DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
(See Section 10)

PHARMACEUTICAL COMPOSITION OF EMPAGLIFLOZIN AND PROCESS THEREOF
Morepen Laboratories Limited,
Morepen Village, Malkumajra, Baddi
Distt. –Solan,
Himachal Pradesh (HP), INDIA

The following application particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to a stable pharmaceutical composition of empagliflozin or its pharmaceutically acceptable salts, solvates thereof along with one or more pharmaceutically acceptable excipients. More specifically, the present invention relates to a process of preparing a stable pharmaceutical composition of empagliflozin.

BACKGROUD OF INVENTION
Empagliflozin also known as D-Glucitol is a potent and selective competitive inhibitor of sodium-glucose co-transporter 2 (SGLT2). The chemical name of empagliflozin is (1S)-1,5-anhydro-1-(4-chloro-3-{4-[(3S)-tetrahydrofuran-3-yloxy]benzyl}phenyl)-D-glucitol, and has the following structure as shown below

Empagliflozin is an orally administered antidiabetic, utilized for the treatment of patients with type 2 diabetes mellitus. The mechanism of its action consists in inhibition of the sodium glucose co- transporter (SGLT2), which results in glycosuria and decrease of glycaemia. Empagliflozin improves glycaemic control in patients with type 2 diabetes by reducing renal glucose reabsorption. The amount of glucose removed by the kidney through this glucuretic mechanism is dependent on blood glucose concentration and glomerular filtration rate (GFR). Inhibition of SGLT2 in patients with type 2 diabetes and hyperglycaemia leads to excess glucose excretion in the urine. In addition, initiation of empagliflozin increases excretion of sodium resulting in osmotic diuresis and reduced intravascular volume.

Empagliflozin is a non-hygroscopic crystalline solid, very slightly soluble in water, sparingly soluble in methanol, slightly soluble in ethanol and acetonitrile, soluble in 50% acetonitrile/water, and practically insoluble in toluene.

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.

Empagliflozin which belongs to glucopyranosyl-substituted benzyl-benzene derivative is first time described in US patent 7,579,449. The said patent also describes the processes for preparing a pharmaceutical composition thereof.

The stable crystalline form of empagliflozin is first described in US patent 7,713,938. The patent generically discloses pharmaceutical compositions or medicament comprising said stable crystalline form but not exemplified anywhere in the patent. Some other crystalline forms of empagliflozin are disclosed in other publications such as US 7,723,309 and US 8,802,842.

Further, PCT publication WO 2010/092126 discloses pharmaceutical compositions comprising a SGLT-2 inhibitor (empagliflozin), pharmaceutical dosage forms, their preparation, use, and methods for treating metabolic disorders. The composition as disclosed within said publication comprises of empagliflozin with a particle size distribution of 1 µm < X90 < 200 µm, binder, disintegrant and other additives, wherein the ratio of disintegrant to binder is 1.5:3.5 and 1:1 and the active ingredient (empagliflozin) is present in amount of 25% or less of the weight of pharmaceutical composition. As per the disclosure, the particle size is a critical factor for the dissolution rate of empagliflozin as it shows advantageous dissolution profile and/or good bioavailability.

It is disclosed that the particle size of empagliflozin, in particular the particle size and the particle size distribution, influence the manufacturability, in particular that too small particles, especially too many small particles, negatively influence the manufacturability by sticking or filming during tableting. On the other hand, too large particles negatively affect the dissolution properties of the pharmaceutical composition and dosage form and thus the bioavailability.

An Indian patent publication IN 4964/CHE/2014 describes the stabilization of amorphous empagliflozin with cyclodextrin wherein empagliflozin and cyclodextrin are dissolved in methanol and isolating the solid dispersion of empagliflozin and cyclodextrin after solvent evaporation.

Another Indian patent publication IN 201741011748 discloses a process of preparing solid dispersion comprising amorphous form of empagliflozin and one or more pharmaceutically acceptable excipients by hot-melt extrusion method. However, hot-melt extrusion process is carried out a high temperature thus causing degradation of some of the empagliflozin used and decreasing the yield of the preparation.

Another Indian patent publication IN 201711026696 discloses a composition comprising amorphous empagliflozin, binder, diluent, disintegrant and lubricant, wherein the empagliflozin particle size is between 5 µm to 50µm and the ratio of disintegrant and binder in the pharmaceutical composition is either less than 0.4:1 or greater than 1.1:1. The composition is prepared by reverse wet granulation process. The said pharmaceutical composition is prepared by dissolving amorphous empagliflozin and povidone in a mixture of methylene chloride and ethanol, spraying the prepared solution on a pharmaceutically acceptable carrier (diluent) to obtain granules, blending the granules with other excipients, finally lubricating the mixture and compressing into tablets.

One another Indian patent application IN 201821022675 discloses a composition comprising empagliflozin with at least one disintegrant and one or more pharmaceutical acceptable excipients.

In most of the documents mentioned above, the pharmaceutical composition either comprises of crystalline or amorphous forms of empagliflozin. Wherever the crystalline form is used, particle size distribution, the ratio of pharmaceutically acceptable excipients, amount of active ingredient (empagliflozin) present in pharmaceutical composition should be carefully controlled to maintain the desired dissolution profile and solubility. However, the amorphous empagliflozin alone is highly unstable and recrystallizes virtually immediately, wherein in some above said patent applications amorphous form is stabilized by preparing solid dispersions or solid solutions by processes such as evaporating the solvent by rotary evaporator or by lyophilization. These procedures are cumbersome, time consuming and are disadvantageous from economical point of view to be used on industrial scale. There is no disclosure in the above prior arts about stable pharmaceutical composition for oral administration of empagliflozin with enhanced dissolution.

In order to overcome the aforementioned drawbacks, there is an urgent need to develop a stable pharmaceutical composition for oral administration of empagliflozin by using minimum amounts of excipients. Therefore, a stable pharmaceutical composition for oral administration is desired which should result in enhanced technical formulation attributes such as dissolution profile, stability, bioequivalence which is simple, reproducible and commercially viable at industrial scale.
OBJECT OF THE INVENTION
The principal object of the present invention is to provide a stable pharmaceutical composition of empagliflozin with desired dissolution profile by using minimum quantity of one or more pharmaceutically acceptable excipients.
Another object of the present invention is to provide a process for the preparation of a stable pharmaceutical composition in form of a tablet or granule for oral administration comprising empagliflozin with one or more pharmaceutically acceptable excipient.
Yet another object of the present invention is to provide an efficient industrially feasible and economical viable process for the preparation of pharmaceutical composition of empagliflozin.

SUMMARY OF INVENTION
Accordingly, the present invention relates to a stable pharmaceutical composition of empagliflozin or its pharmaceutically acceptable salts, solvates thereof along with one or more pharmaceutically acceptable excipients and a process for preparation of the composition thereof.
According to an embodiment, the present invention provides an efficient process for the preparation of stable pharmaceutical composition of empagliflozin, which comprises steps of:
i. providing an intragranular portion,
ii. dissolving empagliflozin in a suitable solvent with one or more pharmaceutical excipients to obtain a solution,
iii. spraying the solution of step (ii) on intragranular portion of step (i) to obtain a granulated blend,
iv. drying the granulated blend of step (iii),
v. blending the dried granulated blend obtained in step (iv) with one or more pharmaceutical excipients to obtain a mixture,
vi. lubricating the mixture with suitable excipients to obtain a final blend,
vii. compressing the final blend of step (vi) into dosage form,
viii. optionally, coating the dosage form with a film coat.
In one embodiment, the pharmaceutical composition according to the present invention, the percentage range of empagliflozin is 15% to 45 % and percentage range of diluent is 43% to 73% w/w.
In another embodiment, the pharmaceutical composition according to the present invention, the ratio of empagliflozin and diluent in the pharmaceutical composition is in the range of 1:0.95 and 1:4.86 (w/w).
In one another embodiment of the present invention provides a stable pharmaceutical composition comprising empagliflozin in an amount of 15% to 45% w/w, diluent ranging from 43% to 73% w/w, binder ranging from 0% to 7% w/w, disintegrant ranging from 0% to 5% w/w, lubricant ranging from 0% to 3% w/w and film coat ranging from 0% to 4% w/w, relative to the total weight of the pharmaceutical dosage form.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an efficient process for the preparation of pharmaceutical composition of empagliflozin comprising empagliflozin along with one or more pharmaceutically acceptable excipients wherein the excipients are selected from diluents, disintegrants, binders, suitable solvent, lubricants or combination thereof. The process eradicates the problems of the prior art and is convenient to operate for commercial production of empagliflozin compositions.

The term “excipient” means a pharmacologically inactive component such as a diluent, disintegrant, binder, surfactant, lubricant, carrier, or the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for veterinary as well as human pharmaceutical use. Reference to an excipient includes both one and more than one such excipient. Co-processed excipients are also covered under the scope of present invention.
The term “empagliflozin” used herein may include but not limited to empagliflozin or its pharmaceutically acceptable salts, solvates thereof. The pharmaceutically acceptable salts can be selected from inorganic or organic acids. Acids may be selected from the group which may include but not limited to hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
As used herein, the term ‘ambient temperature’ represents a temperature 25?± 5?.
The term "stable" as used herein refers to chemical stability of empagliflozin in solid dosage forms wherein there is no significant change in assay values and dissolution, when the dosage form is kept at 40°C/75% RH for 6 months.
The term “intragranular portion” herein refers to one or more pharmaceutically acceptable excipients. Preferably, the intragranular portion to be used in accordance with the present invention is a diluent / disintegrant or combination thereof. According to the present invention the diluent used herein can be used in a granulated or non- granulated form.
Excipients that are mixed with other ingredients (including diluent/disintegrant) prior to granulation, and are thus incorporated within the granules, comprise the intragranular part of the composition. Excipients that are mixed with the dry granules before the complete mixture is compacted comprise the extragranular part of the composition.
The term “granulated blend” herein refers to homogeneous mixture of empagliflozin, intragranular portion and at least one pharmaceutically acceptable excipient in particle form. The particles may be in a powdered form or, alternatively, larger aggregated or agglomerated particles.
The term “final blend” herein refers to homogeneous mixture of empagliflozin, intragranular portion and at least one pharmaceutically acceptable excipient in particle form.
One embodiment of the present invention provides a stable pharmaceutical composition comprising empagliflozin in an amount of 15% to 45% w/w, diluent ranging from 43% to 73% w/w, binder ranging from 0% to 7% w/w, disintegrant ranging from 0% to 5% w/w, lubricant ranging from 0% to 3% w/w and film coat ranging from 0% to 4% w/w, relative to the total weight of the pharmaceutical dosage form.
Another embodiment of the present invention provides empagliflozin or a pharmaceutically acceptable salt, solvates thereof in an amount of 15% to 45% w/w of the total weight of the pharmaceutical dosage form, more preferably from 15% to 30% w/w of the total weight of the pharmaceutical dosage form.
Another embodiment of the present invention provides empagliflozin, wherein the ratio of empagliflozin and diluent in the pharmaceutical composition is between 1:0.95 and 1:4.86 (w/w).
Another embodiment of the present invention provides the pharmaceutical composition comprising about 1.0 mg to 50 mg of empagliflozin. Preferably, 1 mg to 30 mg of empagliflozin. More preferably 10 mg or 25 mg of empagliflozin.
The empagliflozin used in the present composition may be selected from crystalline or amorphous forms. Most preferably crystalline form is used.
The present invention provides an efficient process for the preparation of pharmaceutical composition of empagliflozin, which comprises steps of:
i. providing an intragranular portion,
ii. dissolving empagliflozin in a suitable solvent with one or more pharmaceutical excipients to obtain a solution,
iii. spraying the solution of step (ii) on intragranular portion of step (i) to obtain a granulated blend,
iv. drying the granulated blend of step (iii),
v. blending the dried granulated blend obtained in step (iv) with one or more pharmaceutical excipients to obtain a mixture,
vi. lubricating the mixture with suitable excipients to obtain a final blend,
vii. compressing the final blend of step (vi) into dosage form, and
viii. optionally, coating the dosage form with a film coat.
Intragranular portion to be used in accordance with the present invention in step (i) is a diluent. Preferably, the diluent can be used in its granulated form. The “diluent" used herein can be selected from a group but not limited to lactose, lactose monohydrate, sucrose, dextrose, mannitol, sorbitol, xylitol, lactitol, starch, modified starches, dibasic calcium phosphate, tribasic calcium phosphate, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose and combination thereof. Mannitol is a particularly preferred diluent. Typically, the diluent can be used within the range of 43% to 73% w/w, relative to the total weight of the pharmaceutical dosage form.
Preferably, the empagliflozin that is being used in step (ii) has an average particle size in the range of 1 to 1000 µm, preferably from 5 to 500 µm, more preferably from 5 to 150 µm. Empagliflozin that is involved in step (ii) can be milled or non-milled. There is no requirement for using a particular particle size of empagliflozin in contrast to prior art processes which requires specific control of particle size.
In the pharmaceutical composition of the present invention pharmaceutical excipients used in step (ii) can be selected from binder, surfactant, or a combination thereof.
Furthermore, in the pharmaceutical composition of the present invention suitable “binder” can be selected from polyvinyl pyrrolidone (povidone), polyvinyl alcohol, copolymers of vinylpyrrolidone with other vinyl derivatives (copovidone), hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose, powdered acacia, gelatin, guar gum, carbomer such as carbopol, polymethacrylates and pregelatinized starch. Most preferable, binder used in the composition can be hydroxypropyl methylcellulose. Typically, the weight of the binder can be within the range of 0% to 7% w/w, relative to the total weight of the pharmaceutical dosage form.
In one aspect, a pharmaceutical composition according to the present invention, the suitable “surfactant” can be selected from the group which may include but not limited to Tyloxapol®, Triton X-100®, polysorbates, polyoxyl 35 castoroil, polyoxyl 40 hydrogenated 7 castor oil, polyoxyl 40 stearates, sorbitan monolaureates, sodium lauryl sulphate, polyethylene propylene glycol copolymer (poloxamer), cremophor-40, propylene glycol and combination thereof.
Furthermore, in the pharmaceutical composition of the present invention “solvent” used in step (ii) may include but not limited to water, esters such as ethyl acetate, methyl acetate; ketones such as acetone, methyl ethyl ketone (MEK); alcohols such as methanol, ethanol, isopropanol, butanol; halogenated hydrocarbons such as methylene dichloride (MDC), dichloroethane, chloroform, and combinations thereof. Preferably, the solvent used during wet granulation is the mixture of alcohol and halogenated hydrocarbon. Most preferable, the solvent used during wet granulation is the mixture of isopropyl alcohol and methylene dichloride.
In step (ii), the dissolution of empagliflozin can be performed at an ambient temperature.
In step (iii), the solution of empagliflozin is sprayed on an intragranular portion at a temperature range of 20°C - 45°C to obtain the granulated blend. Most preferable range of temperature for spraying the solution on intragranular portion can be 25°C - 35°C. Thereafter, the granulated blend obtained in step (iii) can be dried at temperature range of 20°C to 45°C. Most preferable the granulated blend can be dried at 25°C - 35°C.
In another embodiment, the pharmaceutical composition of empagliflozin according to the present invention can be prepared by using fluidized bed processer (FBP) which is utilized for spraying the solution of empagliflozin on intragranular portion and drying the obtained granulated blend. The spraying of solution can be carried out either from top, bottom or sideway. The term “fluidized bed processer (FBP)” is recognized as the conventional technology which can be used for spray granulation, drying of granulated blend and particle coating within the same equipment. Optionally, the granulated blend can be sieved to obtain uniform granules.
In another embodiment, the pharmaceutical excipients in step (v) of the present invention can be selected from disintegrant thereof.
In one aspect the suitable “disintegrant” can be selected from croscarmellose sodium, low-substituted hydroxypropyl cellulose, polacrilin potassium, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose, cross-linked calcium carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxy methylcellulose, microcrystalline cellulose, colloidal silicon dioxide, sodium starch glycolate, ion-exchange resins, starch and modified starches including pregelatinized starch, formalin-casein, alginates, gums and combination thereof. Most preferable, disintegrant used in the composition may be croscarmellose sodium. Typically, the weight of the disintegrant can be within the range of 0% to 5% w/w, relative to the total weight of the pharmaceutical dosage form.
In another embodiment, the pharmaceutical composition according to the present invention, the disintegrant used in step (i) and (v) can be added either in intragranular/extragranular part or both.
In another embodiment, pharmaceutical excipients in step (vi) can be selected from lubricant thereof.
In another aspect the suitable “lubricant” can be selected from calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, fumaric acid, sodium stearyl fumarate, stearic acid, talc, vegetable oil, zinc stearate, castor wax and combination thereof. Most preferable, lubricant used in the composition may be magnesium stearate. Typically, the weight of the lubricant can be within the range of 0% to 3% w/w, relative to the total weight of the pharmaceutical dosage form.
A dosage form in step (vii), according to the present invention can be selected from tablets, capsules, powders, pellets and granules. A preferable pharmaceutical dosage form can be tablets, film coated tablets or capsules.
In another embodiment of the present invention the film coat in step (viii), can be selected from a film-forming agent, porosity agent, a plasticizer, an anti-tacking agent and optionally one or more pigments. The film coat may provide taste masking and additional stability to the final tablet. The weight content of the coating material is not particularly limited. Typically, the weight of the coating material can be within the range of 0% to 4.0% w/w, relative to the total weight of the pharmaceutical dosage form. Preferably about 2.0% to about 3.0 % by weight relative to the total weight of the composition
In one aspect the suitable “film-forming agent” can be selected from hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone vinyl acetate copolymer, ethyl cellulose, polyvinyl alcohol and combination thereof. Most preferable, film-forming agent used in the present composition is hydroxypropyl methylcellulose (HPMC).
In one aspect the suitable “porosity agent” can be selected from lactose monohydrate thereof.
In another aspect the suitable “plasticizer” can be selected from low molecular weight polyethylene glycol (PEG), propylene glycol, triethyl citrate, dibutyl sebacate, diethyl phthalate, dextrin, lecithin and triacetin thereof. Most preferable, plasticizer used in the composition can be triacetin.
In another aspect the suitable “anti-tacking agent” can be selected from talc, metal salts of fatty acids, colloidal silicone dioxide or combination thereof. Optionally, the anti-tacking agents can be utilized in the present invention.
The “pigments” used in the above film coat can be selected from iron oxide, preferably including iron oxide red and/or yellow.
In another aspect the film coat as used in pharmaceutical composition of the present invention, is commercially available ready to use coating materials such as Opadry® provided by Colorcon.
The total weight of the pharmaceutical composition may be in the range of 30 mg to 167 mg. Most preferable range is in between 55 mg to 160 mg.
In accordance with another embodiment of the present invention, there is provided a pharmaceutical composition which is stable at 40°C and 75% relative humidity. The level of impurities is controlled within the composition as per ICH/ regulatory guidelines. The following impurities are controlled:
Impurity Refer as
Hydroxy empagliflozin Imp-1
Methoxy empagliflozin Imp-2
Tetra acetyl empagliflozin Imp-3
(3S)-3-(4-(2-Chloro-5-iodobenzyl)phenoxy)tetrahydrofuran Imp-4

In another embodiment, pharmaceutical composition of the present invention exhibits more than 90% of drug release within 30 minutes in 500 ml of 0.1 N HCl (Office of Generic Drugs dissolution database) using a USP I apparatus (basket) at a temperature of 37±0.5° C. and a rotation speed of 100 revolutions per minute.
The pharmaceutical composition of the present invention boosts dissolution properties at physiologic pH. The dissolution studies of compositions comprising empagliflozin or its pharmaceutical salt thereof, having dissolution more than 80 or 90% within 30 minutes wherein empagliflozin is present in an amount of 15-45% of the total weight of the pharmaceutical composition.
The pharmaceutical compositions of empagliflozin suitable for oral administration to humans must have desirable chemical and physical properties, disintegration, dissolution, stability and bioequivalence complying with demanding requirements and regulations of health and medicine regulatory agencies across the world, especially USFDA, EMEA, MHRA, PMDA, Health Canada, ANVISA and TGA.
In an alternate embodiment, the present invention provides a process for preparing pharmaceutical composition of empagliflozin wherein content of residual solvent is controlled as per ICH guidelines.
The invention is further defined by reference to the following examples describing in detail method for the preparation and testing of empagliflozin pharmaceutical composition. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention. Following examples are set out to illustrate the invention and do not limit the scope of the present invention.
Example 1: Tablet containing 25 mg of empagliflozin
S. N. Ingredients Qty/Tablet (mg)
Intragranular
1 Mannitol 44.922
Binder
2 Empagliflozin 25.00
3 HPMC 5.400
4 Methanol qs
5 Methylene dichloride qs
Extragranular
6 Mannitol 9.203
7 Croscarmellose sodium 2.100
Lubrication
8 Magnesium stearate 0.875
Avg wt. of Core Tablet 87.500
Film Coating
9 Opadry yellow 2.500
Avg wt. of Film Coated Tablet 90.000

Procedure:
1. Empagliflozin was dissolved in the mixture of methanol and methylene dichloride along with HPMC.
2. Mannitol was taken in a FBP container and then the solution prepared in step 1 was top sprayed over mannitol.
3. Dried granules were obtained after completion of granulation followed by drying.
4. Mannitol and croscarmellose sodium were added to dried granules obtained in step 3 and then the mixture was blended uniformly in the blender.
5. Magnesium stearate was added to the blender to lubricate the above blend.
6. The final blend of step 5 was compressed into tablet of an average weight of 87.5 mg.
7. The compressed tablet obtained in step 6 was coated by using opadry yellow to get tablet of an average weight of 90 mg.
Example 2: Tablet containing 25 mg of empagliflozin
S. N. Ingredients Qty/Tablet (mg)
Intragranular
1 Mannitol 44.922
2 Croscarmellose sodium 1.050
Binder
3 Empagliflozin 25.00
4 HPMC 5.400
5 Isopropyl alcohol qs
6 Methylene dichloride qs
Extragranular
7 Mannitol 9.203
8 Croscarmellose sodium 1.050
Lubrication
9 Magnesium stearate 0.875
Avg wt. of Core Tablet 87.500
Film Coating
10 Opadry yellow 2.500
Avg wt. of Film Coated Tablet 90.000

Procedure:
1. Empagliflozin was dissolved in the mixture of isopropyl alcohol and methylene dichloride along with HPMC.
2. Mannitol and croscarmellose sodium were taken in a FBP container and then the above solution was top sprayed over mannitol and croscarmellose sodium.
3. Dried granules were obtained after completion of granulation.
4. Mannitol and croscarmellose sodium were added to dried granules obtained in step 3 and then the mixture was blended uniformly in the blender.
5. Magnesium stearate was added to the blender to lubricate the above blend.
6. The final blend was compressed into tablet of an average weight of 87.5 mg.
7. The compressed tablet was coated by using opadry yellow to get tablet of an average weight of 90 mg.
Example 3: Tablet containing 25 mg of empagliflozin
S. N. Ingredients Qty/Tablet (mg)
Intragranular
1 Mannitol 23.040
2 Croscarmellose sodium 0.540
Binder
3 Empagliflozin 25.00
4 HPMC 2.780
5 Isopropyl alcohol qs
6 Methylene dichloride qs
Extragranular
7 Mannitol 0.650
8 Croscarmellose sodium 0.540
Lubrication
9 Magnesium stearate 0.450
Avg wt. of Core Tablet 53.000
Film Coating
10 Opadry yellow 2.000
Avg wt. of Film Coated Tablet 55.000

Procedure:
1. Empagliflozin was dissolved in the mixture of isopropyl alcohol and methylene dichloride along with HPMC.
2. Mannitol and croscarmellose sodium were taken in a FBP container and then the solution prepared in step 1 was top sprayed over mannitol and croscarmellose sodium.
3. Dried granules were obtained after completion of granulation followed by drying.
4. Mannitol and croscarmellose sodium were added to dried granules obtained in step 3 and then the mixture was blended uniformly in the blender.
5. Magnesium stearate was added to the blender to lubricate the above blend.
6. The final blend of step 5 was compressed into tablet of an average weight of 53 mg.
7. The compressed tablet obtained in step 6 was coated by using opadry yellow to get tablet of an average weight of 55 mg.

Example 4: Tablet containing 25 mg of empagliflozin
S. N. Ingredients Qty/Tablet (mg)
Intragranular
1 Mannitol 77.691
2 Croscarmellose sodium 1.820
Binder
3 Empagliflozin 25.00
4 HPMC 9.360
5 Isopropyl alcohol qs
6 Methylene dichloride qs
Extragranular
7 Mannitol 34.292
8 Croscarmellose sodium 1.820
Lubrication

9 Magnesium stearate 1.517
Avg wt. of Core Tablet 151.5
Film Coating
10 Opadry yellow 4.5
Avg wt. of Film Coated Tablet 156.000

Procedure:
1. Empagliflozin was dissolved in the mixture of isopropyl alcohol and methylene dichloride along with HPMC.
2. Mannitol and croscarmellose sodium were taken in a FBP container and then the solution prepared in step 1 was top sprayed over mannitol and croscarmellose sodium.
3. Dried granules were obtained after completion of granulation followed by drying.
4. Mannitol and croscarmellose sodium were added to dried granules obtained in step 3 and then the mixture was blended uniformly in the blender.
5. Magnesium stearate was added to the blender to lubricate the above blend.
6. The final blend of step 5 was compressed into tablet of an average weight of 151.5 mg.
7. The compressed tablet obtained in step 6 was coated by using opadry yellow to get tablet of an average weight of 156 mg.
Example 5: Tablet containing 10 mg of empagliflozin
S. N. Ingredients Qty/Tablet (mg)
Intragranular
1 Mannitol 17.969
2 Croscarmellose sodium 0.420
Binder
3 Empagliflozin 10.00
4 HPMC 2.160
5 Isopropyl alcohol qs
6 Methylene dichloride qs
Extragranular
7 Mannitol 3.681
8 Croscarmellose sodium 0.420
Lubrication

9 Magnesium stearate 0.350
Avg wt. of Core Tablet 35.000
Film Coating
10 Opadry yellow 1.0
Avg wt. of Film Coated Tablet 36.000

Procedure:
1. Empagliflozin was dissolved in the mixture of isopropyl alcohol and methylene dichloride along with HPMC.
2. Mannitol and croscarmellose sodium were taken in a FBP container and then the solution prepared in step 1 was top sprayed over mannitol and croscarmellose sodium.
3. Dried granules were obtained after completion of granulation followed by drying.
4. Mannitol and croscarmellose sodium were added to dried granules obtained in step 3 and then the mixture was blended uniformly in the blender.
5. Magnesium stearate was added to the blender to lubricate the above blend.
6. The final blend of step 5 was compressed into tablet of an average weight of 35 mg.
7. The compressed tablet obtained in step 6 was coated by using opadry yellow to get tablet of an average weight of 36 mg.

Example 6: Stability Studies
The compositions of example 2 were stored at 40°C/75% RH and were tested for impurities at specific intervals. The results of example 2 are tabulated in Table 1.
Table 1: 25 mg Tablet (Example 2)

Time Assay
(95.0 to 105.0%) Imp-1
(NMT 0.2%) Imp-2
(NMT 0.2%) Imp-3
(NMT 0.2%) Imp-4
(NMT 0.2%) Individual unspecified imp (NMT 0.2%)
Total Impurity (NMT 2.0%)
Initial 100.4 ND ND ND ND 0.04 0.11
1 M 97.8 ND ND ND ND 0.05 0.21
3 M 99.6 ND ND ND ND 0.05 0.15
6 M 100.4 ND ND ND ND 0.05 0.19
ND: Not detected; NMT: Not more than
Example 7: Stability Studies
The compositions of example 5 were stored at 40° C/75% RH and were tested for impurities at specific intervals. The results of example 5 are tabulated in Table 2.
Table 2: 10 mg Tablet (Example 5)

Time Assay
(95.0 to 105.0%) Imp-1
(NMT 0.2%) Imp-2
(NMT 0.2%) Imp-3
(NMT 0.2%) Imp-4
(NMT 0.2%) Individual unspecified impurity (NMT 0.2%)
Total Impurity (NMT 2.0%)
Initial 97.0 ND ND ND ND 0.05 0.15
1 M 99.5 ND ND ND ND 0.05 0.16
3 M 100.1 ND ND ND ND 0.05 0.12
6 M 99.5 0.01 ND ND ND 0.05 0.14

ND: Not detected; NMT: Not more than
Example 8: Dissolution Studies
Dissolution studies of compositions of example 2 were conducted in 500 mL 0.1N HCl media with USP Apparatus II (Paddle) and release of empagliflozin at time point of 30 minutes on stability at 40° C/75% RH are as follows in Table 3.

TABLE 3: 25 mg Tablet (Example 2)

Time Point
(Minutes) % Drug Release Initial % Drug Release Initial 1M 0°C/75% RH % Drug Release Initial 2M 40° C/75% RH % Drug Release Initial 3M 40° C/75% RH % Drug Release Initial 6M 40° C /75% RH
30 95% 95% 94% 94% 100%

Example 9: Dissolution Studies
Dissolution studies of compositions of example 5 are conducted in 500 mL 0.1N HCl media with USP Apparatus II (Paddle) and release of empagliflozin at time points of 30 minutes on stability at 40° C/75% RH are as follows in Table 4.
TABLE 4: 10 mg Tablet (Example 5)

Time Point
(Minutes) % Drug Release Initial % Drug Release 1M 0°C/75% RH % Drug Release 2M 40° C/75% RH % Drug Release 3M 40° C/75% RH % Drug Release 6M 40° C/75% RH
30 96% 93% 94% 99% 97%

It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples are provided herein without departing from the spirit and scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of any claims and their equivalents.

,CLAIMS:WE CLAIM
1. A pharmaceutical composition comprising empagliflozin in an amount of 15% to 45 % and diluent ranging from 43% to 73% w/w.

2. The pharmaceutical composition as claimed in claim 1, comprising empagliflozin in an amount of 15% to 45% w/w, diluent ranging from 43% to 73% w/w, binder ranging from 0% to 7% w/w, disintegrant ranging from 0% to 5% w/w, lubricant ranging from 0% to 3% w/w and film coat ranging from 0% to 4% w/w, relative to the total weight of the pharmaceutical dosage form.

3. The pharmaceutical composition as claimed in claims 1&2, wherein diluent is selected from a group consisting to lactose, lactose monohydrate, sucrose, dextrose, mannitol, sorbitol, xylitol, lactitol, starch, modified starches, dibasic calcium phosphate, tribasic calcium phosphate, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose and combination thereof.

4. The pharmaceutical composition as claimed in claim 2, wherein binder is selected from polyvinyl pyrrolidone (povidone), polyvinyl alcohol, copolymers of vinylpyrrolidone with other vinyl derivatives (copovidone), hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose, powdered acacia, gelatin, guar gum, carbomer such as carbopol, polymethacrylates and pregelatinized starch.

5. The pharmaceutical composition as claimed in claim 2, wherein disintegrant is selected from croscarmellose sodium, low-substituted hydroxypropyl cellulose, polacrilin potassium, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose, cross-linked calcium carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxy methylcellulose, microcrystalline cellulose, colloidal silicon dioxide, sodium starch glycolate, ion-exchange resins, starch and modified starches including pregelatinized starch, formalin-casein, alginates, gums and combination thereof; lubricant is selected from a selected from calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, fumaric acid, sodium stearyl fumarate, stearic acid, talc, vegetable oil, zinc stearate, castor wax and combination thereof.

6. The pharmaceutical composition as claimed in claim 2, wherein film coat is selected from selected from a film-forming agent, porosity agent, a plasticizer, an anti-tacking agent and optionally one or more pigments.

7. The pharmaceutical composition as claimed in claim 1, wherein weight ratio of empagliflozin and diluent in the pharmaceutical composition is in the range of 1:0.95 and 1:4.86 (w/w).

8. A process for the preparation of pharmaceutical composition of empagliflozin, which comprises steps of:
i. providing an intragranular portion,
ii. dissolving empagliflozin in a suitable solvent with one or more pharmaceutical excipients to obtain a solution,
iii. spraying the solution of step (ii) on intragranular portion of step (i) to obtain a granulated blend,
iv. drying the granulated blend of step (iii),
v. blending the dried granulated blend obtained in step (iv) with one or more pharmaceutical excipients to obtain a mixture,
vi. lubricating the mixture with suitable excipients to obtain a final blend,
vii. compressing the final blend of step (vi) into dosage form,
viii. optionally, coating the dosage form with a film coat.

9. The process as claimed in claim 9, wherein a suitable solvent is selected from water, esters such as ethyl acetate, methyl acetate; ketones such as acetone, methyl ethyl ketone (MEK); alcohols such as methanol, ethanol, isopropanol, butanol; halogenated hydrocarbons such as methylene dichloride (MDC), dichloroethane, chloroform, and combinations thereof.

10. The pharmaceutical composition as claimed in proceeding claims, wherein empagliflozin is present in an amount of 15-45% of the total weight of the pharmaceutical composition having dissolution more than 90% within 30 minutes.

Dated this 05th day of November 2022
Signature:..................
[Dinesh Kumar]
Senior Manager (IPR)
Morepen Laboratories Limited