WO2013117963A1

WO2013117963A1 - Stable oral tablet dosage form of an antidiabetic compound

Info

Publication number: WO2013117963A1
Application number: PCT/IB2012/050579
Authority: WO
Inventors: Arno Appavoo Enose
Original assignee: Piramal Enterprises Limited
Priority date: 2012-02-09
Filing date: 2012-02-09
Publication date: 2013-08-15

Abstract

The invention relates to a stable oral tablet dosage form comprising an antidiabetic compound (a compound of formula (I) or a pharmaceutically acceptable salt thereof) as the active pharmaceutical ingredient, a non-ionic surfactant and one or more pharmaceutically acceptable excipients. The tablet dosage form contains between 40 % w/w to 80 % w/w of the antidiabetic compound, along with a non-ionic surfactant and one or more other pharmaceutically acceptable excipients. The tablet dosage form is characterized by a specific particle size of the active pharmaceutical ingredient with immediate release pattern and increased bioavailability of the active pharmaceutical ingredient.

Description

STABLE ORAL TABLET DOSAGE FORM OF AN ANTIDIABETIC COMPOUND

FIELD OF THE INVENTION

The present invention relates to a pharmaceutical composition in the form of a stable oral dosage form, particularly an oral tablet dosage form comprising an antidiabetic compound (compound of formula (I) or a pharmaceutically acceptable salt thereof); a non- ionic surfactant and one or more pharmaceutically acceptable excipients; and to methods of preparation of said tablet dosage form. BA CKGROUND OF THE INVENTION

Diabetes mellitus is a group of metabolic diseases characterized by high sugar (glucose) levels in the blood of a person that results due to inability of the body to produce enough insulin, or because fat and muscle cells of the human body do not respond to the insulin that is produced by the body. This high level of glucose in the blood produces the symptoms of polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger). There are two basic types of Diabetes mellitus: namely Type 1 diabetes or insulin dependent diabetic mellitus (IDDM) and Type 2 diabetes or non-insulin dependent diabetic mellitus (NIDDM). Type 1 diabetes or IDDM results from the body's failure to produce insulin and is characterized by loss of the insulin-producing beta cells of the islets of Langerhans in the pancreas leading to insulin deficiency. IDDM is partly inherited and partly triggered by certain infections. Type 2 diabetes mellitus or NIDDM is characterized by insulin resistance because of the reduced insulin sensitivity. NIDDM occurs due to lifestyle and genetic factors and is the more common form of diabetes.

People with Type 2 diabetes require regular monitoring of blood glucose levels and continuing treatment to maintain normal or near normal blood glucose levels. Treatment of NIDDM includes lifestyle adjustments, self-care measures and medicines, which can minimize the risk of diabetes and diabetes related cardiovascular complications. A number of medicines are available to treat NIDDM which include metformin; sulfonyl ureas such as glipizide; GLP antagonists such as exenatide and liraglutide; thiazolidinediones such as pioglitazone and rosiglitazone; DPP- IV inhibitors such as sitagliptin, saxagliptin, and vildagliptin; and alpha-glucosidase inhibitors such as acarbose and miglitol.

Among the anti-diabetic agents discussed above, thiazolidinediones (TZDs), particularly pioglitazone and rosiglitazone were found to be efficacious in the treatment of Type 2 diabetes. The effect of thiazolidinediones on insulin sensitivity was found to be due to activation of the peroxisome proliferation-activated receptor-γ (PPARy). However, despite the benefits associated with PPARy activation, thiazolidinediones (TZDs) were found to be associated with unwanted side effects, such as weight gain, fluid retention, hepato toxicity, congestive heart failure, increased risk of stroke and heart attack, which diminish their appeal as therapeutic agents.

Rosiglitazone (Avandia), the key representative compound of this class of drugs, has been found to be associated with significant adverse side effects, including weight gain, congestive heart failure, fluid retention, increased risk of myocardial infarction and cardiovascular mortality. Based on the concerns regarding cardiovascular safety of rosiglitazone, in 2010, the European Medicines Agency took rosiglitazone off the market in Europe. Moreover, the Food and Drug Administration restricted the use of rosiglitazone in the United States to situations in which other medications are not effective, thereby minimizing its use. Similarly, troglitazone, which is a PPARy activator, has shown several serious side effects like drug-induced hepatitis and potential high liver toxicity (Diabetes Metab (Paris), 27, 2001, 305-313) and thus withdrawn from the UK, US and Japanese market.

In order to avoid the adverse effects of PPARy activation, there is an increasing need to identify insulin sensitizers, which are not PPARy agonists. An effort in this direction has resulted in development of compounds that act as insulin sensitizing agents as disclosed in the PCT publication, WO2008035306. The insulin sensitizing agents disclosed in this PCT publication are 3-amino pyridine derivatives, which do not exhibit PPARy activation, but are useful in the treatment of metabolic disorders related to insulin resistance or hyperglycemia. This PCT publication also discloses processes for the manufacture of 3-amino pyridine derivatives. The compounds disclosed in this patent publication have been reported to be devoid of the adverse effects characteristic of PPARy agonists, making them potential clinical candidates for the treatment of Type 2 diabetes.

Despite the potential of the compounds disclosed in the said PCT publication as effective insulin sensitizing agents, these compounds were found to possess low aqueous solubility and poor bioavailability at all physiological pH conditions, factors that are crucial to provide these compounds in a suitable dosage form to a subject in need thereof. It is a known fact that a given active ingredient, on its own, has a certain therapeutic potential, but without a suitable dosage form, its therapeutic advantages may not be utilized to the fullest. A suitable dosage form is required to ensure stability, which is critical for preserving the active ingredient's or drug's efficacy during storage. Due to the reasons of requirement of stability, economy, simplicity and convenience of dosing, therapeutically active agents are commonly formulated for oral administration which is preferably in the form of tablets (The rd

Theory and Practice of Industrial pharmacy by Leon Lachman and Herbert Liberman, 3 Edition, 1986, pg. 293-295).

There is a need to develop a suitable dosage form, particularly an oral dosage form for the compounds disclosed in PCT publication, WO2008035306. The oral dosage form may be provided in the form of solid oral tablets which are rapidly disintegrating and which can be administered to the patient with ease. If a solid tablet is used to administer a pharmaceutically active agent, the ability of that preparation to rapidly disintegrate on contact with the mucous membrane, such as the buccal cavity or sublingual area of the mouth, and deliver a therapeutically effective dose of the drug would be a major advantage. However, providing a tablet that is capable of such rapid disintegration may require a careful selection of appropriate pharmaceutically acceptable excipients for combining with the active ingredient so that the resulting finished product is not too soft or friable to withstand packaging, shipping, and handling by the patient. Thus, there exists a need for compressed tablets of potential anti-diabetic compounds (as described herein) which are sufficiently hard to withstand the pressure of packaging and handling by patients, yet able to rapidly disintegrate in an aqueous environment. It would further be advantageous if such tablets could be made relatively economically, without the use of organic solvents (The Theory and Practice of rd

Industrial pharmacy by Leon Lachman and Herbert Liberman, 3 Edition, 1986, pg. 293- 295).

There is a need for developing a suitable oral dosage form for the compounds disclosed in the PCT publication WO2008035306, in order to increase the solubility and bioavailability of said compounds. The current invention provides the required pharmaceutical composition in the form of an oral tablet dosage form and the methods for their preparation.

SUMMARY OF THE INVENTION

The present invention provides a pharmaceutical composition in the form of a an oral dosage form comprising a compound of formula (I) (as described herein below) or a pharmaceutically acceptable salt thereof; a non-ionic surfactant and one or more pharmaceutically acceptable excipients.

In one aspect, the pharmaceutical composition of the present invention is provided in the form of an oral tablet dosage form. In one aspect, the present invention provides a stable oral tablet dosage form, designed for immediate release comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient, wherein the tablet dosage form contain particles of the active pharmaceutical ingredient having a mean particle size less than 200 μ.

In a further aspect of the present invention, there are provided processes for the preparation of the stable oral tablet dosage form comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, a non-ionic surfactant and one or more pharmaceutically acceptable excipients.

According to another aspect of the present invention, there is provided a method of treatment of metabolic disorders related to insulin resistance or hyperglycemia in a subject, comprising administering to the subject the stable oral tablet dosage form of the present invention.

According to a further aspect of the present invention, there is provided use of the stable oral tablet dosage form in the treatment of metabolic disorders related to insulin resistance or hyperglycemia.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a stable oral tablet dosage form comprising a compound of formula (I),

Formula (I)

wherein R is selected from phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3,5- dimethylphenyl, 2,4,6- trimethylphenyl, 3-chloro-4-methylphenyl, 4-methoxyphenyl, 2,4- dimethoxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 4-trifluoromethoxyphenyl, 4- fluorophenyl, 2,4-difluorophenyl, 2-chloro-4- fluorophenyl, 2,4-dichlorophenyl, 3,4- dichlorophenyl, 3,5-dichlorophenyl, 4-chlorophenyl, 2-chloro-4-trifluoromethylphenyl, 3- trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-fluoro-4-chlorophenyl; 4-cyanophenyl, phenyl-3-carboxylic acid or 4-acetamidophenyl or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient; a non-ionic surfactant and one or more pharmaceutical acceptable excipients; wherein the tablet dosage form contain particles of the active pharmaceutical ingredient having a mean particle size less than 200 μ.

According to one aspect of the present invention, the stable oral tablet dosage form comprising the compound of formula (I) is designed for immediate release.

The compounds represented by formula (I) are disclosed in PCT Publication

WO2008035306, which is incorporated herein by reference. The compounds of formula (I) finds application in the treatment of metabolic disorders related to insulin resistance or hyperglycemia. A representative compound of formula (I) disclosed in PCT publication WO2008035306 is 2,4-dichloro-N-[5-chloro-6-(isoquinolin-3-yloxy)-pyridin-3-yl]- benzenesulfonamide. The compounds of formula (I) were found to possess low aqueous solubility and hence, were poorly bioavailable at all physiological pH conditions. Accordingly, the objective of the present invention is to increase the bioavailability of the compounds of formula (I) by developing a stable oral tablet dosage form.

In another aspect of the invention, the compound of formula (I) is 2,4-dichloro-N-[5- chloro-6-(isoquinolin-3-yloxy)-pyridin-3-yl]-benzenesulfonamide (hereinafter referred to as Compound A), or a pharmaceutically acceptable salt thereof.

Definitions:

Listed below are definitions, which apply to the terms as they are used throughout the specification and the claims, either individually or as part of a larger group.

The term "pharmaceutically acceptable excipient" refers to a non-therapeutic agent such as diluents, binders, disintegrants, lubricants, glidants, colorants, flavorants, sweeteners and desiccants. The non-therapeutic agents have effects on the physical, chemical and biopharmaceutical properties of the finished dosage form e.g. tablets.

As used herein, the term "pharmaceutically acceptable carrier" refers to a carrier or a diluent that is non-toxic, inert, solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type which is compatible with a subject, preferably a mammal, more preferably a human, and is suitable for delivering a therapeutically active agent to the target site without interfering with the activity of the active pharmaceutical agent.

As used herein, the term "active pharmaceutical ingredient (API)" refers to any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or function of the body. Reference: Manufacturing, Processing, or Holding Active Pharmaceutical Ingredients FDA Guidance. In the context of the present invention the term "active pharmaceutical ingredient" refers to "compounds of formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments of the invention, the term "active pharmaceutical ingredient" may refer to the compound A.

Drug Product is a finished dosage form, for example, a tablet, capsule or solution that contains an active pharmaceutical ingredient, generally, but not necessarily, in association with inactive ingredients. Reference: Manufacturing, Processing, or Holding Active Pharmaceutical Ingredients FDA Guidance. In the context of the present invention, the term "drug product" refers to the stable oral tablet dosage form of the present invention.

The term, "therapeutically effective amount" as used herein means an amount of the compound of formula (I) or a composition comprising the compound of formula (I), effective in producing the desired therapeutic response in a subject in need for the treatment of metabolic disorders related to insulin resistance or hyperglycemia.

The therapeutically effective amount of the active pharmaceutical ingredient in the composition will vary with the particular condition being treated, the age and physical condition of the subject to be treated, the severity of the condition being treated, the duration of the treatment, the nature of concurrent therapy, the specific compound or composition employed, the particular pharmaceutically acceptable carrier utilized, and like factors.

The term "subject" as used herein refers to an animal, preferably a mammal, and most preferably a human.

The term "mammal" used herein refers to warm-blooded vertebrate animals of the class Mammalian, including humans, characterized by a covering of hair on the skin and, in the female, milk-producing mammary glands for nourishing the young. The term mammal includes animals such as cat, dog, rabbit, bear, fox, wolf, monkey, deer, mouse, pig as well as human.

As used herein, the terms "treatment", "treat" and "therapy" and the like refer to alleviate, slow the progression, prophylaxis, attenuation or cure of existing disease or condition (e.g., Type 2 diabetes). Treatment also includes treating the symptoms of the disease or condition.

The term "metabolic disorder" refers to any disorder that involves an alteration in the normal metabolism of carbohydrates, lipids, proteins, nucleic acids or a combination thereof. A metabolic disorder is associated with either a deficiency or excess in a metabolic pathway resulting in an imbalance in metabolism of nucleic acids, proteins, lipids, and/or carbohydrates. Factors affecting metabolism include, and are not limited to, the endocrine (hormonal) control system (e.g., the insulin pathway, the enteroendocrine hormones including GLP-1, PYY or the like), the neural control system (e.g., GLP-1 in the brain) or the like. Examples of metabolic disorders include and are not limited to type 1 diabetes, type 2 diabetes, hyperglycemia, hyperinsulinemia, insulin resistance and obesity.

As used herein, the term "diabetes mellitus" represents a group of diseases of heterogeneous etiology, characterized by chronic hyperglycemia and other metabolic abnormalities, which are due to deficiency of insulin effect. After a long duration of metabolic derangement, specific complications of diabetes (retinopathy, nephropathy, and neuropathy) may occur. Arteriosclerosis is also accelerated. Depending on the severity of the metabolic abnormality, diabetes may be asymptomatic, or may be associated with symptoms (thirst, polyuria, and weight loss), or may progress to ketoacidosis and coma.

The term "antidiabetic compound" used herein refers to a compound used in controlling non-insulin dependent diabetes mellitus (NIDDM). In the context of the present invention the antidiabetic compound refers to a compound of formula (I) or a pharmaceutically acceptable salt thereof; which is in fact an insulin sensitizer or an insulin sensitizing agent.

The term "insulin sensitizers" used herein refers to the compounds which improve insulin action by increasing insulin sensitivity of insulin resistant cells, resulting in a decrease of hyperinsulinaemia.

Stable oral tablet dosage form refers to a dosage form that retains its chemical and physical integrity until it is delivered to its intended site of absorption or application.

As used herein, the term "immediate release tablets" represents tablets which are intended to provide rapid disintegration and drug release.

As used herein, the term "tablet" refers to a solid unit oral dosage form in which a single dose of a drug has been accurately blended with or without other pharmaceutically acceptable excipients such as diluent, binder, lubricant, disintegrant, glidant, desiccant and non-ionic surfactant.

The term "diluent or filler" refers to the inert ingredients that add bulk to the tablet dosage form (Pharmacy practice for Technicians by Durgin and Hanan, 4^th Edition, 2010, pg. 212). Example of diluents or fillers suitable for use herein include, but are not limited to, cellulose derivatives, such as microcrystalline cellulose or wood cellulose or silicified microcrystalline cellulose, anhydrous lactose, lactose monohydrate, lactose fast-flo, directly compressible anhydrous lactose, modified lactose monohydrate, sucrose, starch, pregelatinized starch, dextrose, mannitol, fructose, xylitol, sorbitol, corn starch, modified corn starch, salts such as calcium carbonate, calcium phosphate, dibasic calcium phosphate dehydrate, dicalcium phosphate, calcium sulfate, dextrins, dextrates, maltodextrin, compressible sugars, and other known diluents or fillers, and/or mixtures of two or more thereof.

As used herein, the term "binder" refers to the agent that holds the ingredients in a tablet together. It ensures that tablets and granules can be formed with required mechanical strength, and give volume to the tablets. Examples of binders include, but are not limited to, hydroxypropyl cellulose, corn starch, pregelatinized starch, modified corn starch, polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose, lactose, gum acasia, ethyl cellulose, cellulose acetate, carnauba wax, paraffin, spermaceti, polyethylenes or microcrystalline wax, as well as other conventional binding agents and/or mixtures of two or more thereof.

The term "lubricant" refers to an agent that reduces both the shear strength at the interface between the tablet and die wall and the coefficient of friction and, in turn, the frictional force at a given load (Mixed Metal Nanomaterials by Challa Kumar, 2009, pg. 447). Examples of lubricants suitable for use herein include, but are not limited to, magnesium stearate, zinc stearate, calcium stearate, talc, carnauba wax, stearic acid, palmitic acid, sodium stearyl fumarate, sodium laurel sulfate, glyceryl palmitostearate, palmitic acid, myristic acid and hydrogenated vegetable oils and fats, as well as other known lubricants, and/or mixtures of two or more thereof.

The term "disintegrant" refers to a substance which decreases the disintegration time (DT) of a tablet. Examples of disintegrants suitable for use herein include, but are not limited to, croscarmellose sodium, crospovidone, starch, potato starch, pregelatinized starch, corn starch, sodium starch glycolate, hydroxypropyl cellulose and other known disintegrants. The term "disintegration time" refers to the time required for the tablet to break into particles.

The term "glidant" refers to an agent which is added in a small amount to improve the flow characteristics of granulations. Examples of glidants or anti-adherents suitable for use herein include but are not limited to, silicon dioxide, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc, and other forms of silicon dioxide, such as aggregated silicates and hydrated silica.

The term "desiccant" refers to a substance that absorbs or adsorbs water. It is most commonly used to remove humidity that would normally degrade or even destroy products sensitive to moisture. Examples of desiccants suitable for use herein include but are not limited to, colloidal silicon dioxide, calcium chloride, calcium sulfate, magnesium sulfate, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium chloride, sodium sulfate, sucrose, and/or mixtures of two or more thereof.

The term "non-ionic surfactant" is generally referred to as non-ionic surface- active agent. As used herein the term refers to the surfactant which does not dissociate into ions when added to an aqueous solution. They are good detergents, wetting agents and emulsifiers. Examples of non-ionic surfactants for use herein include, but are not limited to Cremophor^® EL, Cremophor^® RH, ύί- -tocopherol polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, Solutol^® HS 15, sorbitan monooleate, poloxamers, Labrafils^®, Labrasol^®, Gellucire^® 44/14, Softigen^® 767 and mono- and di-fatty acid esters of polyethylene glycol.

The term "granulation" refers to a process of size enlargement whereby small particles are gathered together into larger, permanent aggregates to render them into free flowing state.

The term "wet granulation" means a process of using a liquid binder to lightly agglomerate the powder mixture. The granules formed from this process are punched to form compact tablets.

The term "dry granulation" refers to a process of making granules by light compaction of the powder blend under low pressures. The compacts so-formed are broken up gently to produce granules which are then punched to form tablets.

The term "direct compression" is meant to represent a process in which an active pharmaceutical ingredient (a compound of formula (I)) is blended with the directly compressible diluents and the lubricant, followed by compression to form a tablet.

The term "preservative" is meant to include the substance that meets the following criteria:

a) It must be effective against broad spectrum of microorganisms.

b) It must be physically, chemically and microbiologically stable for the life time of the product.

c) It must be non-toxic, adequately soluble, compatible with other formulation components and acceptable with respect to taste and odor at the concentration used.

As used herein, PPAR gamma refers to the receptor which regulates fatty acid storage and glucose metabolism. The genes activated by PPARy stimulate lipid uptake and adipogenesis by fat cells.

The term "purified water" as used herein refers to water that has been produced through the methods of reverse osmosis, deionization, distillation or other methods that meet U.S.P standards to remove impurities. It contains no added substance. It is intended for use as an ingredient of official preparations, sterile dosage forms other than for parenteral administration.

The term "bioavailability" is defined as the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action (Pharmaceutical Research, 18 (12), 2001, 1645-1650).

Tablet dosage form may be prepared by methods incorporating wet granulation, dry granulation or direct compression techniques. The tablet dosage form, according to the present invention comprises of the active pharmaceutical ingredient along with a non-ionic surfactant and one or more pharmaceutically acceptable excipients comprising diluents, binders, lubricants, disintegrants, glidants, desiccants or combinations thereof.

In one aspect of the invention, the tablet dosage form comprises 40 % to 80 % by weight of the active pharmaceutical ingredient i.e. the compound of formula (I).

In another aspect of the invention, the non-ionic surfactant used in the preparation of the tablet dosage form is selected from one or more of Cremophor^® EL, Cremophor^® RH, d- -tocopherol polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, Solutol^® HS 15, sorbitan monooleate, poloxamers, Labrafils^®, Labrasol^®, Gellucire^® 44/14, Softigen^® 767 and mono- and di-fatty acid esters of polyethylene glycol.

Cremophor EL is a synthetic polyethoxylated castor oil used as a non-ionic surfactant.

Cremophor RH is a non-ionic surfactant produced by reacting hydrogenated castor oil to react with ethylene oxide. The main components of Cremophor^® RH are fatty acid esters of glycerol polyethylene glycol and fatty acid esters of polyethylene glycol, which represent the hydrophobic part of Cremophor^® RH. The hydrophilic part consists of polyethylene glycols and ethoxylated glycerol. Examples of Cremophor RH include Cremophor RH 40 and Cremophor RH 60. Cremophor RH 40 is produced by reacting 40-45 moles of ethylene oxide, and Cremophor RH 60 by reacting 60 moles of ethylene oxide, with 1 mole of glyceride.

i - -Tocopherol polyethylene glycol 1000 succinate is a non-ionic surfactant prepared by reacting a-tocopherol with polyethylene glycol (PEG) oligomer through a succinate diester linker.

Polysorbate 20 is also known as Tween^® 20. It is a polyoxyethylene derivative of sorbitan monolaurate, and is distinguished from the other members in the polysorbate range by the length of the polyoxyethylene chain and the fatty acid ester moiety. Polysorbate 80 is also known as Tween 80. It is a non-ionic surfactant and emulsifier derived from polyethoxylated sorbitan and oleic acid.

Solutol HS 15 is a non-ionic surfactant and emulsifying agent obtained by reacting ethylene oxide with 12-hydroxy stearic acid.

Sorbitan monooleate are oleic acid esters of polyols derived from sorbitols.

Poloxamers are polyoxyethylene-polypropylene block copolymer nonionic surfactants. The poloxamers are a family of multi-block co-polymers which are non-ionic surface-active agents. The primary structure of the biocompatible polymers is H(OCH₂- CH₂)_a(OCHCH₃CH₂)_b(OCH₂CH₂)_aOH (wherein a is an integer). The poloxamer family includes liquids, pastes, gels, and solids with molecular weights from 1000 to 14,000 and polyethylene oxide/polypropylene oxide weight ratios from about 1 :9 to 8:2.

Labrafils^® are non-ionic surfactants composed of triglycerides which have been partially reacted with polyethylene glycol (PEG) of defined chain length to form mixtures of mono-, di- and tri-glycerides and polyethylene glycol mono and diesters. Examples of Labrafils include Labrafil M-1944 CS, Labrafil M-2125 CS.

Labrasol^® (caprylocaproyl macrogol-8 glyceride) is a non-ionic surfactant. Labrasol is comprised of a well-defined mixture of mono-, di- and triglycerides and mono- and di-fatty acid esters of polyethyleneglycol, with the predominant fatty acids being caprylic and capric acids.

Gelucire 44/14 is polyethylene glycol glycerides composed of mono-, di- and triglycerides and mono- and diesters of polyethylene glycol (PEG).

Softigen^® 767 is the oxethylation product of medium chain partial glycerides whose fatty acids are derived from coconut- and palmkernel oil.

Polyethylene Glycol (PEG) esters are non-ionic surfactants prepared by the esterification of fatty acids with polyethylene glycols. Examples of PEG esters include mono- and di-fatty acid esters of PEG 300, 400, or 1750

In a further aspect of the invention, the non-ionic surfactant used in the preparation of the tablet dosage form is a poloxamer.

In an embodiment of the invention, the non-ionic surfactant used in the preparation of the tablet dosage form is Poloxamer 188.

Poloxamer 188 is a type of poloxamer having average molecular weight of 8400 and its hydrophile comprises about 80% of the total molecular weight (H(OCH₂CH₂)38(OCHCH₃CH₂)29(OCH₂CH₂)₃₈0H) (NeuroReport, 15(1), 2004, 171-174). In one aspect of the invention, the diluents or fillers used for preparation of the tablet dosage form are selected from one or more of microcrystalline cellulose, wood cellulose, silicified microcrystalline cellulose, anhydrous lactose, lactose monohydrate, lactose fast-flo, directly compressible anhydrous lactose, modified lactose monohydrate, sucrose, starch, pregelatinized starch, dextrose, mannitol, fructose, xylitol, sorbitol, corn starch, modified corn starch, salts such as calcium carbonate, calcium phosphate, dibasic calcium phosphate dehydrate, dicalcium phosphate or calcium sulfate, dextrins, dextrates, maltodextrin or compressible sugars.

In another aspect of the invention, the diluents or fillers used for preparation of the tablet dosage form are selected from one or more of microcrystalline cellulose, lactose monohydrate or dibasic calcium phosphate dehydrate.

In one aspect of the invention, the binders used for preparation of the tablet dosage form are selected from one or more of hydro xypropyl cellulose, corn starch, pregelatinized starch, modified corn starch, polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose, lactose, gum acasia, ethyl cellulose, cellulose acetate, carnauba wax, paraffin, spermaceti, polyethylenes or microcrystalline wax.

In an embodiment of the invention, the binder used for preparation of the tablet dosage form is hydroxypropyl cellulose.

In one aspect of the invention, the lubricants used for preparation of the tablet dosage form are selected from one or more of magnesium stearate, zinc stearate, calcium stearate, talc, carnauba wax, stearic acid, palmitic acid, sodium stearyl fumarate, sodium laurel sulfate, glyceryl palmitostearate, palmitic acid, myristic acid or hydrogenated vegetable oils and fats.

In an embodiment of the invention, the lubricant used for preparation of the tablet dosage form is magnesium stearate.

In one aspect of the invention, the disintegrants used for preparation of the tablet dosage form are selected from one or more of croscarmellose sodium, crospovidone, starch, potato starch, pregelatinized starch, corn starch, sodium starch glycolate or hydroxypropyl cellulose.

In an embodiment of the invention, the disintegrant used for preparation of the tablet dosage form is sodium starch glycolate.

In one aspect of the invention, the glidants used for preparation of the tablet dosage form are selected from one or more of silicon dioxide, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc, aggregated silicates or hydrated silica.

In an embodiment of the invention, the glidant used for preparation of the tablet dosage form is colloidal silicon dioxide. In one aspect of the invention, the desiccants used for preparation of the tablet dosage form are selected from one or more of colloidal silicon dioxide, calcium chloride, calcium sulfate, magnesium sulfate, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium chloride, sodium sulfate or sucrose.

In an embodiment of the invention, the desiccant used for preparation of the tablet dosage form is colloidal silicon dioxide.

In another aspect of the invention, the tablet dosage form is a rapidly disintegrating tablet and provides an immediate release of the active ingredient i.e. a compound of formula (I)·

In a further aspect of the invention, the tablet dosage form has a disintegration time ranging from 10 sec to 5 min.

Dry granulation refers to the granulation of a formulation without the use of heat and solvent. Dry granulation generally involves slugging or roll compaction. Slugging consists of dry-blending of a formulation and compressing the formulation into larger tablets or slugs on a compressing machine. The resulting tablets or slugs are milled to yield granules. Roller compaction is similar to slugging, but in roller compaction, a roller compactor is used instead of the tableting machines. Dry granulation process is useful in certain cases, e.g., when the active ingredient is sensitive to heat or the solvent (The Theory and Practice of Industrial pharmacy by Leon Lachman and Herbert Liberman, 3 Edition, 1986, pg. 318-320).

In wet granulation technique, solvents and binders are typically added to a formulation to provide larger aggregates of granules. The temperature during granulation can be set at any suitable point, generally not exceeding the melting point of any component of the formulation. Typically the mixture is granulated at about 35 °C to about 60°C for about 20 to 90 min. The granules are typically air dried for a suitable period of time (The Theory and Practice of Industrial pharmacy by Leon Lachman and Herbert Liberman, 3^rd Edition, 1986, pg. 320-323).

In one aspect of the present invention, a process is provided for the preparation of stable oral tablet dosage form of the compound of formula (I) or a pharmaceutically acceptable salt thereof by wet granulation method comprising of following steps:

step a) mixing of the compound of formula (I) or a pharmaceutically acceptable salt thereof with diluents after sifting of the compound of formula (I) or a pharmaceutically acceptable salt thereof and diluents;

step b) preparation of binder solution containing non-ionic surfactant by dissolving the non- ionic surfactant and binding agent in purified water; step c) preparation of granules by adding binder solution to the mixture of step a), passing the resultant mixture through sieves to obtain wet granules, drying the wet granules at a temperature range of 50 °C to 100 °C and passing the dried granules through sieves; and step d) sifting the glidant and disintegrant through sieves, blending the sifted glidant and disintegrant with the granules prepared in step c), adding sifted lubricant to the blend obtained and compressing the final mixture to yield the tablet dosage form.

In an embodiment of the present invention, in the process provided for the preparation of stable oral tablet dosage form by wet granulation method, the compound of formula (I) is the compound A.

In an embodiment of the present invention, the tablet prepared by wet granulation method comprises of poloxamer 188 as the non ionic-surfactant.

In another aspect of the present invention, the diluents used in the wet granulation process for the preparation of the tablet dosage form are selected from dibasic calcium phosphate dihydrate, lactose monohydrate and microcrystalline cellulose or mixture thereof.

Hydroxypropyl cellulose (HPC) is non-ionic water soluble cellulose ether. It is soluble in organic solvents, also has thermoplasticity and surface activity with thickening and solubilizing properties. It is soluble in water below 38 °C. It is highly surface active with low surface and interfacial tensions of solutions. It has a wide range of compatibility with latexes and synthetic and natural colloids (Cosmetics additives: An Industrial Guide by Ernest W. Flick, 1991, pg. 59). Hydroxypropyl cellulose (HPC) is a cellulose derivative employed as coating excipient, encapsulation, foaming agent, flocculant (New trends in Natural and Synthetic Polymer science by Cornelia Vasile, G. E. Zaikov, 2006, pg. 72).

In an embodiment of the present invention, the tablet prepared by wet granulation method comprises of hyroxypropyl cellulose (HPC, LF grade, Klucel^®) as binder.

In an embodiment of the present invention, the disintegrant used in the wet granulation process for the preparation of the tablet dosage form is sodium starch glycolate.

In an embodiment of the invention, the lubricant used in the wet granulation process for the preparation of the tablet dosage form is magnesium stearate.

In an embodiment of the invention, the tablet prepared by wet granulation method comprises of colloidal silicon dioxide as glidant and desiccant.

Direct compression is the simplest and most economical method for the manufacturing of tablets because it requires a few processing steps as compared to the other techniques such as wet granulation and roller compaction. Most pharmaceutical active ingredients cannot be compressed directly into tablets due to lack of flow, cohesion properties and lubrication. Therefore, they must be blended with other directly compressible ingredients to manufacture satisfactory tablets. Disintegration or dissolution is the rate limiting step in absorption in the case of tablets of the compounds of formula (I) prepared by wet granulation. The tablets prepared by direct compression disintegrate into particles instead of granules that directly come into contact with dissolution fluid and exhibits comparatively faster dissolution (International Journal of Current Pharmaceutical Research, 3(1), 2011, 1-7). In the present invention, the tablet prepared by wet granulation method shows disintegration time ranging from 3 min to 5 min.

In one aspect of the present invention, a process is provided for the preparation of stable oral tablet dosage form of the compound of formula (I) or a pharmaceutically acceptable salt thereof; by direct compression method comprising of following steps:

step a) mixing a non-ionic surfactant with a small amount of diluent, microcrystalline cellulose and sifting the mixture through sieves;

step b) blending the mixture of step a) with a sifted mixture of the compound of formula (I) or a pharmaceutically acceptable salt thereof, directly compressible diluents and disintegrants; and

step c) directly compressing the blend of step b) after mixing with sifted lubricant to yield the tablet dosage form.

In an embodiment of the present invention, in the process provided for the preparation of stable oral tablet dosage form by direct compression method, the compound of formula (I) is the compound A.

In an embodiment of the present invention, the tablet prepared by direct compression method comprises of poloxamer 188 as a non ionic-surfactant.

In an embodiment of the present invention, in the direct compression method, microcrystalline cellulose, lactose monohydrate (DCL11) and colloidal silicon dioxides are used as directly compressible vehicle.

In an embodiment of the invention, in the process for the preparation of the stable oral tablet dosage form using direct compression method, sodium starch glycolate is used as a disintegrant.

In an embodiment of the invention, in the process for the preparation of the stable oral tablet dosage form using direct compression method, magnesium stearate is used as a lubricant.

In an embodiment of the invention, the tablet prepared by direct compression method comprises of colloidal silicon dioxide as glidant and desiccant. In the present invention, the tablet prepared by direct compression method shows disintegration time ranging from 10 sec to 1 min.

One of the parameters which induce better bioavailability to the dosage form is the particle size of the particles contained in the oral tablet dosage form. In one aspect of the present invention, an oral tablet dosage form contains particles of the active pharmaceutical ingredient having a particle size less than 200 μ.

In another aspect of the invention, an oral tablet dosage form contains particles having of the active pharmaceutical ingredient a particle size less than 50 μ.

Hardness of a tablet reflects the internal bonding strength of granules/powder which is able to hold composite structure under applied external force. Hardness test gives an idea about the amount of force that is required to fracture the tablet. It will also serve as a guideline in handling, packaging and storage of tablet dosage form. Hardness of the tablet determines the disintegration time of the tablet which ultimately affects dissolution time and absorption process of a tablet.

In an embodiment of the present invention, the hardness of the tablet is 20 N to 175 N.

According to one aspect of the present invention, there is provided a method for the treatment of metabolic disorders related to insulin resistance or hyperglycemia in a subject, comprising administering to the subject, in particular a human the stable oral tablet dosage form comprising of a therapeutically effective amount of a compound of formula (I); a non- ionic surfactant and one or more pharmaceutically acceptable excipients of the present invention.

In an embodiment of the present invention, there is provided a method for the treatment of metabolic disorders related to insulin resistance or hyperglycemia in a subject, comprising administering to the subject, in particular a human the stable oral tablet dosage form comprising of a therapeutically effective amount of compound A, a non-ionic surfactant and one or more pharmaceutically acceptable excipients.

According to the invention, the metabolic disorders related to insulin resistance or hyperglycemia can be selected from type 2 diabetes, obesity, glucose intolerance, dyslipidemia, hyperinsulinemia, atherosclerotic disease, polycystic ovary syndrome, coronary artery disease, hypertension, aging or non alcoholic fatty liver disease.

In an embodiment of the invention, the metabolic disorder related to insulin resistance or hyperglycemia is type 2 diabetes.

According to one aspect of the present invention, there is provided a use of the stable oral tablet dosage form comprising of a therapeutically effective amount of a compound of formula (I); a non-ionic surfactant and one or more pharmaceutically acceptable excipients; for the treatment of metabolic disorders related to insulin resistance or hyperglycemia.

In an embodiment, the compound of formula (I) contained in the stable oral dosage form is compound A which is provided for use in the treatment of metabolic disorders related to insulin resistance or hyperglycemia.

The metabolic disorders related to insulin resistance or hyperglycemia is as described herein above. In an embodiment of the invention, the metabolic disorder related to insulin resistance or hyperglycemia is type 2 diabetes.

According to yet another aspect of the present invention, preferably the subject is a mammal, more particularly a human.

In an aspect of the present invention, there is provided a use of the table dosage form comprising of a therapeutically effective amount of a compound of formula (I); a non-ionic surfactant and one or more pharmaceutically acceptable excipients; for the manufacture of a medicament for the treatment of metabolic disorders related to insulin resistance or hyperglycemia.

The tablet dosage form comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof was subjected to the stability testing. The purpose of stability testing is to provide evidence on how the quality of a drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity, and light, and to establish a re-test period for the drug product or a shelf life for the drug product and recommended storage conditions.

For long-term studies, frequency of testing should be sufficient to establish the stability profile of the drug product. The frequency of testing in a long term storage condition should normally be every 3 months over the first year, every 6 months over the second year, and annually thereafter.

At the accelerated storage condition, a minimum of three time points, including the initial and final time points (e.g., 0, 3, and 6 months), from a 6-month study is recommended.

Testing at the intermediate storage condition is carried out when there is a significant change at the accelerated storage condition, and testing at a minimum of four time points, including the initial and final time points (e.g., 0, 6, 9, 12 months), from a 12-month study is recommended.

In case of long term stability study, the tablet dosage form is kept at 25 °C ± 2 °C at 60 % RH ± 5 % RH or 30 °C ± 2 °C at 65 % RH ± 5 % RH for 12 months. In case of intermediate stability study, the tablet dosage form is kept at 30 °C ± 2 °C at 65 % RH ± 5 % RH for 6 months and in case of accelerated stability study, the drug product is kept at 40 °C ± 2 °C at 75 % RH ± 5 % RH for 6 months.

Stability studies should include testing of those attributes of the tablet dosage form that are susceptible to change during storage and are likely to influence its quality, safety, and/or efficacy. The testing should cover, as appropriate, the physical, chemical, biological, and microbiological attributes, preservative content (e.g., antioxidant, antimicrobial preservative), and functionality tests (e.g., for a dose delivery system). Analytical procedures should be fully validated and stability indicating.

In general, "significant change" for a drug product is defined as:

1. A 5 % change in assay from its initial value; or failure to meet the acceptance criteria for potency when using biological or immunological procedures;

2. Any degradation product's exceeding its acceptance criterion;

3. Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test (e.g., color, phase separation, hardness, weight, dose delivery per actuation); however, some changes in physical attributes may be expected under accelerated conditions;

4. Failure to meet the acceptance criterion for pH; or

5. Failure to meet the acceptance criteria for dissolution for 12 dosage units.

(ICH Topic Q 1 A (R2) Stability Testing of new drug products)

Stability study data indicates that the tablet dosage form of the present invention was stable in stability studies conducted for 6 months.

The following abbreviations or terms are used herein:

A.S.T.M : American Society for Testing and Materials

CDC1₃ : Deuterated chloroform

cfu/g : Colony forming units per gram

CS₂CO₃ : Cesium carbonate

°C : Degree Celsius

DCL11 : Lactose Monohydrate

DMF : Dimethylformamide

DMSO-d₆ : Deuterated Dimethyl Sulfoxide

DT : Disintegration time

Fe : Iron

g : Gram

HC1 : Hydrochloric acid HDPE : High-density polyethylene

HPC : Hydroxypropylcellulose

HPLC : High Performance Liquid Chromatography

LOD : Loss on drying

MCC : Microcrystalline cellulose

min : Minutes

mL : Milliliter

mmol : Millimoles

mg : Milligram

m.p. : Melting Point

N : Newton

NIDDM : Non-insulin dependent diabetes mellitus

NMR : Nuclear Magnetic Resonance spectrum

Pd-C : Palladium on carbon

PEG : Polyethylene glycol

POCl₃ : Phosphoryl Chloride

PPAR : Peroxisome proliferator-activated receptors

PPARy : Peroxisome proliferator-activated gamma receptors

Pt-C : Platinum on Carbon

q.s : Quantity sufficient

RH : Relative humidity

Rh-C : Rhodium on Carbon

sec : Second

SnCl₂ : Tin (II) Chloride

μ : Micron

U.S.P : United States Pharmacopeia

wt : Weight

w/w : Weight by weight

The tablet dosage form of the present invention comprise the compounds of formula (I), which can be prepared by, or in analogy with, standard synthetic methods, and especially according to, or in analogy with, Scheme 1, as incorporated in PCT publication, WO2008035306. As shown in scheme 1, compounds of formula (I) can be prepared by reacting compound of formula (II) wherein Hal is selected from fluorine, chlorine, bromine or iodine with a compound of formula (III), in the presence of a solvent such as dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, dioxane, or acetonitrile, optionally in the presence of a base such as cesium carbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, or potassium fluoride to provide the compound of formula (IV). The nitro group of compound of formula (IV) is reduced to the corresponding amino group to obtain compound of formula (V). Reduction of the nitro group may be carried out by using SnCi₂ in a solvent such as ethyl acetate; or by using Fe/HCl; or in presence of gaseous hydrogen and a catalyst such as Pd-C, Rh-C, Pt-C; or any suitable method known in the art.

Scheme 1

The compound of formula (V) is further converted to the desired compound of formula (I) wherein R is selected from phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3,5- dimethylphenyl, 2,4,6- trimethylphenyl, 3-chloro-4-methylphenyl, 4-methoxyphenyl, 2,4- dimethoxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 4-trifluoromethoxyphenyl, 4- fluorophenyl, 2,4-difluorophenyl, 2-chloro-4- fluorophenyl, 2,4-dichlorophenyl, 3,4- dichlorophenyl, 3,5-dichlorophenyl, 4-chlorophenyl, 2-chloro-4-trifluoromethylphenyl, 3- trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-fluoro-4-chlorophenyl; 4-cyanophenyl, phenyl-3-carboxylic acid or 4-acetamidophenyl; by reacting with one equivalent of Hal- SO₂R wherein Hal is represented by fluorine, chlorine, bromine, or iodine and R is as defined above, in the presence of pyridine or triethyl amine as a base and a solvent selected from acetonitrile, dichlorome thane, chloroform, carbon tetrachloride, tetrahydrofuran, or dioxane.

The compounds of formula (I) may be converted into pharmaceutically acceptable salts by standard procedures known in the literature.

The preparation of 2,4-dichloro-N-[5-chloro-6-(isoquinolin-3-yloxy)-pyridin-3-yl]- benzenesulfonamide (Compound A), the representative example of the compound of formula (I) is disclosed herein below in Example 1.

Examples

Example 1

Step 1: Preparation of 5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine

Step i. Preparation of 2-Hydroxy-3-chloro-5-nitro pyridine

2-Hydroxy-5-nitro pyridine (1 g, 7.14 mmol) was added portion wise to 4.5 mL of concentrated HCl under constant stirring and then heated to 50 °C. To this was added a solution of sodium chlorate (266 mg, 2.5 mmol) in water (4 mL). The reaction was maintained at the same temperature for an additional hour, and then cooled to 0 °C. The precipitate obtained was filtered, washed with water and dried to obtain 2-hydroxy-3-chloro- 5-nitro pyridine. Yield: 850 mg (68.2 %); m.p.: 195-197 °C; H NMR (DMSO-d₆) δ: 8.36 (d, 1H, J = 2.5 Hz), 8.65 (d, 1H, J = 2.5 Hz).

Step ii. Preparation of 2,3-Dichloro-5-nitro pyridine

Quinoline (0.3 mL, 2.34 mmol) was added to POCl₃ (0.5 mL 4.68 mmol) at 0 °C under nitrogen. To this stirred mixture was added 2-hydroxy-3-chloro-5-nitro pyridine (816 mg, 4.68 mmol) (product obtained in step i) The reaction mixture was heated at 120 °C for 2 hours, cooled to 0 °C followed by addition of ice cold water. The precipitate obtained was filtered, washed with water and dried to obtain 2,3-dichloro-5-nitro pyridine. Yield: 630 mg (70.3 %); m.p.: 53 °C; *H NMR (DMSO-d₆) δ: 8.94 (d, 1H, J = 2.5 Hz), 9.16 (d, 1H, J = 2.5 Hz).

Step iii. Preparation of 5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine

Isoquinolin-3-ol was reacted with 2,3-dichloro-5-nitro pyridine in dry DMF and CS₂CO₃ as base at room temperature to obtain 3-(3-chloro-5-nitropyridin-2-yloxy)isoquinoline which was further converted to 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine by reaction with stannous chloride dehydrate as reducing agent at room temperature to obtain 5-chloro-6- (isoquinolin-3-yloxy)pyridin-3-amine. *H NMR (CDC1₃) δ: 5.49 (s, 2H), 7.21 (d, J=2.4 Hz, IH), 7.32 (s, IH), 7.51 (t, J=7.2 Hz, IH), 7.55 (d, J=2.4 Hz, IH), 7.70 (t, J=7.2 Hz, IH), 7.90 (d, J=8.1 Hz, IH), 8.07 (d, J=8.4 Hz, IH), 9.00 (s, IH); MS (ES): 272 (M+l).

Step 2: Preparation of 2,4-Dichloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3- yl)benzenesulfonamide (Compound A)

The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3- amine (obtained as per step 1) and 2,4-dicloro benzenesulfonylchloride in pyridine at room temperature, m.p.: 203 °C - 205 °C; *H NMR (DMSO-d₆) δ: 7.50-7.57 (m, 3H), 7.67-7.71 (m, 2H), 7.77 (d, IH), 7.84-7.87 (m, 2H), 7.97 (d, IH), 8.04 (d, IH), 8.98 (s, IH), 11.06 (s, IH); MS (ES): 479.9 (M-l).

Example 2:

Preparation of a tablet containing 500 mg of Compound A prepared by wet granulation technique

The tablet dosage form of Example 2 was prepared using the ingredients as listed in Table 1. Table 1 lists the ingredients in % of tablet weight and mg/tablet.

Table 1

Ingredients % of tablet wt. mg/tablet

Compound A 62.19 500.0

Microcrystalline cellulose (MCC) 8.21 66.0

(Avicel PH101)

Lactose Monohydrate 9.33 75.0

Dibasic calcium phosphate 9.33 75.0

Dihydrate

Sodium starch glycolate 2.98 24.0

Poloxamer 188 1.0 8.0

Hydroxypropyl cellulose (HPC, LF 2.98 24.0

grade, Klucel^®)

Purified water - q.s.

Sodium starch glycolate 2.98 24.0

Colloidal silicon dioxide 0.5 4.0

Magnesium Stearate 0.5 4.0

Total wt. 100 804.0 In this example the wet granulation technique was followed for preparation of the tablet. All the excipients (MCC, Lactose monohydrate, Dibasic calcium phosphate Dihydrate, Sodium starch glycolate, Poloxamer 188, HPC (LF grade, Klucel ), Colloidal silicon dioxide, Magnesium stearate) and the Compound A were accurately weighed. Compound A was sifted through sieve # 20 (A.S.T.M, 850 μ). Dibasic Calcium Phosphate Dihydrate, Lactose monohydrate, MCC and sodium starch glycolate were sifted through sieve # 40 (A.S.T.M, 420 μ) and mixed with the sifted Compound A in a polybag. A binder solution was prepared by dissolving Poloxamer 188 and HPC LF in purified water. Mixture of the Compound A and other excipients was granulated using the binder solution and then wet granules were passed through sieve # 16 (A.S.T.M, 1204 μ). The granules were then dried at 60 °C in an oven till LOD (loss on drying) was between 1-2 % w/w at 105 °C. The dried granules were then passed through sieve # 20 (A.S.T.M, 850 μ). Colloidal silicon dioxide and sodium starch glycolate were sifted through sieve # 40 (A.S.T.M, 420 μ) and mixed in a polybag with granules as obtained above. Finally this mixture was mixed with magnesium stearate, sifted through sieve # 60 (A.S.T.M, 250 μ) and compressed. The average weight of the tablets made in Example 2 was 781.2 mg to 817.7 mg. Hardness was found to be 99 N tol04 N. Disintegration time recorded was 4 min to 5 min (according to U.S.P Disintegration test for uncoated tablets). The tablet parameters were found satisfactory and reproducible. The tablet parameters are tabulated in the following Table 1A.

Table 1A: Tablet Parameters

Sr. no Parameters Observations

1. Description White, biconvex, capsule shaped tablets

2. Disintegration time 4 min to 5 min.

Example 3:

The tablet dosage form of Example 3 was prepared using the ingredients as listed in Table 2. Table 2 lists the ingredients in % of tablet weight and mg/tablet. Table 2

Ingredients % of tablet wt. mg/tablet

Compound A 62.19 500.0

Microcrystalline cellulose 8.21 66.0

(MCC) (Avicel PH101)

Lactose Monohydrate 9.33 75.0

Dibasic calcium phosphate 9.33 75.0

Dihydrate

Sodium starch glycolate 2.98 24.0

Poloxamer 188 1.0 8.0

Hydroxypropyl cellulose (HPC, 2.98 24.0

LF grade, Klucel^®)

Purified water -- q.s.

Sodium starch glycolate 2.98 24.0

Colloidal silicon dioxide 0.5 4.0

Magnesium Stearate 0.5 4.0

Total wt. 100 804.0

In this example the wet granulation technique was followed for preparation of the tablet. All the excipients (MCC, Lactose monohydrate, Dibasic calcium phosphate Dihydrate, Sodium starch glycolate, Poloxamer 188, HPC (LF grade, Klucel^®), Colloidal silicon dioxide, Magnesium stearate) and Compound A were accurately weighed. Compound A was sifted through sieve # 20 (A.S.T.M, 850 μ). Dibasic Calcium Phosphate Dihydrate, Lactose monohydrate, MCC and sodium starch glycolate were sifted through sieve # 40 (A.S.T.M, 420 μ) and mixed with the sifted Compound A in a polybag. Binder solution was prepared by dissolving Poloxamer 188 and HPC LF in purified water. Mixture of Compound A and other excipients was granulated using binder solution and then wet granules were passed through sieve # 16 (A.S.T.M, 1204 μ). The granules were then dried at 60°C in the oven till LOD (loss on drying) was between 1-2 % w/w at 105°C. These dried granules were then passed through sieve # 20 (A.S.T.M, 850 μ). Colloidal silicon dioxide and sodium starch glycolate were sifted through sieve # 40 (A.S.T.M, 420 μ) and mixed in a polybag with the granules as obtained above. Finally this mixture was further mixed with magnesium stearate, sifted through sieve # 60 (A.S.T.M, 250 μ) and compressed. The average weight of the tablets made in Example 3 was 788.6-810.4 mg. Hardness was found to be 75 N to 90 N. Disintegration time recorded was 4 min to 5 min (according to U.S.P Disintegration test for uncoated tablets). The tablet parameters were satisfactory and reproducible. The final tablets were subjected to stability studies for 6 months in accelerated condition. The tablet parameters are tabulated in Table 2A.

Table 2A: Tablet Parameters

Sr. no Parameters Observations

1. Description White, biconvex, capsule shaped tablets

2. Disintegration time 4 min to 5 min.

Example 4:

Preparation of a tablet containing 100 mg of Compound A prepared by wet granulation technique

The tablet dosage form of Example 4 was prepared using the ingredients as listed in Table 3.

Table 3 lists the ingredients in mg/tablet.

Table 3

Ingredients mg/tablet

Compound A 100.0

Microcrystalline cellulose (MCC) (Avicel 13.2

PHI 02)

Lactose Monohydrate 15.0

Dibasic calcium phosphate Dihydrate 14.2

Sodium starch glycolate 4.8

Poloxamer 188 1.6

HPC (LF grade, Klucel^®) 4.8

Purified water q.s.

Sodium starch glycolate 4.8

Colloidal silicon dioxide 0.8

Magnesium Stearate 0.8

Total wt. 160.0 In this example the wet granulation technique was followed for preparation of the tablet. All the excipients (MCC, Lactose monohydrate, Dibasic calcium phosphate Dihydrate, Sodium starch glycolate, Poloxamer 188, HPC (LF grade, Klucel ), Colloidal silicon dioxide, Magnesium stearate) and Compound A were accurately weighed. Compound A was sifted through sieve # 20 (A.S.T.M, 850 μ). Dibasic Calcium Phosphate Dihydrate, Lactose monohydrate, MCC and sodium starch glycolate were sifted through sieve # 40 (A.S.T.M, 420 μ) and mixed with the sifted Compound A in a polybag. Binder solution was prepared by dissolving Poloxamer 188 and HPC (LF grade, Klucel^®) in purified water. Mixture of the Compound A and other excipients was granulated using binder solution and then wet granules were passed through sieve # 16 (A.S.T.M, 1204 μ). The granules were then dried at 60°C in the oven till LOD was between 1-2 % w/w at 105°C. These dried granules were then passed through sieve # 20 (A.S.T.M, 850 μ). Colloidal silicon dioxide and sodium starch glycolate were sifted through sieve # 40 (A.S.T.M, 420 μ) and mixed in a polybag with above made granules. Finally this mixture was mixed with magnesium stearate, sifted through sieve # 60 (A.S.T.M, 250 μ) and compressed.

The average weight of the tablets made in Example 4 was 157.6-164.2 mg. Hardness was found to be 22 N to 34 N. Disintegration time recorded was 3 min to 4 min (according to U.S.P Disintegration test for uncoated tablets). The tablets had appropriate hardness, negligible friability. The tablets were subjected to stability studies for 6 months at accelerated condition. The tablet parameters are tabulated in Table 3A.

Table 3A: Tablet Parameters

Sr. no Parameters Observations

1. Description White, round, biconvex, tablets

2. Disintegration time 3 min to 4 min.

Example 5:

Preparation of a tablet containing 50 mg of Compound A prepared by direct compression technique

The tablet dosage form of Example 5 was prepared using the ingredients as listed in Table 4. Table 4 lists the ingredients in % of tablet weight and mg/tablet. Table 4

Ingredients % of tablet wt. mg/tablet

Compound A 13.333 50.0

Microcrystalline cellulose (Avicel 46.653 174.95

PHI 02)

Lactose Monohydrate (DCLl l) 30.0 112.5

Sodium starch glycolate 8.0 30.0

Poloxamer 188 1.0 3.75

Colloidal silicon dioxide 0.507 1.9

Magnesium Stearate 0.507 1.9

Total wt. 100 375.0

In this example the direct compression method was followed for preparation of the tablet. All the excipients (MCC, Lactose monohydrate, Sodium starch glycolate, Poloxamer 188, Colloidal silicon dioxide, Magnesium stearate) and Compound A were accurately weighed. Poloxamer was mixed with a little quantity of MCC and sifted through sieve # 60 (A.S.T.M, 250 μ). Compound A was sifted through sieve # 40 (A.S.T.M, 420 μ). The remaining quantity of MCC, DCLl l, sodium starch glycolate and colloidal silicon dioxide were sifted through sieve # 40 (A.S.T.M, 420 μ). All the above blends were mixed together in a polybag. Magnesium Stearate sifted through sieve # 40 (A.S.T.M, 420 μ) was then blended with above mixture. The final blend was then compressed using recommended punches.

The average weight of the tablets, as indicated in Table 4 was 369.8-382.7 mg. Hardness was found to be 140 N to 173 N. Disintegration time (DT) recorded was 1 min (according to U.S.P Disintegration test for uncoated tablets). The tablet dosage form had appropriate hardness, and negligible friability. The tablets were subjected to stability studies for 6 months at accelerated condition. The tablet parameters are tabulated in Table 4A.

Table 4A: Tablet Parameters

Sr. no Parameters Observations

Description White to off white, biconvex, capsule shaped tablets,

Disintegration time 1 min. Example 6:

The tablet dosage form of Example 6 was prepared using the ingredients as listed in Table 5. Table 5 lists the ingredients in % of tablet weight and mg/tablet.

Table 5

Ingredients % of tablet wt. mg/tablet

Compound A 13.333 10.0

Microcrystalline cellulose (Avicel 46.667 35.0

PHI 02)

Lactose Monohydrate (DCL11) 30.0 22.5

Sodium starch glycolate 8.0 6.0

Poloxamer 188 1.0 0.75

Colloidal silicon dioxide 0.50 0.375

Magnesium Stearate 0.50 0.375

Total wt. 100 75.0

In this example the direct compression method was followed for preparation of the tablet. All the excipients (MCC, Lactose monohydrate, Sodium starch glycolate, Poloxamer 188, Colloidal silicon dioxide, Magnesium stearate) and Compound A were accurately weighed. Poloxamer was mixed with little quantity of MCC and sifted through sieve # 60 (A.S.T.M, 250 μ). Compound A was sifted through sieve # 40 (A.S.T.M, 420 μ). Remaining quantity of MCC, DCL11, sodium starch glycolate and colloidal silicon dioxide were sifted through sieve # 40 (A.S.T.M, 420 μ). All the above blends were mixed together in a polybag. Sifted Magnesium Stearate through sieve # 40 (A.S.T.M, 420 μ) was then blended with the above mixture. The final blend was then compressed using recommended punches.

The average weight of the tablets was 70.6 mg to 80.6 mg. Hardness was found to be 20 N to 32 N. Disintegration time (DT) recorded was 10 sec (according to U.S.P Disintegration test for uncoated tablets). The tablet dosage form had appropriate hardness and negligible friability. The tablet dosage form was subjected to stability studies for 6 months at accelerated condition. The tablet parameters are tabulated in Table 5A. Table 5A: Tablet Parameters

Sr. no Parameters Observations

1. Description White to off white, biconvex, round tablets.

2. Disintegration time 10 sec.

Example 7:

Stability study of tablet dosage form

In the stability study of the tablet dosage form, tablets were evaluated for physical appearance, odor, color, weight variation, assay, impurities, dissolution, moisture and microbial content.

Real time studies were carried out at 25 °C ± 2 °C, 60 % ± 5 % RH (relative humidity) for 6 months. The tablets were tested at three time points, initial at 0 month, 3 months and 6 months.

Protocol of stability study: 500 mg tablets comprising of Compound A packed in a high density polyethylene (HDPE) bottle

Purpose: To evaluate stability of the product

Test design: The product was packed in 75 cc white opaque HDPE bottle (for squeeze and turn) containing 30 tablets with 33 mm white opaque polypropylene child resistance closure with cotton absorbent and one silica gel canister and sealed with induction seal liner and it is stored at 25 °C ± 2 °C, 60 % ± 5 % RH for 6 months. The sampling interval was 0, 3 and 6 months.

Parameters to be tested: The Reference standard used for the stability study of the tablet dosage form was a highly purified (> 99 % pure) active pharmaceutical ingredient, 2,4- dichloro-N-[5-chloro-6-(isoquinolin-3-yloxy)-pyridin-3-yl]-benzenesulfonamide (Compound A). The Reference standard was stored at a temperature ranging from 2 °C to 8 °C. The Reference standard was subjected to stability study along with the tablet dosage form at 25 °C ± 2 °C, 60 % ± 5 % RH for 6 months. Following parameters were tested to determine the stability of tablet dosage form: physical appearance, identification of Compound A by retention time, loss on drying at 105 °C, weight variation, impurity content, assay for determination of content of Compound A in mg and microbial assay. Results:

1. Physical appearance: The physical appearance was not changed significantly and it met the requirements of the specification. The specification being white to off white, biconvex, capsule shaped tablet, plain on one side and having break line on the other side.

2. Identification: Identification test was performed by using HPLC method. The HPLC chromatogram showed that the retention time of the Compound A peak corresponded to that of the Reference standard.

3. Loss on drying: Loss on drying was calculated at 105 °C. Initial moisture content was found to be 0.7 % of total tablet weight, at 3^rd month and 6^th month the moisture content was found to be 1.64 % and 1.33 % of total tablet weight respectively.

4. Average weight: Average weight of the tablet did not vary significantly when tested at 3^rd and 6^th month.

5. Dissolution: Tablets met the requirement for dissolution testing. The average dissolution was found to be more than 70 % thus complying with the specified dissolution value.

6. Impurity content: Impurity content was not more than 0.03 % at the end of 6^th month.

7. Assay: Assay of the tablet was carried out to determine exact amount of the compound A when the tablet was subjected to stability study. The results of the assay showed that the tablets contained required amount of active ingredient (Compound A) after 6 months stability study and met the requirement of the assay i.e 90 % to 110 % of labeled amount.

8. Microbiological testing: Total bacterial viable count was not more than 100 cfu/g, Total fungal viable count was not more than 100 cfu/g, Escherichia Coli was absent in lg of the test sample and Salmonella was absent in 10 g of the test sample.

The stability study data over a period of 6 months indicates that the tablet dosage form is stable at the specified condition of temperature and humidity as there is no significant change in its physical, chemical and microbiological parameters. Table 6 represents various parameters of the tablet dosage form which were tested after subjecting the tablet dosage form to stability study at 25 °C ± 2 °C, 60 % ± 5 % RH for 6 months. Table 6:

8. Microbiological quality

Total viable Not more than 1000 Less than 10

count cfu/g cfu/g

(Bacteria)

Total viable Not more than 100 cfu/g Less than 10

count (Fungi) cfu/g

Escherichia Absent in lg Absent

Coli

Salmonella Absent in lOg Absent - -

It should be noted that, as used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the content clearly dictates otherwise. It should also be noted that the term "or" is generally employed in its sense including "and/or" unless the content clearly dictates otherwise.

All publications and patent applications in this specification are indicative of the level of ordinary skill in the art to which this invention pertains.

The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.

Claims

WE CLAIM:

1. A stable oral tablet dosage form comprising of a compound of formula (I),

Formula (I)

wherein R is selected from phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3,5- dimethylphenyl, 2,4,6- trimethylphenyl, 3-chloro-4-methylphenyl, 4-methoxyphenyl, 2,4- dimethoxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 4-trifluoromethoxyphenyl, 4- fluorophenyl, 2,4-difluorophenyl, 2-chloro-4- fluorophenyl, 2,4-dichlorophenyl, 3,4- dichlorophenyl, 3,5-dichlorophenyl, 4-chlorophenyl, 2-chloro-4-trifluoromethylphenyl, 3- trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-fluoro-4-chlorophenyl; 4-cyanophenyl, phenyl-3-carboxylic acid or 4-acetamidophenyl or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient; a non-ionic surfactant and one or more pharmaceutically acceptable excipients; wherein the tablet dosage form contain particles of the active pharmaceutical ingredient having a particle size less than 200 μ.

2. The stable oral tablet dosage form according to claim 1, wherein the compound of formula (I) is 2,4-dichloro-N-[5-chloro-6-(isoquinolin-3-yloxy)-pyridin-3-yl]- benzenesulfonamide (Compound A), or a pharmaceutically acceptable salt thereof.

3. The stable oral tablet dosage form according to claim 1 or claim 2, wherein said tablet dosage form contains 40 % to 80 % by weight of the compound of formula (I).

4. The stable oral tablet dosage form according to any one of the claims 1 to 3, wherein the non-ionic surfactant is selected from Cremophor^® EL, Cremophor^® RH, - -tocopherol polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, Solutol^® HS 15, sorbitan monooleate, poloxamers, Labrafils^®, Labrasol^®, Gellucire^® 44/14, Softigen^® 767 and mono- and di-fatty acid esters of polyethylene glycol or mixtures thereof.

5. The stable oral tablet dosage form according to claim 4, wherein the non-ionic surfactant is a poloxamer.

6. The stable oral tablet dosage form according to claim 5, wherein the poloxamer is poloxamer 188.

7. The stable oral tablet dosage form according to any one of claims 1 to 6, wherein the pharmaceutically acceptable excipients are selected from diluents, binders, lubricants, disintegrants or glidants, desiccants or combinations thereof.

8. The stable oral tablet dosage form according to claim 7, wherein the diluents are selected from microcrystalline cellulose, wood cellulose, silicified microcrystalline cellulose, anhydrous lactose, lactose monohydrate, lactose fast-flo, directly compressible anhydrous lactose, modified lactose monohydrate, sucrose, starch, pregelatinized starch, dextrose, mannitol, fructose, xylitol, sorbitol, corn starch, modified corn starch, salts selected from calcium carbonate, calcium phosphate, dibasic calcium phosphate dehydrate, dicalcium phosphate or calcium sulfate, dextrins, dextrates, maltodextrin or compressible sugars.

9. The stable oral tablet dosage form according to claim 8, wherein the diluents are selected from microcrystalline cellulose, lactose monohydrate or dibasic calcium phosphate dehydrate.

10. The stable oral tablet dosage form according to claim 7, wherein the binders are selected from hydroxypropyl cellulose, corn starch, pregelatinized starch, modified corn starch, polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose, lactose, gum acasia, ethyl cellulose, cellulose acetate, carnauba wax, paraffin, spermaceti, polyethylenes or microcrystalline wax or mixtures thereof.

11. The stable oral tablet dosage form according to claim 10, wherein the binder is hydroxypropyl cellulose.

12. The stable oral tablet dosage form according to claim 7, wherein the lubricants are selected from magnesium stearate, zinc stearate, calcium stearate, talc, carnauba wax, stearic acid, palmitic acid, sodium stearyl fumarate, sodium laurel sulfate, glyceryl palmitostearate, palmitic acid, myristic acid or hydrogenated vegetable oils and fats or mixtures thereof.

13. The stable oral tablet dosage form according to claim 12, wherein the lubricant is magnesium stearate.

14. The stable oral tablet dosage form according to claim 7, wherein the disintegrants are selected from croscarmellose sodium, crospovidone, starch, potato starch, pregelatinized starch, corn starch, sodium starch glycolate or hydroxypropyl cellulose or mixtures thereof.

15. The stable oral tablet dosage form according to claim 14, wherein the disintegrant is sodium starch glycolate.

16. The stable oral tablet dosage form according to claim 7, wherein the glidants are selected from silicon dioxide, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc, aggregated silicates or hydrated silica or mixtures thereof.

17. The stable oral tablet dosage form according to claim 16, wherein the glidant is colloidal silicon dioxide.

18. The stable oral tablet dosage form according to claim 7, wherein the desiccants are selected from colloidal silicon dioxide, calcium chloride, calcium sulfate, magnesium sulfate, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium chloride, sodium sulfate or sucrose or mixtures thereof.

19. The stable oral tablet dosage form according to claim 18, wherein the desiccant is colloidal silicon dioxide.

20. The stable oral tablet dosage form according to any one of the claims 1 to 19, wherein the hardness of the tablet is 20 N to 175 N.

21. The stable oral tablet dosage form according to any one of the claims 1 to 20, wherein the tablet is a rapidly disintegrating tablet having a disintegration time ranging from 10 sec to 5 min.

22. The stable oral tablet dosage form according to any one of the claims 1 to 21, wherein the particles of active pharmaceutical ingredient contained in the tablet dosage form have a particle size less than 50 μ.

23. The stable oral tablet dosage form according to any one of the claims 1 to 22 for use in the treatment of metabolic disorders related to insulin resistance or hyperglycemia.

24. The stable oral tablet dosage form for use according to claim 23, wherein the metabolic disorder related to insulin resistance or hyperglycemia is selected from type 2 diabetes, obesity, glucose intolerance, dyslipidemia, hyperinsulinemia, atherosclerotic disease, polycystic ovary syndrome, coronary artery disease, hypertension, aging or non alcoholic fatty liver disease.

25. The stable oral tablet dosage form for use according to claim 24, wherein the metabolic disorder related to insulin resistance or hyperglycemia is type 2 diabetes.

26. A process for the preparation of a stable oral tablet dosage form, the compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof by wet granulation method, comprising the steps of:

step a) mixing of the compound of formula (I) or a pharmaceutically acceptable salt thereof; with diluents after sifting of the compound and diluents;

step b) preparation of binder solution containing non-ionic surfactant by dissolving the non- ionic surfactant and binding agent in purified water;

step c) preparation of granules by adding binder solution to the mixture of step a), passing the resultant mixture through sieves to obtain wet granules, drying the wet granules at a temperature range of 50 °C to 100 °C and passing the dried granules through sieves; and step d) sifting the glidant and disintegrant through sieves, blending the sifted glidant and disintegrant with the granules prepared in step c), adding sifted lubricant to the blend obtained and compressing the final mixture to yield the tablet dosage form.

27. A process for the preparation of a stable oral tablet dosage form of the compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof, by direct compression process, the steps comprising: step a) mixing a non-ionic surfactant with a small amount of diluent, microcrystalline cellulose and sifting the mixture through sieves;

28. The process for the preparation of the stable oral tablet dosage form according to claim 26 or 27, wherein the compound of formula (I) is compound A.