FIE L D O F T H E INV E NTION:

The present invention relates to sol id oral pharmaceutical compositions ¾ comprising premix of dapagliflozin with at least one pharmaceutically acceptable excipient(s) and process for preparation thereof.

BAC K G R OU ND OF INV E NT ION:

Diabetes is a well-known metabolic disease characterized by improper control of

3a sugar in the blood because the body does not produce enough insulin, or properly use insulin, to maintain safe blood sugar levels. High blood sugar levels lead to many complications including blindness, stroke, and nerve damage, amputation of the lower limbs, kidney failure, and heart attack. The incidence of this disease is growing fast. Each year more than 4 million people die from complications of diabetes including heart

¾ diseases, strokes & kidney failure.

Sodium glucose cotransporter-2 (SG LT-2) has been discovered to be a new target for treating diabetes in recent years. SG LT-2 is mainly distributed in renal proximal tubul es. It was responsi bl e for at I east 90% of the gl ucose reabsorpti on i n the ki dney. da

Dapagliflozin is an inhibitor of sodium dependent glucose transporter which is chemically represented as (1S)-1,5-anhydro-1-C-{4-chloro-3-[(4-ethoxyphenyl)methyl] phenyl} -D-gl uci tol having structural formula as represented by formula (I)

C urrently, Dapagliflozin is approved under the brand name Farxiga E q 5nrg and 10 nrg in the form of tablets, which is marketed by AstraZeneca. U.S. Patent No. 6,515,117 discloses dapagliflozin as a compound. U.S. Patent No. 7,919,598 discloses the (S)-propylene glycol solvate of dapagl iflozin and processes of preparation thereof. The commercial ly available formulations of dapagliflozin contain the Propanediol (propylene glycol) monohydrate solvate of dapagliflozin as the active ingredient

¾ WO 2008/002824 discloses crystalline forms of Dapagliflozin processes for preparing same, intermediates used in preparing same, and methods of treating diseases such as diabetes using such structures.

WO 2012/163546 discloses pharmaceutical compositions comprising cyclodextrin and 3a dapagliflozin, preferably as an incl usion complex.

WO 2014/178040 discloses novel co-crystal forms of dapagliflozin, namely a dapagliflozin lactose co-crystal and a dapagliflozin asparagine co-crystal, to pharmaceutical compositions comprising same, methods for their preparation and uses ¾ thereof for treati ng ty pe 2 di abetes.

The dapagliflozin base is hygroscopic in nature. It absorbs moisture and forms sticky lumps which are difficult to process and handle, and which may ultimately lead to stability and processing problems during manufacturing.

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There is therefore an existing and continual need for stable and therapeutically equivalent oral solid pharmaceutical compositions of Dapagliflozi n. The compositions of the present invention overcome al l the encountered problems exemplified above. tfc SU M MA RY OF T H E INV E NTIO N

The present invention relates to pharmaceutical compositions comprising premix of dapagliflozin with at least one pharmaceutically acceptable excipient(s).

O BEJ E CT IV E S OF I NV E NT IO N:

til Broadly, the object of the invention is to provide sol id oral pharmaceutical compositions comprising of dapagliflozin premix with at least one pharmaceutically acceptable excipient(s). The invention also relates to methods of making a pharmaceutical composition comprising dapagliflozin premix.

Another object of the invention is to provide the pharmaceutical composition ¾ comprising of dapagliflozin premix for use in the treatment or delaying the progression or onset of diabetes.

In yet another object of the invention is to provide solid oral pharmaceutical compositions comprising of dapagliflozin premix prepared by different methods like dry 3a granulation, wet granulation, direct compression and other suitable methods known to the persons sk i 11 ed i n the art

In another object, the present invention further provides pharmaceutical composition comprising dapagliflozin premix in combination therapy with one or more ¾ other active ingredients in a single pharmaceutical composition or separate pharmaceutical composition.

In another object, the present invention further provides pharmaceutical composition comprising premix of dapagliflozin with lactose in combination therapy with iti one or more other active ingredients in a single pharmaceutical composition or separate pharmaceutical composition.

In yet another aspect, the one or more active ingredients which optionally employed in combination therapy may include, but are not limited to other type of ¾ anti di abeti c agents and/or other types of therapeuti c agents.

In another object of the invention is a solid pharmaceutical composition which is bioequivalent to the marketed composition of dapagliflozin tablets . DETAILED DESCRIPTION OFTHE INVENTION:

The present invention relates to solid oral pharmaceutical compositions of dapagliflozin premix with at least one pharmaceutically acceptable excipient(s) and process for preparation thereof. More parti cul airy, pharmaceutical composition is in the form of tablet

¾ ^' Dapagliflozin _. as depicted in formula I used in the present invention is in the form of premix.

In one embodiment Dapagliflozin premix is a premix of dapagliflozin with lactose. The process for the preparation of the premix of dapagliflozin with lactose 3a c ompri si ng the steps of:

(a) providi ng solution of dapagliflozin;

(b) preparing D-P complex of dapagliflozin of formula (II)

wherein n is 3 to 15;

(c) converting D-P complex of dapagliflozin of formula (II) into dapagliflozin;

(d) providing solution of dapagliflozin obtained in step (c);

iti (e) precipitating dapagliflozin by treating the solution of step (d) with an antisolvent;

(f) adding lactose;

(g) isolating premix of dapagliflozin with lactose.

In another embodiment, the weight ratio of dapagliflozin to the lactose is from t¾ about 1 :0.01 to 1 : 100, preferably 1:0.1 to 1 :10.

In one aspect of the present i nvention, Solid oral pharmaceutical compositions of dapagliflozin premix can be formulated in different oral dosage forms. Such as, but are not limited to powders, granules, pellets, tablets (si ngle layered tablets, multi layered tablets, mini tablets, bioadhesive tablets, caplets, matrix tablets, tablet within a tablet mucoadhesive tablets, immediate release tablets, sustained release tablet extended release tablet, modified release tablets, pulsatile release tablets, and timed release tablets), beads, granules, sustained release formulations, capsules, microcapsules, tablets in capsules, ¾ microspheres, matrix formulations, microencapsulation, or capsules.

In another aspect the composition of the present invention can be uncoated or coated form

3a In another aspect, pharmaceutical composition of present inventions can be used for the treatment or prevention of diabetes.

In one embodiment a solid oral pharmaceutical composition is in the form of tablet comprising Dapagliflozin premix and one or more pharmaceutically acceptable ¾ excipient(s) prepared by wet granulation method.

In another embodiment a solid oral pharmaceutical composition is i n the form of tablet comprising Dapagliflozin premix and one or more pharmaceutically acceptable excipient(s) prepared by dry granulation method.

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In yet another embodiment a solid oral pharmaceutical composition is in the form of tablet comprising Dapagliflozin premix and one or more pharmaceutically acceptable excipient(s) prepared by direct compression method. ¾ In another aspect, the present invention further provides pharmaceutical composition comprising dapagliflozin premix in combination therapy with one or more other active ingredients in a single pharmaceutical composition or separate pharmaceutical composition. til In another aspect, the present invention further provides pharmaceutical composition comprising premix of dapagliflozin with lactose in combination therapy with one or more other active ingredients in a single pharmaceutical composition or separate pharmaceutical composition.

In yet another aspect, the one or more active ingredients which optionally ¾ employed in combination therapy may include, but are not limited to other type of antidiabetic agents and/or other types of therapeutic agents.

The other type of antidiabetic agent which optionally employed in combination may include, but are not limited to one or more antidiabetic agents or anti hyperglycemic

3a agents including insulin secretagogues or insulin sensitizers, or other antidiabetic agents preferably having a mechanism of action different from SG LT2 inhibition and may include biguanides, sulfonyl ureas, glucosidase inhi bitors, PPA R .-. agonists such as thiazolidinediones, aP2 inhibitors, PPA R /.-. dual agonists, di peptidyl peptidase IV (DPP4) inhibitors, and/or megl itinides, as well as insulin, glucagon-like peptide-1 (GL P-

¾ 1 ), PT PI B inhibitors, glycogen phosphorylase inhibitors and/or glucos- 6- phosphatase inhi bitors.

The other types of therapeutic agents which are optionally employed in combination may include, but are not li mited to anti-obesity agents, antihypertensive iti agents, anti pi atel et agents, anti atheroscl eroti c agents and/or I i pi d I oweri ng agents.

The term : pharmaceutically acceptable excipient(s) ~ used in the pharmaceutical compositions of invention comprise but are not limited to diluents, bi nders, disintegrants, glidants, lubricants, stabilizers, surfactants, solubility enhancers, coloring agents, ¾ f I avouri ng agents, sweeteni ng agents.

The amount of exci pient(s) employed will depend upon how much active agent is to be used. One excipient(s) can perform more than one function. tin Suitable diluents as used in the present i nvention comprises but are not limited to lactose, microcrystalline cellulose, starch, calcium phosphate, dextrin, dextrose, dextrates, mannitol, sorbitol, sucrose, and the like. Preferably, the diluents are lactose, starch and mi crocrystal I i ne eel I ul ose.

Suitable binders as used in the present invention comprises but are not l imited to, ¾ starches such as potato starch, wheat starch, corn starch; microcrystalline cellulose such as products known under the registered trademarks Avicel, Filtrak, Heweten or Pharmacel; celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxy propyl methyl cellulose ( HPMC), ethyl cellulose, sodium carboxy methyl cellulose; natural gums like acacia, alginic acid, guar gum; liquid glucose, dextrin, 3a povidone, syrup, polyethylene oxide, polyvinyl pyrrolidone, poly-N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth, combi nations thereof and other materials known to one of ordinary skill in the art and mixtures thereof.

Suitable disintegrants as used in the present invention comprises but are not ¾ limited to, alginic acid, calcium phosphate, tribasic, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, docusate sodium, guar gum, low substituted hydroxypropyl cellulose, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, povidone, sodium alginate, sodium starch glycolate, polacrilin potassium, silicified microcrystall ine iti cellulose, starch or pre-gelatinized starch or mixtures thereof.

Suitable lubricants as used in the invention comprises but not limited to magnesi um stearate, calcium stearate, glycerine monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil type I, magnesium ¾ lauryl sulphate, medium-chain triglycerides, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sul phate, sodium stearyl fumarate, stearic acid, talc, sucrose stearate and zinc stearate.

Suitable Glidants as used in the invention comprises but are not limited to, sil icon til dioxide; magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel and other materials known to one of ordinary skil l in the art.

Suitable stabilizers as used in the invention comprises but are not limited to, ¾ sodium bicarbonate, ammonium carbonate, anhydrous sodi um carbonate, sodium carbonate monohydrate, sodium tartrate, sodium potassi um tartrate, sodium citrate, sodium hydroxide, calcium acetate, sodi um acetate, dibasic sodium phosphate, anhydrous dibasic sodium phosphate, diammonium hydrogen phosphate, calcium leavinulate, sodium pyrophosphate, and mixtures thereof.

3-1

Suitable surfactants as used in the invention comprises but are not limited to, 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, polyvinyl ¾ alcohol, fatty alcohols, polyoxyethylene alkyl ether, polyoxyethylene alkylaryl ether, polyethylene glycol fatty acid ester, alkylene glycol fatty acid mono ester, sucrose fatty acid ester, sorbitan fatty acid mono ester, sorbitol mono laurate, polyoxyethylene sorbitan fatty acid ester (polysorbates), and mixtures thereof. iti Suitable solubility enhancers as used in the invention comprises but are not limited to, di methyl isosorbide, polyethylene glycol, propylene glycol, glycerol, sorbitol sodium lauryl sulfate, glycerol monostearate, glycerol behenate, triglycerides, mono- alcohols, higher alcohols, di methyl sulfoxide, dimethylformamide, N, [Nidi methyl acetamide, N-methyl-2-pyrrolidone, N-(2- hydroxyethyl) pyrrolidone, 2- ¾ pyrrol i done, and mi xtures thereof.

Suitable sweetening agents as used in the invention comprises but are not limited to, gluconate, aspartame, cyclamate, sodium saccharine, xylitol and maltitol, or mixtures thereof. Suitable flavoring agents, coloring agents are selected from any FDA approved flavors, colorants for oral use.

The pharmaceutical compositions disclosed herein can further comprise ¾ antioxidants and chelating agents. For example, the pharmaceutical compositions can comprise butylated hydroxyanisole (BHA), butylated hydroxytol uene (BHT), propyl gallate ( PG), sodium metabi sulfite, ascorbyl palmitate, potassium metabi sulfite, disodium E DTA ( ethyl enedi amine tetraacetic acid; also known as disodium edetate), E DTA, tartaric acid, citric acid, citric acid monohydrate, and sodium sulfite.

3-1

Suitable Coating agents as used in the i nvention comprises but are not limited to, cellulose derivatives, e.g., methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxy propyl cellulose, hydroxymethyl ethyl cellulose, hydroxypropy I methyl cellulose, sodium carboxymethyl cell ulose, and ethyl cellulose; vinyl polymers, e.g., ¾ polyvinylpyrrolidones; acrylic polymers; and mixtures thereof. A lternatively, commercial ly available coating compositions comprisi ng fi lm-forming polymers marketed under various trade names, e.g. Opadry÷ , may be used for coating.

The coating additives comprise one or more of plasticizers, glidants or flow iti regulators, lubricants, coloring agents, and opacifiers. Suitable plasticizers are selected from the group comprising castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycols, propylene glycols, triacetin, triethyl citrate, and mixtures thereof. An opacifier such as titanium dioxide may also be present in the coating.

Suitable solvents as used i n the invention for preparing the coati ng sol ution comprises but are not limited to water, methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile, chloroforrn methylene chloride, and mixtures thereof. Al l these excipient(s) can be used at levels well known to the persons skilled in til the art. The following examples are provided to describe the invention i n further detail. These examples, which set forth the best mode presently contemplated for carrying out the i nventi on, are i ntended to i 11 ustrate and not to I i mi t the i nventi on.

¾ E X AM PL E S:

E xample 1 :

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Procedure:

1. Sift Dapagliflozin premix and Lactose.

2. Co-sift microcrystalli ne cellulose, Pregelati nized Starch, Crospovidone and Colloidal sil icon Dioxide.

¾ 3. Load material of Step 1 & 2 into Blender and blend.

4. L ubri cate the bl end of step 3 and compress i nto tabl ets.

5. C oat the tablets of Step 4 with Opadry.

tin E xample 2:

Procedure:

¾ 1. Sift Dapagliflozin premix and Lactose Monohydrate.

2. C o- sift Microcrystal line Cell ulose, C rospovi done and Povidone.

3. Load Step 1 & 2 into blender and mix.

4. Granulate step 3 by using binder solution and dry the granules.

5. L ubri cate the granul es of step 4 and compress i nto tabl ets.a 6. C oat the tablets of Step 5 with Opadry.

R E xample 3:

¾ Procedure:

1. Sift Dapagliflozin Premix and Lactose.

2. Co-sift Microcrystalline Cellulose, Crospovidone, Colloidal Silicon Dioxide and Pregelatinized starch.

3. Load Step 1 & 2 into blender and blend.

3a 4. L ubricate blend of step 3 and compact the powder blend.

5. M i 11 the step 4 c ompacts.

6. Sift Microcrystalline Cellulose, Crospovidone, and Colloidal Silicon Dioxide

7. L oad step 5 & 6 i n bl ender and bl end.

8. L ubri cate the bl end of step 7 and compress i nto tabl ets.

¾ 9. C oat the tablets of Step 8 with Opadry. E xample 4:

Procedure:

¾ 1. Sift Dapagliflozin premix and Lactose anhydrous, Mi croc rystal line Cellulose, and C rospovidone.

2. Load Step 1 i nto rapid mixer granulator and dry mix.

3. Dissolve Povidone into Isopropyl alcohol under sti rring.

4. G ranul ate step 2 by usi ng step 3 bi nder sol uti on.

a 5. D ry the granul es by usi ng rapi d dryer.

6. Sift the dried granules and col loidal silicon dioxide.

7. L oad step 5 granul es and step 6 i n bl ender and bl end.

8. Sift Sodi um Stearyl fumarate, lubricate the blend of step 7 and compress into tablets.

9. Coat the tablet with Opadry. Stability Study- The formulation prepared according to the example 4 is subjected to stability studies at accelerated conditions of temperature and humidity of 40· C and 75% R H. Results of these stability studies are summarized in the table 1.

Not Detected, BQL below Quantitation Limit