DESC:Field of Invention
The present invention relates to pharmaceutical composition of Lobeglitazone and Ursodeoxycholic acid for the treatment of Non-Alcoholic Steatohepatitis (NASH)/ Non-Alcoholic Fatty Liver Disease (NAFLD)
Background of the invention
Lobeglitazone belongs to the thiazolidinedione (TZD) class of drugs, and it primarily acts as an agonist for the peroxisome proliferator-activated receptor gamma (PPAR-?). PPAR-? is a nuclear receptor that plays a significant role in regulating various aspects of lipid and glucose metabolism, as well as inflammation. Lobeglitazone has primarily been used in the management of type 2 diabetes, but its potential therapeutic effects on Non-Alcoholic Steatohepatitis (NASH) has been recently explored in a study by Yong-ho lee and colleagues [Lee YH, et al., J Korean Med Sci. 2017 Jan;32(1):60-69. doi: 10.3346/jkms.2017.32.1.60.]. The study reported that lobeglitazone treatment reduced intrahepatic fat content, as assessed by transient liver elastography, and improved glycemic, liver, and lipid profiles in T2D patients with NAFLD.
The exact mechanism of action is not known but Lobeglitazone's mode of action as a PPAR-? agonist may allow it to target multiple aspects of NASH pathophysiology, including insulin resistance, inflammation, lipid metabolism, and fibrosis. Insulin resistance is a central feature of NASH, leading to increased blood glucose levels and excessive hepatic fat accumulation. Insulin resistance in peripheral tissues and the liver contributes to lipolysis, increased fatty acid influx into the liver, and hepatic steatosis. Lobeglitazone, as a PPAR-? agonist, enhances insulin sensitivity in target tissues. This improvement in insulin sensitivity can lead to better glucose utilization and reduced hyperglycemia, potentially addressing a core component of NASH pathophysiology.
Inflammation also plays a crucial role in the progression of NASH. Chronic inflammation within the liver can result from the accumulation of lipids, oxidative stress, and hepatocellular injury. It contributes to the transition from simple hepatic steatosis to NASH and fibrosis. TZD medications, including lobeglitazone, have demonstrated anti-inflammatory properties. By modulating PPAR-?, lobeglitazone may help mitigate hepatic inflammation in NASH, potentially reducing liver injury and the progression of the disease. Dyslipidemia and impaired lipid metabolism are common features of NASH. Altered lipid homeostasis can lead to lipid droplet accumulation within hepatocytes. PPAR-? activation by lobeglitazone can influence lipid metabolism, potentially promoting the clearance of excess lipids from the liver. This could help address hepatic steatosis, a hallmark of NASH.
Fibrosis, characterized by the deposition of extracellular matrix proteins in the liver, is a critical feature of advanced NASH. It results from persistent inflammation, oxidative stress, and hepatocellular injury. By reducing inflammation and hepatocellular injury, lobeglitazone may indirectly slow down or even reverse the progression of fibrosis in NASH. The anti-fibrotic effects may be attributed to its ability to address underlying factors contributing to fibrosis development.
Ursodeoxycholic acid (UDCA) is another ingredient whose role is also being explored in the therapeutic effect in NASH. Zun Xiang and Colleagues in their systematic review reported the role UDCA plays in NASH. The systematic review concluded that UDCA therapy is effective in NASH, especially when combined with other drugs (UDCA with vitamin E, polyene phosphatidylcholine, silymarin, glycyrrhizin and tiopronin).
NASH is characterized by the accumulation of triglycerides and other lipids within hepatocytes. This accumulation can result from increased influx of free fatty acids into the liver, decreased export of lipids from the liver, or impaired lipid metabolism within hepatocytes. UDCA may influence lipid metabolism in the liver. UDCA being a bile acid itself, may help normalize bile acid metabolism. This normalization could have positive effects on lipid handling and potentially aid in reducing hepatic steatosis.
UDCA can promote the solubilization and excretion of cholesterol, potentially reducing the accumulation of cholesterol and triglycerides within hepatocytes. Lipid accumulation in the liver can lead to oxidative stress, characterized by an imbalance between the production of reactive oxygen species (ROS) and the body's ability to neutralize them. Oxidative stress can cause cellular damage and inflammation. Antioxidant properties of UDCA has been reported in the art, which could help reduce oxidative stress in hepatocytes [Lin X, Mai M, He T, Huang H, Zhang P, Xia E, Guo H., Expert Rev Gastroenterol Hepatol. 2022 Jun;16(6):537-545. doi: 10.1080/17474124.2022.2083605.] By mitigating oxidative damage, UDCA may indirectly contribute to the resolution of hepatic steatosis.
In some cases, hepatic steatosis can progress to non-alcoholic steatohepatitis (NASH), characterized by inflammation and hepatocellular injury. Inflammation in the liver can exacerbate liver damage. UDCA has demonstrated anti-inflammatory properties in various liver conditions. While it may not directly target inflammation associated with steatosis, it could be beneficial in cases where steatosis coexists with inflammation or progresses to NASH. Alterations in bile acid metabolism can impact hepatic lipid homeostasis. Dysregulation of bile acids can affect the solubilization and transport of lipids, contributing to lipid accumulation in hepatocytes.
The present invention for the first time presents a synergistic combination of Lobeglitazone and UDCA for the treatment of NASH.
Synergistic Effects of combination of Lobeglitazone AND UDCA-
Lobeglitazone's insulin-sensitizing effect may enhance glucose control, reducing hyperglycemia, and ameliorating insulin resistance, a common feature in NASH and NAFLD. The anti-inflammatory properties of both lobeglitazone and UDCA can synergistically target hepatic inflammation, potentially leading to greater reductions in liver inflammation. Combining UDCA's anti-fibrotic effects with lobeglitazone's mechanisms may have a more profound impact on fibrosis regression, a critical goal in NASH management. The combination of lobeglitazone and UDCA has the potential to comprehensively address not only liver health but also systemic metabolic effects, such as dyslipidemia, making it a promising approach for individuals with NASH and NAFLD who often have multiple metabolic abnormalities.
Thus the combination of Lobeglitazone and UDCA offers the potential for a synergistic effect in the treatment of NASH and NAFLD by addressing multiple aspects of the disease simultaneously. This dual-action approach may provide improved therapeutic outcomes, potentially leading to better liver health and metabolic control in affected patients.
Summary of Invention
The present invention relates to fixed dose combination of Lobeglitazone and Ursodeoxycholic acid (UDCA) for the treatment of Non-Alcoholic Steatohepatitis (NASH) and Non-Alcoholic Fatty Liver Disease (NAFLD). The therapy involves the use of two drugs: Lobeglitazone and Ursodeoxycholic acid (UDCA). Lobeglitazone is a member of the thiazolidinedione drug class that activates the peroxisome proliferator-activated receptor gamma (PPAR-?), which plays a crucial role in regulating lipid and glucose metabolism and inflammation. While primarily used for managing type 2 diabetes, Lobeglitazone has shown promise in addressing NASH. UDCA being a bile acid itself, normalize bile acid metabolism, promote cholesterol excretion, and reduce oxidative stress and inflammation.
The combination targets multiple aspects of the NASH, including insulin resistance, inflammation, fibrosis, and lipid abnormalities. The dual-action approach holds promise for improving liver health and metabolic control in individuals with NASH and NAFLD, offering a novel and potentially more effective treatment option.
Objective of the Invention
An objective of the invention is to provide a combination therapy comprising Lobeglitazone and UDCA for the treatment of NASH or NAFLD.
Another objective of the invention is to provide a composition comprising a combination of Lobeglitazone and UDCA for the treatment of NASH or NAFLD
Another objective of the present invention is to provide a fixed dose combination of Lobeglitazone and UDCA for the treatment of NASH or NAFLD.
Description
For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are collected here. These definitions should be read in the light of the remainder of the disclosure and understood as by a person of skill in the art. The terms used herein have their meanings recognized and known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below.
The articles “a”, “an” and “the” are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.
The terms “comprise” and “comprising” are used in the inclusive, open sense, meaning that additional elements may be included. It is not intended to be construed as “consists of only”.
Throughout this specification, unless the context requires otherwise the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated element or step or group of element or steps but not the exclusion of any other element or step or group of element or steps.
The term “including” is used to mean “including but not limited to”. “Including” and “including but not limited to” are used interchangeably.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the disclosure, the preferred methods, and materials are now described. All publications mentioned herein are incorporated herein by reference.
The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purposes of exemplification only. Functionally equivalent products and processes are clearly within the scope of the disclosure, as described herein.
The term “pharmaceutical composition” refers to delivery system in which active agents are delivered to the patients. This could be in the form of tablet, capsule, injection, liquid etc.
The term “pharmaceutically acceptable excipient” refers to inert substances other than active ingredients which are used in the preparation of pharmaceutical products.
The term “excipients” as used herein means a component of a pharmaceutical product that is not an active ingredient. The excipients that are useful in preparing a pharmaceutical composition are generally safe and non-toxic.
The term “bilayer tablet” is used to refer tablet obtain by compressing two different formulations into a single solid oral tablet. Bilayer of present invention provides two different layers of immediate release and sustained release delivery.
The term “immediate release” as used herein refers which quickly disintegrate and provide rapid onset of action.
The term “Sustained release” or “extended release” as used herein refers drug delivery system which releases the active agents in sustained or modified or extended for a prolonged period of time.
In an embodiment the present provides a drug delivery system for the sustained delivery of an active ingredient over 24 hours’ period.
In an embodiment the present invention provides a combination therapy comprising PPAR-? agonist and a bile acid for the treatment of NASH or NAFLD.
In an embodiment the PPAR-? agonist are selected from pioglitazone, rosiglitazone, Lobeglitazone, Ciglitazone, Darglitazone, Englitazone, Netoglitazone, Rivoglitazone, Troglitazone. In preferable embodiment the PPAR-? agonist are selected from pioglitazone, rosiglitazone, Lobeglitazone. In a most preferable embodiment the PPAR-? agonist is Lobeglitazone
In an embodiment the bile acids are selected from Cholic acid, Deoxycholic acid, Chenodeoxycholic acid, Taurchenodeoxycholic acid, Lithocholic acid, Ursodeoxycholic acid, Obeticholic acid. In a preferable embodiment the bile acid are selected from Cholic acid, deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, obeticholic acid. In a most preferred embodiment the bile acid is selected from ursodeoxycholic acid.
In an embodiment the present invention provides a combination therapy comprising PPAR- ? agonist and a bile acid for the treatment of NASH or NAFLD, wherein the PPAR-? agonist is Lobeglitazone and wherein the bile acid is UDCA
In embodiment the present invention provides a combination therapy comprising Lobeglitazone and Ursodeoxycholic acid for the treatment of NASH or NAFLD, wherein the combination is for oral consumption and wherein Lobeglitazone exhibits immediate drug release profile and wherein UDCA exhibits sustained drug release profile.
In an embodiment the present invention provides a combination therapy comprising Lobeglitazone and ursodeoxycholic acid for the treatment of NASH or NAFLD, wherein Lobeglitazone exhibits immediate drug release profile and wherein UDCA exhibits both immediate and sustained drug release profile.
In an embodiment the present invention provides a combination therapy comprising PPAR- ? agonist and a bile acid for the treatment of NASH or NAFLD, wherein the PPAR-? agonist is Lobeglitazone and wherein the bile acid is UDCA and wherein the PPAR-? exhibits immediate drug release profile and wherein the bile acid exhibits dual drug release profile, wherein the dual drug release profile comprises of immediate and sustained release of the bile acid.
In an embodiment the pharmaceutical composition of the present invention is present in the form of oral solid dosage forms, wherein the oral solid dosage forms are Conventional tablets, Bilayer tablets, Tablet-in-tablet, Inlaytablets, minitablets, multilayer pellets or multipellets in a capsules.
In a preferred embodiment the pharmaceutical composition of the present invention is present in the form of a Bilayer tablet, tablet-in-tablet, multilayer tablet.
In an embodiment the present invention provides a pharmaceutical composition comprising a combination of Lobeglitazone and UDCA, wherein the composition is composed of an immediate release layer and sustained release layer.
In an embodiment the present invention provides a pharmaceutical composition comprising a combination of Lobeglitazone and UDCA, wherein the composition is composed of an immediate release layer and sustained release layer, wherein the immediate release layer is composed of Lobeglitazone and UDCA and the sustained release is composed of UDCA.
In an embodiment the immediate release layer of the present invention is composed of combination of Lobeglitazone and UDCA, and pharmaceutically acceptable excipients which facilitates immediate release of the drugs. In an embodiment the pharmaceutically acceptable excipients of the present invention which facilitates the immediate release of the drugs are selected from diluent, binder, disintegrant, lubricant, and glidants.
In an embodiment the immediate release layer of the present invention is composed of combination of Lobeglitazone and UDCA and pharmaceutically acceptable excipient which facilitates immediate release of the drugs, wherein pharmaceutically acceptable excipient are one or more diluents, one or more disintegrant, one or more lubricant, a binder, glidant and colorant.
In an embodiment the extended release layer of the present invention is composed of UDCA and pharmaceutically acceptable excipient that facilitated the sustained release of the drug, wherein the pharmaceutically acceptable excipients are selected from sustained release polymer, Diluent, binder, glidant, lubricant.
In a preferred embodiment the extended release layer of the present invention is composed of UDCA and pharmaceutically acceptable excipients that facilitate the sustained release of the drug, wherein the pharmaceutically acceptable excipients are one or more sustained release polymers, diluent, binders, glidant and lubricant.
In a preferred embodiment the present invention provides a bilayer pharmaceutical composition, wherein the bilayer composition is composed of immediate release layer and a sustained release layer, wherein the immediate release layer is composed of combination of Lobeglitazone and UDCA, and pharmaceutically acceptable excipients that facilitates the immediate release of the drugs and wherein the extended release layer is composed of UDCA and pharmaceutically acceptable excipients that facilitates the sustained release of the drug.
In a preferred embodiment the present invention provides a bilayer pharmaceutical composition, wherein the bilayer composition is composed of
i) an immediate release layer comprising Lobeglitazone, UDCA and pharmaceutically acceptable excipients that facilitates immediate release of the drugs, wherein the pharmaceutically acceptable excipients are one or more diluents, one or more disintegrant, one or more lubricant, glidant, binder, and colorant
ii) an extended release layer comprising UDCA and pharmaceutically acceptable excipients that facilitates the sustained release of the drug, wherein the pharmaceutically acceptable excipients are sustained release polymers, diluent, binder, glidant and lubricant
In an embodiment the amount of UDCA present in the immediate release layer and the sustained release layer is in the ratio of 1:1
In an embodiment the pharmaceutical composition of the present invention may optionally comprises of film coating.
In an embodiment the immediate release layer and the sustained release layer of the present invention can be formulated to form a tablet-in-tablet composition, wherein the sustained release layer forms the inner tablet and immediate release layer is compressed over the sustained release layer to form the outer tablet.
In another embodiment the immediate release layer and sustained release layer of the present invention can be formulated as a multilayer tablet by coating the layers over a core.
In another embodiment the present invention provides a pharmaceutical composition comprising a combination of Lobeglitazone and UDCA, wherein the composition is present in the form of capsules, wherein the capsules are composed of a mixture of immediate release pellets or granules and sustained release pellets or granules
In an embodiment the present invention provides a pharmaceutical composition comprising a combination of Lobeglitazone and UDCA, wherein the composition is present in the form of capsule, wherein the capsules comprise a mixture of individual pellets or granules consisting of immediate release pellets comprising Lobeglitazone, immediate release pellets or granules comprising UDCA and Sustained release UDCA pellets or granules.
In an embodiment the present invention provides a fixed dose composition comprising a combination of Lobeglitazone and UDCA, wherein the composition is present in the form of a capsule, wherein the capsules comprises a mixture of immediate release pellets or granules and dual release multilayer pellets, wherein the immediate release pellets comprises of Lobeglitazone and pharmaceutically acceptable excipients that facilitates immediate drug release profile and wherein the dual release pellets comprises of immediate release layer comprising UDCA and sustained release layer comprising UDCA.
In an embodiment the pharmaceutical composition comprising:
a) About 40% w/w to about 90% w/w Ursodeoxycholic acid or a pharmaceutically acceptable salt thereof and;
b) About 0.05 to 10% w/w Lobeglitazone or a pharmaceutically acceptable salt thereof and
c) One or more pharmaceutically acceptable excipients
In an another embodiment the pharmaceutical composition is an oral tablet comprising:
a) About 40% w/w to about 90% w/w Ursodeoxycholic acid or a pharmaceutically acceptable salt thereof and
b) About 0.05 to 10% w/w Lobeglitazone or a pharmaceutically acceptable salt thereof and
c) One or more pharmaceutically acceptable excipients
In an another embodiment the present invention provides a bilayer tablet comprising an immediate release layer and sustained release layer.
In an another embodiment the present invention provides a bilayer tablet comprising
a) An immediate release layer comprising
i. About 0.05 to 10% w/w Lobeglitazone or a pharmaceutically acceptable salt thereof and
ii. About 40% w/w to about 90% w/w Ursodeoxycholic acid or a pharmaceutically acceptable salt thereof and
iii. One or more pharmaceutically acceptable excipients
b) A extended release layer comprising:
i. About 40% w/w to about 90% w/w Ursodeoxycholic acid or a pharmaceutically acceptable salt thereof
ii. One or more pharmaceutically acceptable excipients
In an another embodiment the present invention provides bilayer tablet comprise:
a. An immediate release layer comprises:
i. About 0.05 to 10% w/w Lobeglitazone or a pharmaceutically acceptable salt thereof and;
ii. About 40% w/w to about 90% w/w Ursodeoxycholic acid or a pharmaceutically acceptable salt thereof and
iii. One or more pharmaceutically acceptable excipients selected from one or more diluent, binder, glidant, disintegrant. Surfactant, lubricant
b. extended release layer comprising:
i. About 40% w/w to about 90% w/w Ursodeoxycholic acid or a pharmaceutically acceptable salt thereof
ii. One or more pharmaceutically acceptable excipients selected from one or more diluent, sustained release polymer, binder, glidant and lubricant
In an embodiment Lobeglitazone is present in the amount of 0.06% by weight of the whole composition.
In an embodiment UDCA is present in the amount of 75% by weight of the whole composition.
the pharmaceutical composition further comprises pharmaceutically acceptable excipients, wherein the pharmaceutical excipients are selected from diluents in the amount of 2 to 20% w/w, disintegrants in the amount of 2 to 10% w/w, binders in the amount of 0.5 to 10% w/w, sustained release polymers in the amount of 2 to 20% w/w.
In an embodiment the sustained release polymer that can used in the present invention are selected from but not limited to water soluble polymer such as Hydroxypropyl methylcellulose (HPMC), xanthan gum, guar gum, sodium alginate, carbomers and hydroxyethyl cellulose, water insoluble polymer such as ethylcellulose and waxes and fats such as glyceryl esters of fatty acids including glyceryl monostearate, glyceryl behenate, fatty acids such as stearic acid, fatty alcohols such as cetyl alcohol, stearyl alcohol, cetosteary alcohol, and the likes. In a preferred embodiment the sustained release polymers are water soluble cellulose ethers, like HPMC, Hydoxy ethylcellulose, Carboxymethyl Cellulose and the likes thereof.
In an embodiment the diluents that can be used in the present invention are selected from but not limited to lactose monohydrate, dibasic calcium phosphate, tribasic calcium phosphate, sorbitol, sucrose, trehalose, isomalt, microcrystalline cellulose, mannitol, starch, sodium carbonate, sodium bicarbonate, dextrose, maltodextrin, calcium carbonate, xylitol or the mixtures thereof.
In an embodiment the disintegrants of the present invention are selected from but not limited to several modified starches, modified cellulose polymers, or polycarboxylic acids, such as croscarmellose sodium, sodium starch glycolate, polacrillin potassium, carboxymethylcellulose calcium (CMC Calcium), and crospovidone or a combination thereof.
In an embodiment the binders of the present invention are selected from but are not limited to pregelatinised starch, hydroxypropyl cellulose, sugars, glycose syrups, natural gums, guar gum, gelatins, pullulan, polymetacrylates, collagen, agar, algynate, sodium alginate, hyaluronic acid, pectin, tragacanth gum, carboxymethyl cellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, polyvinyl acetate and their copolymers, hydroxypropyl methyl cellulose, carboxy methyl cellulose, methyl cellulose, microcrystalline cellulose, polyvinylalcohol, carrageenan, carbomer, poloxamer, polyacrylamide, aluminum hydroxide, benthonite, laponite, setostearyl alcohol, polyoxyethylene-alkyl ethers, acacia mucilage, polydextrose, polyethylene oxide or the mixtures thereof.
Examples of Lubricants of the present invention include but not limited to magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated castor oil, and mixtures thereof.
Examples of glidants of the present invention includes but not limited to colloidal silicon dioxide, calcium phosphate tribasic, magnesium silicate, and talc or a combination thereof.
In an another embodiment the surfactant is selected from but not limited to Hydroxypropyl methylcellulose (HPMC), xanthan gum, guar gum, sodium alginate, carbomers and hydroxyethyl cellulose, sodium lauryl sulphate, water insoluble polymer such as ethylcellulose and waxes and fats such as glyceryl esters of fatty acids including glyceryl monostearate, glyceryl behenate, fatty acids such as stearic acid, fatty alcohols such as cetyl alcohol, stearyl alcohol, cetosteary alcohol or combinations thereof.
In an another embodiment the immediate release layer comprising of:
i. 2 to 20% w/w of diluent and
ii. 2 to 10% w/w of binder and;
iii. 0.05 to 10% w/w of glidant and
iv. 2 to 20% w/w of Disintegrant and;
v. 0.05 to 10% w/w of surfactant and;
vi. 0.05 to 10% w/w of lubricant
In an another embodiment the immediate release comprising of:
i. 2 to 20% w/w of lactose, starch and microcrystalline cellulose as diluent and;
ii. 2 to 10% w/w of Polyvinyl pyrrolidone as Binder and;
iii. 0.05 to 10% w/w of Talcum as glidant and;
iv. 2 to 20% w/w of sodium starch glycolate as disintegrant and;
v. 0.05 to 10% w/w of sodium lauryl sulphate as surfactant and
vi. 0.05 to 10% w/w of magnesium stearate as Lubricant
In an another embodiment the extended release layer comprising of:
i. 5 to 20% w/w of sustained release polymer and;
ii. 2 to 10% w/w of diluent and;
iii. 0.05 to 10% w/w of Binder and;
iv. 0.05 to 10% w/w of glidant and;
v. 0.05 to 10% w/w of lubricant
In an another embodiment the extended release layer comprising of:
i. 5 to 20 % w/w of Hydroxypropyl methylcellulose as sustained release polymer and;
ii. 2 to 10% w/w of microcrystalline cellulose as Diluent and;
iii. 0.05 to 10% w/w of colloidal silicon dioxide as Glidant and;
iv. 0.05 to 10% w/w of magnesium stearate as lubricant
In an another embodiment the extended release layer comprising of:
i. 73.58% w/w of Ursodeoxycholic acid and
ii. 6.61% w/w of Microcrystalline cellulose and
iii. 5 to 10% w/w of Hydroxypropyl methylcellulose and
iv. 1.92% of w/w of Polyvinyl Pyrrolidone and
v. 1.44% of w/w of Colloidal silicon dioxide and
vi. 1.44% of w/w of Magnesium stearate
The present invention is illustrated below by reference to the following examples. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the invention, and not to be construed as limiting the invention, as many variations thereof are possible without departing from the spirit and scope of the invention.
Examples-
The scope of the present invention is illustrated by the following examples which are not meant to restrict the scope of the invention in any manner whatsoever.
Example 1- Formulation details
Ingredients %age Function
(Part 1) Lobeglitazone sulfate & Ursodeoxycholic Acid (Immediate release layer)
Lobeglitazone sulfate 0.158 Active
Ursodeoxycholic acid 67.52 Active
Lactose 2.32 Diluent
Starch (Maize) 7.35 Diluent
Col. Ponceau 4R Lake 0.29 Colorant
Binder Preparation
Polyvinyl Pyrrolidone K-30 3.23 Binder
Purified water --- Solvent
Lubrication
Talcum 1.47 Glidant
Microcrystalline Cellulose
(M.C.C PH-102) 7.35 Diluent
Sodium starch glycolate (Primojel) 5.88 Disintegrant
Colloidal silicon dioxide 1.471 Glidant
Sodium lauryl sulphate 0.882 Surfactant
Magnesium stearate 2.05 Lubricant

Ingredients %age Function
(Part-2) Ursodeoxycholic Acid (Extended release layer)
Ursodeoxycholic Acid 73.58 Active
Microcrystalline Cellulose
(M.C.C PH-102) 6.613 Diluent
Hydroxypropyl methylcellulose
(Methocel K4M) 8.26 Sustained release polymer
Binder
Polyvinyl Pyrrolidone (PVP K-30) 1.92 Binder
Purified water Q.S. Solvent
Lubrication
Hydroxypropyl methylcellulose
(Methocel K100 LV) Sustained release polymer 6.73
Colloidal Silicon Dioxide Glidant 1.44
Magnesium Stearate Lubricant 1.44

Example 2- Process of manufacturing:
Preparation of immediate release layer:
1. Sift Lobeglitazone sulfate, Ursodeoxycholic acid, lactose, starch and colouring agent in vibro sifter
2. Mix all the sifted materials for 10 minutes in rapid mixre granulator
3. Prepare binder mixture by dissolving polyvinyl pyrrolidone to obtain transparent, lumpfree binder solution
4. Pour the binder solution slowly in premix material in rapid mixer granulator for 03 to 05 minutes.
5. Pass the wet mass through multi mill at slow speed in multi mill and collect the wet coarse granules in fluidized bed processor (FBP) bowl.
6. Dry the wet granules in FBP at temperature between 50°C-60°C till desired moisture content obtained.
7. Sift the dried granules through sieve with vibro sifter and sift lubricated materials: talcum, sodium starch glycolate, colloidal silicon dioxide, sodium lauryl sulfate and magnesium stearate
8. Take the dried and sifted granules and lubricants into the octagonal blender/rotocuber mixer for 10 minutes. The add sifted magnesium stearate, sodium stearyl fumarate & mix for 5 minutes.
Preparation of extended release layer:
1. Sift Ursodeoxycholic acid, microcrystalline cellulose, Hydroxypropyl methylcellulose in Vibro sifter
2. Prepare the binder solution by dissolving Polyvinyl pyrrolidone in purified water
3. Mix all the sifted materials for 10 minutes in rapid mixing granulator for 10 minutes
4. Pour the binder solution and mix the material intermittently. After addition of binder, mix continuously through impeller and chopper at slow speed for 2 minutes.
5. Pass the wet mass through multi mill and collect the wet coarse granules in FBD bowl.
6. Dry the wet granules in fluidized bed dryer (FBP) at high temperature for 45-60 minutes
7. Sift the dried granules with mechanical sifter and pass the retained granules through multi mill.
8. Sift the lubricants: colloidal silicon dioxide, magnesium stearate and Hydroxypropyl methylcellulose.
9. Transfer the sized, sifted granules & sifted lubricant into octagonal blender/rotocube mixer to mix for 10 minutes at 12 ± 1 RPM. Then add sifted magnesium stearate & blend for 5 minutes at 12 ± 1 RPM
Compressing immediate release and extended release layer:
Compress the granules of immediate release layer and extended release layer to obtain bilayer tablet

Example 3- Stability studies (25°C ±2°C & RH 60% ± 5%)
Test Acceptance criteria Initial testing After 3 months
Description Pink & white coloured, elongated, biconvex, both side plain & uncoated bilayered tablets.
Pink & white coloured, elongated, biconvex, both side plain & uncoated bilayered tablets.
Pink & white coloured, elongated, biconvex, both side plain & uncoated bilayered tablets.

Identification
Identification: (By HPLC) In the assay, the major peaks in the chromatogram obtained with the test solution corresponds to the major peaks in the chromatogram obtained with the standard solution. Complies Complies
Average weight 860.0 mg ± 5.0% 869.01 mg 868.25 mg
Water content (By KF) For record purpose only 4.31%w/w 3.00%w/w
Hardness Not less than 150 N 166.8 N 156.9 N
Dissolution (By HPLC)
Lobeglitazone sulfate Not less than 70% (Q) in 45 minutes Min. 100.55% 98.30%
Max. 103.14% 101.48%
Avg. 101.86% 99.50%
Ursodeoxycholic acid
After 01 hour Between 35% to 65% Min. 61.98% 66.20%
Max. 64.37% 77.69%
Avg. 63.25% 71.33%
After 03 hour Between 55% to 85% Min. 74.07% 85.09%
Max. 83.54% 94.23%
Avg. 78.89% 89.05%
After 12 hour Not less than 80% Min. 90.90% 101.55%
Max. 93.03% 103.28%
Avg. 92.05% 102.31%
Related by substance (by HPLC)
Lobeglitazone sulfate
LB-01 impurity Not more than 1.0 % 0.140% Not Detected
LB-04 impurity-02 Not more than 1.0 % Not Detected Not Detected
LB-03 impurity-01 Not more than 1.0 % Not Detected 0.0167%
LB-02 impurity Not more than 1.0 % Not Detected 0.0448%
Single maximum impurity Not more than 0.5 % 0.224% 0.1265%
Total impurities Not more than 2.0 % 0.557% 0.381%
Ursodeoxycholic acid
Ursodeoxycholic acid impurity A Not more than 1.5% 0.198% 0.256%
Cholic acid impurity Not more than 0.5% Not Detected Not Detected
Single maximum unknown impurity Not more than 0.5% Not Detected 0.031%
Total unknown impurities Not more than 2.0% 0.198% 0.287%
Lithocholic acid:
(By HPLC) Not more than 0.1 % Not Detected Not Detected
Microbial contamination
Total viable count
Total Aerobic Bacterial Count Not more than 1000 cfu/gm <10 cfu/gm -
Total Combined Yeast & Mould Count Not more than 100 cfu/gm <10 cfu/gm -
Test for specified Microorganism
Escherichia coli Should be absent/gm Absent/gm
Salmonella Should be absent/10gm Absent/10gm
Staphylococcus aureus Should be absent/gm Absent/gm
Pseudomonas aeruginosa Should be absent/gm Absent/gm
Shigella Should be absent/10gm Absent/10gm
Bile-Tolerant Gram-Negative Bacteria (Enterobacteria) Should be absent/gm. Absent/gm
Assay: (By HPLC) Each film coated Tablet Contains:
Lobeglitazone Sulfate 0.5 mg
Not less than 0.450 mg & not more than 0.550
mg
(Not less than 90.00% & not more than 110.00%
of label claim) 0.507 mg
(101.40%) 0.501mg
(100.20%)
Lobeglitazone Sulfate 0.5 mg
Not less than 0.450 mg & not more than 0.550
mg
(Not less than 90.00% & not more than 110.00%
of label claim) 0.507 mg
(101.40%) 0.501mg
(100.20%)

The lobeglitazone and UDCA tablet prepared from example 1& 2 was found to be stable after 03 months of Long term Stability Studies (Temp. 25°C ± 2°C & RH 60 % ± 5%).

Example 3b- Temp. 30°C ±2°C & RH 75% ± 5%
Test Acceptance criteria Initial testing After 3 months
Description Pink & white coloured, elongated, biconvex, both side plain & uncoated bilayered tablets.
Pink & white coloured, elongated, biconvex, both side plain & uncoated bilayered tablets.
Pink & white coloured, elongated, biconvex, both side plain & uncoated bilayered tablets.

Identification
Identification: (By HPLC) In the assay, the major peaks in the chromatogram obtained with the test solution corresponds to the major peaks in the chromatogram obtained with the standard solution. Complies Complies
Average weight 860.0 mg ± 5.0% 869.01 mg 870.67 mg
Water content (By KF) For record purpose only 4.31%w/w 2.79%w/w
Hardness Not less than 150 N 166.8 N 161.9 N
Dissolution (By HPLC)
Lobeglitazone sulfate Not less than 70% (Q) in 45 minutes Min. 100.55% 97.33%
Max. 103.14% 100.14%
Avg. 101.86% 98.59%
Ursodeoxycholic acid
After 01 hour Between 35% to 65% Min. 61.98% 41.51%
Max. 64.37% 64.85%
Avg. 63.25% 52.93%
After 03 hour Between 55% to 85% Min. 74.07% 82.39%
Max. 83.54% 91.60%
Avg. 78.89% 86.46%
After 12 hour Not less than 80% Min. 90.90% 99.15%
Max. 93.03% 101.56%
Avg. 92.05% 100.20%
Related by substance (by HPLC)
Lobeglitazone sulfate
LB-01 impurity Not more than 1.0 % 0.140% Not Detected
LB-04 impurity-02 Not more than 1.0 % Not Detected Not Detected
LB-03 impurity-01 Not more than 1.0 % Not Detected Not Detected
LB-02 impurity Not more than 1.0 % Not Detected 0.0700%
Single maximum impurity Not more than 0.5 % 0.224% 0.1439%
Total impurities Not more than 2.0 % 0.557% 0.411%
Ursodeoxycholic acid
Ursodeoxycholic acid impurity A Not more than 1.5% 0.198% 0.229%
Cholic acid impurity Not more than 0.5% Not Detected Not Detected
Single maximum unknown impurity Not more than 0.5% Not Detected 0.030%
Total unknown impurities Not more than 2.0% 0.198% 0.259%
Lithocholic acid:
(By HPLC) Not more than 0.1 % Not Detected Not Detected
Microbial contamination
Total viable count
Total Aerobic Bacterial Count Not more than 1000 cfu/gm <10 cfu/gm -
Total Combined Yeast & Mould Count Not more than 100 cfu/gm <10 cfu/gm -
Test for specified Microorganism
Escherichia coli Should be absent/gm Absent/gm
Salmonella Should be absent/10gm Absent/10gm
Staphylococcus aureus Should be absent/gm Absent/gm
Pseudomonas aeruginosa Should be absent/gm Absent/gm
Shigella Should be absent/10gm Absent/10gm
Bile-Tolerant Gram-Negative Bacteria (Enterobacteria) Should be absent/gm. Absent/gm
Assay: (By HPLC) Each film coated Tablet Contains:
Lobeglitazone Sulfate 0.5 mg
Not less than 0.450 mg & not more than 0.550
mg
(Not less than 90.00% & not more than 110.00%
of label claim) 0.507 mg
(101.40%) 0.502 mg
(100.40%)
Lobeglitazone Sulfate 0.5 mg
Not less than 0.450 mg & not more than 0.550
mg
(Not less than 90.00% & not more than 110.00%
of label claim) 589.07 mg
(98.18%) 592.964 mg
(98.83%)

The lobeglitazone and UDCA tablet prepared from example 1& 2 was found to be stable after 03 months of long term Stability Studies (Temp. 30°C ± 2°C & RH 75% ± 5%).
,CLAIMS:1. A pharmaceutical composition comprising
a. About 40% w/w to about 90% w/w Ursodeoxycholic acid or a pharmaceutically acceptable salt thereof and;
b. About 0.05 to 10% w/w Lobeglitazone or a pharmaceutically acceptable salt thereof and;
c. One or more pharmaceutically acceptable excipients
2. The pharmaceutical composition as claimed in claim 1, wherein Ursodeoxycholic exhibits both immediate and sustained drug release profile and wherein Lobeglitazone exhibits immediate drug release profile.
3. The pharmaceutical composition as claimed in claim 2, wherein the pharmaceutical composition further comprises pharmaceutically acceptable excipients, wherein the pharmaceutical excipients are selected from diluents in the amount of 2 to 20% w/w, disintegrants in the amount of 2 to 10% w/w, binders in the amount of 0.5 to 10% w/w, sustained release polymers in the amount of 2 to 20% w/w.
4. A pharmaceutical composition as claimed in claim 1, wherein the composition is a bilayer tablet comprising:
a. Immediate release layer comprising:
i. About 0.05 to 10% w/w Lobeglitazone or a pharmaceutically acceptable salt thereof and
ii. About 40% w/w to about 90% w/w Ursodeoxycholic acid or a pharmaceutically acceptable salt thereof and
iii. One or more pharmaceutically acceptable excipients
b. extended release layer comprising:
i. About 40% w/w to about 90% w/w Ursodeoxycholic acid or a pharmaceutically acceptable salt thereof
ii. One or more pharmaceutically acceptable excipients
5. The immediate release layer as claimed in claim 4 comprises:
i. 2 to 20% w/w of diluent and
ii. 2 to 10% w/w of binder and;
iii. 0.05 to 10% w/w of glidant and
iv. 2 to 20% w/w of Disintegrant and;
v. 0.05 to 10% w/w of surfactant and;
vi. 0.05 to 10% w/w of lubricant and
And the extended release layer comprises:
i. 5 to 20% w/w of sustained release polymer and;
ii. 2 to 10% w/w of diluent and;
iii. 0.05 to 10% w/w of Binder and;
iv. 0.05 to 10% w/w of glidant and;
v. 0.05 to 10% w/w of lubricant
6. The diluent and disintegrant as claimed in claim 3 and 5 are selected from lactose monohydrate, dibasic calcium phosphate, tribasic calcium phosphate, sorbitol, sucrose, trehalose, isomalt, microcrystalline cellulose, mannitol, starch, sodium carbonate, sodium bicarbonate, dextrose, maltodextrin, calcium carbonate, xylitol, modified starches, modified cellulose polymers, or polycarboxylic acids, such as croscarmellose sodium, sodium starch glycolate, polacrillin potassium, carboxymethylcellulose calcium (CMC Calcium), and crospovidone or a combination thereof.
7. The binder according to claim 3 and 5 are selected from pregelatinised starch, hydroxypropyl cellulose, sugars, glycose syrups, natural gums, guar gum, gelatins, pullulan, polymetacrylates, collagen, agar, algynate, sodium alginate, hyaluronic acid, pectin, tragacanth gum, carboxymethyl cellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, polyvinyl acetate and their copolymers, hydroxypropyl methyl cellulose, carboxy methyl cellulose, methyl cellulose, microcrystalline cellulose, polyvinylalcohol, carrageenan, carbomer, poloxamer, polyacrylamide, aluminum hydroxide, benthonite, laponite, setostearyl alcohol, polyoxyethylene-alkyl ethers, acacia mucilage, polydextrose, polyethylene oxide.
8. The Sustained release polymer according to claim 3 and 5 are selected from Hydroxypropyl methylcellulose (HPMC), xanthan gum, guar gum, sodium alginate, carbomers and hydroxyethyl cellulose, water insoluble polymer such as ethylcellulose and waxes and fats such as glyceryl esters of fatty acids including glyceryl monostearate, glyceryl behenate, fatty acids such as stearic acid, fatty alcohols such as cetyl alcohol, stearyl alcohol, cetosteary alcohol.
9. The Surfactant according to claim 3 and 5 are selected from Hydroxypropyl methylcellulose (HPMC), xanthan gum, guar gum, sodium alginate, carbomers and hydroxyethyl cellulose, sodium lauryl sulphate, water insoluble polymer such as ethylcellulose and waxes and fats such as glyceryl esters of fatty acids including glyceryl monostearate, glyceryl behenate, fatty acids such as stearic acid, fatty alcohols such as cetyl alcohol, stearyl alcohol, cetosteary alcohol or combinations thereof
10. The glidant and lubricant according to claim 3 and 5 are selected from colloidal silicon dioxide, calcium phosphate tribasic, magnesium silicate, and talc, magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated castor oil or combinations thereof.