Pharmaceutical composition for the treatment of a disease

Abstract

The present invention relates to pharmaceutical compositions comprising 5-(4-(2-((6-(4-methoxyphenoxy)pyrimidin-4-yl)(methyl)amino)ethoxy)benzyl)thiazolidine-2,4-dione, and salts and co-crystal forms thereof, for the treatment of diseases, processes for the preparation of such formulations, and pharmacokinetic parameters controlled by the formulations.

Description

[0001] Related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 535,192, filed August 29, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This article discloses orally disintegrating formulations of 5-(4-(2-((6-(4-methoxyphenoxy)pyrimidin-4-yl)(methyl)amino)ethoxy)benzyl)thiazolidin-2,4-dione and its salts and cocrystalline forms for the treatment of diseases, processes for preparing such formulations, and pharmacokinetic parameters controlled by such formulations. Summary of the Invention

[0004] This document discloses orally disintegrating formulations of thiazolidinedione and methods of treating digestive system or gastrointestinal disorders using the orally disintegrating tablet formulations. 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.

[0005] In some implementations, digestive system diseases or gastrointestinal diseases affect digestive organs or tissues selected from the mouth, pharynx (larynx), esophagus, stomach, small intestine, large intestine, rectum, anus, salivary glands, liver, gallbladder, and pancreas.

[0006] In some implementations, the method includes treating gastrointestinal cells selected from absorptive cells (intestinal epithelial cells), goblet cells, pancreatic islet cells, enteroendocrine cells, hepatocytes, Paneth cells, fenestrated hepatic endothelial cells, Kupffer cells, serous cells, gastric chief cells, mucous cells, smooth muscle cells, gastric parietal cells, myoepithelial cells, stem cells, gastric surface mucous cells, pancreatic acinar cells, taste buds, Cajal interstitial cell (ICC) type cells, and neurons.

[0007] In some implementations, the cells are animal cells. In some implementations, the cells are human cells.

[0008] In some implementations, the cells are used in subjects who have or are at risk of gastrointestinal or digestive system diseases or conditions selected from any one or more of the following: abdominal adhesions, adult acid reflux (gastroesophageal reflux disease or GERD), infant acid reflux (GERD), anatomical problems of the lower gastrointestinal tract, appendicitis, Barrett's esophagus, bowel control problems (fecal incontinence), celiac disease, colonic polyps, constipation, Crohn's disease, periodic vomiting syndrome, diarrhea, diverticulosis and diverticulitis, dumping syndrome, food poisoning, Gallstones, flatulence, gastritis, gastroparesis, gastrointestinal bleeding, hemorrhoids, dyspepsia, inguinal hernia, pseudo-obstruction, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), lactose intolerance, liver disease, microscopic colitis, colostomy, pancreatitis, peptic ulcer (gastric ulcer), proctitis, short bowel syndrome, ulcerative colitis, viral gastroenteritis, Zollinger-Ellison syndrome, or related symptoms. In some implementations, the disease or symptom is gastroparesis. In some implementations, gastroparesis is idiopathic gastroparesis, diabetic gastroparesis, postoperative gastroparesis, or drug-induced gastroparesis.

[0009] This document also discloses the use of orally disintegrating formulations of one or more thiazolidinediones selected from pioglitazone, rosiglitazone, lobeglitazone, cycloglitazone, dapaglitazone, empaglitazone, neglitazone, linaglitazone, troglitazone, and baglitazone for the relief of 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 using the ANMS GCSI-DD. In some embodiments, the signs and symptoms of gastroparesis are measured using changes in the GCSI-DD score. In some embodiments, the signs and symptoms of gastroparesis are measured using changes in the GCSI-DD score from baseline to 4 weeks of treatment. In some embodiments, the signs and symptoms of gastroparesis are measured using changes in the GCSI-DD score from baseline to 8 weeks of treatment. In some embodiments, the signs and symptoms of gastroparesis are measured using changes in the GCSI-DD score from baseline to 12 weeks of treatment. In some implementations, the signs and symptoms of gastroparesis are measured by the change in GCSI-DD score from baseline to one year of treatment.

[0010] This document also discloses the use of orally disintegrating formulations of one or more thiazolidinediones selected from pioglitazone, rosiglitazone, lobeglitazone, cycloglitazone, dapaglitazone, empaglitazone, neglitazone, linaglitazone, troglitazone, and baraglitazone for reducing the severity of nausea in subjects with gastroparesis. In some embodiments, the thiazolidinedione is lobeglitazone. In some embodiments, the reduction in nausea severity is measured by the change in nausea severity from baseline to 4 weeks of treatment. In some embodiments, the reduction in nausea severity is measured by the change in nausea severity from baseline to 8 weeks of treatment. In some embodiments, the reduction in nausea severity is measured by the change in nausea severity from baseline to 12 weeks of treatment. In some embodiments, the reduction in nausea severity is measured by the change in nausea severity from baseline to 1 year of treatment.

[0011] This document also discloses the use of orally disintegrating formulations of one or more thiazolidinediones selected from pioglitazone, rosiglitazone, lobeglitazone, cycloglitazone, dapaglitazone, empaglitazone, neglitazone, linaglitazone, troglitazone, and baglitazone for reducing the severity of early satiety in subjects with gastroparesis. In some embodiments, the thiazolidinedione is lobeglitazone. In some embodiments, the reduction in the severity of early satiety is measured by the change in the severity of early satiety from baseline to 4 weeks of treatment. In some embodiments, the reduction in the severity of early satiety is measured by the change in the severity of early satiety from baseline to 8 weeks of treatment. In some embodiments, the reduction in the severity of early satiety is measured by the change in the severity of early satiety from baseline to 12 weeks of treatment. In some embodiments, the reduction in the severity of early satiety is measured by the change in the severity of early satiety from baseline to 1 year of treatment. In some embodiments, the reduction in the severity of early satiety is measured by the change in the severity of early satiety from baseline to more than 1 year of treatment.

[0012] This document also discloses the use of orally disintegrating formulations of one or more thiazolidinediones selected from pioglitazone, rosiglitazone, lobeglitazone, cycloglitazone, dapaglitazone, empaglitazone, neglitazone, linaglitazone, troglitazone, and baraglitazone for reducing the severity of postprandial fullness in subjects with gastroparesis. In some embodiments, the thiazolidinedione is lobeglitazone. In some embodiments, the reduction in the severity of postprandial fullness is measured by the change in the severity of postprandial fullness from baseline to 4 weeks of treatment. In some embodiments, the reduction in the severity of postprandial fullness is measured by the change in the severity of postprandial fullness from baseline to 8 weeks of treatment. In some embodiments, the reduction in the severity of postprandial fullness is measured by the change in the severity of postprandial fullness from baseline to 12 weeks of treatment. In some embodiments, the reduction in the severity of postprandial fullness is measured by the change in the severity of postprandial fullness from baseline to 1 year of treatment. In some implementations, the reduction in the severity of postprandial fullness is measured by the change in the severity of postprandial fullness from baseline to more than 1 year of treatment.

[0013] This document also discloses the use of orally disintegrating formulations of one or more thiazolidinediones selected from pioglitazone, rosiglitazone, lobeglitazone, cycloglitazone, dapaglitazone, empaglitazone, neglitazone, linaglitazone, troglitazone, and baraglitazone for reducing the severity of upper abdominal pain in subjects with gastroparesis. In some embodiments, the thiazolidinedione is lobeglitazone. In some embodiments, the reduction in the severity of upper abdominal pain is measured by the change in the severity of upper abdominal pain from baseline to 4 weeks of treatment. In some embodiments, the reduction in the severity of upper abdominal pain is measured by the change in the severity of upper abdominal pain from baseline to 8 weeks of treatment. In some embodiments, the reduction in the severity of upper abdominal pain is measured by the change in the severity of upper abdominal pain from baseline to 12 weeks of treatment. In some embodiments, the reduction in the severity of upper abdominal pain is measured by the change in the severity of upper abdominal pain from baseline to 1 year of treatment. In some implementations, the reduction in the severity of upper abdominal pain is measured by the change in the severity of upper abdominal pain from baseline to more than one year of treatment.

[0014] This document also discloses the use of orally disintegrating formulations of one or more thiazolidinediones selected from pioglitazone, rosiglitazone, lobeglitazone, cycloglitazone, dapaglitazone, empaglitazone, neglitazone, linaglitazone, troglitazone, and baraglitazone for reducing the frequency of vomiting episodes in subjects with gastroparesis. In some embodiments, the thiazolidinedione is lobeglitazone. In some embodiments, the reduction in the severity of vomiting episodes is measured by the change in the severity of vomiting episodes from baseline to 4 weeks of treatment. In some embodiments, the reduction in the severity of vomiting episodes is measured by the change in the severity of vomiting episodes from baseline to 8 weeks of treatment. In some embodiments, the reduction in the severity of vomiting episodes is measured by the change in the severity of vomiting episodes from baseline to 12 weeks of treatment. In some embodiments, the reduction in the severity of vomiting episodes is measured by the change in the severity of vomiting episodes from baseline to 1 year of treatment. In some embodiments, the reduction in the severity of vomiting episodes is measured by the change in the severity of vomiting episodes from baseline to more than 1 year of treatment.

[0015] This document also discloses the use of orally disintegrating formulations of one or more thiazolidinediones selected from pioglitazone, rosiglitazone, lobeglitazone, cycloglitazone, dapaglitazone, empaglitazone, neglitazone, linaglitazone, troglitazone, and baraglitazone for reducing the overall severity of gastroparesis. In some embodiments, the thiazolidinedione is lobeglitazone. In some embodiments, the reduction in the overall severity of gastroparesis is measured by the change in the severity of the overall severity of gastroparesis from baseline to 4 weeks of treatment. In some embodiments, the reduction in the overall severity of gastroparesis is measured by the change in the severity of the overall severity of gastroparesis from baseline to 8 weeks of treatment. In some embodiments, the reduction in the overall severity of gastroparesis is measured by the change in the severity of the overall severity of gastroparesis from baseline to 12 weeks of treatment. In some implementations, the reduction in the overall severity of gastroparesis is measured by the change in the overall severity of gastroparesis from baseline to one year of treatment.

[0016] This document also discloses the use of orally disintegrating formulations of one or more thiazolidinediones selected from pioglitazone, rosiglitazone, lobeglitazone, cycloglitazone, dapaglitazone, empaglitazone, neglitazone, linaglitazone, troglitazone, and baraglitazone for slowing, stopping, or reversing the progression of digestive system diseases. In some embodiments, the thiazolidinedione is lobeglitazone.

[0017] This document also discloses a method for treating digestive system diseases in mammals, the method comprising administering to the mammal an effective amount of a thiazolidinedione selected from one or more of pioglitazone, rosiglitazone, lobeglitazone, cycloglitazone, dapaglitazone, empaglitazone, neiglitazone, linaglitazone, troglitazone, and baraglitazone. In some embodiments, the digestive system disease is gastroparesis or IBD. In some embodiments, the thiazolidinedione is lobeglitazone.

[0018] In some implementations, gastroparesis is idiopathic gastroparesis, diabetic gastroparesis, postoperative gastroparesis, or drug-induced gastroparesis. Attached Figure Description

[0019] Figure 1 This study describes the mean plasma concentrations of lobeglitazone sulfate in male cynomolgus monkeys following a single oral administration of different tablets. The orally disintegrating lobeglitazone tablets (ODTs) used in the PK studies were 0.4 mg, 0.8 mg, and 1.2 mg. Duvie® tablets contain 0.415 mg of free lobeglitazone base. Detailed Implementation

[0020] This document discloses orally disintegrating tablet (ODT) dosage forms of thioglitazone that achieve significantly better onset of action and pharmacokinetic parameters. In some embodiments, thioglitazone is lobeglitazone. In some embodiments, this formulation is used to treat gastrointestinal disorders. In some embodiments, this formulation is used to treat kidney disorders.

[0021] ODTs are solid dosage forms that disintegrate and dissolve in the oral cavity (on or under the tongue or in the buccal cavity) in the absence of water within 60 seconds or less. ODTs release drugs in the oral cavity for absorption through local oral mucosal tissues and through the pregastric segment (e.g., mouth, pharynx, and esophagus), gastric segment (i.e., stomach), and postgastric segment (e.g., small intestine and large intestine).

[0022] Pharmacokinetics is a branch of pharmacology that studies the changes in the concentration or amount of drug substances and their metabolites in body fluids, tissues, and excretions over time. Generally, pharmacokinetic studies focus on understanding and characterizing drug absorption, distribution, metabolism, and excretion, and their relationships to pharmacodynamics and toxicology. In particular, drug absorption, the transport of the active pharmaceutical ingredient (API) into the bloodstream, represents a key PK process for orally administered drugs. Most APIs are solids under environmental conditions, and most drug products are developed in solid dosage forms and delivered orally. Oral absorption of drugs is typically a two-step process. First, the drug product dissolves in the biological fluids secreted in the gastrointestinal (GI) tract. This releases API molecules, which can then permeate across the gastrointestinal membrane via modes such as passive diffusion or active transport. Therefore, solubility and permeability are two key parameters that significantly affect the efficiency of orally administered drug absorption. In this context, the U.S. Food and Drug Administration (FDA) issued industry guidance to meet the need for identifying and characterizing the solid form of drug molecules and to classify orally administered drugs according to their solubility and permeability via the Biopharmaceutics Classification System (BCS). Regarding the BCS, a drug molecule is considered highly soluble when its highest strength dissolves in less than 250 ml of water within a pH range of 1 to 7.5. Furthermore, a drug molecule is considered highly permeable when, based on mass balance or compared to an intravenous reference dose, its absorption in the body exceeds 90% of the administered dose. It has been noted that approximately 30% of orally administered drugs currently on the market fall into BCS Class II (i.e., low solubility and high permeability). In addition, approximately 70% of new chemical entities (NCEs) under development for potential oral administration also exhibit low solubility. In drug development, much effort has been directed towards improving the water solubility of poorly soluble APIs.

[0023] This article provides an orally disintegrating tablet (ODT) formulation comprising a thiazolidinedione, or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, cocrystal, enantiomer, or deuterated form thereof, wherein the thiazolidinedione is selected from one or more of pioglitazone, rosiglitazone, lobeglitazone, cycloglitazone, dapaglitazone, deuterated R-pioglitazone, empaglitazone, leriglitazone, neiglitazone, linaglitazone, troglitazone, and baraglitazone.

[0024] In some embodiments, thiazolidinedione is lobeglitazone or a pharmaceutically acceptable salt thereof. In some embodiments, thiazolidinedione is not pioglitazone or rosiglitazone.

[0025] 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.

[0026] In some embodiments, 80% of the tablets dissolve within approximately 60 minutes. In some embodiments, 80% of the tablets dissolve within approximately 30 minutes. In some embodiments, 80% of the tablets dissolve within approximately 15 minutes.

[0027] In some embodiments, the formulation further comprises a binder, wherein the binder is hydroxypropyl cellulose.

[0028] In some embodiments, the formulation further comprises a filler, wherein the filler is mannitol.

[0029] In some embodiments, lobeglitazone or a pharmaceutically acceptable salt or ester thereof is present in the formulation at a concentration of 0.01% by weight to 50% by weight of the total formulation.

[0030] This article provides the use of orally disintegrating tablets of thiazolidinediones for the treatment of digestive system disorders selected from abdominal adhesions, achalasia, adult acid reflux (gastroesophageal reflux disease or GERD), infantile acid reflux (GERD), anatomical problems of the lower gastrointestinal tract, appendicitis, Barrett's esophagus, bowel control problems (fecal incontinence), celiac disease, colonic polyps, constipation, Crohn's disease, periodic vomiting syndrome, diarrhea, diverticulosis and diverticulitis, dumping syndrome, food poisoning, gallstones, flatulence, and gastritis. Gastroparesis, gastrointestinal bleeding, hemorrhoids, indigestion (dyspepsia), inguinal hernia, pseudo-intestinal obstruction, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), lactose intolerance, liver disease, microscopic colitis, colostomy, pancreatitis, peptic ulcer (gastric ulcer), proctitis, short bowel syndrome, ulcerative colitis, viral gastroenteritis, and Zollinger-Ellison syndrome or related symptoms.

[0031] In some implementations, thiazolidinedione is lobeglitazone or a pharmaceutically acceptable salt thereof.

[0032] In some implementations, digestive system diseases are gastroparesis, such as idiopathic gastroparesis, diabetic gastroparesis, postoperative gastroparesis, or drug-induced gastroparesis.

[0033] This article provides information on the use of orally disintegrating tablets of thiazolidinediones for the treatment of kidney diseases such as glomerular diseases and nephrotic syndrome.

[0034] In some implementations, thiazolidinedione is lobeglitazone or a pharmaceutically acceptable salt thereof.

[0035] This article provides an orally disintegrating tablet comprising an inner portion comprising a thiazolidinedione or a pharmaceutically acceptable prodrug thereof, a salt, a solvate, a hydrate, a cocrystal, an enantiomer or a deuterated form thereof, ethanol, hydroxypropyl cellulose (HPC), mannitol, microcrystalline cellulose (MCC), polyvinylpyrrolidone (PVP), a sweetener, and croscarmellose sodium; and an outer portion comprising magnesium stearate.

[0036] 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.

[0037] This article provides a granule comprising a thiazolidinedione or a pharmaceutically acceptable prodrug thereof, a salt, a solvate, a hydrate, a cocrystal, an enantiomer or its deuterated form, ethanol, hydroxypropyl cellulose (HPC), mannitol, microcrystalline cellulose (MCC), polyvinylpyrrolidone (PVP), a sweetener, and croscarmellose sodium.

[0038] This article provides an orally disintegrating tablet comprising a plurality of the aforementioned particles.

[0039] In some embodiments, the orally disintegrating tablets described herein can be administered to patients with 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.

[0040] In some embodiments, an orally disintegrating tablet is provided, comprising a plurality of particles dispersed in an extragranular matrix. In some embodiments, the plurality of particles are referred to herein as an intragranular part / portion and dispersed in an extragranular matrix, referred herein as an extragranular part / portion.

[0041] In some embodiments, the composition forming the granules contains 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 granule composition contains about 15% w / w to about 20% w / w of a second filler (e.g., MCC 101). In some embodiments, the granule composition contains 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 granule composition contains about 1% w / w to about 5% w / w of a sweetener (e.g., sucralose). In some embodiments, the granule composition contains about 0.5% w / w to about 3.5% w / w of lobeglitazone free base. In some embodiments, the granule composition contains about 1% w / w to about 3.5% w / w of lobeglitazone sulfate. In some embodiments, the composition of the intraparticle matrix contains about 5% w / w to 10% w / w of a disintegrant (e.g., croscarmellose sodium cellulose).

[0042] In some implementations, the outer portion of the particles contains a lubricant (e.g., magnesium stearate, sodium stearoyl fumarate).

[0043] In some embodiments, the composition of the outer portion of the particles contains about 1% w / w to 3% w / w of a lubricant (e.g., magnesium stearate, sodium stearoyl fumarate) and about 5% w / w to 10% w / w of a disintegrant (e.g., croscarmellose sodium), and in such embodiments, the disintegrant is not present in the inner portion of the particles.

[0044] In some embodiments, the particles have an average particle size of about 1 mm. In some embodiments, the particles have a regular shape (e.g., spherical) and an average diameter of about 1 mm or less, and can be sieved through a 1 mm sieve. In some embodiments, the particles have an irregular shape and a D50 of about 1 mm or less.

[0045] In some embodiments, the granules provide about 90% to about 99% by weight (w / w), about 95% to about 99% by weight, about 92% to about 98% by weight, or about 95% to about 99% by weight, based on the total weight of the tablet, and form the granule portion of the tablet. In some embodiments, the outer portion of the granules provides about 0.5% by weight to about 10% by weight, about 5% by weight to about 9% by weight, or about 0.5% by weight to about 3% by weight, of the orally disintegrating tablet described herein.

[0046] In some embodiments, the filler and sweetener are sieved and mixed together, followed by the 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 sieved through a 9.5 mm sieve. The granules are then dried, ground, and sieved through a 1 mm sieve to provide the granule portion of the orally disintegrating tablets described herein. The granule portion is blended with a lubricant (e.g., magnesium stearate) and a dispersant (e.g., croscarmellose sodium) to provide a final blend, which is then compressed into tablets.

[0047] In some embodiments, the orally disintegrating tablets described herein comprise about 0.8% to about 3.2% (w / w), about 0.8% to about 2% (w / w), or about 1.5% (w / w) to about 3% (w / w) of thiazolidinedione or a pharmaceutically acceptable salt thereof, based on the total weight of the tablet. In some embodiments, the orally disintegrating tablets described herein comprise 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 thiazolidinedione or a pharmaceutically acceptable salt thereof. In some embodiments, the orally disintegrating tablets described herein comprise about 0.9% (w / w) of lobeglitazone sulfate. In some embodiments, the orally disintegrating tablets described herein comprise about 1.9% (w / w) of lobeglitazone sulfate. In some embodiments, the orally disintegrating tablets described herein comprise about 2.8% (w / w) of lobeglitazone sulfate. In some embodiments, the orally disintegrating tablets described herein contain about 0.8% w / w lobeglitazone free base. In some embodiments, the orally disintegrating tablets described herein contain about 2.4% w / w lobeglitazone free base.

[0048] In some embodiments, the orally disintegrating tablets described herein contain about 1% w / w to about 5% w / w or about 1% w / w to about 3% w / w of a binder (e.g., hydroxypropyl cellulose). In some embodiments, the orally disintegrating tablets described herein contain 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, the orally disintegrating tablets described herein contain about 2% w / w of hydroxypropyl cellulose.

[0049] In some embodiments, the orally disintegrating tablets described herein contain about 60% w / w to about 80% w / w, about 66% w / w to about 78% w / w, or about 70% w / w to about 72% w / w of a first filler (e.g., mannitol). In some embodiments, the orally disintegrating tablets described herein contain about 70% w / w of mannitol. In some embodiments, the orally disintegrating tablets described herein contain about 71% w / w of mannitol. In some embodiments, the orally disintegrating tablets described herein contain about 72% w / w of mannitol.

[0050] In some embodiments, the orally disintegrating tablets described herein contain about 10% w / w to about 20% w / w or about 14% w / w to about 18% w / w of a second filler (e.g., microcrystalline cellulose). In some embodiments, the orally disintegrating tablets described herein contain about 16% w / w of microcrystalline cellulose.

[0051] In some embodiments, the orally disintegrating tablets described herein contain about 4% w / w to about 10% w / w or about 6% w / w to about 8% w / w of a disintegrant (e.g., croscarmellose sodium). In some embodiments, the orally disintegrating tablets described herein contain about 7% w / w of croscarmellose sodium.

[0052] In some embodiments, the orally disintegrating tablets described herein contain about 0.1% w / w to about 3% w / w or about 0.1% w / w to about 2% w / w of a lubricant (e.g., magnesium stearate). In some embodiments, the orally disintegrating tablets described herein contain about 1% w / w of magnesium stearate.

[0053] In some embodiments, the orally disintegrating tablets described herein contain about 0.1% w / w to about 2% w / w of a sweetener (e.g., sucralose). In some embodiments, the orally disintegrating tablets described herein contain about 1% w / w of sucralose. In some embodiments, the orally disintegrating tablets described herein contain about 1.5% w / w of sucralose.

[0054] In some embodiments, the orally disintegrating tablets described herein are prepared from a solution comprising a thiazolidinedione and about 20% w / w to about 35% w / w ethanol, or about 23% w / w to about 33% w / w ethanol. In some embodiments, the orally disintegrating tablets described herein are prepared from a solution comprising about 20% w / w, about 25% w / w, about 30% w / w, or about 35% w / w ethanol. In some embodiments, the orally disintegrating tablets described herein are prepared from a solution comprising about 23% w / w ethanol. In some embodiments, the orally disintegrating tablets described herein are prepared from a solution comprising about 33% w / w ethanol.

[0055] In some embodiments, the orally disintegrating tablets described herein comprise 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 of magnesium stearate. In some embodiments, the orally disintegrating tablets described herein comprise about 0.8% w / w of lobeglitazone free base, 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 of magnesium stearate.

[0056] In some embodiments, the orally disintegrating tablets described herein comprise 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 of magnesium stearate. In some embodiments, the orally disintegrating tablets described herein comprise about 0.8% w / w of lobeglitazone free base, 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 of magnesium stearate.

[0057] In some embodiments, the orally disintegrating tablets described herein comprise 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 of magnesium stearate. In some embodiments, the orally disintegrating tablets described herein comprise about 0.8% w / w of lobeglitazone free base, 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 of magnesium stearate.

[0058] In some embodiments, the orally disintegrating tablets described herein comprise 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 of magnesium stearate. In some embodiments, the orally disintegrating tablets described herein comprise about 2.4% w / w of lobeglitazone free base, 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 of magnesium stearate.

[0059] In some embodiments, the orally disintegrating tablets described herein comprise 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 of magnesium stearate. In some embodiments, the orally disintegrating tablets described herein comprise about 2.4% w / w of lobeglitazone free base, 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 of magnesium stearate.

[0060] In some embodiments, the orally disintegrating tablets described herein comprise 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 of magnesium stearate. In some embodiments, the orally disintegrating tablets described herein comprise about 2.4% w / w of lobeglitazone free base, 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 of magnesium stearate.

[0061] In some embodiments, the orally disintegrating tablets described herein comprise 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 of magnesium stearate. In some embodiments, the orally disintegrating tablets described herein comprise about 2.4% w / w of lobeglitazone free base, 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 of magnesium stearate.

[0062] In some embodiments, the orally disintegrating tablets described herein comprise 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 of magnesium stearate. In some embodiments, the orally disintegrating tablets described herein contain about 0.8% w / w lobeglitazone free base, about 72.7% w / w mannitol 200SD, about 16% w / w microcrystalline cellulose 101, about 1.5% w / w HPMC E5, about 1% w / w sucralose, about 7% w / w croscarmellose sodium, and about 1% w / w magnesium stearate.

[0063] In some embodiments, the orally disintegrating tablets described herein comprise 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 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 of magnesium stearate. In some embodiments, the orally disintegrating tablets described herein comprise about 0.8% w / w lobeglitazone free base, about 72.7% w / w mannitol 200SD, about 16% w / w microcrystalline cellulose 101, about 1.5% w / w polyvinylpyrrolidone, about 1% w / w sucralose, about 7% w / w croscarmellose sodium, and about 1.5% w / w magnesium stearate.

[0064] In some embodiments, the orally disintegrating tablets described herein comprise 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 of magnesium stearate. In some embodiments, the orally disintegrating tablets described herein comprise about 0.8% w / w lobeglitazone free base, about 72.7% w / w mannitol 200SD, about 16% w / w microcrystalline cellulose 101, about 1.5% w / w HPC EXF, about 1% w / w sucralose, about 7% w / w croscarmellose sodium, and about 1% w / w magnesium stearate.

[0065] In some embodiments, the orally disintegrating tablets described herein comprise 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 of magnesium stearate. In some embodiments, the orally disintegrating tablets described herein contain about 2.4% w / w lobeglitazone free base, about 70.6% w / w mannitol 200SD, about 16% w / w microcrystalline cellulose 101, about 1.5% w / w HPC EXF, about 1.5% w / w sucralose, about 7% w / w croscarmellose sodium, and about 1% w / w magnesium stearate.

[0066] In some embodiments, the orally disintegrating tablets described herein comprise 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 of magnesium stearate. In some embodiments, the orally disintegrating tablets described herein comprise about 2.4% w / w of lobeglitazone free base, 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 of magnesium stearate.

[0067] In some embodiments, the orally disintegrating tablets described herein comprise 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 of magnesium stearate. In some embodiments, the orally disintegrating tablets described herein contain about 2.4% w / w lobeglitazone free base, about 69.6% w / w mannitol 200SD, about 16% w / w microcrystalline cellulose 101, about 2.5% w / w HPC EXF, about 1.5% w / w sucralose, about 7% w / w croscarmellose sodium, and about 1% w / w magnesium stearate.

[0068] In some embodiments, the orally disintegrating tablets described herein comprise 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 of magnesium stearate. In some embodiments, the orally disintegrating tablets described herein comprise about 2.4% w / w of lobeglitazone free base, 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 of magnesium stearate.

[0069] In some embodiments, the orally disintegrating tablets described herein comprise 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 of magnesium stearate. In some embodiments, the orally disintegrating tablets described herein contain about 2.4% w / w lobeglitazone free base, about 74% w / w mannitol 200SD, about 16% w / w microcrystalline cellulose 101, about 1.5% w / w HPMC E5, about 0.5% w / w sucralose, about 5% w / w croscarmellose sodium, and about 1% w / w magnesium stearate.

[0070] In some embodiments, the orally disintegrating tablets described herein comprise 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 of magnesium stearate. In some embodiments, the orally disintegrating tablets described herein comprise about 2.4% w / w lobeglitazone free base, about 72.1% w / w mannitol 200SD, about 16% w / w microcrystalline cellulose 101, about 1.5% w / w HPMC E5, about 1% w / w sucralose, about 7% w / w croscarmellose sodium, and about 1% w / w magnesium stearate.

[0071] In some embodiments, the orally disintegrating tablets described herein comprise 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 of magnesium stearate. In some embodiments, the orally disintegrating tablets described herein contain about 2.4% w / w lobeglitazone free base, about 70.6% w / w mannitol 200SD, about 16% w / w microcrystalline cellulose 101, about 1.5% w / w HPC EXF, about 1.5% w / w sucralose, about 7% w / w croscarmellose sodium, and about 1% w / w magnesium stearate.

[0072] In some embodiments, the orally disintegrating tablets described herein comprise 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 of sodium stearoyl fumarate. In some embodiments, the orally disintegrating tablets described herein comprise about 2.4% w / w of lobeglitazone free base, 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 of sodium stearoyl fumarate.

[0073] In some embodiments, the orally disintegrating tablets described herein comprise 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 of sodium stearoyl fumarate. In some embodiments, the orally disintegrating tablets described herein comprise about 2.4% w / w of lobeglitazone free base, 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 of sodium stearoyl fumarate.

[0074] In some embodiments, the orally disintegrating tablets described herein comprise 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 of magnesium stearate. In some embodiments, the orally disintegrating tablets described herein contain about 2.4% w / w lobeglitazone free base, about 73.6% w / w mannitol 200SD, about 16% w / w microcrystalline cellulose 101, about 1.5% w / w HPMC E5, about 0.5% w / w sucralose, about 5% w / w croscarmellose sodium, and about 1% w / w magnesium stearate.

[0075] In some embodiments, the orally disintegrating tablets described herein comprise about 0.6% w / w to about 1.2% w / w lobeglitazone sulfate, about 65% w / w to about 80% w / w mannitol 200SD, about 14% w / w to about 18% w / w microcrystalline cellulose 101, about 1% w / w to about 4% w / w HPC EF, about 0.1% w / w to about 4% w / w sucralose, about 2% w / w to about 10% w / w croscarmellose sodium, and about 0.1% w / w to about 2% w / w magnesium stearate. In some embodiments, the orally disintegrating tablets described herein comprise about 0.96% w / w lobeglitazone sulfate, about 72% w / w mannitol 200SD, about 16% w / w microcrystalline cellulose 101, about 2% w / w HPC EF, about 1% w / w sucralose, about 7% w / w croscarmellose sodium, and about 1% w / w magnesium stearate.

[0076] In some embodiments, the orally disintegrating tablets described herein comprise about 1% w / w to about 3% w / w lobeglitazone sulfate, about 65% w / w to about 80% w / w mannitol 200SD, about 14% w / w to about 18% w / w microcrystalline cellulose 101, about 1% w / w to about 4% w / w HPC EF, about 0.1% w / w to about 4% w / w sucralose, about 2% w / w to about 10% w / w croscarmellose sodium, and about 0.1% w / w to about 2% w / w magnesium stearate. In some embodiments, the orally disintegrating tablets described herein comprise about 1.9% w / w lobeglitazone sulfate, about 71% w / w mannitol 200SD, about 16% w / w microcrystalline cellulose 101, about 2% w / w HPC EF, about 1% w / w sucralose, about 7% w / w croscarmellose sodium, and about 1% w / w magnesium stearate.

[0077] In some embodiments, the orally disintegrating tablets described herein comprise about 1% w / w to about 3% w / w lobeglitazone sulfate, about 65% w / w to about 80% w / w mannitol 200SD, about 14% w / w to about 18% w / w microcrystalline cellulose 101, about 1% w / w to about 4% w / w HPC EF, about 0.1% w / w to about 4% w / w sucralose, about 2% w / w to about 10% w / w croscarmellose sodium, and about 0.1% w / w to about 2% w / w magnesium stearate. In some embodiments, the orally disintegrating tablets described herein comprise about 2.8% w / w lobeglitazone sulfate, about 70% w / w mannitol 200SD, about 16% w / w microcrystalline cellulose 101, about 2% w / w HPC EF, about 1% w / w sucralose, about 7% w / w croscarmellose sodium, and about 1% w / w magnesium stearate.

[0078] Gastrointestinal diseases

[0079] Digestive system disorders are conditions of the digestive tract, sometimes referred to as the gastrointestinal (GI) tract. Digestive system disorders and ailments are any condition related to the digestive system, including the throat, stomach, and intestines. Diagnoses may include acute, short-term ailments. Gastrointestinal disorders can also include more chronic diagnoses and may require long-term specialized treatment.

[0080] Symptoms can range from mild to severe. Some common problems include heartburn, cancer, irritable bowel syndrome (IBS), and lactose intolerance. Other digestive system disorders include gallstones, cholecystitis, cholangitis, rectal disorders (e.g., anal fissures, hemorrhoids, proctitis, and rectal prolapse), esophageal disorders (e.g., strictures and achalasia, and esophagitis), stomach disorders (e.g., gastritis, stomach ulcers usually caused by Helicobacter pylori infection, and cancer), liver disorders (e.g., hepatitis B or C, cirrhosis, liver failure, and autoimmune hepatitis and alcoholic hepatitis), pancreatitis and pancreatic pseudocysts, intestinal disorders (e.g., polyps and cancer, infections, celiac disease, Crohn's disease, ulcerative colitis, diverticulitis, malabsorption, short bowel syndrome, and intestinal ischemia), gastroesophageal reflux disease (GERD), peptic ulcer disease, and hiatal hernia.

[0081] Of all digestive system disorders, gastroparesis is characterized by delayed gastric emptying (DGE) in the absence of mechanical obstruction. Symptoms are chronic with episodic exacerbations. The idiopathic form of this condition (which accounts for the largest number of cases) primarily affects young adult women. Gastroparesis is also frequently associated with diabetes (diabetic gastroparesis), which may occur due to impaired neural control of gastric motility. Furthermore, acute hyperglycemia may slow gastric emptying and reduce the effectiveness of prokinetic drugs.

[0082] At the molecular level, gastroparesis may be caused by the loss of neural nitric oxide expression, due to the secretion of nitric oxide by cells in the gastrointestinal tract. This important signaling molecule plays various roles in the gastrointestinal tract and muscles throughout the body. When nitric oxide levels are low, smooth muscle and other organs may fail to function properly. Another important component of the stomach is the interstitial cells of Cajal (ICC), which act as pacemakers as they transduce signals from motor neurons to generate electrical rhythms in smooth muscle cells. Lower nitric oxide levels are also associated with the loss of ICC cells, which ultimately leads to the loss of function of smooth muscle in the stomach and other areas of the gastrointestinal tract. The pathogenesis of symptoms in diabetic gastroparesis includes: loss of gastric neurons containing nitric oxide synthase (NOS) leading to defects in the containment reflex, which results in early saturation and postprandial fullness; impaired electromechanical activity in the myenteric plexus leading to delayed gastric emptying, resulting in nausea and vomiting; sensory neuropathy in the gastric wall potentially causing upper abdominal pain; and abnormal pacemaker activity (tachycardia and bradycardia) may generate harmful signals transmitted to the CNS to cause nausea and vomiting.

[0083] Macrophages play a role in the development and progression of gastroparesis. Specifically, macrophages can penetrate the smooth muscle layer of the stomach in individuals with gastroparesis and release pro-inflammatory molecules that lead to damage and dysfunction of the gastric muscles. In diabetic gastroparesis, high blood sugar levels may activate macrophages, leading to inflammation and damage to the nerves and muscles of the stomach. Two distinct subtypes of macrophages exist in the immune system with different functions: M1 macrophages and M2 macrophages. M1 macrophages participate in the inflammatory response and are activated in response to pro-inflammatory signals. They are important in fighting infection and promoting tissue damage and repair. M1 macrophages produce pro-inflammatory cytokines and reactive oxygen species, which help kill invading pathogens and promote the recruitment of other immune cells to the site of infection. On the other hand, M2 macrophages participate in tissue repair and immune regulation and are activated in response to anti-inflammatory signals. They are important in the resolution of inflammation and promoting tissue remodeling and healing. M2 macrophages produce anti-inflammatory cytokines and growth factors, which help repair damaged tissue and promote angiogenesis. In general, M1 and M2 macrophages represent two distinct functional states of macrophages, allowing them to respond to different signals and perform different roles in the immune system. The balance between M1 and M2 macrophages is important for maintaining immune homeostasis and promoting appropriate immune responses. Drugs that can inhibit M1 macrophages, promote M2 macrophages, and / or facilitate M1-to-M2 macrophage repolarization may be able to treat digestive system disorders, including gastroparesis.

[0084] Because the signs and symptoms of gastroparesis overlap with other gastrointestinal symptoms, gastroparesis may be misdiagnosed as intestinal obstruction, functional dyspepsia, irritable bowel syndrome, or peptic ulcer disease. In patients with signs and symptoms suggestive of gastroparesis, finding DGE in the absence of obstruction or alternative diagnoses provides crucial support for the diagnosis of gastroparesis and can be evaluated using gastric emptying scintillation scanning, gastric emptying breath test, or the SmartPill™ motor test system.

[0085] Approved medications for treating gastroparesis can be divided into two distinct groups. The first group provides only temporary relief for some symptoms, such as nausea and vomiting. Medications that help relieve nausea and vomiting include diphenhydramine and ondansetron, and if nausea and vomiting persist, prochlorperazine is used. The second group consists of medications that stimulate the stomach muscles. Medications that stimulate the stomach muscles include metoclopramide (e.g., Reglan®) and erythromycin. Metoclopramide carries a risk of serious side effects. The prescribing information for Reglan®, approved by the U.S. Food and Drug Administration (FDA), lists a boxed warning that patients are at risk of developing tardive dyskinesia with prolonged use of Reglan and its generic counterparts. Erythromycin may lose its effectiveness over time and may cause side effects such as diarrhea. Clearly, there is an urgent medical need to develop safe and effective therapies for patients with gastroparesis.

[0086] Digestive system disorders caused by damage to the digestive system include, but are not limited to, abdominal adhesions, adult acid reflux (gastroesophageal reflux disease or GERD), infant acid reflux (GERD), anatomical problems of the lower gastrointestinal tract, appendicitis, Barrett's esophagus, bowel control problems (fecal incontinence), celiac disease, colonic polyps, constipation, Crohn's disease, periodic vomiting syndrome, diarrhea, diverticulosis and diverticulitis, dumping syndrome, food poisoning, gallstones, flatulence, gastritis, gastroparesis, gastrointestinal bleeding, hemorrhoids, dyspepsia, inguinal hernia, pseudo-obstruction, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), lactose intolerance, liver disease, microscopic colitis, colostomy, pancreatitis, peptic ulcer (gastric ulcer), proctitis, short bowel syndrome, ulcerative colitis, viral gastroenteritis, and Zollinger-Ellison syndrome or related symptoms.

[0087] The signs and symptoms of gastroparesis include nausea, vomiting, postprandial fullness, early satiety, and epigastric pain. Patients may experience any combination of signs and symptoms with varying severity. Pain is more common in patients with idiopathic gastroparesis than in those with diabetic gastroparesis. Patients with diabetic gastroparesis may experience further disturbances in glucose control due to unpredictable gastric emptying and altered absorption of orally administered hypoglycemic agents.

[0088] Understanding the symptoms associated with gastroparesis is important for treating patients with this condition. In gastroparesis, symptom experience and severity are obtained from the patient. Therefore, patient-reported symptom scales that capture the overall severity of gastroparesis are necessary for assessing treatment. Well-defined patient-reported outcomes (PROs) tools that measure clinically important signs and symptoms of gastroparesis would be useful assessment tools for clinical trials to support label claims for the treatment of gastroparesis. The American College of Neurogastroenterology and Exercise Science Gastroparesis Major Symptom Index-Daily Diary (ANMS GCSI-DD) is a patient-reported outcome tool that captures daily symptoms associated with gastroparesis. The ANMS GCSI-DD is designed to assess gastrointestinal symptoms associated with idiopathic gastroparesis and diabetic gastroparesis. The ANMS GCSI-DD includes five items: nausea, vomiting, early satiety, postprandial fullness, and epigastric pain. Four of the items (nausea, early satiety, postprandial fullness, and epigastric pain) were rated as none (0), mild (1), moderate (2), severe (3), and very severe (4) based on the most severe symptoms in the past 24 hours. Vomiting was assessed as the number of vomiting episodes in the past 24 hours, with a maximum of four episodes (range 0 to 4). The ANMS GCSI-DD total score is a useful patient-reported outcome for gastroparesis and serves as an endpoint in clinical trials of gastroparesis.

[0089] Kidney disease

[0090] The kidneys are bean-shaped organs located just below the rib cage, one on each side of the spine. Each day, the two kidneys filter about 120 to 150 quarts of blood to produce about 1 to 2 quarts of urine, which consists of waste products and extra fluid.

[0091] Blood enters the kidneys through arteries, which branch into tiny loops of blood vessels within the kidney. Each loop is called a glomerulus. There are approximately one million glomeruli, or filters, in each kidney. Glomeruli attach to the openings of small fluid-collecting ducts called tubules. Blood is filtered in the glomeruli, and excess fluid and waste products enter the tubules and become urine. Finally, urine flows from the kidneys into the bladder through larger tubes called ureters. Each unit of glomerulus and tubule is called a nephron. Each kidney consists of approximately one million nephrons. In a healthy nephron, the glomerular membrane, which separates the blood vessels from the tubules, allows waste products and excess water to enter the tubules while retaining blood cells and proteins in the blood.

[0092] Many diseases affect kidney function by attacking the glomeruli, the tiny units within the kidneys that clean the blood. Glomerular diseases encompass a wide range of conditions with various genetic and environmental causes, but they fall into two main categories: (1) glomerulonephritis, which involves inflammation of the membrane tissue in the kidneys that acts as a filter, separating waste products and excess fluid from the blood; and (2) glomerulosclerosis, which involves scarring or hardening of the tiny blood vessels within the kidneys. Although glomerulonephritis and glomerulosclerosis have different causes, both can lead to kidney failure.

[0093] Signs and symptoms of glomerular disease include albuminuria (i.e., a large amount of protein in the urine), hematuria (i.e., blood in the urine), decreased glomerular filtration rate (i.e., inefficient filtration of waste products from the blood), hypoproteinemia (i.e., low blood protein), and edema (i.e., swelling in various parts of the body). One or more of these symptoms may be the first sign of kidney disease.

[0094] Patients with glomerular disease have significant amounts of protein in their urine; if the levels are very high, it can be described as "nephrotic range." Red blood cells are also common in urine, especially in some forms of glomerular disease. Urinalysis provides information about kidney damage by showing the levels of protein and red blood cells in the urine. Blood tests measure levels of waste products such as creatinine and urea nitrogen to determine if the kidneys' filtering capacity is impaired. If these lab tests indicate kidney damage, a doctor may recommend an ultrasound or X-ray to see if the kidneys are abnormal in shape or size. These tests are called kidney imaging. Because glomerular disease causes problems at the cellular level, a doctor may also recommend a biopsy. A biopsy can help confirm glomerular disease and identify the cause.

[0095] Many different diseases can cause glomerular disease. It may be a direct result of infection or a drug that is toxic to the kidneys, or it may be caused by a disease that affects the whole body, such as diabetes or lupus. Many different kinds of diseases can cause swelling or scarring of nephrons or glomeruli. Sometimes glomerular disease is idiopathic, meaning it occurs without any 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 diseases, 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 disease (MCD); and (6) chronic kidney disease.

[0096] Kidney failure is an acute or chronic loss of 85% or more of kidney function. End-stage renal disease (ESRD) is kidney failure that is treated with dialysis or kidney transplantation. Depending on the form of glomerular disease, kidney function may be lost within days or weeks, or it may slowly and gradually deteriorate over decades.

[0097] Acute kidney failure encompasses several forms of glomerular disease that cause a very rapid decline in kidney function. For example, PSGN can lead to severe symptoms (hematuria, proteinuria, edema) within 2 to 3 weeks of a sore throat or skin infection. Patients may temporarily require dialysis to replace kidney function. This rapid loss of kidney function is called acute kidney failure (ARF). Although ARF can be life-threatening while it persists, kidney function usually recovers once the underlying cause of the kidney failure is 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.

[0098] When patients develop kidney failure, they undergo dialysis (hemodialysis or peritoneal dialysis) or receive a new kidney through transplantation. Patients with chronic kidney disease who are nearing kidney failure should learn as much as possible about their treatment options so they can make an informed decision when the time is right. With the help of dialysis or transplantation, many people with kidney failure continue to lead fulfilling and productive lives.

[0099] Nephrotic syndrome is a condition characterized 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 group of symptoms, not the disease itself. It can occur alongside many other conditions, so prevention depends on controlling the underlying disease. Treatment for nephrotic syndrome focuses on identifying and treating the underlying cause (if possible) and lowering high cholesterol, blood pressure, and proteinuria through diet, medication, or both. Once the underlying cause (if known) is treated, nephrotic syndrome may resolve. However, kidney disease is often the underlying cause and is incurable. In these cases, the kidneys may gradually lose their ability to filter waste and excess water from the blood. If kidney failure occurs, the patient will need to undergo dialysis or have a kidney transplant.

[0100] Minimal change disease (MCD) is the most common cause of childhood nephrotic syndrome, and corticosteroids induce remission in over 90% of children with MCD. In contrast, most children with the second most common cause, FSGS, do not respond to oral glucocorticoids. Children with idiopathic nephrotic syndrome who do not enter remission after one month of corticosteroid therapy are typically classified as having SRNS. However, evidence from adults suggests that longer courses (3–6 months) of oral corticosteroids improve their response rate. In children with steroid-sensitive nephrotic syndrome (SSNS), compelling evidence from systematic reviews suggests that longer initial courses of corticosteroids (at least 3 months) reduce the likelihood of subsequent relapse. Furthermore, the dosage of oral corticosteroids may also affect the number of relapses. The efficacy of glucocorticoids in idiopathic nephrotic syndrome may be attributed to the immunosuppressive effects of these drugs; their direct effects on podocytes, which are cells surrounding the capillaries of the glomeruli within Bowman's capsule in the kidney; or potentially a combination of these effects.

[0101] Nephrotic syndrome is one of the most common kidney diseases seen in children and adults. It is a relapsing and relapsing disease characterized by the massive loss of serum proteins into the urine through a damaged glomerular filtration barrier, leading to hypoalbuminemia and generalized swelling (edema). Podocytes are a key component of the renal filtration barrier, and during nephrotic syndrome, they undergo significant structural changes in the foot processes that attach these cells to the glomerular basement membrane. The most widely accepted experimental models for simulating podocyte damage during nephrotic syndrome in humans include puromycin aminonucleoside (PAN) injections in rats and PAN treatment of cultured podocytes. For the past 50 years, the primary treatment for nephrotic syndrome has been oral glucocorticoids (GCs). Unfortunately, GCs have serious side effects, and in approximately 20% of patients, they are ineffective in inducing clinical remission of the disease (i.e., steroid-resistant nephrotic syndrome). Therefore, there is an urgent need for alternative therapies with higher efficacy and / or less severe side effects. Thiazolidinediones represent a novel treatment strategy that can slow, halt, or reverse the underlying disease process in diseases involving glomerular diseases, kidney failure, and end-stage renal diseases such as acute kidney failure, renal failure, and nephrotic syndrome.

[0102] Thiazolidinediones represent a novel treatment strategy that can slow, halt, or reverse underlying disease processes in diseases involving the digestive system (e.g., gastroparesis) and kidney (e.g., glomerular diseases and nephrotic syndrome).

[0103] Thiazolidinedione

[0104] The method of this invention is based on the surprising discovery that thiazolidinediones can significantly protect the digestive system from damage, such as that determined by inflammation. Therefore, the use of one or more thiazolidinediones in the treatment of digestive system disorders is disclosed herein.

[0105] The term "thiazolidinedione" refers to a class of heterocyclic glitazone compounds comprising a five-membered C3NS ring, including its prodrugs, salts, solvates, hydrates, cocrystals, enantiomers, and deuterated forms. As used herein, thiazolidinediones include, but are not limited to, one or more of pioglitazone, rosiglitazone, lobeglitazone, cycloglitazone, dapaglitazone, empaglitazone, neglitazone, linaglitazone, troglitazone, baraglitazone, and other thiazolidinedione molecules. In some embodiments disclosed herein, the method includes the use of any thiazolidinedione. In some embodiments, the thiazolidinedione is lobeglitazone. In some embodiments, the method specifically excludes the use of one or more thiazolidinediones disclosed herein. In some embodiments, the thiazolidinedione is not pioglitazone. In some embodiments, the thiazolidinedione is neither pioglitazone nor rosiglitazone.

[0106] Lobeglitazone (Duvie®, Chung Kun Tang) is a thiazolidinedione with the chemical name 5-(4-(2-((6-(4-methoxyphenoxy)pyrimidin-4-yl)(methyl)amino)ethoxy)benzyl)thiazolidin-2,4-dione. As an agonist of both PPARα and PPARγ, lobeglitazone acts as an insulin sensitizer by binding to PPAR receptors in adipocytes and increasing cellular sensitivity to insulin.

[0107] definition

[0108] As used herein, the terms “treat,” “treating,” or “treatment” mean to relieve, reduce, or eliminate one or more symptoms or features of a disease, and can be curative, palliative, preventative, or slow the progression of the disease.

[0109] The term "effective amount" means an amount that will result in a reduction (as applicable or specified) of damage to the digestive system and lead to the desired effect or outcome. The term "therapeutic effective amount" means an amount of thiazolidinedione, including but not limited to one or more of pioglitazone, rosiglitazone, lobeglitazone, cycloglitazone, dapaglitazone, empaglitazone, neglitazone, linaglitazone, troglitazone, baraglitazone, and other thiazolidinedione molecules, alone or in combination with other active ingredients, that will elicit a desired biological or pharmacological response, such as effectively preventing, alleviating, or improving symptoms of a disease or condition; slowing, stopping, or reversing an underlying disease process or progression; partially or completely restoring cellular function; or prolonging the survival of the treated subject. In some embodiments, the thiazolidinedione is not pioglitazone.

[0110] The terms "patient" or "subject" include 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 yet another embodiment, the patient or subject is of any age.

[0111] "Particles" refer to solid, dry aggregates containing thiazolidinediones that are robust enough to withstand handling during the formulation and / or mixing of the thiazolidinediones. Particles may have irregular shapes or may be compressed (e.g., to form regularly shaped pellets). Particles may be formulated into tablets.

[0112] Mannitol 50C refers to mannitol with an average particle size of approximately 50 μm. PEARLITOL® 50C is an example of mannitol 50C.

[0113] Mannitol 160C refers to mannitol with an average particle size of approximately 160 μm. PEARLITOL® 160C is an example of mannitol 160C.

[0114] Mannitol 200SD refers to mannitol with an average particle size of approximately 150 μm. PEARLITOL® 200SD is an example of mannitol 200SD.

[0115] HPC EF refers to hydroxypropyl cellulose with a weight-average molecular weight of approximately 80,000 Daltons (e.g., Klucel™ EF).

[0116] HPC EXF refers to hydroxypropyl cellulose with a weight-average molecular weight of approximately 1,150,000 Daltons (e.g., Klucel™ EXF).

[0117] The terms “significant” or “significantly” are determined by a t-test at a significance level of 0.05.

[0118] As used herein, the terms “digestion” and “gastrointestinal tract” are used interchangeably and refer to the organs, cells, tissues and diseases associated with the gastrointestinal tract, including but not limited to the mouth, pharynx (larynx), esophagus, stomach, small intestine, large intestine, rectum and anus, as well as the salivary glands, liver, pancreas and gallbladder.

[0119] Uses of the disclosed formulation

[0120] In some aspects, this disclosure provides a method for exerting a protective effect in cells, the method comprising contacting cells with an effective amount of a thiazolidinedione from an orally disintegrating tablet. As used herein, the term "effective amount" refers to the amount of thiazolidinedione that will result in a desired effect or outcome, such as an amount that will result in a protective effect.

[0121] In some aspects, this disclosure provides a method for reducing inflammation, including the step of contacting cells with an effective amount of thiazolidinedione from an orally disintegrating tablet.

[0122] In some aspects, this disclosure provides a method for increasing cell lifespan, including the step of contacting cells with an effective amount of thiazolidinedione from an orally disintegrating tablet.

[0123] In some embodiments, the cells are animal cells, such as mammalian cells. In some embodiments, the cells are human cells or non-human cells. In some embodiments, the cells are diseased cells. In some embodiments, the cells are diseased cells from patients suffering from the diseases or conditions disclosed herein.

[0124] This document also discloses methods for treating animals suffering from diseases or conditions that would benefit from cellular protective effects, or for preventing or reducing the risk of animals suffering from diseases or conditions, the method comprising administering to the animal a therapeutically effective amount of an orally disintegrating tablet formulation containing a thiazolidinedione. In some embodiments, the animal is a mammal. In some embodiments, the mammal is a human mammal or a non-human mammal. In some embodiments, the mammal is a human. In some embodiments, the disease or condition is a kidney disease or a gastrointestinal disease. In some embodiments, the disease or condition is caused by impairment of the function of the digestive system. In some embodiments, the disease is selected from one or more digestive system diseases or associated symptoms. In some embodiments, the disease is gastroparesis. In some embodiments, the disease is idiopathic gastroparesis, diabetic gastroparesis, or vector-induced gastroparesis.

[0125] This article also discloses methods for treating diseases or conditions that cause damage or inflammation to the digestive system or kidneys of patients, or for prolonging the lifespan of cells in patients suffering from diseases or conditions that cause damage to the digestive system or kidneys.

[0126] In some embodiments, the method includes the step of administering a therapeutically effective amount of an orally disintegrating tablet formulation containing a thiazolidinedione to an animal. In some embodiments, the animal is a mammal. In some embodiments, the mammal is a human mammal or a non-human mammal.

[0127] In some implementations, the disease or condition is selected from, but is not limited to, abdominal adhesions, adult acid reflux (gastroesophageal reflux disease or GERD), infant acid reflux (GERD), anatomical problems of the lower gastrointestinal tract, appendicitis, Barrett's esophagus, bowel control problems (fecal incontinence), celiac disease, colonic polyps, constipation, Crohn's disease, periodic vomiting syndrome, diarrhea, diverticulosis and diverticulitis, dumping syndrome, food poisoning, gallstones, flatulence, gastritis, gastroparesis, gastrointestinal bleeding, hemorrhoids, indigestion (dyspepsia), inguinal hernia, pseudo-obstruction, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), lactose intolerance, liver disease, microscopic colitis, colostomy, pancreatitis, peptic ulcer (gastric ulcer), proctitis, short bowel syndrome, ulcerative colitis, viral gastroenteritis, Zollinger-Ellison syndrome, or related symptoms.

[0128] In some implementations, the disease or condition is selected from age-related glomerulonephropathy, AL amyloidosis, Alport syndrome, amyloidosis (amyloid nephropathy), ANCA vasculitis, anti-GBM disease (Goodpasture syndrome), C1q nephropathy, C3 glomerulonephropathy, collapsed glomerulonephropathy, collapsed glomerulonephropathy, Finnish congenital nephrotic syndrome (CNSF), cryoglobulinemia, diabetes, Denys-Drash syndrome, diabetic glomerulonephropathy, diabetic nephropathy, diffuse mesangial sclerosis (DMS), Fabry disease. The disease includes, but is not limited to, fibrotic glomerulonephritis (GN), focal segmental glomerulosclerosis (FSGS), heavy chain deposition disease, hypertensive nephropathy, IgA vasculitis, IgA nephropathy, IgM nephropathy, immune and inflammatory glomerulonephropathy, immune-like glomerulonephropathy, 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 disease (TBM), thrombotic microangiopathy (TMA), or related symptoms. In some implementations, nephrotic syndrome is frequently relapsing nephrotic syndrome, steroid-dependent nephrotic syndrome, or steroid-resistant nephrotic syndrome.

[0129] This article also discloses methods for treating gastroparesis. In some implementations, gastroparesis includes idiopathic gastroparesis, diabetic gastroparesis, postoperative gastroparesis, and drug-induced gastroparesis. In some implementations, primary gastroparesis is idiopathic. In some implementations, secondary gastroparesis is caused by diseases such as diabetes, cancer, or infection, or by drug side effects or surgery.

[0130] On the other hand, this article provides methods for reducing inflammation in the gastrointestinal tract for the treatment of digestive system disorders such as gastroparesis and IBD.

[0131] On the other hand, this article provides methods to reduce the risk of overall severity of nausea, early satiety, postprandial fullness, upper abdominal pain, vomiting episodes, and gastroparesis.

[0132] On the other hand, this article provides methods to slow, stop, or reverse the progression of diseases to digestive system disorders such as gastroparesis and IBD.

[0133] On the other hand, this article provides methods to slow, stop, or reverse the progression of a disease, such as that indicated by the overall severity of nausea, early satiety, postprandial fullness, upper abdominal pain, vomiting episodes, and gastroparesis.

[0134] On the other hand, this document discloses a method for treating animals suffering from a disease or condition that has symptoms that can be prevented, alleviated, or improved by cellular protection; or a disease process or progression that can be slowed, stopped, or reversed by cellular protection; the method comprising administering a therapeutically effective amount of an ODT containing a thiazolidinedione. In some embodiments, the thiazolidinedione is lobeglitazone.

[0135] In related aspects, this article discloses methods for treating gastroparesis. In one implementation, gastroparesis includes idiopathic gastroparesis, diabetic gastroparesis, postoperative gastroparesis, and drug-induced gastroparesis.

[0136] This disclosure further provides the use of thiazolidinedione in the preparation of an ODT medicament for treating a person suffering from any of the diseases or conditions disclosed herein, or in any method of administering thiazolidinedione to a person as described in this disclosure.

[0137] This document also discloses a method for treating nephrotic syndrome in mammals, comprising administering to the mammal an effective amount of an ODT containing a thiazolidinedione, said thiazolidinedione being selected from one or more of rosiglitazone, lobeglitazone, cycloglitazone, dapaglitazone, empaglitazone, neglitazone, linaglitazone, troglitazone, and baraglitazone. In some embodiments, the nephrotic syndrome is FRNS or SDNS.

[0138] This document also discloses a method for treating glomerular diseases in mammals, comprising administering to the mammal an effective amount of an ODT containing a thiazolidinedione, said thiazolidinedione being selected from one or more of rosiglitazone, lobeglitazone, cycloglitazone, dapaglitazone, empaglitazone, neglitazone, linaglitazone, troglitazone, and baraglitazone. In some embodiments, the glomerular disease is focal segmental glomerulosclerosis (FSGS), minimal change disease, or membranous nephropathy.

[0139] Orally disintegrating tablets

[0140] The disclosed pharmaceutical formulation is an orally disintegrating tablet.

[0141] The pharmaceutical compositions disclosed herein comprise a therapeutically effective amount of thiazolidinedione and at least one pharmaceutically acceptable excipient. The term "excipient" refers to a pharmaceutically acceptable inactive substance used as a carrier of the pharmaceutically active ingredient thiazolidinedione, and includes anti-adhesion agents, binders, coatings, disintegrants, fillers, diluents, solvents, flavoring agents, swelling agents, coloring agents, flow aids, dispersants, wetting agents, lubricants, preservatives, adsorbents, and sweeteners. The selection of excipients will depend on factors such as the specific method of administration and the nature of the dosage form. pH can be adjusted using acids or bases (such as hydrochloric acid or sodium hydroxide).

[0142] Non-limiting exemplary disintegrants include crospovidone, calcium carboxymethyl cellulose, carboxymethyl cellulose, sodium crospovidone carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, corn starch, and sodium starch glycolate, or combinations thereof. The amount of disintegrant in orally disintegrating tablets typically ranges from 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%, including all ranges and subranges therein. In a particular embodiment, the disintegrant is selected from the group consisting of crospovidone, calcium carboxymethyl cellulose, carboxymethyl cellulose, and sodium crospovidone carboxymethyl cellulose. In a more specific embodiment, the disintegrant is sodium crospovidone carboxymethyl cellulose.

[0143] Non-limiting exemplary fillers include sugars, sugar alcohols, starches, and celluloses, as well as inorganic excipients, or combinations thereof. Examples of sugars include lactose, sucrose, fructooligosaccharides, glucose, palatinose, maltose, reduced maltose, powdered sugar, powdered candy, fructose, isomerized lactose, honey sugar, or combinations thereof. Examples of sugar alcohols include mannitol, erythritol, xylitol, maltitol, sorbitol, or combinations thereof. Examples of starches include corn starch, potato starch, rice starch, partially pregelatinized starch, pregelatinized starch, or combinations thereof. Examples of celluloses include crystalline cellulose, microcrystalline cellulose (MCC), powdered cellulose, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, or combinations thereof. Examples of inorganic excipients include synthetic hydrotalcite, precipitated calcium carbonate, hydrated silica, light anhydrous silica, magnesium silicatealuminate magnesium hydroxide, or combinations thereof. The amount of filler in orally disintegrating tablets typically ranges from 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 11%, 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%, and all ranges and subranges therein. In a particular embodiment, the filler is selected from the group consisting of crystalline cellulose, microcrystalline cellulose (MCC), mannitol, or combinations thereof. In a more particular embodiment, the filler is microcrystalline cellulose (MCC), mannitol, or combinations thereof.

[0144] Non-limiting exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, sodium fumarate stearate, talc, or combinations thereof. The amount of lubricant in orally disintegrating tablets typically ranges from 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%, encompassing all ranges and subranges therein. In a particular embodiment, the lubricant is selected from magnesium stearate, calcium stearate, stearic acid, or combinations thereof. In a more specific embodiment, the lubricant is magnesium stearate.

[0145] Non-limiting exemplary sweeteners include sodium saccharin, saccharin, aspartame, acesulfame potassium, dipotassium glycyrrhizate, sucralose, thomaline, or combinations thereof. The amount of sweetener in orally disintegrating tablets typically ranges from 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%, encompassing all ranges and subranges therein. In a particular embodiment, the sweetener is selected from sodium saccharin, saccharin, aspartame, sucralose, or combinations thereof. In a more specific embodiment, the sweetener is sucralose.

[0146] Non-limiting exemplary binders include sugars, sugar alcohols, starches, and celluloses, as well as inorganic excipients, or combinations thereof. Examples of sugars include lactose, sucrose, fructooligosaccharides, glucose, palaginose, maltose, reduced maltose, powdered sugar, fructose, isomerized lactose, honey sugar, or combinations thereof. Examples of sugar alcohols include mannitol, erythritol, xylitol, maltitol, sorbitol, or combinations thereof. Examples of starches include corn starch, potato starch, rice starch, partially pregelatinized starch, pregelatinized starch, or combinations thereof. Examples of celluloses include crystalline cellulose, microcrystalline cellulose (MCC), powdered cellulose, hydroxypropyl cellulose (HPC EF), carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, or combinations thereof. Examples of inorganic excipients include synthetic hydrotalcite, precipitated calcium carbonate, hydrated silica, light anhydrous silicic acid, magnesium aluminate silicate magnesium hydroxide, or combinations thereof. The amount of binder in orally disintegrating tablets typically ranges from 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 11%, 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%, and all ranges and subranges therein. In a particular embodiment, the binder is selected from the group consisting of lactose, sucrose, mannitol, hydroxypropyl cellulose (HPC EF), or combinations thereof. In a more specific embodiment, the binder is hydroxypropyl cellulose (HPC EF).

[0147] Dosage can vary depending on the dosage form used, patient sensitivity, and route of administration. Adjustments to dosage and administration are made to provide adequate levels of the active agent or to maintain the desired effect. Factors that may be considered include the severity of the disease state, the subject's overall health, the subject's age, weight and sex, diet, timing and frequency of administration, drug combination, response sensitivity, and tolerance / response to the therapy.

[0148] In one implementation, the daily dose of thiazolidinedione administered to the 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. mg, 4,000 mg or at least 5,000 mg.In another embodiment, the daily dose is 0.01-0.02 mg, 0.02-0.05 mg, 0.05-0.08 mg, 0.08-0.1 mg, 0.1-0.2 mg, 0.2-0.4 mg, 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, 10-15 mg, 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, 45-50 mg. mg, 50-75 mg, 75-100 mg, 100-125 mg, 125-150 mg, 150-175 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 defined by a pair of these values.

[0149] In another embodiment, the single dose of thiazolidinedione administered to the 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, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg. 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 defined by a pair of these values. In one embodiment, a single dose is administered orally. In some embodiments, the thiazolidinedione is lobeglitazone.

[0150] As a non-limiting example, the dose of the thiazolidinedione (such as lobeglitazone) administered orally may be from about 0.01 to 50 mg per day, administered in divided doses.

[0151] In embodiments of any of the above methods and compositions, the thiazolidinedione or its salts, solvates, hydrates, and cocrystals are racemic mixtures of the R enantiomer and the S enantiomer, or are rich in the R enantiomer (i.e., the ratio of the applied R enantiomer to the S enantiomer is 1.1:1 to 1,000:1, 10:1 to 10,000:1, or 100:1 to 100,000:1, or at least 98% of all thiazolidinedione enantiomers in the composition). The composition contains at least 98% of the R enantiomers, 99.5% of the R enantiomers, 99.9% of the R enantiomers, or contains no observable amount of the S enantiomers, or is rich in the S enantiomers (i.e., the ratio of the S enantiomers to the R enantiomers is 1.1:1 to 1,000:1, 10:1 to 10,000:1 or 100:1 to 100,000:1, or at least 98% of all thiazolidinedione enantiomers in the composition, or contains no observable amount of the R enantiomers).

[0152] Another embodiment of this disclosure includes the use of thiazolidinediones for reducing cell damage or improving cell survival.

[0153] Another embodiment of this disclosure includes the use of thiazolidinedione for the treatment of gastroparesis or IBD.

[0154] Another embodiment of this disclosure includes the use of thiazolidinediones to reduce the core signs and symptoms of gastroparesis as measured by ANMS GCSI-DD.

[0155] Another embodiment of this disclosure includes the use of thiazolidinedione to reduce the severity of nausea.

[0156] Another embodiment of this disclosure includes the use of thiazolidinediones to reduce the severity of premature satiety.

[0157] Another embodiment of this disclosure includes the use of thiazolidinediones to reduce the severity of postprandial fullness.

[0158] Another embodiment of this disclosure includes the use of thiazolidinedione for reducing the severity of upper abdominal pain.

[0159] Another embodiment of this disclosure includes the use of thiazolidinedione to reduce the severity of vomiting episodes.

[0160] Another embodiment of the invention includes the use of thiazolidinediones to reduce the overall severity of gastroparesis.

[0161] Example

[0162] The scope of this invention is not limited to the specific embodiments described herein. In fact, various modifications to the invention, other than those described herein, will be apparent to those skilled in the art from the foregoing description and drawings. Such modifications are intended to fall within the scope of the appended claims.

[0163] It should also be understood that all values ​​are approximations and are provided for descriptive purposes. All references cited and discussed in this specification are incorporated herein by reference in their entirety, as if each reference were individually incorporated by reference.

[0164] HPLC determination was performed on a ZORBAX SB-C18 column (3.5 μm, 4.6 mm × 50 mm).

[0165] Example 1: Formulation Development of Lobexiglitazone Orally Disintegrating Tablets

[0166] filler

[0167] The filler type was evaluated by comparing the dissolution profile and disintegration time of tablets prepared with different fillers. A series of fillers with different types were designed. Table 1 summarizes the formulation components of the filler types, Table 2 summarizes the disintegration time, and Table 3 summarizes the dissolution results.

[0168] Orally disintegrating tablets are manufactured using the following process:

[0169] wet granulation

[0170] Step 1. Sieve the particle components through a #20 ASTM (850 μm) sieve.

[0171] • Step 2. Transfer the intraparticle components from Step 1 to a high-shear mixer and premix at a paddle speed of 250 rpm for 10 minutes. Add API and HPC EF to anhydrous ethanol and stir until dissolved and clear.

[0172] • Step 3. Add API solution over 7-13 minutes, with the paddle speed at 250 rpm and the shredder speed at 1000 rpm. Then, add flush line water over 5-7 minutes, with the paddle speed at 250 rpm and the shredder speed at 1000 rpm. After adding water, stop and run for another 0-3 minutes. Pass the wet particles through a Comil with a 9.5 mm screen at 1500 rpm.

[0173] dry

[0174] Step 4. Dry the particles from Step 3 in a fluidized bed at an inlet temperature of 60°C until the LOD is NMT2.0%.

[0175] Grinding

[0176] • Step 5. Pass the particles from step 4 through a Comil with a 1.0 mm sieve at a speed of 3000 rpm.

[0177] lubricating

[0178] Step 6. Sieve magnesium stearate through a #40 ASTM (425 μm) sieve.

[0179] • Step 7. Lubricate the particles from Step 5 with magnesium stearate from Step 6 at 20 rpm for 3 minutes. Sieve with crosslinked sodium carboxymethyl cellulose to obtain the final blend.

[0180] compression

[0181] • Step 8. For 50 mg tablets, compress the final blend from step 7 into tablets using a 5.0 mm round punch.

[0182] Table 1. Formulation components for filler types.

[0183]

[0184] Table 2. Disintegration time of tablets.

[0185]

[0186] Table 3. Dissolution results of tablets.

[0187]

[0188] Conclusions: Based on the formulation, disintegration time, and dissolution results, we draw the following conclusions. First, the disintegration time of the formulation using mannitol 160C is not less than 30 s. Therefore, mannitol 160C was not selected. The disintegration times of the formulations using mannitol 50C and 200SD are both less than 30 s, but the formulation using mannitol 200SD has a shorter disintegration time. Second, the dissolution of the formulations using mannitol 50C and 200SD is similar, but the formulation using mannitol 160C has a slower dissolution time at 1 min. In conclusion, mannitol 200SD was selected.

[0189] Disintegrant ratio and supplier

[0190] Disintegrant ratios and suppliers were evaluated by comparing dissolution profiles and disintegration times. A series of disintegrants with different ratios and suppliers were designed. Table 4 summarizes the formulation components, Table 5 summarizes the disintegration times, and Table 6 summarizes the dissolution results.

[0191] Table 4. Formulation component ratios and suppliers of disintegrants.

[0192]

[0193] Table 5. Disintegration time of tablets.

[0194]

[0195] Table 6. Dissolution results of tablets.

[0196]

[0197] Conclusions: Based on the formulation, disintegration time, and dissolution results, we draw several conclusions. First, the disintegration times of formulations using 5.0% croscarmellose sodium from Supplier 1 and Supplier 2 differ. The formulation using 5.0% croscarmellose sodium from Supplier 2 exhibits the shortest disintegration time. Therefore, Supplier 2 is selected. Second, the disintegration times of 7% and 9% croscarmellose sodium are similar, but they are superior to those of 5% croscarmellose sodium. Third, the dissolution rates of formulations using different proportions and suppliers of croscarmellose sodium are similar. In conclusion, the proportion of croscarmellose sodium is selected as 7%.

[0198] Adhesive type and ratio

[0199] The type and proportion of binders were evaluated by comparing dissolution profiles and disintegration times. A series of binders with different types and proportions were designed. Table 7 summarizes the formulation components of different binder types and proportions, Table 8 summarizes the disintegration times, and Table 9 summarizes the dissolution results.

[0200] Table 7. Adhesive type and proportion of formulation components.

[0201]

[0202] Table 8. Disintegration time of tablets.

[0203]

[0204] Table 9. Dissolution results of tablets.

[0205]

[0206] Conclusions: Based on the formulation, disintegration time, and dissolution results, we draw the following conclusions. First, the disintegration times of the 0.4 mg formulations using 1.5% HPMC E5, 1.5% PVP K30, and 1.5% HPC EXF differed. The formulation using 1.5% HPC EXF had the shortest disintegration time. The dissolution rates of the 0.4 mg formulations using 1.5% HPMC E5, 1.5% PVP K30, and 1.5% HPC EXF were similar. Therefore, HPC EXF was chosen. Second, the disintegration times and dissolution rates of 1.5%, 2.0%, and 2.5% HPC EXF were similar. Therefore, 1.5%–2.5% HPC EXF is acceptable. In conclusion, HPC EXF was chosen, and the proportion of HPC EXF was selected as 2.0%.

[0207] sweeteners

[0208] The proportions of sweeteners were evaluated by comparing taste feedback. A series of sweeteners with different proportions were designed, and Table 10 summarizes the formulation component proportions of the sweeteners.

[0209] Table 10. Proportion of sweetener formulation components.

[0210]

[0211] Conclusion: Based on the formulation and taster feedback, we draw the following conclusions. Adding sucralose improves the taste. For the three sucralose ratios of 0.5%, 1.0%, and 1.5%, subjects preferred the taste of 1.0% sucralose. In conclusion, the optimal sucralose ratio was 1.0%.

[0212] lubricant

[0213] Lubricant type and proportion were evaluated by comparing dissolution profile and disintegration time. A series of lubricants with different types and proportions were designed. Table 11 summarizes the formulation components of lubricant type and proportion, Table 12 summarizes the appearance, Table 13 summarizes the disintegration time, and Table 14 summarizes the dissolution results.

[0214] Table 11. Formulation components of lubricant type and proportion.

[0215]

[0216] Table 12. Appearance of tablets.

[0217]

[0218] Table 13. Disintegration time of tablets.

[0219]

[0220] Table 14. Dissolution results of tablets.

[0221]

[0222] Conclusions: Based on the formulation, tablet appearance, disintegration time, and dissolution results, we draw the following conclusions. First, the tablets of formulations using 1.0% and 1.5% sodium stearoyl fumarate have a sticky appearance, but the tablets of formulations using 1.0% magnesium stearate do not. Therefore, magnesium stearate is more suitable. Second, the dissolution rates of 1.0% and 1.5% sodium stearoyl fumarate and 1.0% magnesium stearate are similar. The disintegration times of 1.5% sodium stearoyl fumarate and 1.0% magnesium stearate are similar. Different lubricant types do not affect disintegration time and dissolution. Therefore, 1.0% magnesium stearate is acceptable. In conclusion, magnesium stearate is chosen, and the magnesium stearate ratio is selected as 1.0%.

[0223] Final formulation

[0224] Three strengths of 0.4 mg, 0.8 mg, and 1.2 mg were produced using the final formulation and process.

[0225] Table 15 lists the formulation components. Table 16 summarizes the content uniformity results, and Table 17 summarizes other test results for the tablets.

[0226] Table 15. Formulation components.

[0227]

[0228] Table 16. Content uniformity of lobeglitazone tablets.

[0229]

[0230] Table 17. Other test results for lobeglitazone tablets.

[0231]

[0232] Conclusion: The results, assays, impurities, dissolution, disintegration time, residual solvent and friability of the three strengths of CU (0.4 mg, 0.8 mg and 1.2 mg) are acceptable.

[0233] Example 2: Stability Study

[0234] Accelerated stability study

[0235] Three strengths, 0.4 mg, 0.8 mg, and 1.2 mg, were produced using the final formulation and process, and accelerated stability studies were conducted at 40°C / 75% RH. Data are presented in Table 18, Table 19, and Table 20.

[0236] Table 18. Stability results of lobeglitazone ODT 0.4 mg (batch number 103613601).

[0237]

[0238] Note: ND- not detected.

[0239] Table 19. Stability results of lobeglitazone ODT 0.8 mg (batch number 103613401).

[0240]

[0241] Note: ND- not detected.

[0242] Table 20. Stability results of lobeglitazone ODT 1.2 mg (batch number 103613001).

[0243]

[0244] Note: ND- not detected.

[0245] Conclusion: After 3 months of accelerated stability testing, for the 1.2 mg strength, dissolution was slightly reduced before 30 minutes, and no other significant changes were observed in lobeglitazone ODT.

[0246] Stability of API solutions

[0247] The stability time of API solutions is important for the production process. Table 21 lists the stability results of API solutions.

[0248] Table 21. Stability results of API solutions.

[0249]

[0250] Note: ND- not detected.

[0251] Conclusion: No significant changes were observed in the lobeglitazone solution after the solution had stabilized for 24 h.

[0252] Example 3: Pharmacokinetic study of lobeglitazone sulfate in cynomolgus monkeys after a single oral administration

[0253] The aim of this study was to determine the pharmacokinetic parameters of orally disintegrating lobeglitazone sulfate tablets in plasma of non-initial cynomolgus monkeys following a single oral administration. Plasma concentrations of lobeglitazone sulfate collected at different time points were analyzed using LC-MS / MS.

[0254] The test product (tablets) was used as received from the sponsor. Lobexiglitazone orally disintegrating tablets were manufactured to support this study, as shown in Table 22.

[0255] Table 22. Description of the test product.

[0256]

[0257] Experimental Design

[0258] Study design: Twelve (12) male non-primitive cynomolgus monkeys were randomly divided into four groups according to their body weight (Table 23).

[0259] Table 23. Weight of individual animals.

[0260]

[0261] *All animals were fasted overnight (10-18 hours) before administration and fed 4 hours after administration.

[0262] After administration of the dose, each animal received 5-10 mL of reverse osmosis water via oral tube feeding.

[0263] Test product administration: Groups 1-4: Single oral administration

[0264] Sample collection intervals: For each animal, plasma samples were collected before administration and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours.

[0265] Blood collection and plasma preparation: Collect approximately 1 mL / blood sample from the animal via a hind limb vein at appropriate time points. Collect the blood into appropriately labeled tubes containing heparin sodium as an anticoagulant. Gently invert the tubes several times to ensure mixing and immediately place them on ice until centrifuged.

[0266] 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 frozen for storage at approximately -80°C.

[0267] Plasma samples were stored in an ultra-low temperature freezer (approximately -80°C) prior to analysis. All plasma samples were labeled with detailed information such as study number, animal number, matrix, collection time point, and collection date.

[0268] Sample Analysis: Sample analysis was performed by the analytical science department of the testing facility using LC-MS / MS. The analytical results were confirmed using quality control samples used to determine internal variation. The accuracy of quality control samples with >66% variability should be between 80% and 120% of the known value.

[0269] Pharmacokinetic Analysis: Phoenix WinNonlin® 7.0 software (Pharsight, USA) was used to calculate PK parameters via the non-compartmental analysis module. Calculations included C... 最大值 T 最大值 T 1 / 2 AUC 0-t AUC 0-∞ MRT 0-t and MRT 0-∞ PK parameters, including C. When calculating pharmacokinetic parameters, C... 最大值 The concentration of previous BLQ samples (including those shown as "no peak") was recorded as 0, and C 最大值 Subsequent BLQ samples (including those that result in "no peak") are not included in the calculation.

[0270] result

[0271] No abnormalities were observed in any of the animals during the experiment.

[0272] Group 1: Male cynomolgus monkeys were administered one tablet / animal (lobeglitazone orally disintegrating tablet, 0.4 mg) via a single oral administration under fasting conditions. Individual and mean plasma concentrations of lobeglitazone sulfate are shown in Table 24. Mean drug concentration-time curves are presented in... Figure 1 Presented in the middle.

[0273] Table 24. Individual and mean plasma concentrations (ng / mL) of lobeglitazone sulfate in male cynomolgus monkeys after a single oral administration of one tablet / animal (lobeglitazone orally disintegrating tablet, 0.4 mg) under fasting conditions.

[0274]

[0275] BLQ: Below the limit of quantitation (LLOQ = 1 ng / mL); ND: Not determined.

[0276] Group 2: Male cynomolgus monkeys were administered one tablet per animal (lobeglitazone orally disintegrating tablet, 0.8 mg) via a single oral administration under fasting conditions. Individual and mean plasma concentrations of lobeglitazone sulfate are shown in Table 25.

[0277] Table 25. Individual and mean plasma concentrations (ng / mL) of lobeglitazone sulfate in male cynomolgus monkeys after a single oral administration of one tablet / animal (lobeglitazone orally disintegrating tablet, 0.8 mg) under fasting conditions.

[0278]

[0279] BLQ: Below the limit of quantitation (LLOQ = 1 ng / mL); ND: Not determined.

[0280] Group 3: Male cynomolgus monkeys were administered one tablet per animal (lobeglitazone orally disintegrating tablet, 1.2 mg) via a single oral administration under fasting conditions. Individual and mean plasma concentrations of lobeglitazone sulfate are shown in Table 26.

[0281] Table 26. Individual and mean plasma concentrations (ng / mL) of lobeglitazone sulfate in male cynomolgus monkeys after a single oral administration of one tablet / animal (lobeglitazone orally disintegrating tablet, 1.2 mg) under fasting conditions.

[0282]

[0283] BLQ: Below the limit of quantitation (LLOQ = 1 ng / mL); ND: Not determined.

[0284] Group 4: Male cynomolgus monkeys were administered one tablet per animal (Duvie® tablet, 0.5 mg) via a single oral administration under fasting conditions. Individual and mean plasma concentrations of lobeglitazone sulfate are shown in Table 27.

[0285] Table 27. Individual and mean plasma concentrations (ng / mL) of lobeglitazone sulfate in male cynomolgus monkeys after a single oral administration of one tablet / animal (Duvie® tablet, 0.5 mg) under fasting conditions.

[0286]

[0287] BLQ: Below the limit of quantitation (LLOQ = 1 ng / mL); ND: Not determined.

[0288] in conclusion

[0289] The main pharmacokinetic parameters of lobeglitazone sulfate in cynomolgus monkey plasma following a single oral administration are summarized in Table 28. These data indicate that the orally disintegrating tablets (i.e., 0.4 mg, 0.8 mg, and 1.2 mg formulations) presented herein have similar relative oral bioavailability to Duvie®. The improved orally disintegrating formulations / tablets presented herein reduce the side effects of Duvie®, which is an ingested / swallowed pill, due to the oral absorption of lobeglitazone achieved through the orally disintegrating tablets described herein.

[0290] Under fasting conditions, in male cynomolgus monkeys, following a single oral administration of one tablet / animal (lobeglitazone orally disintegrating tablet, 0.4 mg), the mean T plasma levels of lobeglitazone sulfate were [data missing]. 1 / 2The mean temperature was 1.09 ± 0.24 h, and the mean temperature was C. 最大值 The concentration was 258.90 ± 111.93 ng / mL, with an average AUC of 258.90 ± 111.93 ng / mL. (0-t) The concentration was 584.15 ± 235.97 h*ng / mL, with an average AUC of (0-∞) The value was 591.73 ± 244.11 h*ng / mL.

[0291] Under fasting conditions, in male cynomolgus monkeys, following a single oral administration of one tablet / animal (lobeglitazone orally disintegrating tablet, 0.8 mg), the mean T plasma levels of lobeglitazone sulfate were [data missing]. 1 / 2 The mean temperature was 1.00 ± 0.06 h, and the mean temperature was C. 最大值 The concentration was 333.68 ± 112.57 ng / mL, with an average AUC of 1000 ng / mL. (0-t) The concentration was 830.45 ± 163.36 h*ng / mL, with an average AUC of 100000. (0-∞) The value was 836.74 ± 165.96 h*ng / mL.

[0292] Table 28. Individual primary pharmacokinetic parameters of lobeglitazone sulfate in the plasma of male cynomolgus monkeys after a single oral administration of different tablets (orally disintegrating tablets: G1, G2, G3; immediate-release tablet: G4).

[0293]

[0294] Under fasting conditions, in male cynomolgus monkeys, the mean T plasma concentration of lobeglitazone sulfate was [data missing - likely related to a specific metric]. 1 / 2 The duration was 1.94 ± 1.43 h, with an average C 最大值 The concentration was 811.78 ± 266.38 ng / ml, with an average AUC of 100 mg / ml. (0-t) The mean AUC was 1769.02 ± 558.72 h*ng / ml. (0-∞) The value was 1781.00±554.95 h*ng / ml.

[0295] Under fasting conditions, in male cynomolgus monkeys, the mean T plasma levels of lobeglitazone sulfate after a single oral administration of one tablet / animal (Duvie® tablet, 0.5 mg) were [not specified]. 1 / 2 The mean C was 1.13 ± 0.11 h. 最大值 The concentration was 329.87 ± 87.35 ng / ml, with an average AUC of 100 mg / ml. (0-t) The mean AUC was 747.78 ± 59.24 h*ng / ml. (0-∞) It was 755.53±60.95 h*ng / ml.

[0296] Unless otherwise stated, all figures used in the specification and claims to indicate the amount and properties of components (such as molecular weight, reaction conditions, etc.) should be understood to be modified by the term "about" in all cases. As used herein, the terms "about" and "approximately" mean within 10% to 15%, preferably within 5% to 10%. Therefore, unless otherwise indicated, the numerical parameters listed in the specification and appended claims are approximate values ​​that may vary according to the desired properties sought to be obtained according to the invention. At least, and without attempting to limit the application of the doctrine of equivalence to the scope of the claims, each numerical parameter should be interpreted at least according to the number of significant figures reported and by applying ordinary rounding techniques. Although the numerical ranges and parameters that illustrate the broad scope of the invention are approximate values, the values ​​set forth in the specific embodiments are reported as precisely as possible. However, any numerical value inherently contains some errors, which are necessarily caused by the standard deviation found in their respective test measurements.

[0297] The terms “a,” “an,” “the,” and similar designations used in the context of describing the invention (especially in the context of the appended claims) should be interpreted as encompassing both the singular and plural, unless otherwise stated herein or obviously contradicted by the context. The descriptions of numerical ranges herein are intended merely as a shorthand method of individually referring to each individual value falling within that range. Unless otherwise stated herein, each individual value is incorporated into the specification as if it were described separately herein. All methods described herein can be performed in any suitable order unless otherwise stated herein or obviously contradicted by the context. The use of any and all examples or exemplary language (e.g., “such as”) provided herein is intended merely to better illustrate the invention and not to limit the scope of the invention. No language in the specification should be construed as indicating any unclaimed element essential to the practice of the invention.

[0298] The grouping of alternative elements or embodiments of the invention disclosed herein should not be considered limiting. Each member of a group may be mentioned and claimed individually or in any combination with other members of that group or other elements found herein. It is contemplated that one or more members of a group may be included in or removed from the group for convenience and / or patentability reasons. When any such inclusion or removal occurs, this specification is deemed to include the group as modified, thereby satisfying the written description of all Markush groups as used in the appended claims.

[0299] The specific embodiments disclosed herein may be further limited in the claims using the language of "consisting of" or "substantially consisting of". When used in the claims, whether filed or added according to amendments, the transitional term "consisting of" excludes any element, step, or ingredient not specified in the claims. The transitional term "substantially consisting of" limits the scope of the claims to the specified materials or steps and those that do not substantially affect the essential and novel features. Embodiments of the invention thus claimed are inherently or explicitly described and implemented herein.

[0300] Furthermore, numerous references have been made to patents and print publications throughout this specification. Each of the references and print publications cited above is incorporated herein by reference in its entirety.

[0301] Finally, it should be understood that the embodiments of the invention disclosed herein exemplify the principles of the invention. Other modifications may be employed within the scope of the invention. Therefore, alternative configurations of the invention can be utilized based on the teachings herein, rather than as examples or limitations. Consequently, the invention is not limited to those precisely shown and described.

Claims

1. An orally disintegrating tablet (ODT) formulation comprising a thiazolidinedione, or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, cocrystal, enantiomer, or deuterated form thereof, wherein the thiazolidinedione is selected from one or more of pioglitazone, rosiglitazone, lobeglitazone, cycloglitazone, dapaglitazone, deuterated R-pioglitazone, empaglitazone, letaglitazone, neiglitazone, linaglitazone, troglitazone, and baraglitazone.

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

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

4. The formulation according to 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 according to claim 1, wherein 80% of the tablets dissolve within about 60 minutes, or preferably within about 30 minutes, or more preferably within about 15 minutes.

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

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

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

9. The use of orally disintegrating tablets of thiazolidinediones for the treatment of digestive system disorders selected from abdominal adhesions, achalasia, adult acid reflux (gastroesophageal reflux disease or GERD), infantile acid reflux (GERD), anatomical problems of the lower gastrointestinal tract, appendicitis, Barrett's esophagus, bowel control problems (fecal incontinence), celiac disease, colonic polyps, constipation, Crohn's disease, periodic vomiting syndrome, diarrhea, diverticulosis and diverticulitis, dumping syndrome, food poisoning. Toxins, gallstones, flatulence, gastritis, gastroparesis, gastrointestinal bleeding, hemorrhoids, indigestion, inguinal hernia, pseudo-obstruction, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), lactose intolerance, liver disease, microscopic colitis, colostomy, pancreatitis, peptic ulcer (gastric ulcer), proctitis, short bowel syndrome, ulcerative colitis, viral gastroenteritis, and Zollinger-Ellison syndrome or related symptoms.

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 system disease is gastroparesis, such as idiopathic gastroparesis, diabetic gastroparesis, postoperative gastroparesis, or drug-induced gastroparesis.

12. The use of orally disintegrating tablets of thiazolidinediones for the treatment of 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: The granular portion comprises a thiazolidinedione or a pharmaceutically acceptable prodrug thereof, a salt, a solvate, a hydrate, a cocrystal, an enantiomer or its deuterated form, ethanol, hydroxypropyl cellulose (HPC), mannitol, microcrystalline cellulose (MCC), polyvinylpyrrolidone (PVP), a sweetener, and croscarmellose sodium; and The outer portion of the particles contains 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 thereof, a salt, a solvate, a hydrate, a cocrystal, an enantiomer or a deuterated form thereof, ethanol, hydroxypropyl cellulose (HPC), mannitol, microcrystalline cellulose (MCC), polyvinylpyrrolidone (PVP), a sweetener, and croscarmellose sodium.

18. The particles according to claim 17 have an average diameter of about 1 mm.

19. An orally disintegrating tablet comprising a plurality of particles according to claim 17 dispersed in an extragranular matrix.

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

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