FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition comprising amorphous empagliflozin or pharmaceutically acceptable salts, esters, solvates, polymorphs thereof along with one or more pharmaceutically acceptable excipients. Further, it also relates to a process of preparing such pharmaceutical composition and its use to treat diabetes.
BACKGROUND OF THE INVENTION
An approximate of 415 million people live with diabetes worldwide, and an estimated 193 million people have undiagnosed diabetes. Type-2 diabetes accounts for more than 90% of patients with diabetes and leads to microvascular and macrovascular complications that cause profound psychological and physical distress to both patients and carers and put a huge burden on health-care systems. Type-2 diabetes mellitus is a chronic metabolic condition characterised by chronic hyperglycaemia due to deficiency in the secretion and/or function of insulin (i.e. insulin resistance). Both the incidence and prevalence of Type-2 diabetes mellitus are increasing worldwide, particularly in developing countries, in conjunction with increased obesity rates and westernisation of lifestyle. Type-2 diabetes mellitus is known to be associated with a reduced life expectancy and increased morbidity. Although cardiovascular disease is the commonest cause of mortality and morbidity, Type-2 diabetes mellitus is also associated with an increased risk of other diseases including cancer, chronic liver disease, cognitive decline and accelerated arthritis, in addition to the microvascular and macrovascular complications.
After long duration of disease, most patients with Type-2 diabetes will eventually, fail on oral therapy and become insulin dependent with the necessity for daily injections and multiple daily glucose measurements.
Oral antidiabetic drugs conventionally used in therapy (such as e.g. first- or second-line, and/or mono- or (initial or add-on) combination therapy) include, without

being restricted thereto, metformin, sulphonylureas, thiazolidinediones, glinides and a-glucosidase inhibitors.
The high incidence of therapeutic failure is a major contributor to the high rate of long-term hyperglycaemia-associated complications or chronic damages (including micro- and macrovascular complications such as e.g. diabetic nephropathy, retinopathy or neuropathy, or cardiovascular complications) in patients with Type-
2 diabetes.
Renal filtration and reuptake of glucose contributes, among other mechanisms, to the steady state plasma glucose concentration and can therefore serve as an antidiabetic target. Reuptake of filtered glucose across epithelial cells of the kidney proceeds via sodium-dependent glucose cotransporters (SGLTs) located in the brush-border membranes in the tubuli along the sodium gradient. There are at least
3 SGLT isoforms that differ in their expression pattern as well as in their physico-
chemical properties. SGLT2 is exclusively expressed in the kidney, whereas
SGLT1 is expressed additionally in other tissues like intestine, colon, skeletal and
cardiac muscle. SGLT3 has been found to be a glucose sensor in interstitial cells of
the intestine without any transport function.
SGLT2 inhibitors represent a class of agents that are being developed for the treatment or improvement in glycemic control in patients with Type-2 diabetes. Glucopyranosyl-substituted benzene derivative are described in the following refrences as SGLT2 inhibitors, for example in WO 01/27128, WO 03/099836, WO 2005/092877, WO 2006/034489, WO 2006/064033, WO 2006/117359, WO 2006/117360, WO 2007/025943, WO 2007/028814, WO 2007/031548, WO 2007/093610, WO 2007/128749, WO 2008/049923, WO 2008/055870, WO 2008/055940. The glucopyranosyl-substituted benzene derivatives are proposed as inducers of urinary sugar excretion and as medicaments in the treatment of diabetes. Drugs in the SGLT2 inhibitors class include, but are not limited to canagliflozin, dapagliflozin, empagliflozin and the like.

Empagliflozin is a SGLT2 (sodium/glucose cotransporter-2) inhibitor that is described for the treatment or improvement in glycemic control in patients with Type-2 diabetes mellitus. Empagliflozin is chemically known as (1S)-1, 5-anhydro-l-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl] oxy] phenyl] methyl] phenyl]-D-glucitol (Formula I).

Formula I
Empagliflozin is marketed in US, Europe and other countries under the brand name Jardiance, which is indicated as an adjunct to diet and exercise to improve glycemic control in adults with Type-2 diabetes mellitus and to reduce the risk of cardiovascular death in adult patients with Type-2 diabetes mellitus and established cardiovascular disease.
There are several references known in the literature, which describe the different polymorphic forms of Empagliflozin and pharmaceutical composition of the same, which is used as an adjunct to diet and exercise to improve glycemic control in adults with Type-2 diabetes mellitus and to reduce the risk of cardiovascular death in adult patients with Type-2 diabetes mellitus and established cardiovascular disease.
US Patent No. 7,579,449 discloses empagliflozin as a product.
US Patent No. 7,713,938 discloses a crystalline form of empagliflozin and a pharmaceutical composition or medicament comprising the crystalline form.

U.S. Patent No. 8,802,842 discloses a method for preparing a crystalline form of empagliflozin. It also discloses empagliflozin characterized by a purity above 99%.
US Patent Publication No. 2011/0014284 of Boehringer relates to a composition comprising empagliflozin, binder, disintegrant, wherein ratio of disintegrant: binder is 1.5:3.5 and 1:1. More particularly, the invention relates to a composition wherein empagliflozin is in crystalline form.
Indian Patent Publication No. 4964/CHE/2014 of Mylan covers an amorphous empagliflozin complex with a cyclodextrin.
Indian Patent Publication No. 1985/MUM/2013 of Cadila covers an amorphous form of empagliflozin and pharmaceutical composition comprising amorphous empagliflozin. It further relates to the amorphous solid dispersion of empagliflozin and polymer using equipment such as Buchi Rotavapor, spray drying, agitated thin film drying ("ATFD"), and freeze drying (lyophilization).
Empagliflozin is very slightly soluble in aqueous media between pH 1-7.5 and has low intestinal permeability. The solubility of empagliflozin proportionally enhances the bioavailability. Crystalline solids normally require a significant amount of energy for dissolution due to their highly organized, lattice like structures. For example, the energy required for a drug molecule to escape from a crystal is more than from an amorphous or a non-crystalline form.
The prior published references illustrated above define either empagliflozin in a crystalline dosage form utilizing a predefined particle size in order to achieve better dissolution or a process to convert the crystalline form into amorphous to enhance the dissolution of the same using economically inconvenient procedures and equipment such as spray drying or freeze drying or lyophilization etc.

In view of the above, it is therefore, desirable to provide a pharmaceutical composition of amorphous empagliflozin using industrial friendly, cost effective process and by using routine equipment as used in the industry such as fluidized bed dryer or processor.
SUMMARY OF THE INVENTION
The present invention provides a pharmaceutical composition comprising empagliflozin or a pharmaceutically acceptable salts, esters, solvates, polymorphs thereof and one or more pharmaceutically acceptable excipients and process of preparation thereof.
One aspect of the present invention provides a pharmaceutical composition comprising amorphous empagliflozin or pharmaceutically acceptable salts, ester, solvates, polymorphs thereof and one or more pharmaceutically acceptable
excipients.
One embodiment of the present invention provides a pharmaceutical composition, wherein the pharmaceutical composition is in the form of granules, pellets, solid dispersion, drug coated inert core, beads, spheroids, a tablet, a minitablet, a microtablet, a capsule, granules in a capsule, pellets in a capsule, microtablets in a capsule and minitablets in a capsule.
Another embodiment of the present invention provides a pharmaceutical composition, wherein the pharmaceutical composition is in the form of a tablet.
Another embodiment of the present invention provides a pharmaceutical composition, wherein the pharmaceutical composition is further film coated.
Another embodiment of the present invention provides a pharmaceutical composition, wherein the pharmaceutically acceptable excipients are selected from

the group comprising diluents, binders, disintegrants, glidants, lubricants, surfactants, polymers and/or combination thereof.
Another embodiment of the present invention provides a pharmaceutical composition, wherein the polymer is hydrophilic or hydrophobic.
Another embodiment of the present invention provides a pharmaceutical composition, wherein the ratio of disintegrant and binder in the pharmaceutical composition is either less than 0.4:1 or greater than 1.1:1.
Another embodiment of the present invention provides a pharmaceutical composition, wherein the empagliflozin has particle size less than 50(im.
Another embodiment of the present invention provides a pharmaceutical composition, wherein said pharmaceutical composition is useful in the treatment of diabetes.
Another aspect of the present invention provides a process for preparing a pharmaceutical composition comprising amorphous empagliflozin or pharmaceutically acceptable salts, ester, solvates, polymorphs thereof and one or more pharmaceutically acceptable excipients, wherein said process comprises the steps of:
(1) preparing a solution of empagliflozin optionally with one or more pharmaceutically acceptable excipients in a suitable solvent;
(2) spraying the obtained solution of step (1) on an inert core to obtain granules of drug coated inert core;
(3) the granules of step (2) are further blended with one or more pharmaceutically acceptable excipients;

(4) the mixture obtained in step (3) is lubricated with suitable excipient(s);
(5) formulating the lubricated mixture of step (4) into final dosage form;
(6) optionally, coating the final dosage form.

DESCRIPTION OF THE INVENTION
The present invention relates to a composition of empagliflozin using an industrial friendly process and utilizing routine equipment such as fluidized bed dryer or processor.
The present invention provides a pharmaceutical composition comprising empagliflozin or pharmaceutically acceptable salts, esters, solvates, polymorphs thereof along with one or more pharmaceutically acceptable excipients. Empagliflozin may be present in crystalline form or in amorphous form. More preferably, in amorphous form. The pharmaceutical composition of the present invention comprises about 1 mg to about 50 mg of empagliflozin.
Salt form of empagliflozin for pharmaceutical use may be physiologically acceptable salts with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
The present invention provides a pharmaceutical composition comprising empagliflozin along with one or more pharmaceutically acceptable excipients wherein the excipients are selected from diluents, fillers, disintegrants, binders, surfactants, polymers, glidants, lubricants or combination thereof. The ratio of disintegrant: binder in the pharmaceutical composition is either less than 0.4:1 or greater than 1.1:1.
The pharmaceutical composition of the present invention is formulated using reverse wet granulation process.
Reverse wet granulation or reverse-phase wet granulation is a new development in the wet granulation technique that involves the mixing of drug with a solution or

suspension of a polymer to form a drug-polymer slurry. Granules* can then be formed by combining the other pharmaceutically acceptable excipients with the drug-polymer slurry. It is purported that this technique improves the dissolution characteristics of the poorly water-soluble drugs by allowing uniform distribution of the binder that acts as a wetting agent and enable adequate wetting of the drug substance during granulation.
The process of preparing the pharmaceutical composition of the present invention comprises the steps of: (1) preparing a solution or dispersion of empagliflozin optionally with one or more pharmaceutically acceptable excipients in a suitable solvent; (2) spraying the obtained solution of step (1) on an inert core to obtain granules; (3) blending the granules obtained in step (2) with one or more pharmaceutically acceptable excipients; (4) lubricating the mixture obtained in step (3) with suitable excipient(s); (5) formulating the mixture obtained in step (4) into a final dosage form; (6) optionally film-coating the final dosage form with a film coat.
Suitable inert core according to the invention can be selected from group comprising, but not limited to, sugar, sucrose, sorbitol, xylitol, mannitol, lactose, dicalcium phosphate, microcrystalline cellulose, maltodextrin, starch, a hydrophilic cellulosic polymer, or a crosslinked hydrophilic synthetic polymer or can be selected from any filler or diluent.
Solvent used to prepare the solution or dispersion of empagliflozin may be an aqueous or organic or inorganic solvent or a combination thereof.
Optionally, the solution or dispersion, prior to any solids formation, was filtered to remove any undissolved solids, solid impurities prior to removal of the solvent. Any filtration system and filtration techniques known in the art can be used.

Suitable organic solvent may be selected from, but not limited to, acetic acid, acetone, acetonitrile, benzene, 1-butanol, 2-butanol, 2-butanone, t-butyl alcohol, carbon tetrachloride, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethane, dehydrated alcohol, diethylene glycol, diethyl ether, diglyme (diethylene glycol dimethyl ether), 1,2-dimethoxy- ethane (glyme, DME), dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), 1,4-dioxane ethanol, ethyl acetate, ethylene glycol, glycerine, heptane, Hexamethylphosphoramide (HMPA), Hexamethylphosphorous triamide (HMPT), hexane, methanol, methyl t-butyl ether (MTBE), methylene chloride, N-methyl-2-pyrrolidinone (NMP), nitromethane, pentane, Petroleum ether (ligroine), 1-propanol, 2-propanol, pyridine, tetrahydrofuran (THF), toluene, triethyl amine, o-xylene, m-xylene, p-xylene etc., or a combination thereof.
Suitable inorganic solvent may be selected from, but not limited to, water, aqueous solutions containing special additives (surfacants, detergents, PH buffers, inhibitors), liquid anhydrous Ammonia, concentrated sulfuric acid, sulfuryl chloride fluoride, liquid sulfur dioxide, sulfuryl chloride and, phosphoryl chloride, dinitrogen tetroxide, antimony trichloride, bromine pentafluoride, hydrogen fluoride etc., or a combination thereof.
The pharmaceutically acceptable excipients are selected form the group comprising diluents, binders, disintegrants, glidants, lubricants, surfactants, polymers and/ or combination thereof.
Suitable polymers are selected from hydrophilic or hydrophobic polymers or a combination of polymers thereof.
The hydrophilic polymers are water soluble polymers. They include cellulose methyl ethers like methyl cellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, polyacrylic acid, polyacrylamides, N-(2-Hydroxypropyl) methacrylamide, divinyl

ether-maleic anhydride, polyoxazoline, polyphosphates, polyphosphazenes, xanthan gum, pectins, chitosan derivatives, dextran, carrageenan, guar gum, hyaluronic acid, albumin, starch its derivatives or a combination thereof
The hydrophobic polymers are selected from, but not limited to, ethyl cellulose, polyvinyl alcohol, HPMC acetate succinate, methacrylic acid copolymers.
Suitable binders are selected from the group comprising povidone, copovidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, xanthan gum, gum acacia, gum arable, tragacanth, sorbitol, dextrose, sucrose, mannitol, gelatin, pullulan, sodium alginate, propylene glycol, polyvinyl alcohol, corn syrup, methacrylates, carboxyvinyl polymers like carbomers, or mixtures thereof.
Suitable fillers/ diluents include, without limitation, starch, corn starch, potato starch, pregelatinized starch, dry starch, disaccharides, lactose, cellulose, cellulose derivatives, such as silicified microcrystalline cellulose, microcrystalline cellulose (e.g., cellulose MK GR), mannitol, sorbitol, xylitol, trehalose, colloidal silica, sucrose or other sugars or sugar derivatives, calcium hydrogen phosphate, dicalcium phosphate, low-substituted hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, and combinations thereof.
Suitable disintegrants according to the invention are cross linked sodium carboxymethyl starch, crospovidone, cross linked sodium carboxymethylcellulose, sodium starch glycolate, L-HPC, microcrystalline cellulose, polacrilin potassium, starch and mixtures thereof.
Suitable lubricants according to the invention are stearic acid as well as salts thereof including talc, calcium stearate, zinc stearate, magnesium stearate, sodium stearyl fumarate, glyceryl monostearate, polyethylene glycols, hydrogenated castor oil, fatty acid, for example fumaric acid, and salts of fatty acids such as but not limited

to calcium, magnesium, sodium or potassium salts thereof, for example calcium behenate, calcium stearate, sodium stearyl fumarate or magnesium stearate (for example (e.g. HyQual®, Mallinckrodt), glycerides such as glyceryl behenate (Compritol® 888), Dynasan® 118 or Boeson® VP.
Suitable glidants according to the invention are silicon dioxide, particularly colloidal silicon dioxide (e.g. Aerosil®, Cab-O-Sil®), stearic acid as well as salts thereof including sodium stearate, calcium stearate, zinc stearate, magnesium stearate, magnesium silicate, calcium silicate, magnesium trisilicate and talc.
Suitable surfactants are selected from the group comprising sodium lauryl sulfate, sodium dodecyl sulfate, ammonium, lauryl sulfate, benzalkonium chloride, alkyl poly (ethylene oxide), copolymers of poly (ethylene oxide) and poly (propylene oxide) commercially called as poloxamers or poloxamines, fatty alcohols, polysorbates e.g., Tween 20, Tween 80, or mixtures thereof.
The final dosage form of the present invention is in the form of granules, pellets, solid dispersion, drug coated inert core, beads, spheroids, a tablet, a minitablet, a microtablet, a capsule, granules in a capsule, pellets in a capsule, microtablets in a capsule and minitablets in a capsule.
The present invention provides a pharmaceutical composition, wherein the pharmaceutical composition is used as an adjunct to diet and exercise to improve glycemic control in adults with Type-2 diabetes mellitus. Further, the pharmaceutical composition of present invention is used to reduce the risk of cardiovascular death in adult patients with Type-2 diabetes mellitus and established cardiovascular disease.
The pharmaceutical composition of the present invention may be administered or contain one or more other antidiabetic drugs selected from DPP IV inhibitors, biguanides, angiotensin receptor blockers, anti-anginal agents, anti-arrhythmic

agents, anti-hypertensive, beta adrenergic, calcium channel blockers, diuretics and other cardiovascular drugs.
The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Example- 1: Pharmaceutical composition of Empagliflozin

Process:
1. Sift all the ingredients through appropriate sieve (100% should pass through sieve).
2. Empagliflozin and povidone are added to the mixture of alcohol and methylene chloride respectively and mixed till a solution is observed.
3. The drug solution of step 2 is sprayed onto the lactose monohydrate by top spraying process.
4. The dried granules obtained from step 3 need to be sized through appropriate sieve to obtain uniform granules.
5. Blend the granules obtained from step 4 in a suitable blender along with pre-sifted croscarmellose sodium.
6. Lubricate the blend from step 6 with zinc stearate in a blender.
7. Compress the blend of step 6 into tablets.
8. Coat the tablets obtained in step 7.
9. Pack the tablets as per requirement.
Example- 2: Pharmaceutical composition of Empagliflozin

Process:
1. Sift all the ingredients through appropriate sieve (100% should pass through sieve).
2. Empagliflozin and povidone are added to the mixture of alcohol and methylene chloride respectively and mixed till a solution is observed.
3. The drug solution of step 2 is sprayed onto the mannitol by top spraying process.
4. The dried granules obtained from step 3 need to be sized through appropriate sieve to obtain uniform granules.
5. Blend the granules obtained from step 4 in a suitable blender along with pre-sifted croscarmellose sodium, colloidal silicon dioxide and Pearlitol flash.
6. Lubricate the blend from step 6 with zinc stearate in a blender.
7. Compress the blend of step 6 into tablets.
8. Coat the tablets obtained in step 7.
9. Pack the tablets as per requirement.
Example- 3: Pharmaceutical composition of Empagliflozin

1. Sift all the ingredients through appropriate sieve (100% should pass through sieve).
2. Empagliflozin and povidone are added to the mixture of alcohol and methylene chloride respectively and mixed till a solution is observed.
3. The drug solution of step 2 is sprayed onto the microcrystalline cellulose by top spraying process.
4. The dried granules obtained from step 3 need to be sized through appropriate sieve to obtain uniform granules.
5. Blend the granules obtained from step 4 in a suitable blender along with pre-sifted croscarmellose sodium, colloidal silicon dioxide and Pearlitol flash.
6. Lubricate the blend from step 6 with zinc stearate in a blender.
7. Compress the blend of step 6 into tablets.
8. Coat the tablets obtained in step 7.
9. Pack the tablets as per requirement.

Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention.

WE CLAIM
1. A pharmaceutical composition comprising amorphous empagliflozin or pharmaceutically acceptable salts, ester, solvates, polymorphs thereof and one or more pharmaceutically acceptable excipients.
2. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical composition is in the form of tablet.
3. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutically acceptable excipients are selected form the group comprising diluents, binders, disintegrants, glidants, lubricants, surfactants, polymers and/ or combination thereof.
4. The pharmaceutical composition as claimed in claim 3, wherein the ratio of disintegrant and binder in the pharmaceutical composition is either less than 0.4:1 or greater than 1.1:1.
5. The pharmaceutical composition as claimed in claim 1, wherein the empagliflozin has particle size less than 50|im.
6. The pharmaceutical composition as claimed in claim 1, wherein the composition is prepared by reverse wet granulation process.
7. A process for preparing pharmaceutical composition comprising amorphous empagliflozin or pharmaceutically acceptable salts, ester, solvates, polymorphs thereof and one or more pharmaceutically acceptable excipients, wherein said process comprises the steps of:
(1) preparing a solution of empagliflozin optionally with one or more pharmaceutically acceptable excipients in a suitable solvent;

(2) spraying the obtained solution of step (1) on an inert core to obtain granules of drug coated inert core;
(3) blending the granules of step (2) with one or more pharmaceutically acceptable excipients;
(4) lubricating the mixture obtained in step (3) with suitable excipient(s);
(5) formulating the mixture obtained in step (4) into final dosage form.
(6) optionally, coating the final dosage form obtained in step (5).
The process for preparing pharmaceutical composition as claimed in claim 7, wherein inert core is selected from group comprising sugar, sucrose, sorbitol, xylitol, mannitol, lactose, dicalcium phosphate, microcrystalline cellulose, maltodextrin, starch, a hydrophilic cellulosic polymer, or a crosslinked hydrophilic synthetic polymer.
A process for preparing pharmaceutical composition comprising amorphous empagliflozin or pharmaceutically acceptable salts, ester, solvates, polymorphs thereof and one or more pharmaceutically acceptable excipients, wherein said process comprises the steps of:
(1) preparing a solution of empagliflozin with povidone in a solvent mixture of alcohol and methylene chloride;
(2) spraying the obtained solution of step (1) on microcrystalline cellulose to obtain granules;
(3) blending the granules of step (2) with croscarmellose sodium, colloidal silicon dioxide and pearlitol flash;
(4) lubricating the mixture obtained in step (3) with zinc stearate to form lubricated granules;
(5) compressing the granules obtained in step (4) into tablet;
(6) optionally, coating the tablets obtained in step (5).

10. The pharmaceutical composition as claimed in claim 1, is useful for the treatment of diabetes.