WO2025049710A1

WO2025049710A1 - Pharmaceutical composition for use in the disease treatments

Info

Publication number: WO2025049710A1
Application number: PCT/US2024/044377
Authority: WO
Inventors: Ning SHAN
Original assignee: Aclipse Two Inc
Current assignee: Aclipse Two Inc
Priority date: 2023-08-29
Filing date: 2024-08-29
Publication date: 2025-03-06
Anticipated expiration: 2026-02-28

Abstract

This invention relates to pharmaceutical compositions comprising 5-(4-(2-((6-(4-methoxyphenoxy)pyrimidin-4-yl)(methyl)amino)ethoxy)benzyl)thiazolidine-2,4-dione and its salt and cocrystal forms thereof useful for the treatment of diseases, processes for preparing such formulations, and pharmacokinetic parameters controlled by the same.

Description

Pharmaceutical Composition for Use in the Disease Treatments

RELATED APPLICATIONS

[0001] This application claims the priority of U.S. Provisional Patent Application No. 63/535,192, filed August 29, 2023, the entire content of which is incorporated herein by reference.

FIELD

[0002] Disclosed herein are orally disintegrating formulations of 5-(4-(2-((6-(4- methoxyphenoxy)pyrimidin-4-yl)(methyl)amino)ethoxy)benzyl)thiazolidine-2, 4-dione and salt and cocrystal forms thereof useful for the treatment of diseases, processes for preparing such formulations, and pharmacokinetic parameters controlled by the same.

SUMMARY

[0003] Disclosed herein are orally disintegrating formulations of thiazolidinediones and methods of treating digestive or gastrointestinal diseases with the orally disintegrating tablet formulations. The thiazolidinedione is selected from one or more of pioglitazone, rosiglitazone, lobeglitazone, ciglitazone, darglitazone, englitazone, netoglitazone, rivoglitazone, troglitazone, and balaglitazone. In some embodiments, the thiazolidinedione is lobeglitazone.

[0004] In some embodiments, the digestive or gastrointestinal disease affects a digestive organ or tissue selected from mouth, pharynx (throat), esophagus, stomach, small intestine, large intestine, rectum, anus, salivary glands, liver, gallbladder, and pancreas.

[0005] In some embodiments, method comprises treating a gastrointestinal system cell selected from an absorptive cell (enterocyte), a goblet cell, a pancreatic islet cell, an enteroendocrine cell, a hepatocyte, a paneth cell, a fenestrated hepatic endothelial cell, a kupffer cell, a serous cell, a gastric chief cell, a mucous cell, a smooth muscle cell, a gastric parietal cell, a myoepithelial cell, a stem cell, a gastric surface mucous cell, a pancreatic acinar cell, a taste bud, a type of interstitial cells of Cajal (ICC), and a neuronal cell.

[0006] In some embodiments, the cell is an animal cell. In some embodiments, the cell in a human cell.

[0007] In some embodiments, the cell is in a subject having a gastrointestinal or digestive disease or disorder or is at risk of the gastrointestinal or digestive disease or disorder, selected from any one or more of abdominal adhesions, acid reflux (gastroesophageal reflux disease or GERD) in adults, acid reflux (GERD) in infants, anatomic problems of the lower Gl tract, appendicitis, Barrett's esophagus, bowel control problems (fecal incontinence), celiac disease, colon polyps, constipation, Crohn's disease, cyclic vomiting syndrome, diarrhea, diverticulosis and diverticulitis, dumping syndrome, food poisoning, gallstones, gas, gastritis, gastroparesis, Gl bleeding, hemorrhoids, indigestion (dyspepsia), inguinal hernia, intestinal pseudoobstruction, inflammatory bowel disease (IEBD), irritable bowel syndrome (IBS), lactose intolerance, liver disease, microscopic colitis, ostomy surgery of the bowel, pancreatitis, peptic ulcers (stomach ulcers), proctitis, short bowel syndrome, ulcerative colitis, viral gastroenteritis, Zollinger-Ellison syndrome, or a condition associated therewith. In some embodiments, the disease or disorder is gastroparesis. In some embodiments, the gastroparesis is idiopathic gastroparesis, diabetic gastroparesis, post-surgical gastroparesis, or medication-induced gastroparesis.

[0008] Also disclosed herein is the use of an orally disintegrating formulation of a thiazolidinedione selected from one or more of pioglitazone, rosiglitazone, lobeglitazone, ciglitazone, darglitazone, englitazone, netoglitazone, rivoglitazone, troglitazone, and balaglitazone to relieve one or more signs and/or symptoms of gastroparesis. In some embodiments, the thiazolidinedione is lobeglitazone. In some embodiments, the signs and symptoms of gastroparesis are measured by the ANMS GCSI-DD. In some embodiments, the signs and symptoms of gastroparesis are measured by the change of GCSI-DD. In some embodiments, the signs and symptoms of gastroparesis are measured by the change of GCSI- DD score from baseline to 4-week treatment. In some embodiments, the signs and symptoms of gastroparesis are measured by the change of GCSI-DD score from baseline to 8-week treatment. In some embodiments, the signs and symptoms of gastroparesis are measured by the change of GCSI-DD score from baseline to 12-week treatment. In some embodiments, the signs and symptoms of gastroparesis are measured by the change of GCSI-DD score from baseline to 1 -year treatment. In some embodiments, the signs and symptoms of gastroparesis are measured by the change of GCSI-DD score from baseline to more than 1-year treatment.

[0009] Also disclosed herein is the use of an orally disintegrating formulation of a thiazolidinedione selected from one or more of pioglitazone, rosiglitazone, lobeglitazone, ciglitazone, darglitazone, englitazone, netoglitazone, rivoglitazone, troglitazone, and balaglitazone to decrease the severity of nausea in a subject with gastroparesis. In some embodiments, the thiazolidinedione is lobeglitazone. In some embodiments, the decrease the severity of nausea is measured by the change of severity of nausea from baseline to 4-week treatment. In some embodiments, the decrease the severity of nausea is measured by the change of severity of nausea from baseline to 8-week treatment. In some embodiments, the decrease the severity of nausea is measured by the change of severity of nausea from baseline to 12-week treatment. In some embodiments, the decrease the severity of nausea is measured by the change of severity of nausea from baseline to 1-year treatment. [0010] Also disclosed herein is the use of an orally disintegrating formulation of a thiazolidinedione selected from one or more of pioglitazone, rosiglitazone, lobeglitazone, ciglitazone, darglitazone, englitazone, netoglitazone, rivoglitazone, troglitazone, and balaglitazone to decrease the severity of early satiety in a subject with gastroparesis. In some embodiments, the thiazolidinedione is lobeglitazone. In some embodiments, the decrease the severity of early satiety is measured by the change of severity of early satiety from baseline to 4-week treatment. In some embodiments, the decrease the severity of early satiety is measured by the change of severity of early satiety from baseline to 8-week treatment. In some embodiments, the decrease the severity of early satiety is measured by the change of severity of early satiety from baseline to 12-week treatment. In some embodiments, the decrease the severity of early satiety is measured by the change of severity of early satiety from baseline to 1-year treatment. In some embodiments, the decrease the severity of early satiety is measured by the change of severity of early satiety from baseline to more than 1- year treatment.

[0011] Also disclosed herein is the use of an orally disintegrating formulation of a thiazolidinedione selected from one or more of pioglitazone, rosiglitazone, lobeglitazone, ciglitazone, darglitazone, englitazone, netoglitazone, rivoglitazone, troglitazone, and balaglitazone to decrease the severity of postprandial fullness in a subject with gastroparesis. In some embodiments, the thiazolidinedione is lobeglitazone. In some embodiments, the decrease the severity of postprandial fullness is measured by the change of severity of postprandial fullness from baseline to 4-week treatment. In some embodiments, the decrease the severity of postprandial fullness is measured by the change of severity of postprandial fullness from baseline to 8-week treatment. In some embodiments, the decrease the severity of postprandial fullness is measured by the change of severity of postprandial fullness from baseline to 12-week treatment. In some embodiments, the decrease the severity of postprandial fullness is measured by the change of severity of postprandial fullness from baseline to 1-year treatment. In some embodiments, the decrease the severity of postprandial fullness is measured by the change of severity of postprandial fullness from baseline to more than 1-year treatment.

[0012] Also disclosed herein is the use of an orally disintegrating formulation of a thiazolidinedione selected from one or more of pioglitazone, rosiglitazone, lobeglitazone, ciglitazone, darglitazone, englitazone, netoglitazone, rivoglitazone, troglitazone, and balaglitazone to decrease the severity of upper abdominal pain in a subject with gastroparesis. In some embodiments, the thiazolidinedione is lobeglitazone. In some embodiments, the decrease the severity of upper abdominal pain is measured by the change of severity of upper abdominal pain from baseline to 4-week treatment. In some embodiments, the decrease the severity of upper abdominal pain is measured by the change of severity of upper abdominal pain from baseline to 8-week treatment. In some embodiments, the decrease the severity of upper abdominal pain is measured by the change of severity of upper abdominal pain from baseline to 12-week treatment. In some embodiments, the decrease the severity of upper abdominal pain is measured by the change of severity of upper abdominal pain from baseline to 1 -year treatment. In some embodiments, the decrease the severity of upper abdominal pain is measured by the change of severity of upper abdominal pain from baseline to more than 1 - year treatment.

[0013] Also disclosed herein is the use of an orally disintegrating formulation of a thiazolidinedione selected from one or more of pioglitazone, rosiglitazone, lobeglitazone, ciglitazone, darglitazone, englitazone, netoglitazone, rivoglitazone, troglitazone, and balaglitazone to decrease the frequency of vomiting episodes in a subject with gastroparesis. In some embodiments, the thiazolidinedione is lobeglitazone. In some embodiments, the decrease the severity of vomiting episodes is measured by the change of severity of vomiting episodes from baseline to 4-week treatment. In some embodiments, the decrease the severity of vomiting episodes is measured by the change of severity of vomiting episodes from baseline to 8-week treatment. In some embodiments, the decrease the severity of vomiting episodes is measured by the change of severity of vomiting episodes from baseline to 12-week treatment. In some embodiments, the decrease the severity of vomiting episodes is measured by the change of severity of vomiting episodes from baseline to 1-year treatment. In some embodiments, the decrease the severity of vomiting episodes is measured by the change of severity of vomiting episodes from baseline to more than 1-year treatment.

[0014] Also disclosed herein is the use of an orally disintegrating formulation of a thiazolidinedione selected from one or more of pioglitazone, rosiglitazone, lobeglitazone, ciglitazone, darglitazone, englitazone, netoglitazone, rivoglitazone, troglitazone, and balaglitazone to decrease the overall severity of gastroparesis. In some embodiments, the thiazolidinedione is lobeglitazone. In some embodiments, the decrease the severity of overall severity of gastroparesis is measured by the change of severity of overall severity of gastroparesis from baseline to 4-week treatment. In some embodiments, the decrease the severity of overall severity of gastroparesis is measured by the change of severity of overall severity of gastroparesis from baseline to 8-week treatment. In some embodiments, the decrease the severity of overall severity of gastroparesis is measured by the change of severity of overall severity of gastroparesis from baseline to 12-week treatment. In some embodiments, the decrease the severity of overall severity of gastroparesis is measured by the change of severity of overall severity of gastroparesis from baseline to 1-year treatment. In some embodiments, the decrease the severity of overall severity of gastroparesis is measured by the change of severity of overall severity of gastroparesis from baseline to more than 1 -year treatment.

[0015] Also disclosed here is the use of an orally disintegrating formulation of a thiazolidinedione selected from one or more of pioglitazone, rosiglitazone, lobeglitazone, ciglitazone, darglitazone, englitazone, netoglitazone, rivoglitazone, troglitazone, and balaglitazone, to slow down, stop, or reverse disease progress of digestive disease. In some embodiments, the thiazolidinedione is lobeglitazone.

[0016] Also disclosed herein are methods of treating a digestive disease in a mammal comprising administering an effective amount of a thiazolidinedione selected from one or more of pioglitazone, rosiglitazone, lobeglitazone, ciglitazone, darglitazone, englitazone, netoglitazone, rivoglitazone, troglitazone, and balaglitazone to the mammal. In some embodiments, the digestive disease is gastroparesis or IBD. In some embodiments, the thiazolidinedione is lobeglitazone.

[0017] In some embodiments, gastroparesis is idiopathic gastroparesis, diabetic gastroparesis, post-surgical gastroparesis, or medication-induced gastroparesis.

BRIEF DESCRIPTION OF THE DRAWINGS

[0018] FIG 1 depicts the mean plasma concentration profiles of lobeglitazone sulfate in male cynomolgus monkeys following single oral administration of different tablets. Lobeglitazone orally disintegrating tablet (ODT) doses used in the PK study was 0.4 mg, 0.8 mg and 1 .2 mg. Duvie® tablet contains 0.415 mg of lobeglitazone free base.

DETAILED DESCRIPTION

[0019] Disclosed herein are orally disintegrating tablet (ODT) dosage formulations of thioglitazones that can achieve significantly better onset and pharmacokinetic parameters. In some embodiments, the thioglitazone is lobeglitazone. In some embodiments, the formulations are for treating gastrointestinal disorders. In some embodiments, the formulations are for treating kidney disorders.

[0020] An ODT is a solid dosage form that disintegrates and dissolves in the mouth (either on or beneath the tongue or in the buccal cavity) without water within 60 seconds or less. ODTs release drug in the mouth for absorption through local oromucosal tissues and through pregastric (e.g., oral cavity, pharynx, and esophagus), gastric (i.e., stomach), and postgastric (e.g., small and large intestines) segments of the gastrointestinal tract. [0021] Pharmacokinetics is a subdivision of pharmacology which addresses the concentrations or quantities of drug substances and their metabolites in biological fluids, tissues and excreta as a function of time. In general, pharmacokinetic studies focus upon the understanding and characterization of drug absorption, distribution, metabolism and excretion, as well as their relationships to pharmacodynamics and toxicology. Particularly, drug absorption, the transport of active pharmaceutical ingredients (APIs) into blood circulation, represents a critical PK process for orally administered drugs. Most APIs are solids under ambient conditions and most drug products are developed and orally delivered as solid dosage forms. The oral absorption of a drug is typically a two-step process. Firstly, the drug product dissolves into the biological fluids secreted in the gastrointestinal (Gl) tract. This releases API molecules that can then permeate across the Gl membrane via modes such as passive diffusion or active transport. Solubility and permeability are therefore two critical parameters that significantly impact the efficiency of oral drug absorption. In this context, the United States Food and Drug Administration (FDA) issued a Guidance for Industry to address the need to identify and characterize solid forms of drug molecules and classify orally administrated drugs, via the Biopharmaceutics Classification System (BCS), according to their solubility and permeability. With respect to BCS, a drug molecule is considered highly soluble when the highest dose strength dissolves in less than 250 ml of water over a pH range from 1 to 7.5. Also, a drug molecule is considered highly permeable when the extent of absorption in humans is determined to be more than 90% of the administered dose based on mass-balance or in comparison to an intravenous reference dose. It has been noted that ca. 30% of the orally administered drugs currently on the market belong to BCS class II (i.e. , low solubility and high permeability). Moreover, approximately 70% of the new chemical entities (NCEs) under development, potentially for oral administration, also exhibit low solubilities. In drug development, much effort has been directed towards improving the aqueous solubility of poorly soluble APIs.

[0022] Provided herein is an orally disintegrating tablet (ODT) formulation comprising a thiazolidinedione, selected from one or more of pioglitazone, rosiglitazone, lobeglitazone, ciglitazone, darglitazone, deuterium-stabilized R-pioglitazone, englitazone, leriglitazone, netoglitazone, rivoglitazone, troglitazone, and balaglitazone, or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, cocrystal, enantiomer, or deuterated form thereof.

[0023] In some embodiments, the thiazolidinedione is lobeglitazone or a pharmaceutically acceptable salt thereof. In some embodiments, the thiazolidinedione is not pioglitazone or rosiglitazone.

[0024] In some embodiments, the dose of lobeglitazone is about 0.01 to 100 mg, or preferably about 0.1 to 10 mg, or more preferably about 0.4 to 2 mg. [0025] In some embodiments, 80% of the tablet is dissolved within about 60 min. In some embodiments, 80% of the tablet is dissolved within about 30 min. In some embodiments, 80% of the tablet is dissolved within about 15 min.

[0026] In some embodiments, the formulation further comprises a binder, wherein the binder is hydroxypropyl cellulose.

[0027] In some embodiments, the formulation further comprises a filler, wherein the filler is mannitol.

[0028] In some embodiments, lobeglitazone or the pharmaceutically acceptable salt or ester thereof is present in the formulation at a concentration from 0.01% to 50% weight by weight of the total formulation.

[0029] Provided herein is the use of an orally disintegrating tablet of thiazolidinedione for the treatment digestive diseases selected from abdominal adhesions, achalasia, acid reflux (gastroesophageal reflux disease or GERD) in adults, acid reflux (GERD) in infants, anatomic problems of the lower Gl tract, appendicitis, Barrett's esophagus, bowel control problems (fecal incontinence), celiac disease, colon polyps, constipation, Crohn's disease, cyclic vomiting syndrome, diarrhea, diverticulosis and diverticulitis, dumping syndrome, food poisoning, gallstones, gas, gastritis, gastroparesis, Gl bleeding, hemorrhoids, indigestion (dyspepsia), inguinal hernia, intestinal pseudo-obstruction, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), lactose intolerance, liver disease, microscopic colitis, ostomy surgery of the bowel, pancreatitis, peptic ulcers (stomach ulcers), proctitis, short bowel syndrome, ulcerative colitis, viral gastroenteritis, and Zollinger-Ellison syndrome, or a condition associated therewith.

[0030] In some embodiments, the thiazolidinedione is lobeglitazone, ora pharmaceutically acceptable salt thereof.

[0031] In some embodiments, the digestive disease is gastroparesis, such as idiopathic gastroparesis, diabetic gastroparesis, post-surgical gastroparesis, or medication-induced gastroparesis.

[0032] Provided herein is the use of an orally disintegrating tablet of thiazolidinedione for the treatment of kidney diseases such as glomerular diseases and nephrotic syndrome.

[0033] In some embodiments, the thiazolidinedione is lobeglitazone, ora pharmaceutically acceptable salt thereof.

[0034] Provided herein is an orally disintegrating tablet comprising an intragranular portion including a thiazolidinedione, or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, cocrystal, enantiomer, or deuterated form thereof, ethanol, hydroxy propyl cellulose (HPC), mannitol, microcrystalline cellulose (MCC), polyvinylpyrrolidone (PVP), a sweetener, and croscarmellose sodium; and an extragranular portion including magnesium stearate.

[0035] In some embodiments of the tablet, the thiazolidinedione is lobeglitazone, or a pharmaceutically acceptable salt thereof. In some embodiments of the tablet, the thiazolidinedione is not pioglitazone or rosiglitazone.

[0036] Provided herein is a granule comprising a thiazolidinedione, or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, cocrystal, enantiomer, or deuterated form thereof, ethanol, hydroxy propyl cellulose (HPC), mannitol, microcrystalline cellulose (MCC), polyvinylpyrrolidone (PVP), a sweetener, and croscarmellose sodium.

[0037] Provided herein is an orally disintegrating tablet comprising a plurality of said granules.

[0038] In some embodiments, the orally disintegrating tablets provided herein can be administered to patients who have difficulty swallowing (dysphagia). In some embodiments, the orally disintegrating tablets described herein reduce nausea and vomiting due to swallowing, avoid the use of water, and thereby improve patient compliance.

[0039] In some embodiments, provided is an orally disintegrating tablet comprising a plurality of granules dispersed in an extragranular matrix. In some embodiments, the plurality of granules are referred to herein as the intragranular part/portion and are dispersed in an extragranular matrix which is referred to herein as the extragranular part/portion.

[0040] In some embodiments, the composition of the granules forming the intragranular part includes from about 70% w/w to about 80% w/w of a first filler such as mannitol (e.g., mannitol 50C, 160C, or 200 SD). In some embodiments, the composition of the granules includes from about 15% w/w to about 20% w/w of a second filler (e.g., MCC 101). In some embodiments, the composition of the granules includes from about 1 % w/w to about 10% w/w of a binder (e.g., PVP, HPMC E5, HPC EXF, or HPC EF). In some embodiments, the composition of the granules includes from about 1% w/w to about 5% w/w of a sweetener (e.g., sucralose). In some embodiments, the composition of the granules includes from about 0.5% w/w to about 3.5% w/w of lobeglitazone free base. In some embodiments, the composition of the granules includes from about 1% w/w to about 3.5% w/w of lobeglitazone sulfate. In some embodiments the composition of the intragranular matrix includes from about 5% w/w to 10% w/w of a disintegrating agent (e.g., croscarmellose sodium). [0041] In some embodiments, the extragranular part includes a lubricant ((e.g., magnesium stearate, sodium stearyl fumarate).

[0042] In some embodiments the composition of the extragranular part includes from about 1% w/w to 3% w/w of a lubricant (e.g., magnesium stearate, sodium stearyl fumarate), and from about 5% w/w to 10% w/w of a disintegrating agent (e.g., croscarmellose sodium), and in such embodiments, the disintegrating agent is not present in the intragranular part.

[0043] In some embodiments, the granules have a mean particle diameter of about 1 mm. In some embodiments, a granule has a regular shape (e.g. spherical) and has an average diameter of about 1 mm, or less than 1 mm, and can be sifted through a 1 mm screen. In some embodiments, granules have irregular shapes and have a D50 of about 1 mm, or less than 1 mm.

[0044] In some embodiments, the granules provide from about 90% to about 99% weight by total weight of the tablet (w/w), from about 95% w/w about 99% w/w, from about 92% w/w about 98% w/w, or from about 95% w/w about 99% w/w of an orally disintegrating tablet described herein and form the intragranular portion of the tablet. In some embodiments, the extragranular portion provides from about 0.5% w/w to about 10% w/w, from about 5% w/w to about 9% w/w, or from about 0.5% w/w to about 3% w/w of an orally disintegrating tablet described herein.

[0045] In some embodiments, the fillers and sweetener are sifted and mixed together followed by addition of a solution of lobeglitazone free base or lobeglitazone sulfate and binder in ethanol. The wet mixture is stirred on a paddle mixer and the wet granules are sifted throught a 9.5 mm screen. The granules are then dried, milled, and sifted throught a 1 mm screen to provide the intragranular portion of an orally disintegrating tablet described herein. The intragranular portion is blended with a lubricant (e.g., magnesium stearate) and a dispersant (e.g., croscarmellose sodium) to provide the final blend which is compressed into tablets.

[0046] In some embodiments, an orally disintegrating tablet described herein comprises from about 0.8% to about 3.2% weight by total weight of the tablet (w/w), from about 0.8% to about 2% w/w, or from about 1.5% w/w to about 3% w/w of a thiazolidinedione, or a pharmaceutically acceptable salt thereof. In some embodiments, an orally disintegrating tablet described herein comprises about 0.8% w/w, about 0. 9% w/w, about 1 % w/w, about 1.5% w/w, about 2% w/w, about 2.5% w/w or about 3% w/w of a thiazolidinedione, or a pharmaceutically acceptable salt thereof. In some embodiments, an orally disintegrating tablet described herein comprises about 0.9% w/w of lobeglitazone sulfate. In some embodiments, an orally disintegrating tablet described herein comprises about 1 .9% w/w of lobeglitazone sulfate. In some embodiments, an orally disintegrating tablet described herein comprises about 2.8% w/w of lobeglitazone sulfate. In some embodiments, an orally disintegrating tablet described herein comprises about 0.8% w/w of lobeglitazone free base. In some embodiments, an orally disintegrating tablet described herein comprises about 2.4% w/w of lobeglitazone free base.

[0047] In some embodiments, an orally disintegrating tablet described herein comprises from about 1 % w/w to about 5% w/w, or from about 1 % w/w to about 3% w/w of a binder (e.g., hydroxy propyl cellulose). In some embodiments, an orally disintegrating tablet described herein comprises about 1 % w/w, about 2% w/w, about 3% w/w, about 4% w/w or about 5% w/w of a binder. In some embodiments, an orally disintegrating tablet described herein comprises about 2% w/w of hydroxy propyl cellulose.

[0048] In some embodiments, an orally disintegrating tablet described herein comprises from about 60% w/w to about 80% w/w, from about 66% w/w to about 78% w/w, or from about 70% w/w to about 72% w/w of a first filler (e.g., mannitol). In some embodiments, an orally disintegrating tablet described herein comprises about 70% w/w of mannitol. In some embodiments, an orally disintegrating tablet described herein comprises about 71 % w/w of mannitol. In some embodiments, an orally disintegrating tablet described herein comprises about 72% w/w of mannitol.

[0049] In some embodiments, an orally disintegrating tablet described herein comprises from about 10% w/w to about 20% w/w, or from about 14% w/w to about 18% w/w of a second filler (e.g., microcrystalline cellulose). In some embodiments, an orally disintegrating tablet described herein comprises about 16% w/w of microcrystalline cellulose.

[0050] In some embodiments, an orally disintegrating tablet described herein comprises from about 4% w/w to about 10% w/w or from about 6% w/w to about 8% w/w of a disintegrant (e.g., croscarmellose sodium). In some embodiments, an orally disintegrating tablet described herein comprises about 7% w/w of croscarmellose sodium.

[0051] In some embodiments, an orally disintegrating tablet described herein comprises from about 0. 1% w/w to about 3% w/w or from about 0. 1 % w/w to about 2% w/w of a lubricant (e.g., magnesium stearate). In some embodiments, an orally disintegrating tablet described herein comprises about 1 % w/w of magnesium stearate.

[0052] In some embodiments, an orally disintegrating tablet described herein comprises from about 0. 1 % w/w to about 2% w/w of a sweetener (e.g., sucralose). In some embodiments, an orally disintegrating tablet described herein comprises about 1 % w/w of sucralose. In some embodiments, an orally disintegrating tablet described herein comprises about 1.5% w/w of sucralose. [0053] In some embodiments, an orally disintegrating tablet described herein is prepared from a solution comprising a thiazolidinedione and about 20 % w/w to about 35% w/w of ethanol, or from about 23% w/w to about 33% w/w of ethanol. In some embodiments, an orally disintegrating tablet described herein is prepared from a solution comprising about 20% w/w, about 25% w/w, about 30% w/w or about 35% w/w of ethanol. In some embodiments, an orally disintegrating tablet described herein is prepared from a solution comprising about 23% w/w of ethanol. In some embodiments, an orally disintegrating tablet described herein is prepared from a solution comprising about 33% w/w of ethanol.

[0054] In some embodiments, an orally disintegrating tablet described herein comprises about 0.6% w/w to about 1 .2% w/w of lobeglitazone free base, about 65% w/w to about 80% w/w of mannitol 50C, about 14% w/w to about 18% w/w of microcrystalline cellulose 101 , about 1 % w/w to about 4% w/w of polyvinylpyrrolidone, about 2% w/w to about 10% w/w of croscarmellose sodium, and about 0.1% w/w to about 2% w/w magnesium stearate. In some embodiments, an orally disintegrating tablet described herein comprises about 0.8% w/w of lobeglitazone freebase, about 75.2% w/w of mannitol 50C, about 16% w/w of microcrystalline cellulose 101 , about 2% w/w of polyvinylpyrrolidone, about 5% w/w croscarmellose sodium, and about 1% w/w magnesium stearate.

[0055] In some embodiments, an orally disintegrating tablet described herein comprises about 0.6% w/w to about 1 .2% w/w of lobeglitazone free base, about 65% w/w to about 80% w/w of mannitol 160C, about 14% w/w to about 18% w/w of microcrystalline cellulose 101 , about 1% w/w to about 4% w/w of polyvinylpyrrolidone, about 2% w/w to about 10% w/w of croscarmellose sodium, and about 0.1% w/w to about 2% w/w magnesium stearate. In some embodiments, an orally disintegrating tablet described herein comprises about 0.8% w/w of lobeglitazone freebase, about 75.2% w/w of mannitol 50C, about 16% w/w of microcrystalline cellulose 101 , about 2% w/w of polyvinylpyrrolidone, about 5% w/w of croscarmellose sodium, and about 1% w/w magnesium stearate.

[0056] In some embodiments, an orally disintegrating tablet described herein comprises about 0.6% w/w to about 1 .2% w/w of lobeglitazone free base, about 65% w/w to about 80% w/w of mannitol 200SD, about 14% w/w to about 18% w/w of microcrystalline cellulose 101 , about 1% w/w to about 4% w/w of polyvinylpyrrolidone, about 2% w/w to about 10% w/w of croscarmellose sodium, and about 0.1% w/w to about 2% w/w magnesium stearate. In some embodiments, an orally disintegrating tablet described herein comprises about 0.8% w/w of lobeglitazone freebase, about 75.2% w/w of mannitol 50C, about 16% w/w of microcrystalline cellulose 101 , about 2% w/w of polyvinylpyrrolidone, about 5% w/w of croscarmellose sodium, and about 1% w/w magnesium stearate. [0057] In some embodiments, an orally disintegrating tablet described herein comprises about 1 % w/w to about 3% w/w of lobeglitazone free base, about 65% w/w to about 80% w/w of mannitol 200SD, about 14% w/w to about 18% w/w of microcrystalline cellulose 101 , about 1% w/w to about 4% w/w of polyvinylpyrrolidone, about 2% w/w to about 10% w/w of croscarmellose sodium, and about 0.1% w/w to about 2% w/w magnesium stearate. In some embodiments, an orally disintegrating tablet described herein comprises about 2.4% w/w of lobeglitazone freebase, about 74% w/w of mannitol 200SD, about 16% w/w of microcrystalline cellulose 101 , about 1.5% w/w of polyvinylpyrrolidone, about 5% w/w of croscarmellose sodium, and about 1% w/w magnesium stearate.

[0058] In some embodiments, an orally disintegrating tablet described herein comprises about 1 % w/w to about 3% w/w of lobeglitazone free base, about 65% w/w to about 80% w/w of mannitol 200SD, about 14% w/w to about 18% w/w of microcrystalline cellulose 101 , about 1% w/w to about 4% w/w of polyvinylpyrrolidone, about 2% w/w to about 10% w/w of croscarmellose sodium, and about 0.1% w/w to about 2% w/w magnesium stearate. In some embodiments, an orally disintegrating tablet described herein comprises about 2.4% w/w of lobeglitazone freebase, about 73.6% w/w of mannitol 200SD, about 16% w/w of microcrystalline cellulose 101 , about 1.5% w/w of polyvinylpyrrolidone, about 5% w/w of croscarmellose sodium, and about 1.5% w/w magnesium stearate.

[0059] In some embodiments, an orally disintegrating tablet described herein comprises about 1 % w/w to about 3% w/w of lobeglitazone free base, about 65% w/w to about 80% w/w of mannitol 200SD, about 14% w/w to about 18% w/w of microcrystalline cellulose 101 , about 1% w/w to about 4% w/w of polyvinylpyrrolidone, about 2% w/w to about 10% w/w of croscarmellose sodium, and about 0.1% w/w to about 2% w/w magnesium stearate. In some embodiments, an orally disintegrating tablet described herein comprises about 2.4% w/w of lobeglitazone freebase, about 72% w/w of mannitol 200SD, about 16% w/w of microcrystalline cellulose 101 , about 1.5% w/w of polyvinylpyrrolidone, about 7% w/w of croscarmellose sodium, and about 1% w/w magnesium stearate.

[0060] In some embodiments, an orally disintegrating tablet described herein comprises about 1 % w/w to about 3% w/w of lobeglitazone free base, about 65% w/w to about 80% w/w of mannitol 200SD, about 14% w/w to about 18% w/w of microcrystalline cellulose 101 , about 1% w/w to about 4% w/w of polyvinylpyrrolidone, about 2% w/w to about 10% w/w of croscarmellose sodium, and about 0.1% w/w to about 2% w/w magnesium stearate. In some embodiments, an orally disintegrating tablet described herein comprises about 2.4% w/w of lobeglitazone freebase, about 70% w/w of mannitol 200SD, about 16% w/w of microcrystalline cellulose 101 , about 1.5% w/w of polyvinylpyrrolidone, about 9% w/w of croscarmellose sodium, and about 1% w/w magnesium stearate. [0061] In some embodiments, an orally disintegrating tablet described herein comprises about 0.6 % w/w to about 1 .2% w/w of lobeglitazone free base, about 65% w/w to about 80% w/w of mannitol 200SD, about 14% w/w to about 18% w/w of microcrystalline cellulose 101 , about 1% w/w to about 4% w/w of HPMC E5, about 0.1% w/w to about 4% w/w of sucralose, about 2% w/w to about 10% w/w of croscarmellose sodium, and about 0.1% w/w to about 2% w/w magnesium stearate. In some embodiments, an orally disintegrating tablet described herein comprises about 0.8% w/w of lobeglitazone freebase, about 72.7% w/w of mannitol 200SD, about 16% w/w of microcrystalline cellulose 101 , about 1.5% w/w of HPMC E5, about 1% w/w of sucralose, about 7% w/w of croscarmellose sodium, and about 1% w/w magnesium stearate.

[0062] In some embodiments, an orally disintegrating tablet described herein comprises about 0.6 % w/w to about 1 .2% w/w of lobeglitazone free base, about 65% w/w to about 80% w/w of mannitol 200SD, about 14% w/w to about 18% w/w of microcrystalline cellulose 101 , about 1% w/w to about 4% w/w of polyvinylpyrrolidione, about 0.1% w/w to about 4% w/w of sucralose, about 2% w/w to about 10% w/w of croscarmellose sodium, and about 0.1% w/w to about 2% w/w magnesium stearate. In some embodiments, an orally disintegrating tablet described herein comprises about 0.8% w/w of lobeglitazone freebase, about 72.7% w/w of mannitol 200SD, about 16% w/w of microcrystalline cellulose 101 , about 1.5% w/w of polyvinylpyrrolidione, about 1% w/w of sucralose, about 7% w/w of croscarmellose sodium, and about 1 .5% w/w magnesium stearate.

[0063] In some embodiments, an orally disintegrating tablet described herein comprises about 0.6 % w/w to about 1 .2% w/w of lobeglitazone free base, about 65% w/w to about 80% w/w of mannitol 200SD, about 14% w/w to about 18% w/w of microcrystalline cellulose 101 , about 1% w/w to about 4% w/w of HPC EXF, about 0.1% w/w to about 4% w/w of sucralose, about 2% w/w to about 10% w/w of croscarmellose sodium, and about 0.1% w/w to about 2% w/w magnesium stearate. In some embodiments, an orally disintegrating tablet described herein comprises about 0.8% w/w of lobeglitazone freebase, about 72.7% w/w of mannitol 200SD, about 16% w/w of microcrystalline cellulose 101 , about 1.5% w/w of HPC EXF, about 1% w/w of sucralose, about 7% w/w of croscarmellose sodium, and about 1% w/w magnesium stearate.

[0064] In some embodiments, an orally disintegrating tablet described herein comprises about 1 % w/w to about 3% w/w of lobeglitazone free base, about 65% w/w to about 80% w/w of mannitol 200SD, about 14% w/w to about 18% w/w of microcrystalline cellulose 101 , about 1% w/w to about 4% w/w of HPC EXF, about 0.1% w/w to about 4% w/w of sucralose, about 2% w/w to about 10% w/w of croscarmellose sodium, and about 0.1% w/w to about 2% w/w magnesium stearate. In some embodiments, an orally disintegrating tablet described herein comprises about 2.4% w/w of lobeglitazone freebase, about 70.6% w/w of mannitol 200SD, about 16% w/w of microcrystalline cellulose 101 , about 1.5% w/w of HPC EXF, about 1.5% w/w of sucralose, about 7% w/w of croscarmellose sodium, and about 1% w/w magnesium stearate.

[0065] In some embodiments, an orally disintegrating tablet described herein comprises about 1 % w/w to about 3% w/w of lobeglitazone free base, about 65% w/w to about 80% w/w of mannitol 200SD, about 14% w/w to about 18% w/w of microcrystalline cellulose 101 , about 1% w/w to about 4% w/w of HPC EXF, about 2% w/w to about 10% w/w of croscarmellose sodium, and about 0.1% w/w to about 2% w/w magnesium stearate. In some embodiments, an orally disintegrating tablet described herein comprises about 2.4% w/w of lobeglitazone freebase, about 71.6% w/w of mannitol 200SD, about 16% w/w of microcrystalline cellulose 101 , about 2% w/w of HPC EXF, about 7% w/w of croscarmellose sodium, and about 1% w/w magnesium stearate.

[0066] In some embodiments, an orally disintegrating tablet described herein comprises about 1 % w/w to about 3% w/w of lobeglitazone free base, about 65% w/w to about 80% w/w of mannitol 200SD, about 14% w/w to about 18% w/w of microcrystalline cellulose 101 , about 1% w/w to about 4% w/w of HPC EXF, about 0.1% w/w to about 4% w/w of sucralose, about 2% w/w to about 10% w/w of croscarmellose sodium, and about 0.1% w/w to about 2% w/w magnesium stearate. In some embodiments, an orally disintegrating tablet described herein comprises about 2.4% w/w of lobeglitazone freebase, about 69.6% w/w of mannitol 200SD, about 16% w/w of microcrystalline cellulose 101 , about 2.5% w/w of HPC EXF, about 1.5% w/w of sucralose, about 7% w/w of croscarmellose sodium, and about 1% w/w magnesium stearate.

[0067] In some embodiments, an orally disintegrating tablet described herein comprises about 1 % w/w to about 3% w/w of lobeglitazone free base, about 65% w/w to about 80% w/w of mannitol 200SD, about 14% w/w to about 18% w/w of microcrystalline cellulose 101 , about 1% w/w to about 4% w/w of HPC EXF, about 2% w/w to about 10% w/w of croscarmellose sodium, and about 0.1% w/w to about 2% w/w magnesium stearate. In some embodiments, an orally disintegrating tablet described herein comprises about 2.4% w/w of lobeglitazone freebase, about 71.6% w/w of mannitol 200SD, about 16% w/w of microcrystalline cellulose 101 , about 2% w/w of HPC EXF, about 7% w/w of croscarmellose sodium, and about 1% w/w magnesium stearate.

[0068] In some embodiments, an orally disintegrating tablet described herein comprises about 1 % w/w to about 3% w/w of lobeglitazone free base, about 65% w/w to about 80% w/w of mannitol 200SD, about 14% w/w to about 18% w/w of microcrystalline cellulose 101 , about 1 % w/w to about 4% w/w of HPMC E5, about 0.1 % w/w to about 4% w/w of sucralose, about 2% w/w to about 10% w/w of croscarmellose sodium, and about 0.1% w/w to about 2% w/w magnesium stearate. In some embodiments, an orally disintegrating tablet described herein comprises about 2.4% w/w of lobeglitazone freebase, about 74% w/w of mannitol 200SD, about 16% w/w of microcrystalline cellulose 101 , about 1.5% w/w of HPMC E5, about 0.5% w/w of sucralose, about 5% w/w of croscarmellose sodium, and about 1% w/w magnesium stearate.

[0069] In some embodiments, an orally disintegrating tablet described herein comprises about 1 % w/w to about 3% w/w of lobeglitazone free base, about 65% w/w to about 80% w/w of mannitol 200SD, about 14% w/w to about 18% w/w of microcrystalline cellulose 101 , about 1 % w/w to about 4% w/w of HPMC E5, about 0.1 % w/w to about 4% w/w of sucralose, about 2% w/w to about 10% w/w of croscarmellose sodium, and about 0.1% w/w to about 2% w/w magnesium stearate. In some embodiments, an orally disintegrating tablet described herein comprises about 2.4% w/w of lobeglitazone freebase, about 72.1% w/w of mannitol 200SD, about 16% w/w of microcrystalline cellulose 101 , about 1.5% w/w of HPMC E5, about 1% w/w of sucralose, about 7% w/w of croscarmellose sodium, and about 1% w/w magnesium stearate.

[0070] In some embodiments, an orally disintegrating tablet described herein comprises about 1 % w/w to about 3% w/w of lobeglitazone free base, about 65% w/w to about 80% w/w of mannitol 200SD, about 14% w/w to about 18% w/w of microcrystalline cellulose 101 , about 1% w/w to about 4% w/w of HPC EXF, about 0.1% w/w to about 4% w/w of sucralose, about 2% w/w to about 10% w/w of croscarmellose sodium, and about 0.1% w/w to about 2% w/w magnesium stearate. In some embodiments, an orally disintegrating tablet described herein comprises about 2.4% w/w of lobeglitazone freebase, about 70.6% w/w of mannitol 200SD, about 16% w/w of microcrystalline cellulose 101 , about 1.5% w/w of HPC EXF, about 1.5% w/w of sucralose, about 7% w/w of croscarmellose sodium, and about 1% w/w magnesium stearate.

[0071] In some embodiments, an orally disintegrating tablet described herein comprises about 1 % w/w to about 3% w/w of lobeglitazone free base, about 65% w/w to about 80% w/w of mannitol 200SD, about 14% w/w to about 18% w/w of microcrystalline cellulose 101 , about 1% w/w to about 4% w/w of HPMC E5, about 2% w/w to about 10% w/w of croscarmellose sodium, and about 0.1% w/w to about 2% w/w sodium stearyl fumarate. In some embodiments, an orally disintegrating tablet described herein comprises about 2.4% w/w of lobeglitazone freebase, about 70.1% w/w of mannitol 200SD, about 16% w/w of microcrystalline cellulose 101 , about 1.5% w/w of HPMC E5, about 9% w/w of croscarmellose sodium, and about 1% w/w sodium stearyl fumarate. [0072] In some embodiments, an orally disintegrating tablet described herein comprises about 1 % w/w to about 3% w/w of lobeglitazone free base, about 65% w/w to about 80% w/w of mannitol 200SD, about 14% w/w to about 18% w/w of microcrystalline cellulose 101 , about 1% w/w to about 4% w/w of HPMC E5, about 2% w/w to about 10% w/w of croscarmellose sodium, and about 0.1% w/w to about 2% w/w sodium stearyl fumarate. In some embodiments, an orally disintegrating tablet described herein comprises about 2.4% w/w of lobeglitazone freebase, about 73.6% w/w of mannitol 200SD, about 16% w/w of microcrystalline cellulose 101 , about 1.5% w/w of HPMC E5, about 5% w/w of croscarmellose sodium, and about 1.5% w/w sodium stearyl fumarate.

[0073] In some embodiments, an orally disintegrating tablet described herein comprises about 1 % w/w to about 3% w/w of lobeglitazone free base, about 65% w/w to about 80% w/w of mannitol 200SD, about 14% w/w to about 18% w/w of microcrystalline cellulose 101 , about 1 % w/w to about 4% w/w of HPMC E5, about 0.1 % w/w to about 4% w/w of sucralose, about 2% w/w to about 10% w/w of croscarmellose sodium, and about 0.1% w/w to about 2% w/w magnesium stearate. In some embodiments, an orally disintegrating tablet described herein comprises about 2.4% w/w of lobeglitazone freebase, about 73.6% w/w of mannitol 200SD, about 16% w/w of microcrystalline cellulose 101 , about 1.5% w/w of HPMC E5, about 0.5% w/w of sucralose, about 5% w/w of croscarmellose sodium, and about 1% w/w magnesium stearate.

[0074] In some embodiments, an orally disintegrating tablet described herein comprises about 0.6 % w/w to about 1.2% w/w of lobeglitazone sulfate, about 65% w/w to about 80% w/w of mannitol 200SD, about 14% w/w to about 18% w/w of microcrystalline cellulose 101 , about 1% w/w to about 4% w/w of HPC EF, about 0.1% w/w to about 4% w/w of sucralose, about 2% w/w to about 10% w/w of croscarmellose sodium, and about 0.1% w/w to about 2% w/w magnesium stearate. In some embodiments, an orally disintegrating tablet described herein comprises about 0.96% w/w of lobeglitazone sulfate, about 72% w/w of mannitol 200SD, about 16% w/w of microcrystalline cellulose 101 , about 2% w/w of HPC EF, about 1% w/w of sucralose, about 7% w/w of croscarmellose sodium, and about 1% w/w magnesium stearate.

[0075] In some embodiments, an orally disintegrating tablet described herein comprises about 1 % w/w to about 3% w/w of lobeglitazone sulfate, about 65% w/w to about 80% w/w of mannitol 200SD, about 14% w/w to about 18% w/w of microcrystalline cellulose 101 , about 1% w/w to about 4% w/w of HPC EF, about 0.1% w/w to about 4% w/w of sucralose, about 2% w/w to about 10% w/w of croscarmellose sodium, and about 0.1% w/w to about 2% w/w magnesium stearate. In some embodiments, an orally disintegrating tablet described herein comprises about 1 .9% w/w of lobeglitazone sulfate, about 71% w/w of mannitol 200SD, about

sucralose, about 7% w/w of croscarmellose sodium, and about 1% w/w magnesium stearate.

[0076] In some embodiments, an orally disintegrating tablet described herein comprises about 1 % w/w to about 3% w/w of lobeglitazone sulfate, about 65% w/w to about 80% w/w of mannitol 200SD, about 14% w/w to about 18% w/w of microcrystalline cellulose 101 , about 1% w/w to about 4% w/w of HPC EF, about 0.1% w/w to about 4% w/w of sucralose, about 2% w/w to about 10% w/w of croscarmellose sodium, and about 0.1% w/w to about 2% w/w magnesium stearate. In some embodiments, an orally disintegrating tablet described herein comprises about 2.8% w/w of lobeglitazone sulfate, about 70% w/w of mannitol 200SD, about 16% w/w of microcrystalline cellulose 101 , about 2% w/w of HPC EF, about 1% w/w of sucralose, about 7% w/w of croscarmellose sodium, and about 1% w/w magnesium stearate.

[0077] Gastrointestinal Disorders

[0078] Digestive diseases are disorders of the digestive tract, which is sometimes called the gastrointestinal (Gl) tract. Digestive diseases and illnesses are any ailments linked to the digestive system, including the throat, stomach, and intestines. Diagnoses may include acute, short-term illnesses. Gl diseases may also include more chronic diagnoses and may require long-term, specialty treatment.

[0079] Conditions may range from mild to serious. Some common problems include heartburn, cancer, irritable bowel syndrome (IBS), and lactose intolerance. Other digestive diseases include gallstones, cholecystitis, cholangitis, rectal diseases (e.g., anal fissure, hemorrhoids, proctitis, and rectal prolapse), esophagus diseases (e.g., stricture and achalasia and esophagitis), stomach diseases (e.g., gastritis, gastric ulcers usually caused by Helicobacter pylori infection and cancer), liver diseases (e.g., hepatitis B or hepatitis C, cirrhosis, liver failure, and autoimmune and alcoholic hepatitis), pancreatitis and pancreatic pseudocyst, intestinal diseases (e.g., polyps and cancer, infections, celiac disease, Crohn disease, ulcerative colitis, diverticulitis, malabsorption, short bowel syndrome, and intestinal ischemia), gastroesophageal reflux disease (GERD), peptic ulcer disease, and hiatal hernia.

[0080] Among all digestive diseases, gastroparesis is a disorder characterized by delayed gastric emptying (DGE) in the absence of mechanical obstruction. Symptoms are chronic with episodic exacerbation. The idiopathic form of the disorder, which accounts for the greatest number of cases, predominantly affects young adult females. Gastroparesis is also frequently associated with diabetes (diabetic gastroparesis), which likely occurs because of impaired neural control of gastric motility. In addition, acute hyperglycemia has the potential to slow gastric emptying and decrease the effects of prokinetic drugs. [0081] On the molecular level, gastroparesis can be caused by the loss of neuronal nitric oxide expression since the cells in the Gl tract secrete nitric oxide. This important signaling molecule has various responsibilities in the Gl tract and in muscles throughout the body. When nitric oxide levels are low, the smooth muscle and other organs may not be able to function properly. Other important components of the stomach are the interstitial cells of Cajal (ICC) which act as a pacemaker since they transduce signals from motor neurons to produce an electrical rhythm in the smooth muscle cells. Lower nitric oxide levels also correlate with loss of ICC cells, which can ultimately lead to the loss of function in the smooth muscle in the stomach, as well as in other areas of the gastrointestinal tract. Pathogenesis of symptoms in diabetic gastroparesis include loss of gastric neurons containing nitric oxide synthase (NOS) is responsible for defective accommodation reflex, which leads to early satiety and postprandial fullness; impaired electromechanical activity in the myenteric plexus is responsible for delayed gastric emptying, resulting in nausea and vomiting; sensory neuropathy in the gastric wall may be responsible for epigastric pain; abnormal pacemaker activity (tachybradyarrhythmia) may generate a noxious signal transmitted to the CNS to evoke nausea and vomiting.

[0082] Macrophages can play a role in the development and progression of gastroparesis. In particular, macrophages can infiltrate the smooth muscle layer of the stomach in people with gastroparesis and release pro-inflammatory molecules that contribute to the damage and dysfunction of the stomach muscles. In cases of diabetic gastroparesis, high blood sugar levels may activate macrophages, leading to inflammation and damage to the nerves and muscles of the stomach. There are two different subtypes of macrophages that have different functions in the immune system, i.e., M1 and M2 macrophages. M1 macrophages are involved in the inflammatory response and are activated in response to pro-inflammatory signals. They are important in fighting infections and in promoting tissue damage and repair. M1 macrophages produce pro-inflammatory cytokines and reactive oxygen species, which help to kill invading pathogens and promote the recruitment of other immune cells to the site of infection. On the other hand, M2 macrophages are involved in tissue repair and immune regulation, and are activated in response to anti-inflammatory signals. They are important in resolving inflammation and promoting tissue remodeling and healing. M2 macrophages produce anti-inflammatory cytokines and growth factors that help to repair damaged tissues and promote angiogenesis. Overall, M1 and M2 macrophages represent two different functional states of macrophages that allow them to respond to different signals and perform different roles in the immune system. The balance between M1 and M2 macrophages is important in maintaining immune homeostasis and promoting proper immune responses. Drugs that can inhibit M1 macrophage, promote M2 macrophage and/or enable M1-to-M2 macrophage repolarization may be able to treat digestive diseases including gastroparesis.

[0083] Because the signs and symptoms of gastroparesis overlap with other Gl conditions, gastroparesis may be incorrectly diagnosed as bowel obstruction, functional dyspepsia, irritable bowel syndrome, or peptic ulcer disease. In a patient with signs and symptoms suggestive of gastroparesis, a finding of DGE in the absence of an obstruction or alternative diagnosis provides critical support for the diagnosis of gastroparesis and can be assessed using either gastric emptying scintigraphy, the gastric emptying breath test, or the SmartPill™ motility testing system.

[0084] Approved medications to treat gastroparesis can be categorized into two different groups. The first group of medications only provides temporary relief to some disease symptoms such as nausea and vomiting. Drugs that help to ease nausea and vomiting include diphenhydramine, ondansetron, and prochlorperazine is used if nausea and vomiting persist. The second group of medications is to stimulate the stomach muscles. Medications to stimulate the stomach muscles include metoclopramide (e.g., Reglan®) and erythromycin. Metoclopramide has a risk of serious side effects. The prescribing information of Reglan® approved by the US Food and Drug Administration (FDA) listed a black box warning, advising patients about the dangers of developing tardive dyskinesia after long-term use of Reglan and its generic counterparts. Erythromycin may lose its effectiveness over time, and can cause side effects, such as diarrhea. Clearly, there is an urgent medical need for development of safe and effective therapies to treat patients with gastroparesis.

[0085] Digestive diseases that are driven by injury to the digestive system include, but are not limited to, abdominal adhesions, acid reflux (gastroesophageal reflux disease or GERD) in adults, acid reflux (GERD) in infants, anatomic problems of the lower Gl tract, appendicitis, Barrett's esophagus, bowel control problems (fecal incontinence), celiac disease, colon polyps, constipation, Crohn's disease, cyclic vomiting syndrome, diarrhea, diverticulosis and diverticulitis, dumping syndrome, food poisoning, gallstones, gas, gastritis, gastroparesis, Gl bleeding, hemorrhoids, indigestion (dyspepsia), inguinal hernia, intestinal pseudo-obstruction, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), lactose intolerance, liver disease, microscopic colitis, ostomy surgery of the bowel, pancreatitis, peptic ulcers (stomach ulcers), proctitis, short bowel syndrome, ulcerative colitis, viral gastroenteritis, Zollinger-Ellison syndrome, or a condition associated therewith.

[0086] The signs and symptoms of gastroparesis are nausea, vomiting, postprandial fullness, early satiety, and upper abdominal pain. Patients may experience any combination of signs and symptoms with varying degrees of severity. Pain is more prevalent in patients with idiopathic gastroparesis than it is in patients with diabetic gastroparesis. Patients with diabetic gastroparesis may experience further derangement of glucose control because of unpredictable gastric emptying and altered absorption of orally administered hypoglycemic drugs.

[0087] Understanding the relevant symptoms of gastroparesis is important in treating patients with this disorder. In gastroparesis, the symptom experience and severity are obtained from the patient. Consequently, patient-reported symptom scales that capture overall gastroparesis severity are necessary for evaluating treatments for gastroparesis. A well- defined patient reported outcome (PRO) instrument that measures clinically important signs and symptoms of gastroparesis would be a useful assessment tool for clinical trials to support labeling claims for treatment of gastroparesis. The American Neurogastroenterology and Motility Society Gastroparesis Cardinal Symptom Index-Daily Diary (ANMS GCSI-DD) is a patient-reported outcome instrument that captures the daily relevant symptoms of gastroparesis. The ANMS GCSI-DD is designed to assess gastrointestinal symptoms associated with idiopathic and diabetic gastroparesis. The ANMS GCSI-DD is designed to assess symptoms associated with idiopathic and diabetic gastroparesis. The ANMS GCSI-DD includes 5 items, i.e., nausea, vomiting, early satiety, postprandial fullness, and upper abdominal pain. Four of these (nausea, early satiety, postprandial fullness, and upper abdominal pain) are rated as none (0), mild (1), moderate (2), severe (3), very severe (4) scale on the worst severity of the symptom over the last 24 hours. Vomiting is assessed as the number of emesis episodes over the last 24 hours, with the maximum number capped at four (0 to 4 range). The ANMS GCSI-DD total score is a useful patient reported outcome for gastroparesis and as an endpoint in gastroparesis clinical trials.

[0088] Kidney Disorders

[0089] The kidneys are bean-shaped organs located just below the rib cage, one on each side of the spine. Every day, the two kidneys filter about 120 to 150 quarts of blood to produce about one to two quarts of urine, composed of wastes and extra fluid.

[0090] Blood enters the kidneys through arteries that branch inside the kidneys into tiny clusters of looping blood vessels. Each cluster is called a glomerulus. There are approximately 1 million glomeruli, or filters, in each kidney. The glomerulus is attached to the opening of a small fluid-collecting tube called a tubule. Blood is filtered in the glomerulus, and extra fluid and wastes pass into the tubule and become urine. Eventually, the urine drains from the kidneys into the bladder through larger tubes called ureters. Each glomerulus-and-tubule unit is called a nephron. Each kidney is composed of about 1 million nephrons. In healthy nephrons, the glomerular membrane that separates the blood vessel from the tubule allows waste products and extra water to pass into the tubule while keeping blood cells and protein in the bloodstream.

[0091] Many diseases affect kidney function by attacking the glomeruli, the tiny units within the kidney where blood is cleaned. Glomerular diseases include many conditions with a variety of genetic and environmental causes, but they fall into two major categories: (1) glomerulonephritis comprising inflammation of the membrane tissue in the kidney that serves as a filter, separating wastes and extra fluid from the blood, and (2) glomerulosclerosis comprising te scarring or hardening of the tiny blood vessels within the kidney. Although glomerulonephritis and glomerulosclerosis have different causes, they can both lead to kidney failure.

[0092] The signs and symptoms of glomerular disease include albuminuria (i.e., large amounts of protein in the urine), hematuria (i.e., blood in the urine), reduced glomerular filtration rate (i.e., inefficient filtering of wastes from the blood), hypoproteinemia (i.e., low blood protein), and edema (i.e., swelling in parts of the body). One or more of these symptoms can be the first sign of kidney disease.

[0093] Patients with glomerular diseases have significant amounts of protein in the urine, which may be referred to as "nephrotic range" if levels are very high. Red blood cells in the urine are a frequent finding as well, particularly in some forms of glomerulardisease. Urinalysis provides information about kidney damage by indicating levels of protein and red blood cells in the urine. Blood tests measure the levels of waste products such as creatinine and urea nitrogen to determine whetherthe filtering capacity of the kidneys is impaired. If these lab tests indicate kidney damage, the doctor may recommend ultrasound or an x-ray to see whether the shape or size of the kidneys is abnormal. These tests are called renal imaging. Since glomerular disease causes problems at the cellular level, the doctor may also recommend a kidney biopsy. A biopsy may be helpful in confirming glomerular disease and identifying the cause.

[0094] A number of different diseases can result in glomerular disease. It may be the direct result of an infection or a drug toxic to the kidneys, or it may result from a disease that affects the entire body, like diabetes or lupus. Many different kinds of diseases can cause swelling or scarring of the nephron or glomerulus. Sometimes glomerular disease is idiopathic, meaning that it occurs without an apparent associated disease. These disease categories include: (1) autoimmune diseases, such as systemic lupus erythematosus (SLE), anti-GBM (Goodpasture's) disease, and immunoglobulin A (IgA) nephropathy; (2) hereditary nephritis or Alport syndrome; (3) infection-related glomerular disease, such as acute post-streptococcal glomerulonephritis (PSGN), bacterial endocarditis, and human immunodeficiency disease {HIV); (4) sclerotic diseases, such as diabetic nephropathy and focal segmental glomerulosclerosis (FSGS); (5) other glomerular diseases, such as membranous nephropathy and minimal change diseases (MCD); and (6) chronic kidney disease.

[0095] Kidney failure is the acute or chronic loss of 85 percent or more kidney function. End-stage renal disease (ESRD) is kidney failure that is treated by dialysis or kidney transplant. Depending on the form of glomerular disease, kidney function may be lost in a matter of days or weeks or may deteriorate slowly and gradually over the course of decades.

[0096] Acute renal failure includes a few forms of glomerular disease cause very rapid deterioration of kidney function. For example, PSGN can cause severe symptoms (hematuria, proteinuria, edema) within 2 to 3 weeks after a sore throat or skin infection develops. The patient may temporarily require dialysis to replace renal function. This rapid loss of kidney function is called acute renal failure (ARF). Although ARF can be life-threatening while it lasts, kidney function usually returns after the cause of the kidney failure has been treated. In many patients, ARF is not associated with any permanent damage. However, some patients may recover from ARF and subsequently develop chronic kidney disease.

[0097] When suffering from kidney failure, a patient undergo dialysis (hemodialysis or peritoneal dialysis) or receive a new kidney through transplantation. Patients with chronic kidney disease who are approaching kidney failure should learn as much about their treatment options as possible so they can make an informed decision when the time comes. With the help of dialysis or transplantation, many people continue to lead full, productive lives with kidney failure.

[0098] Nephrotic syndrome is a condition marked by very high levels of protein in the urine; low levels of protein in the blood; swelling, especially around the eyes, feet, and hands; and high cholesterol. Nephrotic syndrome is a set of symptoms, not a disease in itself. It can occur with many diseases, so prevention relies on controlling the diseases that cause it. Treatment of nephrotic syndrome focuses on identifying and treating the underlying cause, if possible, and reducing high cholesterol, blood pressure, and protein in the urine through diet, medication, or both. Nephrotic syndrome may go away once the underlying cause, if known, is treated. However, often a kidney disease is the underlying cause and cannot be cured. In these cases, the kidneys may gradually lose their ability to filter wastes and excess water from the blood. If kidney failure occurs, the patient will need to undergo dialysis or have a kidney transplant.

[0099] Minimal-change disease (MCD) is the most common cause of nephrotic syndrome during childhood and corticosteroids induce remission in more than 90% of children with MCD. By contrast, the majority of children with the second most common etiology, FSGS, do not respond to oral glucocorticoids. A child presenting with idiopathic nephrotic syndrome who does not enter remission following one month of corticosteroid therapy is typically classified as having SRNS. Evidence from adults, however, suggests that a prolonged (3-6-month) course of oral glucocorticoids improves their response rate. In children with steroid-sensitive nephrotic syndrome (SSNS), compelling evidence from a systematic review indicates that a longer course of initial corticosteroids (minimum of 3 months) decreases the likelihood of subsequent relapses. Moreover, the dose of oral corticosteroids might also influence the number of relapses. The efficacy of glucocorticoids in idiopathic nephrotic syndrome might be attributable to the immunosuppressive effects of these agents, their direct action on the podocytes which are cells in the Bowman's capsule in the kidneys that wrap around capillaries of the glomerulus, or, potentially, a combination of these effects.

[0100] Nephrotic syndrome is one of the most common kidney diseases seen in children and adults. It is a remitting and relapsing disease characterized by massive loss of serum proteins into the urine through a damaged glomerular filtration barrier, leading to hypoalbuminemia and swelling throughout the body (edema). Podocytes are a key component of the kidney's filtration barrier, and during nephrotic syndrome, they undergo dramatic structural alterations in the foot processes that attach these cells to the glomerular basement membrane. The most widely accepted experimental models used to mimic the podocyte injury that occurs during nephrotic syndrome in humans include puromycin aminonucleoside (PAN) injection of rats and PAN treatment of cultured podocytes. For the last 50 years the primary therapy for nephrotic syndrome has been oral glucocorticoids (GC). Unfortunately, GCs have serious side effects, and in -20% of patients, they are ineffective in inducing clinical remission of disease (i.e., steroid-resistant nephrotic syndrome). Thus, alternative therapies with greater efficacy and/or less severe side effects are critically needed. Thiazolidinediones represents a novel therapeutic strategy that could slow, halt, or reverse the underlying disease process in diseases involving glomerular diseases, kidney failures and end-stage renal diseases, such as acute renal failure, kidney failure and nephrotic syndrome.

[0101] Thiazolidinediones represents a novel therapeutic strategy that could slow, halt, or reverse the underlying disease process in diseases involving digestive diseases (e.g., gastroparesis) and kidney diseases (e.g., glomerular diseases and nephrotic syndrome).

[0102] Thiazolidinediones

The present methods are predicted on the surprising finding that thiazolidinediones can significantly protect digestive system against damage, as determined by inflammation. Therefore, disclosed herein is the use of one or more thiazolidinedione for the treatment of digestive diseases. [0103] The term “thiazolidinedione” refers to a class of heterocyclic glitazones compounds which comprise a five-membered C3NS ring, including prodrugs, salts, solvates, hydrates, cocrystals, enantiomers, and deuterated forms thereof. As used herein, a thiazolidinedione includes, but is not limited to, one or more of pioglitazone, rosiglitazone, lobeglitazone, ciglitazone, darglitazone, englitazone, netoglitazone, rivoglitazone, troglitazone, balaglitazone, and otherthiazolidinedione molecules. In some embodiments disclosed herein, the methods include using any thiazolidinedione. In some embodiments, the thiazolidinedione is lobeglitazone. In some embodiments, the methods specifically exclude use of one or more thiazolidinedione disclosed herein. In some embodiments, the thiazolidinedione is not pioglitazone. In some embodiments, the thiazolidinedione is not pioglitazone or rosiglitazone.

[0104] Lobeglitazone (Duvie®, Chong Kun Dang) is a thiazolidinedione with a chemical name of 5-(4-(2-((6-(4-Methoxyphenoxy)pyrimidin-4-yl)(methyl)amino)ethoxy)benzyl) thiazolidine-2, 4-dione. As an agonist for both PPARa and PPARy, lobeglitazone works as an insulin sensitizer by binding to the PPAR receptors in fat cells and making the cells more responsive to insulin.

[0105] Definitions

[0106] As used herein, the terms “treat”, “treating”, or “treatment” means to alleviate, reduce or abrogate one or more symptoms or characteristics of a disease and may be curative, palliative, prophylactic or slow the progression of the disease.

[0107] The term “effective amount” means an amount that will result in reduction of, as applicable or specified, damage to digestive system, and in a desired effect or result. The term “therapeutically effective amount” means an amount of a thiazolidinedione comprising, but not limited to, one or more of pioglitazone, rosiglitazone, lobeglitazone, ciglitazone, darglitazone, englitazone, netoglitazone, rivoglitazone, troglitazone, balaglitazone, and other thiazolidinedione molecules, alone or combined with other active ingredients, that will elicit a desired biological or pharmacological response, e.g., effective to prevent, alleviate, or ameliorate symptoms of a disease or disorder; slow, halt or reverse an underlying disease process or progression; partially or fully restore cellular function; or prolong the survival of the subject being treated. In some embodiments, the thiazolidinedione is not pioglitazone.

[0108] The term “patient” or “subject” includes mammals, including non-human animals and especially humans. In one embodiment the patient or subject is a human. In another embodiment, the patient or subject is a human male. In another embodiment, the patient or subject is a human female. In another embodiment, the patient or subject is of any age.

[0109] “Granules” refers to solid dry aggregates comprising a thiazolidinedione that are sufficiently robust to withstand handling during formulation and/or compounding of the thiazolidinedione. Granules may have irregular shapes, or may be compressed (e.g., to form pellets of a regular shape). Granules may be formulated into tablets.

[0110] Mannitol 50C refers to mannitol having an average mean particle diameter of about 50 pm. PEARLITOL® 50C is an example of mannitol 50C.

[0111] Mannitol 160C refers to mannitol having an average mean particle diameter of about 160 pm. PEARLITOL® 160C is an example of mannitol 160C.

[0112] Mannitol 200SD refers to mannitol having an average mean particle diameter of about 150 pm. PEARLITOL® 200SD is an example of mannitol 200SD.

[0113] HPC EF refers to a hydroxypropyl cellulose (e.g., Klucel™ EF) having a weight average molecular weight of about 80,000 Daltons.

[0114] HPC EXF refers to a hydroxypropyl cellulose (e.g, Klucel™ EXF) having a weight average molecular weight of about 1 ,150,000 Daltons.

[0115] The term “significant” or “significantly” is determined by t-test at 0.05 level of significance.

[0116] As used herein the terms “digestive” and “gastrointestinal” are used interchangeably and refer to organs, cell, tissue, and diseases associated with the gastrointestinal tract, including but not limited to the mouth, pharynx (throat), esophagus, stomach, small intestine, large intestine, rectum, and anus, along with the salivary glands, liver, pancreas, and gallbladder.

[0117] Use of the Disclosed Formulations

[0118] In some aspects, the present disclosure provides a method of exerting protective effects in a cell, comprising contacting the cell with an effective amount of a thiazolidinedione from an orally disintegrating tablet formulation. As used herein, the term “effective amount” refers to an amount of thiazolidinedione that will result in the desired effect or result, e.g., an amount that will result in protective effect.

[0119] In some aspects, the disclosure provides a method of decreasing inflammation, comprising the step of contacting the cell with an effective amount of a thiazolidinedione from an orally disintegrating tablet formulation.

[0120] In some aspects, the disclosure provides a method of increasing cell lifespan, comprising the step of contacting the cell with an effective amount of a thiazolidinedione from an orally disintegrating tablet formulation.

[0121] In some embodiments, the cell is an animal cell, e.g., a mammalian cell. In some embodiments, the cell in a human cell or non-human cell. In some embodiments, the cell is a diseased cell. In some embodiments, the cell is diseased cell from a patient suffering from a disease or disorder disclosed herein.

[0122] Also disclosed herein are methods of treating an animal having a disease or disorder that would benefit from the protective effect on cells, or for preventing or reducing the risk of acquiring a disease or disorder in an animal, the method comprising the step of administering a therapeutically effective amount of an orally disintegrating tablet formulation comprising a thiazolidinedione to the animal. In some embodiments, the animal is a mammal. In some embodiments, the mammal is a human or a non-human mammal. In some embodiments, the mammal is a human. In some embodiments, the disease or disorder is a kidney disorder or a gastrointestinal disorder. In some embodiments, the disease or disorder is caused by damage that reduces function of the digestive system. In some embodiments, the disease is selected from one or more of digestive disease, or a condition associated therewith. In some embodiments, the disease is gastroparesis. In some embodiments, the disease is idiopathic gastroparesis, diabetic gastroparesis, or mediation-induced gastroparesis.

[0123] Also disclosed herein are methods for treating a disease or disorder resulting in damage or inflammation of digestive system or a kidney in a patient, or increasing the lifespan of a cell in a patient with a disease or disorder resulting in damage to digestive system or a kidney.

[0124] In some embodiments, the method comprising the step of administering a therapeutically effective amount of an orally disintegrating tablet formulation comprising a thiazolidinedione to the animal. In some embodiments, the animal is a mammal. In some embodiments, the mammal is a human or a non-human mammal.

[0125] In some embodiments, the disease or disorder is selected from, but not limited to, abdominal adhesions, acid reflux (gastroesophageal reflux disease or GERD) in adults, acid reflux (GERD) in infants, anatomic problems of the lower Gl tract, appendicitis, Barrett's esophagus, bowel control problems (fecal incontinence), celiac disease, colon polyps, constipation, Crohn's disease, cyclic vomiting syndrome, diarrhea, diverticulosis and diverticulitis, dumping syndrome, food poisoning, gallstones, gas, gastritis, gastroparesis, Gl bleeding, hemorrhoids, indigestion (dyspepsia), inguinal hernia, intestinal pseudo-obstruction, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), lactose intolerance, liver disease, microscopic colitis, ostomy surgery of the bowel, pancreatitis, peptic ulcers (stomach ulcers), proctitis, short bowel syndrome, ulcerative colitis, viral gastroenteritis, Zollinger-Ellison syndrome, or a condition associated therewith. [0126] In some embodiments, the disease or disorder is selected from age-associated glomerulonephropathy, AL amyloidosis, Alport syndrome, amyloidosis (amyloid nephropathy), ANCA vasculitis, anti-GBM disease (Goodpasture syndrome), C1 q nephropathy, C3 glomerulopathy, collapsing glomerulopathy, collapsing glomerulonephropathy, congenital nephrotic syndrome of the Finnish type (CNSF), cryoglobulinemia, diabetes, Denys-Drash Syndrome, diabetic glomerulonephropathy, diabetic nephropathy, diffuse mesangial sclerosis (DMS), Fabry disease, fibrillary glomerulonephritis (GN), focal segmental glomerulosclerosis (FSGS), heavy chain deposition disease, hypertensive nephropathy, IgA vasculitis, IgA nephropathy, IgM nephropathy, immune and inflammatory glomerulonephropathy, immunotactoid glomerulopathy, light chain deposition disease, lupus, lupus nephritis, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), mesangial proliferation, mesangial sclerosis, myeloma kidney, minimal change disease, nephrotic syndrome, post-infectious glomerulonephritis (GN), thin basement membrane (TBM), thrombotic microangiopathy (TMA), or a condition associated therewith. In some embodiments, the nephrotic syndrome is frequent relapsing nephrotic syndrome, steroiddependent nephrotic syndrome, or steroid resistant nephrotic syndrome.

[0127] Also disclosed herein are methods of treating gastroparesis. In some embodiments, gastroparesis includes idiopathic gastroparesis, diabetic gastroparesis, post- surgical gastroparesis, and medication-induced gastroparesis. In some embodiments, the primary gastroparesis is idiopathic. In some embodiments, the secondary gastroparesis is caused by a disease such as diabetes, cancer, or infections, or a drug side effect, or a surgery.

[0128] In another aspect, provided herein are methods of reducing inflammation in the Gl tract for treatment of digestive diseases such as gastroparesis and IBD.

[0129] In another aspect, provided herein are methods of reducing the risk for nausea, early satiety, postprandial fullness, upper abdominal pain, vomiting episodes, and overall severity of gastroparesis.

[0130] In another aspect, provided herein are methods of slowing, stopping, or reversing disease progression to digestive disease such as gastroparesis and IBD.

[0131] In another aspect, provided herein are methods of slowing, stopping, or reversing disease progression, as indicated by nausea, early satiety, postprandial fullness, upper abdominal pain, vomiting episodes, and overall severity of gastroparesis.

[0132] In another aspect, disclosed herein are methods of treating an animal having a disease or disorder with a symptom that is prevented, alleviated, or ameliorated by cell protection; or with a disease process or progression that slowed, halted or reversed by cell protection; the method comprising administering a therapeutically effective amount of a ODT comprising a thiazolidinedione. In some embodiments, the thiazolidinedione is lobeglitazone.

[0133] In a related aspect, disclosed herein are methods of treating gastroparesis. In one embodiment, gastroparesis includes idiopathic gastroparesis, diabetic gastroparesis, post- surgical gastroparesis, and medication-induced gastroparesis.

[0134] The present disclosure further provides of the use of a thiazolidinedione for the preparation of an ODT medicament for treating a human having any one of the diseases or disorders disclosed herein or for use in any method of the present disclosure involving the administration of a thiazolidinedione to a human.

[0135] Also disclosed herein are methods of treating nephrotic syndrome in a mammal comprising administering an effective amount of an ODT comprising a thiazolidinedione selected from one or more of rosiglitazone, lobeglitazone, ciglitazone, darglitazone, englitazone, netoglitazone, rivoglitazone, troglitazone, and balaglitazone to the mammal. In some embodiments, the nephrotic syndrome is FRNS or SDNS.

[0136] Also disclosed herein are methods of treating glomerular disease in a mammal comprising administering an effective amount of an ODT comprising a thiazolidinedione selected from one or more of rosiglitazone, lobeglitazone, ciglitazone, darglitazone, englitazone, netoglitazone, rivoglitazone, troglitazone, and balaglitazone to the mammal. In some embodiments, the glomerular disease is focal segmental glomerulosclerosis (FSGS), minimal change disease, or membranous nephropathy.

[0137] Orally Disintegrating Tablet Formulation

[0138] A pharmaceutical formulation of the present disclosure is an orally disintegrating tablet.

[0139] The pharmaceutical compositions of the present disclosure comprise a therapeutically effective amount of a thiazolidinedione and at least one pharmaceutically acceptable excipient. The term “excipient” refers to a pharmaceutically acceptable, inactive substance used as a carrier for the pharmaceutically active ingredient thiazolidinedione, and includes antiadherents, binders, coatings, disintegrants, fillers, diluents, solvents, flavors, bulkants, colors, glidants, dispersing agents, wetting agents, lubricants, preservatives, sorbents and sweeteners. The choice of excipient(s) will depend on factors such as the particular mode of administration and the nature of the dosage form.. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.

[0140] Non-limiting exemplary disintegrants include crospovidone, carmellose calcium, carmellose, croscarmellose sodium, low substitution hydroxypropylcellulose, corn starch, and sodium starch glycolate, or a combination thereof. The amount of disintegrant in the orally disintegrating tablet is typically in the range of about 0.1 % to about 10% by weight, including about 0.1%, about 0.5%, about 0.7%, about 1 %, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%, inclusive of all ranges and subranges therebetween. In a particular embodiment, the disintegrant is selected from the group consisting of crospovidone, carmellose calcium, carmellose and croscarmellose sodium. In a more particular embodiment, the disintegrant is croscarmellose sodium.

[0141] Non-limiting exemplary fillers include sugars, sugar alcohols, starches and celluloses, and inorganic excipients, or a combination thereof. Examples of the sugars include lactose, sucrose, fructooligosaccharide, glucose, palatinose, maltose, reduced maltose, powdered sugar, powdered candy, fructose, isomerized lactose, honey sugar, or a combination thereof. Examples of the sugar alcohols include mannitol, erythritol, xylitol, maltitol, sorbitol, or a combination thereof. Examples of starches include corn starch, potato starch, rice starch, partially pregelatinized starch, pregelatinized starch, or a combination thereof. Examples of the celluloses include crystalline cellulose, microcrystalline cellulose (MCC), powdered cellulose, low-degree-of-substitution hydroxypropyl cellulose, carmellose, carmellose calcium, croscarmellose sodium, or a combination thereof. Examples of the inorganic excipient include synthetic hydrotalcite, precipitated calcium carbonate, hydrous silicon dioxide, light anhydrous silicic acid, magnesium silicate aluminate magnesium hydroxide, or a combination thereof. The amount of filler in the orally disintegrating tablet is typically in the range of about 0.1% to about 99% by weight, including about 0.1 %, about 0.5%, about 0.7%, about 1 %, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 1 1%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21 %, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 33%, about 35%, about 37%, about 40%, about 43%, about 45%, about 47%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, inclusive of all ranges and subranges therebetween. In a particular embodiment, the filler is selected from the group consisting of crystalline cellulose, microcrystalline cellulose (MCC), mannitol, or a combination thereof. In a more particular embodiment, the filler is microcrystalline cellulose (MCC), mannitol, or a combination thereof.

[0142] Non-limiting exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, sodium stealylate fumarate, talc, or a combination thereof. The amount of lubricant in the orally disintegrating tablet is typically in the range of about 0.1 % to about 10% by weight, including about 0.1%, about 0.5%, about 0.7%, about 1 %, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%, inclusive of all ranges and subranges therebetween. In a particular embodiment, the lubricant is selected from magnesium stearate, calcium stearate, stearic acid, or a combination thereof. In a more particular embodiment, the lubricant is magnesium stearate.

[0143] Non-limiting exemplary sweetening agents include saccharin sodium, saccharin, aspartame, acesulfame potassium, dipotassium glycyrrhizinate, sucralose, thaumatin, or a combination thereof. The amount of sweetening agent in the orally disintegrating tablet is typically in the range of about 0.1% to about 10% by weight, including about 0.1 %, about 0.5%, about 0.7%, about 1 %, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%, inclusive of all ranges and subranges therebetween. In a particular embodiment, the sweetening agent is selected from saccharin sodium, saccharin, aspartame, sucralose, or a combination thereof. In a more particular embodiment, the sweetening agent is sucralose.

[0144] Non-limiting exemplary binding agents include sugars, sugar alcohols, starches and celluloses, and inorganic excipients, or a combination thereof. Examples of the sugars include lactose, sucrose, fructooligosaccharide, glucose, palatinose, maltose, reduced maltose, powdered sugar, powdered candy, fructose, isomerized lactose, honey sugar, or a combination thereof. Examples of the sugar alcohols include mannitol, erythritol, xylitol, maltitol, sorbitol, or a combination thereof. Examples of starches include corn starch, potato starch, rice starch, partially pregelatinized starch, pregelatinized starch, or a combination thereof. Examples of the celluloses include crystalline cellulose, microcrystalline cellulose (MCC), powdered cellulose, hydroxypropyl cellulose (HPC EF), carmellose, carmellose calcium, croscarmellose sodium, or a combination thereof. Examples of the inorganic excipient include synthetic hydrotalcite, precipitated calcium carbonate, hydrous silicon dioxide, light anhydrous silicic acid, magnesium silicate aluminate magnesium hydroxide, or a combination thereof. The amount of binder in the orally disintegrating tablet is typically in the range of about 0.1 % to about 99% by weight, including about 0.1 %, about 0.5%, about 0.7%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 1 1 %, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about

18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 33%, about 35%, about

37%, about 40%, about 43%, about 45%, about 47%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about

99%, inclusive of all ranges and subranges therebetween. In a particular embodiment, the binder is selected from the group consisting of lactose, sucrose, mannitol, hydroxypropyl cellulose (HPC EF), or a combination thereof. In a more particular embodiment, the binder is hydroxypropyl cellulose (HPC EF). [0145] The dose may vary depending upon the dosage form employed, sensitivity of the patient, and the route of administration. Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors, which may be taken into account, include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy.

[0146] In one embodiment, the daily dose of thiazolidinedione administered to a patient is selected from up to 200 mg, 175 mg, 150 mg, 125 mg, 100 mg, 90 mg, 80 mg, 70 mg, 60 mg, 50 mg, 30 mg, 25 mg, 20 mg, 15 mg, 14 mg, 13 mg, 12 mg, 11 mg, 10 mg, 9 mg, 8 mg, 7 mg, 6 mg, 5 mg, 4 mg, 3 mg, 2 mg, 1 mg, 0.9 mg, 0.8 mg, 0.7 mg, 0.6 mg, 0.5 mg, 0.45 mg, 0.4 mg, 0.3 mg, 0.2 mg, 0.1 mg, 0.08 mg, 0.05 mg, 0.03 mg, 0.02 mg or up to 0.01 mg. In another embodiment, the daily dose is at least 0.01 mg, 0.02 mg, 0.05 mg, 0.08 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 12 mg, 13 mg, 14 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1 ,000 mg, 2,000 mg, 3,000 mg, 4,000 mg, or at least 5,000 mg. In another embodiment, the daily dose is 0.01-0.0.2 mg, 0.02-0.05 mg, 0.05-0.08 mg, 0.08-0.1 mg, 0.1-0.2 mg, 0.2-0.4mg, 0.4-0.6 mg, 0.6-0.8 mg, 0.8-1 mg, 1- 2 mg, 2-4 mg, 1-5 mg, 5-7.5 mg, 7.5-10 mg, 10-15mg, 10-12.5 mg, 12.5-15 mg, 15-17.7 mg, 17.5-20 mg, 20-25 mg, 20-22.5 mg, 22.5-25 mg, 25-30 mg, 25-27.5 mg, 27.5-30 mg, 30-35 mg, 35-40 mg, 40-45 mg, or 45-50 mg, 50-75 mg, 75-100 mg, 100-125 mg, 125-150 mg, ISO- 175 mg, 175-200 mg, 5-200 mg, 5-300 mg, 5-400 mg, 5-500 mg, 5-600 mg, 5-700 mg, 5-800 mg, 5-900 mg, 5-1 ,000 mg, 5-2,000 mg, 5-5,000 mg or more than 5,000 mg, or any range bound by a pair of these values..

[0147] In another embodiment, a single dose of thiazolidinedione administered to a patient is selected from: 0.01 mg, 0.02 mg, 0.05 mg, 0.08 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 100 mg, 1 10 mg, 120 mg, 130 mg, 140 mg ,150 mg, 160 mg, 170 mg, 180 mg, 190 mg,

200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg,

410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg 490 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1 ,000 mg, 2,000 mg, 3,000 mg, 4,000 mg, or 5,000 mg, or any range bound by a pair of these values. In one embodiment, the single dose is administered by oral administration. In some embodiments, the thiazolidinedione is lobeglitazone. [0148] As a non-limited example, the dose of a thiazolidinedione, such as lobeglitazone, administered by oral administration may be about 0.01 to 50 mg per day to be administered in divided doses.

[0149] In an embodiment of any of the above methods and compositions, a thiazolidinedione, or its salt, solvates, hydrates, and co-crystals thereof, is a racemic mixture of R and S enantiomers, or enriched in R enantiomer (i.e. , the ratio of R to S enantiomer being administered, is from 1.1 :1 to 1 ,000:1 , from 10:1 to 10,000:1 , or from 100:1 to 100,000:1 , or over all thiazolidinedione enantiomers in the composition is at least 98% R enantiomer, 99% enantiomer, 99.5% enantiomer, 99.9% enantiomer, or is free of any observable amount of S enantiomer), or enriched in S enantiomer (i.e., the ratio of S to R enantiomer is from 1.1 :1 to 1 ,000:1 , from 10:1 to 10,000:1 , or from 100:1 to 100,000:1 , or over all thiazolidinedione enantiomers in the composition is at least 98% S enantiomer, 99% enantiomer, 99.5% enantiomer, 99.9% enantiomer, or is free of any detectable amount of R enantiomer).

[0150] Another embodiment of the present disclosure includes use of a thiazolidinedione to decrease the cell damage or improve cell survival.

[0151] Another embodiment of the present disclosure includes use of a thiazolidinedione to treat gastroparesis or IBD.

[0152] Another embodiment of the present disclosure includes use of a thiazolidinedione to decrease core signs and symptoms of gastroparesis, measured by ANMS GCSI-DD.

[0153] Another embodiment of the present disclosure includes use of a thiazolidinedione to decrease the severity of nausea.

[0154] Another embodiment of the present disclosure includes use of a thiazolidinedione to decrease the severity of early satiety.

[0155] Another embodiment of the present disclosure includes use of a thiazolidinedione to decrease the severity of postprandial fullness.

[0156] Another embodiment of the present disclosure includes use of a thiazolidinedione to decrease the severity of upper abdominal pain.

[0157] Another embodiment of the present disclosure includes use of a thiazolidinedione to decrease the severity of vomiting episodes.

[0158] Another embodiment of the present disclosure includes use of a thiazolidinedione to decrease the overall severity of gastroparesis. EXAMPLES

[0159] The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will be apparent to those skilled in the art from the foregoing description and the accompanying Figures. Such modifications are intended to fall within the scope of the appended claims.

[0160] It is further to be understood that all values are approximate and are provided for description. All references cited and discussed in this specification are incorporated herein by reference in their entirety and to the same extent as if each reference was individually incorporated by reference.

[0161] HPLC assays were conducted on a ZORBAX SB-C18 column (3.5 m,4.6mmx50mm).

Example 1: Formulation development of lobeqlitazone orally disintegrating tablet

[0162] Filler

[0163] The filler type was evaluated by comparing the dissolution profile and disintegration time of tablets prepared with different fillers. A series of filler with different type were designed, Table 1 summarized the formulation components of filler type, Table 2 summarized the disintegration time, and Table 3 summarized the dissolution results.

[0164] Orally disintegrating tablets were produced by the following process:

[0165] Wet Granulation

• Step 1 .Sift the intra-granular ingredients through a #20 ASTM (850 pm) screen.

• Step 2. Transfer the intra-granular ingredients from Step 1 into a high shear mixer and pre-mix for 10 min with paddle speed at 250 rpm. Add API and HPC EF to anhydrous ethanol and stir until dissolved and transparent.

• Step 3. Add API solution within 7-13 min with paddle speed at 250 rpm and chopper speed at 1000 rpm. Then, add flushing line water within 5-7 min with paddle speed at 250 rpm and chopper speed at 1000 rpm. Stop until another 0-3 min running after finishing adding water. Pass the wet granules through the Comil with 9.5 mm screen at the speed of 1500rpm.

[0166] Drying

• Step 4. Dry the granules from Step 3 in a fluid bed at inlet temperature 60°C until the LOD is NMT 2.0%. [0167] Milling

• Step 5. Pass granules from Step 4 through the Comil with 1 .0 mm screen at the speed of 3000rpm.

[0168] Lubrication

• Step 6. Sift Magnesium stearate through a #40 ASTM (425 pm).

• Step 7. Lubricate the granules from Step 5 with the magnesium stearate from Step 6 for 3 min running at 20 rpm. Sift with croscarmellose sodium to get the final blend.

[0169] Compression

Step 8. Compress the final blend from Step 7 into tablets using 5.0 mm round punches for 50 mg weight tablets.

Table 1. Formulation components of filler type.

Table 2. Disintegration time of tablets.

Table 3. Dissolution results of tablets.

[0170] Conclusion: Based on the preparation formulation, disintegration time and dissolution results, we drew some conclusions. Firstly, disintegration time of the formulation using mannitol 160C was not less than 30s. Thus, mannitol 160C was not selected. Disintegration time of the formulation using mannitol 50C and 200SD were both less than 30s, but the formulation using mannitol 200SD had a shorter disintegration time. Secondly, dissolution of the formulation using mannitol 50C and 200SD was similar, but the formulation using mannitol 160C had a slower dissolution at 1min. In conclusion, mannitol 200SD was selected.

[0171] Disintegration Agent Proportion and Vendor

[0172] The disintegration agent proportion and vendor were evaluated by comparing the dissolution profile and disintegration time. A series of disintegration agents with different proportion and vendor were designed, Table 4 summarized the formulation components, Table 5 summarized the disintegration time, and Table 6 summarized the dissolution results.

Table 4. Formulation components of disintegration agent proportion and vendor.

Table 5. Disintegration time of tablets.

Table 6. Dissolution results of tablets.

[0173] Conclusion: Based on the preparation formulation, disintegration time and dissolution results, we drew some conclusions. Firstly, disintegration time of the formulation using 5.0% croscamnellose sodium from Vendor 1 and Vendor 2 was different. The formulation using 5.0% croscamnellose sodium from Vendor 2 had the shorted disintegration time. Thus, Vendor 2 was selected. Secondly, disintegration time of 7% and 9% croscamnellose sodium was similar, but they were better than 5% croscamnellose sodium. Thirdly, the dissolution of the formulation using different proportion and vendor of croscarmellose sodium was similar. In conclusion, proportion of croscarmellose sodium was selected at 7%.

[0174] Binder Type and Proportion

The binder type and proportion were evaluated by comparing the dissolution profile and disintegration time. A series of binder with different type and proportion were designed, Table 7 summarized the formulation components of binder type and proportion, Table 8 summarized the disintegration time, and Table 9 summarized the dissolution results.

Table 7. Formulation components of binder type and proportion.

Table 8. Disintegration time of tablets.

Table 9. Dissolution results of tablets.

[0175] Conclusion: Based on the preparation formulation, disintegration time and dissolution results, we drew some conclusions. Firstly, disintegration time of the 0.4mg strength formulation using 1.5% HPMC E5, 1.5% PVP K30 and 1.5% HPC EXF was different. The formulation using 1.5% HPC EXF had the shortest disintegration time. Dissolution of the 0.4mg strength formulation using 1 .5% HPMC E5, 1 .5% PVP K30 and 1 .5% HPC EXF was similar. Thus, HPC EXF was selected. Secondly, disintegration time and dissolution of 1.5%, 2.0% and 2.5% HPC EXF was similar. Thus, 1.5%-2.5% HPC EXF was acceptable. In conclusion, HPC EXF was selected, proportion of HPC EXF was selected at 2.0%.

[0176] Sweetening Agent

[0177] The sweetening agent proportion was evaluated by comparing the taste feedback. A series of sweetening agent with different proportion were designed, Table 10 summarized the formulation components of sweetening agent proportion.

[0178] Table 10. Formulation components of binder type and proportion.

[0179] Conclusion: Based on the preparation formulation and taster feedback, we drew some conclusions. The addition of sucralose could improve the taste. Forthe three proportions of 0.5%, 1.0% and 1.5% sucralose, subjects preferred the taste of 1.0% sucralose. In conclusion, proportion of sucralose was selected at 1.0%.

[0180] Lubricant

[0181] The lubricant type and proportion were evaluated by comparing the dissolution profile and disintegration time. A series of lubricant with different type and proportion were designed, Table 11 summarized the formulation components of lubricant type and proportion, Table 12 summarized the appearance, Table 13 summarized the disintegration time, and Table 14 summarized the dissolution results.

Table 11 Formulation components of lubricant type and proportion.

Table 12. Appearance of tablets.

Table 13. Disintegration time of tablets.

Table 14. Dissolution results of tablets.

[0182] Conclusion: Based on the preparation formulation, tablet appearance, disintegration time and dissolution results, we drew some conclusions. Firstly, tablets appearance of the formulation using 1 .0% and 1.5% sodium stearyl fumarate was sticking, but using 1.0% magnesium stearate was no sticking. Thus, magnesium stearate was more suitable. Secondly, dissolution of 1.0% and 1.5% sodium stearyl fumarate and 1.0 % magnesium stearate was similar. Disintegration time of 1 .5% sodium stearyl fumarate and 1 .0 % magnesium stearate was similar. Different lubricant type did not affect disintegration time and dissolution. Thus, 1.0% magnesium stearate was acceptable. In conclusion, magnesium stearate was selected, proportion of magnesium stearate was selected at 1 .0%.

[0183] Final Formulation

[0184] Three strengths of 0.4mg, 0.8mg and 1.2mg were produced with final formula and process.

Table 15 listed the formulation components. Table 16 summarized the content uniformity results and Table 17 summarized the others test results of tablets.

Table 15. Formulation components.

Table 16. Content uniformity of lobeglitazone tablets.

Table 17. Other test results of lobeglitazone tablets.

[0185] Conclusion: CD results, assay, impurity, dissolution, disintegration time, residual solvent and friability of three strengths of 0.4mg, 0.8mg and 1 ,2mg were acceptable.

Example 2: Stability studies

[0186] Accelerated Stability Study [0187] Three strengths of 0.4mg, 0.8mg and 1.2mg were produced with final formula and process and studied on accelerated stability conditions of 40°C /75% RH. The data was presented in Tablet 18, Table 19 and Table 20.

Table 18. Stability results of lobeglitazone ODT 0.4mg (Batch No.103613601).

Note: ND-Not detected.

Table 19. Stability results of lobeglitazone ODT 0.8mg (Batch No.103613401).

Note: ND-Not detected.

Table 20. Stability results of lobeglitazone ODT 1.2mg (Batch No.103613001).

Note: ND-Not detected.

[0188] Conclusions: After 3 months accelerated stability, for 1.2mg strength, there is a slight decrease in dissolution before 30 minutes and no other obvious change was observed in lobeglitazone ODT.

[0189] Stability of API Solution

[0190] Stability time of API solution is important for production process. Table 21 listed the stability results of API solution.

Table 21. Stability results of API solution.

Note: ND-Not detected. [0191] Conclusions: After 24h solution stability, no obvious change was observed in lobeglitazone solution.

Example 3: Pharmacokinetic Study of Lobeqlitazone Sulfate in Cynomolgus Monkeys Following Single Oral Administration

[0192] The purpose of this study is to determine the pharmacokinetics parameters in plasma of lobeglitazone sulfate orally disintegrating tablets in non-naive cynomolgus monkeys after single oral administration. The plasma concentration of lobeglitazone sulfate collected at different time points will be analyzed by LC-MS/MS method.

[0193] The test article (tablets) was used as received from the sponsor. Lobeglitazone orally disintegrating tablets were manufactured to support this study, as shown in Table 22.

Table 22. Description of test articles.

[0194] Experimental Design

[0195] Study Design: Twelve (12) male non-naTve cynomolgus monkeys were randomly assigned to four groups per to body weight (Table 23).

Table 23. Body weight of individual animals.

All animals were fasted overnight (10-18 hours) prior to dosing and fed at 4 hours after dosing.

[0196] Following dose administration, each animal received 5~10 ml_ of reverse osmosis water via oral gavage.

[0197] Test Articles Administration: Group 1 ~4: single oral administration

[0198] Sample Collection Intervals: for each animal, plasma samples were collected at predose, 0.5, 1 , 1.5, 2, 3, 4, 6, 8, 24 hours

[0199] Blood Collection and Plasma Preparation: Approximately 1 mL/sample of blood was collected from animals via hindlimb vein at appropriate time points. Blood was collected into appropriately labeled tubes containing sodium heparin as the anticoagulant. The tubes were gently inverted several times to ensure mixing and immediately placed on ice until centrifuged.

[0200] Plasma was obtained within 1 hour of collection by centrifugation at 2200 g and 2- 8°C for 10 minutes and the resulting plasma was separated and stored frozen at approximately -80°C.

[0201] Plasma samples were stored in the ultra-low temperature freezer (approximately - 80°C) before analysis. All the plasma samples were labeled with detailed information such as study number, animal number, matrix, time points of collection and date of collection.

[0202] Sample Analysis: The sample analysis was performed by the analytical sciences division of the testing facility by means of LC-MS/MS. The analytical results were confirmed using quality control samples for intra-assay variation. The accuracy of >66% of the quality control samples should be between 80-120% of the known value(s).

[0203] Pharmacokinetics Analysis: Phoenix WinNonlin® 7.0 software (Pharsight, USA) was applied to calculate the PK parameters with non-compartmental analysis modules. PK parameters including C_max, T_max ,TI/2, AUCo-t, AUCo-~, MRTo-t and MRTo-~ were calculated. When calculating pharmacokinetic parameters, the concentrations of BLQ samples before C_max (including those shown as "No peak") were recorded as 0, and BLQ samples after C_max (including samples leading to "No peak") were not included in the calculation.

[0204] Results

[0205] All animals showed no abnormalities during the experiment.

[0206] Group 1 : Male cynomolgus monkeys were administrated 1 tablet/animal (lobeglitazone orally disintegrating tablet, 0.4 mg) via single oral administration under fasted condition. The individual and mean plasma concentrations of lobeglitazone sulfate are shown in Table 24. The mean drug concentration-time curves are presented in Figure 1. Table 24. Individual and Mean Plasma Concentrations (ng/mL) of Lobeglitazone Sulfate in Male Cynomolgus Monkeys Following Single Oral Administration of 1 Tablet/Animal (Lobeglitazone Orally Disintegrating Tablet, 0.4 mg) under Fasted Condition.

Lobeglitazone Sulfate

Lobeglitazone orally disintegrating tablet, 0.4 mg

PO Time (h) 101 102 103 Mean PO SD CV (%)

Predose BLQ BLQ BLQ ND ± ND ND

0.50 210.255 31.023 217.274 152.851 ± 105.564 69.064

1.00 205.096 139.009 386.926 243.677 ± 128.383 52.686

1.50 134.598 95.806 266.178 165.527 ± 89.298 53.948

2.00 88.994 179.521 183.534 150.683 ± 53.462 35.480

3.00 59.984 89.412 100.882 83.426 ± 21.096 25.287

4.00 36.586 36.314 87.743 53.548 ± 29.615 55.305

6.00 6.957 5.653 20.496 11.035 ± 8.219 74.480

8.00 2.474 1.560 8.847 4.294 ± 3.970 92.462

24.00 BLQ BLQ BLQ ND ± ND ND

BLQ: Below Limit of Quantitation (LLOQ=1 ng/mL); ND: Not Determined.

[0207] Group 2: Male cynomolgus monkeys were administrated 1 tablet/animal (lobeglitazone orally disintegrating tablet, 0.8 mg) via single oral administration under fasted condition. The individual and mean plasma concentrations of lobeglitazone sulfate are shown in Table 25.

Table 25. Individual and Mean Plasma Concentrations (ng/mL) of Lobeglitazone Sulfate in Male Cynomolgus Monkeys Following Single Oral Administration of 1 Tablet/Animal (Lobeglitazone Orally Disintegrating Tablet, 0.8 mg) under Fasted Condition.

Lobeglitazone Sulfate

Lobeglitazone orally disintegrating tablet, 0.8 mg

PO Time (h) 201 202 203 Mean PO SD CV (%)

Predose BLQ BLQ BLQ ND ± ND ND

0.50 70.948 460.029 116.133 215.703 ± 212.795 98.652

1.00 143.821 389.716 291.646 275.061 ± 123.784 45.002

1.50 234.510 274.289 275.571 261.457 ± 23.345 8.929

2.00 244.071 182.641 296.927 241.213 ± 57.197 23.712

3.00 134.671 88.206 180.654 134.510 ± 46.224 34.365

4.00 51.858 51.044 103.130 68.677 ± 29.840 43.450 6.00 10.897 13.849 22.649 15.798 ± 6.113 38.696

8.00 2.718 3.617 6.577 4.304 ± 2.019 46.918

24.00 BLQ BLQ BLQ ND ± ND ND

BLQ: Below Limit of Quantitation (LLOQ=1 ng/mL); ND: Not Determined.

[0208] Group 3: Male cynomolgus monkeys were administrated 1 tablet/animal (lobeglitazone orally disintegrating tablet, 1.2 mg) via single oral administration under fasted condition. The individual and mean plasma concentrations of lobeglitazone sulfate are shown in Table 26.

Table 26. Individual and Mean Plasma Concentrations (ng/mL) of Lobeglitazone Sulfate in Male Cynomolgus Monkeys Following Single Oral Administration of 1 Tablet/Animal (Lobeglitazone Orally Disintegrating Tablet, 1.2 mg) under Fasted Condition.

Lobeglitazone Sulfate

Lobeglitazone orally disintegrating tablet, 1.2 mg

PO Time (h) 301 302 303 Mean PO SD CV (%)

Predose BLQ BLQ BLQ ND ± ND ND

0.50 649.523 1089.180 156.887 631.863 ± 466.397 73.813

1.00 788.144 744.388 558.003 696.845 ± 122.215 17.538

1.50 619.587 520.416 432.335 524.113 ± 93.681 17.874

2.00 452.134 286.318 272.148 336.867 ± 100.076 29.708

3.00 275.384 166.320 180.950 207.551 ± 59.198 28.522

4.00 205.546 68.901 134.473 136.307 ± 68.341 50.138

6.00 73.056 18.277 37.273 42.869 ± 27.815 64.885

8.00 27.310 5.941 10.796 14.682 ± 11.203 76.300

24.00 1.764 BLQ BLQ ND ± ND ND

BLQ: Below Limit of Quantitation (LLOQ=1 ng/mL); ND: Not Determined.

[0209] Group 4: Male cynomolgus monkeys were administrated 1 tablet/animal (Duvie® tablet, 0.5 mg) via single oral administration under fasted condition. The individual and mean plasma concentrations of lobeglitazone sulfate are shown in Table 27.

Table 27. Individual and Mean Plasma Concentrations (ng/mL) of Lobeglitazone Sulfate in Male Cynomolgus Monkeys Following Single Oral Administration of 1 Tablet/Animal (Duvie® Tablet, 0.5 mg) under Fasted Condition.

Lobeglitazone Sulfate

Duvie® tablet, 0.5 mg

PO Time (h) 401 402 403 Mean PO SD CV (%)

Predose BLQ BLQ BLQ ND 1 ND ND

0.50 377.478 383.068 105.117 288.554 1 158.886 55.063

1.00 329.892 308.607 181.551 273.350 1 80.209 29.343

1.50 209.471 233.206 224.452 222.376 1 12.003 5.398

2.00 147.906 157.357 229.063 178.109 1 44.380 24.917

3.00 66.361 101.922 125.289 97.857 1 29.674 30.323

4.00 39.925 61.274 75.099 58.766 1 17.721 30.155

6.00 11.407 17.767 17.784 15.652 1 3.677 23.489

8.00 3.857 5.686 4.710 4.751 1 0.915 19.262

24.00 BLQ BLQ BLQ ND 1 ND ND

BLQ: Below Limit of Quantitation (LLOQ=1 ng/mL); ND: Not Determined.

[0210] Conclusion

[0211] The main pharmacokinetic parameters of lobeglitazone sulfate in plasma of cynomolgus monkeys after single oral administration are summarized in Table 28. These data demonstrated that the orally disintegrating tablets provided herein (i.e., 0.4, 0.8, and 1.2 mg formulations) have a similar relative oral bioavailability to Duvie®. The improved orally disintegrating formulations/tablets provided herein mitigate the side effects of Duvie®, which is an ingested/swallowed pill, due to the oral absorption of lobeglitazone enabled by the orally disintegrating tablets described herein.

[0212] After a single oral administration of 1 tablet/animal (lobeglitazone orally disintegrating tablet, 0.4 mg) in male cynomolgus monkeys under fasted condition, the mean T1/2 of lobeglitazone sulfate in plasma was 1.09±0.24 h, the mean C_max was 258.90±1 1 1.93 ng/mL, the mean AUC<o-t) was 584.15±235.97 h*ng/mL, the mean AUC(o- ;was 591 .73 244.11 h*ng/mL.

[0213] After a single oral administration of 1 tablet/animal (lobeglitazone orally disintegrating tablet, 0.8 mg) in male cynomolgus monkeys under fasted condition, the mean T1/2 of lobeglitazone sulfate in plasma was 1.0010.06 h, the mean C_max was 333.6811 12.57 ng/mL, the mean AUC(o-t) was 830.451163.36 h*ng/mL, the mean AUC_ra- was 836.741165.96 h*ng/mL. Table 28. The Individual Main Pharmacokinetic Parameters of Lobeglitazone Sulfate in Plasma of Male Cynomolgus Monkeys Following Single Oral Administration of Different Tablets (Orally Disintegrating Tablets: G1, G2, G3; Immediate-Release Tablet: G4).

[0214] After a single oral administration of 1 tablet/animal (lobeglitazone orally disintegrating tablet, 1.2 mg) in male cynomolgus monkeys under fasted condition, the mean Tie of lobeglitazone sulfate in plasma was 1.9411.43 h, the mean C_max was 811.781266.38 ng/mL, the mean AUC(o-t) was 1769.02±558.72 h*ng/ml_, the mean AUC<o- - ; was 1781.001554.95 h*ng/mL.

[0215] After a single oral administration of 1 tablet/animal (Duvie® tablet, 0.5 mg) in male cynomolgus monkeys under fasted condition, the mean T1/2 of lobeglitazone sulfate in plasma was 1.1310.1 1 h, the mean C_max was 329.87187.35 ng/mL, the mean AUC(o-t) was 747.78159.24 h*ng/mL, the mean AUC₍o- ; was 755.53160.95 h*ng/mL.

[0216] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” As used herein the terms "about" and “approximately” means within 10 to 15%, preferably within 5 to 10%. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0217] The terms “a,” “an,” “the” and similar referents used in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope

507987239.6 of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0218] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[0219] Specific embodiments disclosed herein may be further limited in the claims using consisting of or consisting essentially of language. When used in the claims, whether as filed or added per amendment, the transition term “consisting of’ excludes any element, step, or ingredient not specified in the claims. The transition term “consisting essentially of’ limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s). Embodiments of the invention so claimed are inherently or expressly described and enabled herein.

[0220] Furthermore, numerous references have been made to patents and printed publications throughout this specification. Each of the above-cited references and printed publications are individually incorporated herein by reference in their entirety.

[0221] In closing, it is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the present invention. Other modifications that may be employed are within the scope of the invention. Thus, by way of example, but not of limitation, alternative configurations of the present invention may be utilized in accordance with the teachings herein. Accordingly, the present invention is not limited to that precisely as shown and described.

507987239.6

Claims

CLAIMS What is claimed is:

1 . An orally disintegrating tablet (ODT) formulation comprising a thiazolidinedione, selected from one or more of pioglitazone, rosiglitazone, lobeglitazone, ciglitazone, darglitazone, deuterium-stabilized R-pioglitazone, englitazone, leriglitazone, netoglitazone, rivoglitazone, troglitazone, and balaglitazone, or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, cocrystal, enantiomer, or deuterated form thereof.

2. The formulation of claim 1 , wherein the thiazolidinedione is lobeglitazone or a pharmaceutically acceptable salt thereof.

3. The formulation of claim 1 , wherein the thiazolidinedione is not pioglitazone or rosiglitazone.

4. The formulation of claim 1 , wherein the dose of lobeglitazone is about 0.01 to 100 mg, or preferably about 0.1 to 10 mg, or more preferably about 0.4 to 2 mg.

5. The formulation of claim 1 , wherein the 80% of tablet is dissolved within about 60 min, or preferably within about 30 min, or more preferably within about 15 min.

6. The formulation of claim 1 , further comprising a binder, wherein the binder is hydroxypropyl cellulose.

7. The formulation of claim 1 , further comprising a filler, wherein the filler is mannitol.

8. The formulation of claim 1 , wherein lobeglitazone or the pharmaceutically acceptable salt or ester thereof is present at a concentration from 0.01 % to 50% weight by weight of the total formulation.

9. The use of an orally disintegrating tablet of thiazolidinedione for the treatment digestive diseases selected from abdominal adhesions, achalasia, acid reflux (gastroesophageal reflux disease or GERD) in adults, acid reflux (GERD) in infants, anatomic problems of the lower Gl tract, appendicitis, Barrett's esophagus, bowel control problems (fecal incontinence), celiac disease, colon polyps, constipation, Crohn's disease, cyclic vomiting syndrome, diarrhea, diverticulosis and diverticulitis, dumping syndrome, food poisoning, gallstones, gas, gastritis, gastroparesis, Gl bleeding, hemorrhoids, indigestion (dyspepsia), inguinal hernia, intestinal pseudo-obstruction, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), lactose intolerance, liver disease, microscopic colitis, ostomy surgery of the bowel, pancreatitis, peptic ulcers (stomach ulcers), proctitis, short bowel syndrome, ulcerative colitis, viral gastroenteritis, and Zollinger-Ellison syndrome, or a condition associated therewith.

10. The method of claim 9, wherein the thiazolidinedione is lobeglitazone, or a pharmaceutically acceptable salt thereof.

11 . The method of claim 9, wherein the digestive disease is gastroparesis, such as idiopathic gastroparesis, diabetic gastroparesis, post-surgical gastroparesis, or medication- induced gastroparesis.

12. The use of an orally disintegrating tablet of thiazolidinedione for the treatment kidney diseases such as glomerular diseases and nephrotic syndrome.

13. The method of claim 12, wherein the thiazolidinedione is lobeglitazone, or a pharmaceutically acceptable salt thereof.

14. An orally disintegrating tablet comprising an intragranular portion including a thiazolidinedione, or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, cocrystal, enantiomer, or deuterated form thereof, ethanol, hydroxy propyl cellulose (HPC), mannitol, microcrystalline cellulose (MCC), polyvinylpyrrolidone (PVP), a sweetener and croscarmellose sodium; and an extragranular portion including magnesium stearate.

15. The tablet of claim 14, wherein the thiazolidinedione is lobeglitazone, or a pharmaceutically acceptable salt thereof.

16. The tablet of claim 14, wherein the thiazolidinedione is not pioglitazone or rosiglitazone.

17. A granule comprising a thiazolidinedione, or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, cocrystal, enantiomer, or deuterated form thereof, ethanol, hydroxy propyl cellulose (HPC), mannitol, microcrystalline cellulose (MCC), polyvinylpyrrolidone (PVP), a sweetener and croscarmellose sodium.

18. The granule of claim 17, having an average diameter of about 1 mm.

19. An orally disintegrating tablet comprising a plurality of the granules of claim 17 dispersed in an extragranular matrix.

20. The orally disintegrating tablet of claim 19, wherein the extragranular matrix comprises magnesium stearate.