by 66%, 64%, 66% and 47%, (p<0.05) respectively, following single intraperitoneal administration of ondansetron at 2 mg/kg.

TABLE 3: % inhibition of plasma IL-ip, IL-18, TNFa, and IL-6 levels

Conclusion: [0397] The ondansetron significantly reduced the generation of pro-inflammatory cytokines post inflammasome activation.

Example 3. Pharmacological Study of the intracolonic administration of ondansetron in TNBS-induced colitis model for UC

Aim:

[0398] To evaluate the ability of ondansetron for the treatment of UC.

Materials and Methods:

Animals:

[0399] 6-10 weeks old Balb/c male mice were housed and kept in acclimatization for a period of 5-7 days before the initiation of experiments. All experiments were conducted in accordance with the guidelines of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), Government of India Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). Animals were housed group wise (5-6 animals per cage) in controlled environmental conditions at a temperature of 22 ± 30°C; 50 ±20 % humidity, in 12-hour light-dark cycle and 15-20 fresh air changes per hour. Animals were maintained on normal rodent chow ad libitum and given free access to fresh autoclaved potable drinking water.

Test Compound and Reagents:

[0400] Intracolonic formulation of ondansetron: In-situ gel of ondansetron hydrochloride. In situ gel was prepared with the components as given in Table 4 for intracolonic administration.

TABLE 4. Composition of in situ gel for intracolonic administration

Positive control drug:

[0401] Infliximab injection intraperitoneally (i.p).

Reagents:

[0402] 2,4,6-trinitrobenzenesulfonic acid (TNBS)

Method:

Randomization and treatment:

[0403] Animals were randomized into different groups as indicated, such that there was less than 10% intergroup variation for body weight. Cages were identified by cage cards indicating the study design code, group number, sex, dose, cage number, number of animals and animal number details.

[0404] Group 1 and 2 animals were dosed with vehicle. Group 1 : Sham control animals were neither treated with TNBS to induce colitis nor given ondansetron, Group 2: Pathological control animals were induced with colitis after TNBS treatment, but ondansetron was not given. Group 3 animals were treated with reference standard infliximab at the dose of 5 mg/kg, ip. Groups 4 and 5 animals were treated with 1 and 2 mg/kg ondansetron (intracolonic daily via intrarectal route, starting from 7 days prior to induction of colitis till day 2 after TNBS treatment), respectively as given in Table 5:

TABLE 5. Dosing Groups

Induction of colitis:

[0405] At day -7, the animals were sensitized with 150 JJ.1 of 1 % TNBS mixed with acetone: olive oil (4:1). Colitis was induced by administering 1.5% TNBS intrarectally in 50% ethanol through PE tubing 4 cm prior to anus. Body weight and clinical observations such as diarrhea and bleeding from rectum were recorded daily post colitis induction.

Evaluation Indices:

[0406] 1. Body weight

2. Stool consistency

3. Occult blood in faeces

4. Disease activity index (DAI)

5. Adverse histopathological condition

Clinical scoring:

[0407] The animals were observed for body weight loss, stool consistency as well as occult blood in feces. A score from 0 to 4 was assigned to assess the extent of inflammation in the animal. All animals were treated individually, and samples were collected, stored and analyzed individually unless otherwise stated. The table depicting the score as well as the criteria for scoring is given below:

[0408] Assessment of inflammation by clinical and macroscopic score

DAI = (Body weight score + Stool consistency score + Occult blood score)/3

[0409] Standard of score is given in Table 6.

TABLE 6. Standard of score

Study Termination (Animal sacrifice and tissue collection):

[0410] Colon was collected, and weight & length were measured from each mouse individually. The colon was cut longitudinally and was swiss-rolled and preserved in 10% neutral buffered formalin for histopathology.

Histopathology:

[0411] Colon (Swiss roll) was used for histopathological processing. Paraffin embedded sections were stained with H&E and assessed for qualitative assessment (HP severity index) as per the scoring criteria below as given in Table 7.

TABLE 7. Qualitative assessment (HP severity index) scoring criteria

Statistical Analysis:

[0412] Data were expressed as mean ± standard deviation (mean ± S.E.M.), data are analyzed using one-way ANOVA followed by Dunnett’s multiple comparison test were used for comparison between groups. P<0.05 was considered statistically significant.

Results:

[0413] Effect of the ondansetron intracolonic formulation on body weight, stool consistency, occult blood in feces, DAI and crypt damage of TNBS -induced UC mice was analyzed. [0414] As demonstrated in the Table 8 below, mice treated by ondansetron (intracolonic) exhibit a major improvement in the inflammatory condition of colon as represented by % Inhibition in AUC.

TABLE 8: % inhibition in AUC (0-2days)

[0415] As infliximab represents one of the standards of care for inflammatory GI disease, the efficacy to ondansetron intracolonic was compared with infliximab. Compared to pathological controls (pc) both intracolonic delivery of ondansetron and intraperitoneal delivery of infliximab reduced the body weight score, Stool Consistency Score [pc=3.5 ± 0.5, infliximab=1.8 ± 0.8, p=0.07, ondansetron (2 mg/kg)=1.4 ± 0.7, p=0.03], Occult Blood Score (OBS) [pc=2.6 ± 0.2, infliximab=1.3 ± 0.5, p=0.01, ondansetron (2 mg/kg)=1.3 ± 0.6, p=0.04], Disease Activity Index (DAI) [pc=2.8 ± 0.4, infliximab=1.9 ± 0.5, p=0.20, ondansetron (2 mg/kg)=l.l ± 0.5, p=0.02], and crypt damage (pc=3.8 ± 0.7, infliximab=2.1 ± 0.6, p=0.09, ondansetron (2 mg/kg)=1.3 ± 0.7, p=0.03) as shown in figures 2 A to 2E. Interestingly, intracolonic delivery of ondansetron was more effective than infliximab at reducing the DAI, and preventing crypt damage in vivo.

[0416] The histopathological observation of distal colon from sham control group animal stained with hematoxylin and eosin under different magnifications revealed normal architecture. The histopathological observation of distal colon from pathological control group animal stained with hematoxylin and eosin under different magnifications reveal marked loss of cryptic architecture with mixed infiltration and submucosal oedema. The histopathological observation of distal colon from Infliximab (5mg/kg) i.p. and ondansetron (2 mg/kg) group animal stained with hematoxylin and eosin under different magnifications reveal reduced loss of cryptic architecture, mixed infiltration and submucosal oedema as shown in figures 2F to 2J.

Example 4. Pharmacological Study of the intracolonic and oral administration of ondansetron in TNBS-induced colitis model for UC

Aim:

[0417] The TNBS-induced mice model of colitis was used to perform a preliminary evaluation of intracolonic and oral administration of ondansetron for treating UC.

Materials:

Animals:

[0418] Balb/c male mice of 6-10 weeks old were numbered and kept in acclimatization for a period of 5-7days before the initiation of experiments. All experiments were conducted in accordance with the guidelines of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), Government of India Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). Animals were housed group wise (5-6 animals per cage) in controlled environmental conditions at a temperature of 22 ± 30°C; 50 ±20 % humidity, in 12-hour light-dark cycle and 15-20 fresh air changes per hour. Animals were maintained on normal rodent chow ad libitum and given free access to fresh autoclaved potable drinking water.

Test compound and Reagents: [0419] Tested medicine: ondansetron intracolonic in situ gel and ondansetron oral

Ondansetron Intracolonic:

[0420] In-situ gel preparation: In situ gel was prepared as given in example 2, Table 4.

Ondansetron Oral:

[0421] Ondansetron HC1 resuspended in saline was administered orally.

[0422] Positive control drug: Infliximab injection intravenously (i.v).

[0423] Reagents: 2,4,6-trinitrobenzenesulfonic acid (TNBS)

Method:

Randomization and treatment:

[0424] Animals were randomized into different groups as indicated, such that there was less than 10% intergroup variation for body weight. Cages were identified by cage cards indicating the study design code, group number, sex, dose, cage number, number of animals and animal number details.

Administration of drugs:

[0425] The drug was either administered intracolonically, daily, starting from 2 days prior to induction of colitis till day 2 after TNBS treatment at the dosing regimen discussed in Table 9. Group 1 and 2 animals were treated intracolonically with vehicle. Group 1 : Sham control animals were neither treated with TNBS to induce colitis nor given ondansetron. Group 2: Pathological control animals were induced with colitis after TNBS treatment, but ondansetron was not given. Groups 3 animals were treated with reference standard Infliximab at the dose of 5mg/kg, intravenously. Groups 4 and 5 animals were treated with ondansetron intracolonically. Group 6 was treated with ondansetron orally at a concentration of 2 mg/kg as per the details in the Table 9 below:

TABLE 9. Dosing Group

Induction of colitis:

[0426] At day -7, the animals were sensitized with 150 JJ.1 of 1 % TNBS mixed with acetone: olive oil (4:1). Colitis was induced by administering 1.5% TNBS intrarectally in 50% ethanol through PE tubing 4 cm prior to anus. Body weight and clinical observations such as diarrhea and bleeding from rectum were recorded daily post colitis induction.

Evaluation Indices:

[0427] 1. Body weight

2. Stool consistency

3. Occult blood in faeces

4. Adverse histopathological conditions

• infiltration of leukocytes,

• extent of infiltration of leukocytes,

• oedema and

• crypt damage

5. Drug concentration in plasma

Clinical scoring:

[0428] The animals were observed for body weight loss, stool consistency as well as occult blood in feces. A score from 0 to 4 was assigned to assess the extent of inflammation in the animal. All animals were treated individually, and samples collected, stored and analyzed individually unless otherwise stated. The table depicting the score as well as the criteria for scoring is given below: Assessment of inflammation by clinical and macroscopic score:

[0429] DAI = (Body weight score + Stool consistency score + Occult blood score)/3

[0430] Standard of score is given in Table 10 as follows:

TABLE 10. Standard of score

Study Termination (Animal sacrifice and tissue collection):

[0431] On day 2, post 2 hours of test compound administration, all animals were subjected to mild isoflurane anesthesia and blood was collected by retro-orbital bleeding in K2-EDTA tubes to determine drug concentration in plasma.

[0432] Colon was collected. Weight & length were measured from each mouse individually. The colon was cut longitudinally and was swiss-rolled and preserved in 10% neutral buffered formalin for observing histopathological conditions.

Adverse Histopathological Condition:

[0433] Colon (Swiss roll) was used for histopathological processing. Paraffin embedded sections were stained with H&E and assessed for qualitative assessment (HP severity index) of Infiltration of leukocytes, extent of infiltration of leukocyte, oedema, and crypt damage as per the scoring criteria given in Table 11 below:

TABLE 11 : Scoring Criteria

Drug Concentration in plasma:

[0434] Plasma samples were analyzed by discovery grade bio analytical method developed for estimation of test compound in plasma using LC-MS/MS systems.

Statistical Analysis:

[0435] Data were expressed as mean ± standard deviation (mean ± S.E.M.), data are analyzed using one-way ANOVA followed by Dunnett’s multiple comparison test were used for comparison between groups. P<0.05 was considered statistically significant.

Results:

[0436] Effect of the ondansetron Intracolonic formulation on Body Weight, stool consistency, occult blood in feces and DAI of TNBS -induced UC mice was analyzed.

[0437] As demonstrated in the Table 12 below, mice treated by ondansetron (intracolonic) exhibit a major improvement in the inflammatory condition of colon as represented by % Inhibition in AUC.

TABLE 12. % Inhibition in AUC

[0438] Compared to pathological controls (pc), both intracolonic delivery of ondansetron and intraperitoneal delivery of infliximab significantly reduced the body weight score (pc=4.9 ± 0.5, infliximab=3.2 ± 0.6, p=0.0498, ondansetron (Oral 2mg/kg)=3.6 ± 0.3, p=0.0466, ondansetron (intracolonic 2mg/kg)=2.3 ± 0.7, p=0.0062), Stool Consistency Score (pc=3.9 ± 0.5, infliximab=1.2 ± 0.4, p=0.0004, ondansetron (oral 2 mg/kg)=1.5 ± 0.4, p=0.0016, ondansetron (intracolonic 2 mg/kg)=l.l ± 0.5, p=0.0008) Occult Blood Score (OBS) (pc=3.3 ± 0.2, infliximab=1.0 ± 0.4, p=0.0001, ondansetron (Oral 2mg/kg)=1.7 ± 0.4, p=0.0034, ondansetron (intracolonic 2mg/kg)=l.l ± 0.4, p=0.0002), Disease Activity Index (DAI) (pc=4 ± 0.3, infliximab=1.8 ± 0.4, p=0.0002, ondansetron (Oral 2mg/kg)=2.3 ± 0.2, p=0.0004, ondansetron (Intracolonic 2mg/kg)=1.6 ± 0.4, p=0.0002), as shown in figure 3A to 3D.

[0439] Compared to pathological controls (pc), the use of intravenous Infliximab and 2 mg/kg Ondansetron (both with intracolonic and oral route) significantly alleviated pathological symptoms of TNBS-induced colitis such as body weight score, stool consistency score, occult blood score and DAI score with comparable efficiency to infliximab. Also, intracolonic treatment of ondansetron was more efficient than oral treatment.

[0440] Effect of the ondansetron Intracolonic formulation on adverse histopathological condition of colon in TNBS-induced UC mice was analyzed.

TABLE 13: % inhibition in AUC (0-2)

[0441] Compared to pathological controls (pc), both intracolonic delivery of ondansetron and intraperitoneal delivery of infliximab reduced the Infiltration score (pc=2.8 ± 0.4, infliximab=1.6 ± 0.4, p=0.0320, ondansetron (Oral 2mg/kg)=2.9 ± 0.3, p=0.8437, ondansetron (Intracolonic 2mg/kg)=1.4 ± 0.4, p=0.0285), extent of infiltration score (pc=6.2 ± 0.8, infliximab=3.4 ± 0.9, p=0.0352, ondansetron (Oral 2mg/kg)=5.4 ± 0.8, p=0.4825, ondansetron (Intracolonic 2mg/kg)=2.8 ± 0.9, p=0.0126), crypt damage score (pc=5.8 ± 1.1, infliximab=1.5 ± 0.6, p=0.0032, ondansetron (Oral 2mg/kg)=4.4 ± 1.3, p=0.4156, ondansetron (Intracolonic 2mg/kg)=2.8 ± 1.3, p=0.0884), oedema score (pc=1.5 ± 0.3, infliximab=0.9 ± 0.4, p=0.2546, ondansetron (Oral 2mg/kg)=1.4 ± 0.3, p=0.8201, ondansetron (Intracolonic 2mg/kg)=0.7 ± 0.3, p=0.0831), and cumulative histopathological score (pc=16.3 ± 2.2, infliximab=7.5 ± 2.2, p=0.0102, ondansetron (Oral 2 mg/kg)=14.1 ± 2.3, p=0.4990, ondansetron (Intracolonic 2mg/kg)=7.7 ± 2.9, p=0.0284), as shown in figures 3E to 31.

[0442] Compared to pathological controls (pc), intracolonic delivery, oral administration of ondansetron and intraperitoneal delivery of infliximab reduced the infiltration of leukocytes, extent of infiltration of leukocytes, oedema, crypt damage and cumulative score. Interestingly, intracolonic delivery of ondansetron showed comparative efficacy as infliximab. Also, intracolonic treatment with ondansetron was more efficient than oral treatment as given in

Table 13

[0443] Further, the histopathological observation of distal colon from sham control group animal stained with hematoxylin and eosin under different magnifications revealed normal architecture as shown in figure 3 J.

[0444] The histopathological observation of distal colon from pathological control group animal stained with hematoxylin and eosin revealed marked loss of cryptic architecture with mixed infiltration and submucosal oedema as shown in figure 3K

[0445] The histopathological observation of distal colon from Infliximab (5mg/kg) i.p. and Ondansetron (oral and intracolonic) group animal stained with hematoxylin and eosin under different magnifications reveal reduced loss of cryptic architecture, mixed infiltration and submucosal oedema as shown in figure 3L to 30.

[0446] The histopathological observation of distal colon from ondansetron (2mg/Kg intracolonic) group animal stained with hematoxylin and eosin under different magnifications reveal reduced loss of cryptic architecture, mixed infiltration and submucosal oedema compared to ondansetron (2mg/Kg oral) group.

Drug Concentration in plasma:

[0447] Drug concentration in plasma on day 2, after 2 hours of drug administration was given in the Table 14 below:

TABLE 14: Plasma Drug concentration of Ondansetron.

[0448] Intracolonic administration of Ondansetron (2 mg/kg) showed higher efficiency than oral administration and lower plasma concentration of ondansetron which corelates to systemic absorption and is associated with lesser adverse effects as shown in figure 3P.

Conclusion:

[0449] In this study, the TNBS-induced mice model of colitis was used to evaluate the treating effect of ondansetron intracolonic formulation. As shown in the results, the use of Infliximab and 2 mg/kg ondansetron (both with intracolonic and oral route) significantly alleviated pathological symptoms of TNBS-induced colitis such as body weight loss, diarrhea, rectal bleeding.

[0450] The use of Infliximab and 2 mg/kg Ondansetron (both with intracolonic and oral route) significantly alleviated symptoms of TNBS-induced colitis such as body weight score, stool consistency score, occult blood score.

[0451] The use of Infliximab and 2 mg/kg ondansetron (both with intracolonic and oral route) significantly alleviated symptoms of TNBS-induced colitis such as DAI score with comparable efficiency to Infliximab.

[0452] Also, intracolonic treatment of Ondansetron is more efficient than oral treatment. Intracolonic administration of Ondansetron (2 mg/kg) displayed significant reduction in infiltration of leukocytes, extent of infiltration of leukocyte, oedema and crypt damage score, comparable to infliximab and higher than oral treatment.

[0453] Intracolonic administration of ondansetron (2 mg/kg) showed lower plasma concentration of ondansetron and higher efficiency than oral administration as shown in figure 3P which corelates to lesser systemic absorption and is associated with lesser adverse effects. Therefore, colon specific delivery of ondansetron is a potential therapy for ulcerative colitis. [0454] Considering aforesaid indices, the ondansetron colonic release formulation had a significantly improving effect on the colitis in mice, having a certain therapeutical effect on UC.

[0455] While the disclosure has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the disclosure. For example, effective dosages other than the particular dosages as set forth herein above may be applicable as a consequence of variations in responsiveness of the subject. The specific pharmacological responses observed may vary according to and depending upon the active compounds selected along with the present pharmaceutical carriers. Further, there responses may vary depending upon the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present disclosure. It is intended, therefore, that the disclosure be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.

INCORPORATION BY REFERENCE

[0456] All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated by reference in their entireties for all purposes. However, mention of any reference, article, publication, patent, patent publication, and patent application cited herein is not, and should not be taken as, an acknowledgment or any form of suggestion that they constitute valid prior art or form part of the common general knowledge in any country in the world.

Claims

CLAIMS What is claimed is:

1. A method for treating or preventing gastrointestinal (GI) inflammatory disease in a subject in need thereof, comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides targeted release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon.

2. A method for treating or reducing adverse histopathological condition in colon of a subject in need thereof, comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides targeted release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon.

3. The method according to claim 2, wherein the adverse histopathological condition comprises at least one of crypt damage, oedema, infiltration of leukocytes, and extent of infiltration of leukocyte.

4. The method according to claim 2, wherein the adverse histopathological condition in colon is associated with GI inflammatory disease.

5. The method according to claim 1 or 4, wherein the GI inflammatory disease is selected from the group consisting of celiac disease, diverticulitis, duodenal ulcer, intestinal polyps, irritable bowel syndrome, proctitis, protein-losing enteropathy, hemorrhoids, postoperative ileus, pouchitis, stress ulcer, ileitis, lactose intolerance, antibiotic enterocolitis, autoimmune enteropathy, dyspepsia, non-infectious gastroenteritis, eosinophilic duodenitis, peptic ulcers, appendicitis, atrophic gastritis, gastric ulcer, NSAID-induced ulcer, acute pancreatitis, gallstones, gallstone pancreatitis, alcoholic pancreatitis, eosinophilic gastritis, peritonitis, bile acid diarrhea and IBD.

6. The method according to claim 1 or 4, wherein the GI inflammatory disease is IBD.

7. The method according to claim 6, wherein the IBD is ulcerative colitis (UC) or Crohn’s disease (CD).

8. The method according to claim 1 or 4, wherein the GI inflammatory disease is UC.

88

9. The method according to claim 1 or 2, wherein the targeted release comprises delayed release, sustained release, delayed release followed by sustained release, delayed release followed by immediate release, pulsatile release, or a combination thereof.

10. The method according to claim 1 or 2, wherein the pharmaceutical formulation provides at least about 20% reduced relative plasma concentration of ondansetron compared to the conventional non-targeted oral (IR) delivery having an equivalent amount of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof.

11. The method according to claim 1 or 2, wherein the pharmaceutical formulation provides at least about 30% reduced relative plasma concentration of ondansetron compared to the conventional non-targeted oral (IR) delivery having an equivalent amount of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof.

12. The method according to claim 1 or 2, wherein the pharmaceutical formulation provides at least about 50% reduced relative plasma concentration of ondansetron compared to the conventional non-targeted oral (IR) delivery having an equivalent amount of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof.

13. The method according to claim 1 or 2, wherein the pharmaceutical formulation provides at least about 20% better efficacy of ondansetron in treating or preventing GI inflammatory disease compared to the conventional non-targeted oral (IR) delivery having the same amount of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof.

14. The method according to claim 1 or 2, wherein the pharmaceutical formulation provides at least about 30% better efficacy of ondansetron in treating or preventing GI inflammatory disease compared to the conventional non-targeted oral (IR) delivery having the same amount of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof.

15. The method according to claim 1 or 2, wherein the pharmaceutical formulation provides at least about 50% better efficacy of ondansetron in treating or preventing GI inflammatory disease compared to the conventional non-targeted oral (IR) delivery having the same amount of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof.

89

16. The method according to claim 1 or 2, wherein the pharmaceutical formulation comprises an enteric coating formulated to release ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof at about pH 5.0 or above.

17. The method according to claim 1 or 2, wherein the pharmaceutical formulation comprises an enteric coating formulated to release ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof at about pH 6.0.

18. The method according to claim 1 or 2, wherein the pharmaceutical formulation comprises an enteric coating formulated to release ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof at about pH 6.5.

19. The method according to claim 1 or 2, wherein the pharmaceutical formulation comprises an enteric coating formulated to release ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof at about pH 7.0.

20. The method according to claim 1 or 2, wherein the pharmaceutical formulation comprises a polysaccharide coating susceptible to attack by colonic bacteria.

21. The method according to claim 1 or 2, wherein the daily dose of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof is from about 2 mg to about 32 mg.

22. The method according to claim 1 or 2, wherein the daily dose of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof is from about 2 mg to about 20 mg.

23. The method according to claim 1 or 2, wherein the pharmaceutical formulation is administered once daily, twice daily, once in two days, once in three days, once a week, once in two weeks, once in three weeks or once a month.

24. The method according to claim 1 or 2, wherein the pharmaceutical formulation is a tablet, capsule, caplets, suspension, pellets, granules, or gel.

25. The method according to claim 1 or 2, wherein the pharmaceutical formulation further comprises one or more second therapeutic agent.

26. A method for treating or preventing UC in a subject in need thereof, comprising administering to the subject a pharmaceutical formulation comprising ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical

90 formulation provides a targeted release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon.

27. The method according to claim 26, wherein the daily dose of ondansetron or pharmaceutically acceptable salt and/or hydrate thereof is from about 2 mg to about 32 mg.

28. The method according to claim 27, wherein the daily dose of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof is about 2 to about 20 mg.

29 The method according to claim 26, wherein the pharmaceutical formulation is a tablet, capsule, caplets, suspension, pellets, granules, or gel.

30. A pharmaceutical formulation for use in treating or preventing GI inflammatory disease in a subject in need thereof, wherein the pharmaceutical formulation comprises an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides target release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon.

31. A pharmaceutical formulation for use in treating or reducing adverse histopathological condition in colon of a subject in need thereof, wherein the pharmaceutical formulation comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides target release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon.

32. The pharmaceutical formulation for use according to claim 31, wherein the adverse histopathological condition comprises at least one of crypt damage, oedema, infiltration of leukocytes, and reducing extent of infiltration of leukocyte.

33. The pharmaceutical formulation for use according to claim 31 or 32, wherein the adverse histopathological condition in colon is associated with GI inflammatory disease.

34. The pharmaceutical formulation for use according to claim 30 or 33, wherein the GI inflammatory disease is selected from the group consisting of celiac disease, diverticulitis, duodenal ulcer, intestinal polyps, irritable bowel syndrome, proctitis, protein-losing enteropathy, hemorrhoids, postoperative ileus, pouchitis, stress ulcer, ileitis, lactose intolerance, antibiotic enterocolitis, autoimmune enteropathy, dyspepsia, non-infectious gastroenteritis, eosinophilic duodenitis, peptic ulcers, appendicitis, atrophic gastritis, gastric

91 ulcer, NSAID-induced ulcer, acute pancreatitis, gallstones, gallstone pancreatitis, alcoholic pancreatitis, eosinophilic gastritis, peritonitis, bile acid diarrhea and IBD.

35. The pharmaceutical formulation for use according to any one of claims 30 to 34, wherein the formulation is a tablet, capsule, caplet, suspension, pellets, granules or gels.

36. The pharmaceutical formulation for use according to embodiment 35, wherein the pellets can be suspended, compressed as tablet or filled in capsule.

37. The pharmaceutical formulation for use according to any one of claims 30 to 36, wherein ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof is administered at a dosage that treats GI inflammatory disease with reduced or no adverse effects.

38. The pharmaceutical formulation for use according to claim 30 or 31, wherein ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof is administered to said subject (e.g., human) at a dosage in the range of from about 2 mg to about 32 mg.

39. The pharmaceutical formulation for use according to claim 38, wherein ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof is administered to said subject (e.g., human) at a dosage in the range of from about 2 mg to about 20 mg.

40. The pharmaceutical formulation for use according to claim 30 or 31, wherein the pharmaceutical formulation provides about 70%, about 60%, about 50%, about 40%, about 30%, about 20% or about 10% reduced relative plasma concentration of ondansetron compared to the conventional non-targeted oral (IR) delivery having an equivalent amount of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof.

41. The pharmaceutical formulation for use according to claim 30 or 31, wherein the pharmaceutical formulation provides about 70%, about 60%, about 50%, about 40%, about 30%, about 20% or about 10% better efficacy of ondansetron compared to the conventional non-targeted oral (IR) delivery having an equivalent amount of ondansetron or the pharmaceutically acceptable salt and/ or hydrate thereof.

42. A pharmaceutical formulation for use in treating or preventing UC in a subject in need thereof, wherein the pharmaceutical formulation comprises an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the

92 pharmaceutical formulation provides target release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon.

43. A pharmaceutical formulation for use in treating or reducing adverse histopathological condition in colon of a subject associated with UC, wherein the pharmaceutical formulation comprising an effective amount of ondansetron or a pharmaceutically acceptable salt and/or hydrate thereof, wherein the pharmaceutical formulation provides target release of ondansetron or the pharmaceutically acceptable salt and/or hydrate thereof in the colon.

44. The pharmaceutical formulation for use according to claim 43, wherein the histopathological condition comprising at least one of crypt damage, oedema, infiltration of leukocytes, and reducing extent of infiltration of leukocyte.

45. A formulation for targeted release in the colon comprising ondansetron and a two- component coating, wherein the first component is a pH trigger, and wherein the second component is a microbiota trigger.

46. The formulation according to claim 45, wherein the pH trigger is triggered at a pH between 6.8 and 7.2.

47. The formulation according to claim 45, wherein the microbiota trigger comprises modified starch.

93