A pharmaceutical composition comprising empagliflozin and metformin

Abstract

The present invention relates to an immediate release monolithic tablet comprising a) granules comprising Metformin or its pharmaceutically acceptable salt, hydroxypropyl methylcellulose and at least one more pharmaceutically acceptable excipient, and b) powder mixture consisting essentially of Empagliflozin or its pharmaceutically acceptable salts, low substituted hydroxypropyl cellulose and at least one diluent, wherein said immediate release monolithic tablet doesn't comprise copovidone. The said tablet has a desirable pharmacokinetic characteristic, favorable storage stability and comparative dissolution properties. The invention further relates to a process for the preparation of said pharmaceutical composition and use thereof as medicament in the treatment of diabetes.

Description

[0001] A PHARMACEUTICAL COMPOSITION COMPRISING EMPAGLIFLOZIN AND METFORMIN

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to an immediate release monolithic tablet comprising a) granules comprising Metformin or its pharmaceutically acceptable salt, hydroxypropyl methylcellulose and at least one more pharmaceutically acceptable excipient, and b) powder mixture consisting essentially of Empagliflozin or its pharmaceutically acceptable salts, low substituted hydroxypropyl cellulose and at least one diluent, wherein said immediate release monolithic tablet doesn’t comprise copovidone. The said tablet has a desirable pharmacokinetic characteristic, favorable storage stability and comparative dissolution properties. The invention further relates to a process for the preparation of said pharmaceutical composition and use thereof as medicament in the treatment of diabetes.

[0004] BACKGROUND OF THE INVENTION

[0005] Empagliflozin is chemically known as (1 S)-1 ,5-anhydro-1-(4-chloro-3-{4-[(3S)- tetrahydrofuran-3-yloxy] benzyl} pheny l)-D-glucitol , having the following formula (I),

[0006] Empagliflozin is a selective inhibitor of sodium / glucose co-transporter-2 (SGLT2) and is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes (T2DM). The sodium glucose cotransporter 2 (SGLT-2) is a low-affinity, high-capacity, active sodium glucose symporter expressed at the apical membrane of epithelial cells lining the proximal renal tubule. SLGT-2 is responsible for reabsorbing the majority of the glucose filtered at the glomerulus. In other words, SGLT-2 accounts for about 90 percent of glucose reabsorption into the blood. Inhibition of SGLT-2 by Empagliflozin decreases glucose reabsorption and promotes urinary glucose excretion. Urinary glucose loss is the primary mechanism by which Empagliflozin lowers blood glucose. Empagliflozin is marketed under the brand name Jardiance® in Europe since 2014.

[0007] Empagliflozin is available on the market in the form of a free base and is sold under trade name Jardiance®, as an oral tablet in 10 mg and 25 mg strengths. Further it is available on the market as a combination product with Metformin and a combination product with Linagliptin.

[0008] Metformin is chemically known as 1 ,1-dimetylbiguanidine hydrochloride, having the following formula (II),

[0009] Metformin is a biguanide antihyperglycemic agent and first-line pharmacotherapy used in the management of type II diabetes. Metformin improves hyperglycaemia primarily through its suppresion of hepatic glucose production and decreases absorption of glucose from the gastrointestinal tract. Metformin, belonging to the biguanide class, is the first-line drug of choice for the treatment of type 2 diabetes, in particular in overweight and obese people and those with normal kidney function. It is used singly or in combination with sulfonylureas, alpha glucosidase inhibitors, or insulin. Oral doses of metformin are generally recommended in the range of 500 mg to 2500 mg a day and a single dose may vary from 500 mg to 850 mg. The biguanide antihyperglycemic agent metformin is disclosed in US Patent No. 3, 174, 901. Metformin was approved in Canada in 1972 and received subsequent FDA approval in the US in 1995.

[0010] Fixed dose combination of Empagliflozin and Metformin is sold under the trade name of Synjardy® as an oral film coated tablet in the strengths of 5 mg / 850 mg, 5 mg / 1000 mg, 12.5 mg / 850 mg & 12.5 mg / 1000 mg.

[0011] Synjardy® is indicated for the treatment of adults with type 2 diabetes mellitus as an adjunct to diet and exercise:

[0012] - in patients insufficiently controlled on their maximally tolerated dose of Metformin alone

[0013] - in combination with other medicinal products for the treatment of diabetes, in patients insufficiently controlled with Metformin and these medicinal products

[0014] - in patients already being treated with the combination of Empagliflozin and Metformin as separate tablets.

[0015] Synjardy® contains maize starch, copovidone (K-value nominally 28), colloidal anhydrous silica, magnesium stearate, hypromellose, macrogol 400, titanium dioxide (E171), talc, iron oxide yellow (E 172) & iron oxide red (E 172) as excipient.

[0016] Empagliflozin & its process for the preparation first time disclosed in WO 2005 / 092877. WO ‘877 also discloses the preparation of pharmaceutical composition comprising Empagliflozin and use thereof for the treatment of diabetes.

[0017] WO 2006 / 117359 A1 discloses stable a crystalline form of Empagliflozin and a pharmaceutical composition comprising the crystalline form. Additional crystalline forms of Empagliflozin are disclosed in WO 2006 / 117360 A1 and WO 2011 / 039107A1.

[0018] WO 2016169534 A1 discloses novel forms of amorphous Empagliflozin, processes for preparing the same and the use thereof in dosage forms. These solid forms of amorphous Empagliflozin can be advantageously used to increase the chemical and polymorphic stability of amorphous Empagliflozin.

[0019] According to Public Assessment Report of Synjardy® of European Medical Agency (EMA), it is challenging to combine the low amount of Empagliflozin with the relatively high quantity of Metformin hydrochloride and to obtain the product with desired content uniformity and the quality target product profile (QTPP).

[0020] EP 2482806 B1 discloses the preparation of a fixed dose combination of Empagliflozin and Metformin with desired QTPP. In EP ‘806, several water-soluble polymers including polyvinyl alcohol (PVA), hypromellose (HPMC), hydroxypropyl cellulose (HPC), methyl cellulose (MC), povidone (PVP) and copovidone were tested to improve compactability (compression force-crushing strength profile). Inventor of EP ‘806 also submitted additional experimental evidences during the examination of EP ‘806 at EPO, in which the effect of binders selected from copovidone, povidone, hypromellose, hydroxypropyl cellulose and polyvinyl alcohol on manufacturing and tableting process have studied. According to the said submitted evidences, the composition comprising the binder povidone and copovidone, in particular copovidone, showed the best powder behavior due to high bulk density and tapped density. On the other hand, the use of hypromellose, hydroxypropyl cellulose or polyvinyl alcohol resulted in granulates, which were not able for tableting due to low bulk density. It was also mentioned that the use of polyvinyl alcohol was critical with respect to manufacturability, as the risk of blocking during fluid bed granulation process has been strongly increased. Further, the viscosity of HPC & HPMC granulation liquid was rather high compared to copovidone and povidone, which deemed not preferable from the manufacturing process point of view. On the other hand, the viscosity of the copovidone and povidone granulation liquid was comparably low, and the fluid bed granulation process run without any blocking problem.

[0021] CN 106924237 B discloses a pharmaceutical composition containing Metformin hydrochloride, Empagliflozin, filler, adhesive, glidant & lubricant, wherein the filler is microcrystalline cellulose, and adhesive is copovidone va64, and glidant is silica, lubricant for magnesium stearate; wherein the copovidone va64 is added in the preparation with the concentration of 22-24.8% g / ml.

[0022] CN 114404436 A discloses a tablet comprising Metformin & Empagliflozin and a preparation method thereof. The said tablet is prepared from the raw materials in parts by mass: 500 parts of Metformin hydrochloride, 5 parts of Empagliflozin, 30.13 parts of com starch, 47.2 parts of povidone, 2.95 parts of colloidal silicon dioxide, 4.72 parts of magnesium stearate and 29.5 parts of film coating premix.

[0023] CN 114848604 A discloses a composition comprising Empagliflozin granules and Metformin hydrochloride granules; the Empagliflozin granules comprise Empagliflozin, polacrilin potassium, maltose-cyclodextrin, a disintegrating agent and a binding agent; the Metformin hydrochloride granules comprise Metformin hydrochloride, a diluent, a disintegrant and a binder; wherein the particle size d0.9 of the Empagliflozin is not more than 30 micron.

[0024] CN 115154456 A discloses a preparation method of a pharmaceutical composition of Metformin and Empagliflozin, which comprises the following steps: S1 ) mixing part of the adhesive with water to obtain an adhesive aqueous solution; mixing the adhesive aqueous solution with the Empagliflozin to obtain a suspension; mixing Metformin and / or Metformin salt, a filler and the rest of the binder to obtain a dry mixture; and S2) mixing the dry mixture and the suspension, granulating, and drying to obtain the pharmaceutical composition of the Metformin and the Empagliflozin..

[0025] However, there still exist a need for a pharmaceutical composition comprising immediate release of Empagliflozin or its pharmaceutically acceptable salt and Metformin or its pharmaceutically acceptable salt, which is physically and chemically stable, showing favorable dissolution profile, having easy to scale up, suitable on a commercial scale and allows an effective production with regard to time and costs of pharmaceutical dosage forms. The inventors of the present invention have surprisingly developed a stable pharmaceutical composition comprising Empagliflozin or its pharmaceutically acceptable salt and Metformin or its pharmaceutically acceptable salt without using copovidone and without facing any manufacturing and tableting problems of prior art. Also, inventors have found simple manufacturing process to save time and cost to produce monolithic tablet of Metformin and Empagliflozin. The composition of the present invention is not only stable but also exhibits a similar dissolution profile when compared to the reference product Synjardy® tablet.

[0026] OBJECT OF THE INVENTION

[0027] An object of the present invention is to provide an immediate release monolithic tablet comprising Empagliflozin or its pharmaceutically acceptable salt and Metformin or its pharmaceutically acceptable salt having similar in-vitro profile to the reference product i.e. , Synjardy® tablet.

[0028] Another object of the present invention is to provide an immediate release monolithic tablet comprising Empagliflozin or its pharmaceutically acceptable salt and Metformin or its pharmaceutically acceptable salt, which has desired content uniformity for both the active ingredients.

[0029] Another object of the present invention is to provide an immediate release monolithic tablet comprising Empagliflozin or its pharmaceutically acceptable salt and Metformin or its pharmaceutically acceptable salt, which allows an effective commercial scale manufacturing with regard to time and costs of pharmaceutical dosage forms.

[0030] Another object of the present invention is to provide an immediate release monolithic tablet comprising Empagliflozin or its pharmaceutically acceptable salt and Metformin or its pharmaceutically acceptable salt, which reduces sticking and capping during the production process of the composition. Yet another object of the present invention is to provide an immediate release monolithic tablet comprising Empagliflozin or its pharmaceutically acceptable salt and Metformin or its pharmaceutically acceptable salt with simple and robust process.

[0031] Yet another object of the present invention is to provide an immediate release monolithic tablet comprising Empagliflozin or its pharmaceutically acceptable salt and Metformin or its pharmaceutically acceptable salt, which remains stable during manufacturing and stability.

[0032] Yet another object of the present invention is to provide an immediate release monolithic tablet comprising Empagliflozin or its pharmaceutically acceptable salt and Metformin or its pharmaceutically acceptable salt, which overcomes the problems of the prior art.

[0033] Yet another object of the present invention is to provide a pharmaceutical composition as mentioned herein above in combination with one or more additional therapeutic agent.

[0034] Yet another object of the present invention is to provide a pharmaceutical composition as mentioned herein above in combination with Linagliptin.

[0035] SUMMARY OF THE INVENTION

[0036] In one aspect, the present invention provides an immediate release monolithic tablet comprising: a) granules comprising Metformin or its pharmaceutically acceptable salt, hydroxypropyl methylcellulose and at least one more pharmaceutically acceptable excipient, and b) powder mixture consisting essentially of Empagliflozin or its pharmaceutically acceptable salts, low substituted hydroxypropyl cellulose and at least one diluent, wherein said immediate release monolithic tablet doesn’t comprise copovidone.

[0037] In another aspect, the present invention provides an immediate release monolithic tablet comprising: a) granules comprising Metformin or its pharmaceutically acceptable salt, hydroxypropyl methylcellulose and at least one more pharmaceutically acceptable excipient, and b) powder mixture consisting essentially of Empagliflozin or its pharmaceutically acceptable salts, low substituted hydroxypropyl cellulose and at least one diluent, wherein said immediate release monolithic tablet doesn’t comprise copovidone and wherein Empagliflozin or its pharmaceutically acceptable salt is present in amount of about from 0.1 % to 8 % by weight based on the total weight of the tablet.

[0038] In another aspect, the present invention provides an immediate release monolithic tablet comprising: a) granules comprising Metformin or its pharmaceutically acceptable salt, hydroxypropyl methylcellulose and at least one more pharmaceutically acceptable excipient, and b) powder mixture consisting essentially of Empagliflozin or its pharmaceutically acceptable salts, low substituted hydroxypropyl cellulose and at least one diluent, wherein said immediate release monolithic tablet doesn’t comprise copovidone and wherein Metformin or its pharmaceutically acceptable salt is present in amount of about from 40 % to 90 % by weight based on the total weight of the tablet.

[0039] In another aspect, the present invention provides an immediate release monolithic tablet comprising: a) granules comprising Metformin or its pharmaceutically acceptable salt, hydroxypropyl methylcellulose and at least one more pharmaceutically acceptable excipient, and b) powder mixture consisting essentially of Empagliflozin or its pharmaceutically acceptable salts, low substituted hydroxypropyl cellulose and at least one diluent, wherein said immediate release monolithic tablet doesn’t comprise copovidone and wherein hydroxypropyl methylcellulose is present in amount of about from 2 % to 10 % by weight based on the total weight of the tablet.

[0040] In another aspect, the present invention provides an immediate release monolithic tablet comprising: a) granules comprising Metformin or its pharmaceutically acceptable salt, hydroxypropyl methylcellulose and at least one more pharmaceutically acceptable excipient, and b) powder mixture consisting essentially of Empagliflozin or its pharmaceutically acceptable salts, low substituted hydroxypropyl cellulose and at least one diluent, wherein said immediate release monolithic tablet doesn’t comprise copovidone and wherein low substituted hydroxypropyl cellulose is present in amount of about from 0.05 % to 5 % by weight based on the total weight of the tablet.

[0041] In another aspect, the present invention provides an immediate release monolithic tablet comprising: a) granules comprising Metformin or its pharmaceutically acceptable salt, hydroxypropyl methylcellulose and at least one more pharmaceutically acceptable excipient, and b) powder mixture consisting essentially of Empagliflozin or its pharmaceutically acceptable salts, low substituted hydroxypropyl cellulose and at least one diluent, wherein said immediate release monolithic tablet doesn’t comprise copovidone and wherein Metformin or its pharmaceutically acceptable salt is present in amount of about from 40 % to 90 % and hydroxypropyl methylcellulose is present in amount of about from 2 % to 10 % by weight based on the total weight of the tablet.

[0042] In another aspect, the present invention provides an immediate release monolithic tablet comprising: a) granules comprising Metformin or its pharmaceutically acceptable salt, hydroxypropyl methylcellulose and at least one more pharmaceutically acceptable excipient, and b) powder mixture consisting essentially of Empagliflozin or its pharmaceutically acceptable salts, low substituted hydroxypropyl cellulose and at least one diluent, wherein said immediate release monolithic tablet doesn’t comprise copovidone and wherein Empagliflozin or its pharmaceutically acceptable salt is present in amount of about from 0.1 % to 8 % and low substituted hydroxypropyl cellulose is present in amount of about from 0.05 % to 5 % by weight based on the total weight of the tablet.

[0043] In another aspect, the present invention provides an immediate release monolithic tablet comprising: a) granules comprising Metformin or its pharmaceutically acceptable salt, hydroxypropyl methylcellulose and at least one more pharmaceutically acceptable excipient, and b) powder mixture consisting essentially of Empagliflozin or its pharmaceutically acceptable salts, low substituted hydroxypropyl cellulose and at least one diluent, wherein said immediate release monolithic tablet doesn’t comprise copovidone, and wherein Metformin or its pharmaceutically acceptable salt is present in amount of about from 40 % to 90 %; hydroxypropyl methylcellulose is present in amount of about from 2 % to 10 %; Empagliflozin or its pharmaceutically acceptable salt is present in amount of about from 0.1 % to 8 % and low substituted hydroxypropyl cellulose is present in amount of about from 0.05 % to 5 % by weight based on the total weight of the tablet.

[0044] In another aspect, the present invention provides an immediate release monolithic tablet comprising: a) granules comprising i) about 40 wt% to 90 wt% of Metformin or its pharmaceutically acceptable salt, ii) about 2 wt% to 10 wt% of hydroxypropyl methylcellulose, iii) about 1 wt% to 8 wt% of at least one more pharmaceutically acceptable excipient, b) powder mixture consisting essentially of i) about 0.1 wt% to 8 wt% of Empagliflozin or its pharmaceutically acceptable salt, ii) about 0.05 wt% to 5 wt% of low substituted hydroxypropyl cellulose, iii) about 5 wt% to 15 wt% of at least one diluent, c) about 0 wt% to 5 wt% of one or more of disintegrants, d) about 0 wt% to 3 wt% of one or more glidant, and e) about 0.1 wt% to 5 wt% of one or more lubricant based on the total weight of the tablet, and wherein said immediate release monolithic tablet doesn’t comprise copovidone.

[0045] In another aspect of the present invention, Empagliflozin is present in crystalline or amorphous form.

[0046] In another aspect, a manufacturing process of the present invention comprises simple mixing of Metformin granules and powder mixture of Empagliflozin. In another aspect, the manufacturing process of the present invention comprises simple mixing of wet granulated granules of Metformin and powder mixture of Empagliflozin.

[0047] In another aspect, the present invention provides a pharmaceutical composition of any of the above aspects, wherein the said composition remains stable after storage for at least 1 month at 40°C and 75% relative humidity (RH).

[0048] In another aspect, the present invention provides a pharmaceutical composition as mentioned herein above in combination with one or more additional therapeutic agent.

[0049] In another aspect, the present invention provides a pharmaceutical composition as mentioned herein above in combination with Linagliptin.

[0050] In another aspect, the present invention discloses a use of such pharmaceutical composition as medicament in the treatment of diabetes.

[0051] The details of one or more embodiments of the present invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description.

[0052] DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0053] The present invention will now be more specifically illustrated as hereunder.

[0054] The term %, wt% used in this specification means the percentage by weight unless otherwise stipulated.

[0055] The term "about" can indicate a difference of 10 percent of the value specified. Numerical ranges as used herein are meant to include every number and subset of numbers enclosed within that range, whether particularly disclosed or not. Further, these numerical ranges should be construed as providing support for a claim directed to any number or subset of numbers in that range.

[0056] The term ' Empagliflozin ' as used in the present invention includes, but is not limited to, Empagliflozin per se, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, and pharmaceutically acceptable prodrugs thereof, and also its various crystalline and amorphous forms.

[0057] The term ' Metformin ' as used in the present invention includes, but is not limited to, Metformin per se, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, and pharmaceutically acceptable prodrugs thereof, and also its various crystalline and amorphous forms.

[0058] The term "similarity factor" or f2 factor as used herein refers to one way of comparing dissolution profiles of two different products (Multisource Pharmaceutical Products: Guidelines on Registration Requirements to establish Interchangeability, Quality Assurance and Safety: Medicines, Essential Drugs and Medicines Policy, World Health Organization, 1211 Geneva 27, Switzerland). This model independent mathematical approach compares the dissolution profile of the two products: test and reference (or two strengths, or pre- and post-approved products from the same manufacturer). Tests are recommended to be performed under the same test conditions. The dissolution time points for both the profiles should be the same, for example for immediate release products e.g., 10, 15, 30, 45, 60 minutes and for extended release products, e.g., 1 , 2, 3, 5 and 8 hours. Only one time point should be considered after 85% dissolution of the reference product. An f2 value of 50 or greater (50-100) ensures sameness or equivalence of the two curves, and thus the performance of the two products. The similarity factor f2 should be computed using the equation: f2 =50 log {[l+(l / n) t=1 n (Rt - Tt )2 ]-0-5 100} where Rt and Tt are the cumulative percentage of the drug dissolved at each of the selected n time points of the comparator (reference) and (test) product respectively .

[0059] The term “powder mixture” as used herein the present invention refers to two or more powders, in other words, the mass of two or more solid species including active ingredient and one or more pharmaceutically acceptable excipient. The powder mixture of the present invention is obtained by simply mixing process i.e. without using any dry or wet granulation process. In the powder mixture, two or more different powders or solid species may be homogeneously dispersed or may be present in an in homogeneous state.

[0060] In general embodiment, a present invention provides an immediate release monolithic tablet comprising: a) granules comprising Metformin or its pharmaceutically acceptable salt, hydroxypropyl methylcellulose and at least one more pharmaceutically acceptable excipient, and b) powder mixture consisting essentially of Empagliflozin or its pharmaceutically acceptable salts, low substituted hydroxypropyl cellulose and at least one diluent, wherein said immediate release monolithic tablet doesn’t comprise copovidone.

[0061] In one embodiment, a composition of the present invention comprises active ingredient Metformin or its pharmaceutically acceptable salt in the amount about from 40 wt% to 90 wt% based on the total weight of the tablet.

[0062] In one embodiment, a composition of the present invention comprises active ingredient Empagliflozin or its pharmaceutically acceptable salt in the amount about from 0.1 wt% to 8 wt% based on the total weight of the tablet. In one embodiment, a composition of the present invention comprises hydroxypropyl methylcellulose in amount about from 2 wt% to 10 wt% based on the total weight of the tablet.

[0063] In one embodiment, a composition of the present invention comprises low substituted hydroxypropyl cellulose in amount about from 0.05 wt% to 5 wt% based on the total weight of the tablet.

[0064] In one embodiment, a manufacturing process of the present invention comprises simple mixing of Metformin granules and powder mixture of Empagliflozin.

[0065] In one embodiment, the manufacturing process of the present invention comprises simple mixing of wet granulated granules of Metformin and powder mixture of Empagliflozin.

[0066] In another embodiment, an immediate release monolithic tablet of the present invention further comprises one or more pharmaceutically acceptable excipients. The excipients to be used in accordance with the present invention are well known and are those excipients which are conventionally used by the person skilled in the art. Depending on the dosage form chosen for the pharmaceutical composition, the person skilled in the art will be able to select suitable pharmaceutically acceptable excipients. The pharmaceutically acceptable excipient can be selected from diluent, disintegrant, lubricant and glidant.

[0067] Diluent includes, but are not limited to, lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, pregelatinized starch, dextrates, dextran, dextrin, dextrose, maltodextrin, calcium carbonate, dibasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, and mixtures thereof.

[0068] The total amount of diluent is preferably from about 1 wt% to 30 wt%, more preferably from about 2 wt% to 20 wt% based on the total weight of the tablet. The amount of diluent used in granules of Metformin or its pharmaceutically acceptable salt is preferably from about 0.1 wt% to 10 wt%, more preferably from about 1 wt% to 8 wt% based on the total weight of the tablet.

[0069] The amount of diluent used in powder mixture of Empagliflozin or its pharmaceutically acceptable salt is preferably from about 1 wt% to 20 wt%, more preferably from about 5 wt% to 15 wt% based on the total weight of the tablet. Preferable diluent is microcrystalline cellulose, pregelatinized starch or mixture thereof.

[0070] Disintegrant includes, but are not limited to, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, starch, sodium alginate and mixtures thereof.

[0071] The amount of the disintegrant used in the present invention is preferably from about 0 wt% to 5 wt%, more preferably from about 0.5 wt% to 3 wt% based on the total weight of the tablet.

[0072] Lubricant / glidants includes, but are not limited to, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyethylene glycols, com starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc, waxes, DL-leucine, sodium lauryl sulfate, magnesium lauryl sulfate, colloidal silicon dioxide and mixtures thereof.

[0073] The amount of the glidant used in the present invention is preferably from about 0 wt% to about 3 wt%, more preferably from about 0.2 wt% to 1 wt% based on the total weight of the tablet. The amount of the lubricant used in the present invention is preferably from about 0.1 wt% to about 5 wt%, more preferably from about 0.2 wt% to about 3 wt% based on the total weight of the tablet.

[0074] The metformin granules of the present invention can be obtained by using known conventional methods i.e. wet granulation or dry granulation. The process to obtain the said granules includes, but is not limited to, wet granulation, fluid bed granulation, spray drying, or dry granulation, slugging & roller compaction.

[0075] Wet granulation can be carried out by using suitable solvent optionally contains binder, wherein solvent includes, but is not limited to, purified water, ethanol, methanol, isopropanol, acetone, N, N-dimethylformamide etc.

[0076] The powder mixture of Empagliflozin of the present invention can be obtained by simple mixing of Empagliflozin or its pharmaceutically acceptable salt, low-substituted hydroxypropyl cellulose and at least one diluent in suitable equipment until homogeneous blend obtained.

[0077] The immediate release monolithic tablet of the present invention can be obtained mixing a) granules comprising Metformin or its pharmaceutically acceptable salt, hydroxypropyl methylcellulose and at least one more pharmaceutically acceptable excipient, and b) powder mixture consisting essentially of Empagliflozin or its pharmaceutically acceptable salt, low substituted hydroxypropyl cellulose and at least one diluent. The obtained final blend of both the active ingredients is further mixed with disintegrant, lubricant and glidant and then compressed into tablet.

[0078] The pharmaceutical composition of the present invention may further be coated with a film- forming polymer and one or more pharmaceutically acceptable excipients, using techniques well known in the art e.g., spray coating in a conventional coating pan, or a fluidized bed processor, or dip coating. Alternatively, coating can also be performed using a hot melt technique. The film coating may contain one or more film-forming polymers, and optionally one or more pharmaceutically acceptable excipients. A suitable film-forming polymer is selected from the group comprising hydroxypropyl methyl cellulose, ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose phthalate, cellulose acetate trimellitate, methacrylic acid copolymers e.g., Eudragit®, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, or mixtures thereof. A preferred film forming polymer is hydroxypropyl methyl cellulose. Other suitable film forming polymers which are known in art may also be used. The film coating may also contain opacifiers like titanium dioxide, flow aids like talc and pigment like iron oxide yellow.

[0079] The pharmaceutical composition in accordance with the present invention may be used as a medicament for the treatment of diabetes.

[0080] The pharmaceutical composition of the present invention may be used in combination with one or more other types of antidiabetic agents and / or one or more other types of therapeutic agents which may be administered orally in the same dosage form, in a separate oral dosage form or by injection. The other type of antidiabetic agent which may be optionally employed in combination with the pharmaceutical composition of the present invention may be one or more antidiabetic agents or antihyperglycemic agents including insulin secretagogues or insulin sensitizers, biguanides, sulfonylureas, glucosidase inhibitors, PPAR y agonists such as thiazolidinediones, aP2 inhibitors, PPAR a / y dual agonists, dipeptidyl peptidase IV (DPP4) inhibitors such as sitagliptin or linagliptin, and / or meglitinides, as well as insulin, glucagon-like peptide-1 (GLP-1), PTP1 B inhibitors, glycogen phosphorylase inhibitors and / or glucos-6-phosphatase inhibitors. In preferred embodiment, the pharmaceutical composition of the present invention is used in combination with linagliptin for the treatment of diabetes.

[0081] Moreover, the pharmaceutical composition of the present invention is very suitable for production on commercial scale making use of equipment and techniques commonly used in industry. The following examples are intended to illustrate the scope of the present invention but not to limit it thereto.

[0082] Examples:

[0083] Example 1: Preparation of monolithic tablet of Empagliflozin & Metformin hydrochloride

[0084] Table-1

[0085] (q.s.: Quantum satis) Process for the Preparation:

[0086] 1. Empagliflozin, microcrystalline cellulose, pregelatinized starch and low substituted hydroxypropyl cellulose were sieved through a suitable mesh size and added into the container and mixed.

[0087] 2. Metformin hydrochloride and pregelatinized starch were sieved through a suitable mesh size.

[0088] 3. Hydroxypropyl methylcellulose was dissolved in the required amount of purified water.

[0089] 4. Obtained blend at step 2 was loaded into fluid bed granulator and was granulated with binder solution of step 3.

[0090] 5. Obtained granules of step 4 were dried and sieved through a suitable mesh size.

[0091] 6. Obtained powder mixture of Empagliflozin at step 1 and obtained granules of Metformin hydrochloride at step 5 were loaded into container and mixed.

[0092] 7. Colloidal silicon dioxide and croscarmellose sodium were sifted through a suitable mesh size and added into blend of step 6 and mixed.

[0093] 8. Magnesium stearate was sieved through a suitable mesh and added into the blend of step 7 and mixed.

[0094] 9. The obtained blend of step 8 was compressed into tablets.

[0095] 10. Purified water and Opadry brown were loaded into container and mixed continuously by using mechanical stirrer to obtain proper dispersion. 11. The obtained tablets of step 9 were loaded into coating pan and the coating solution of step 10 was sprayed on to core tablets until the target film tablet weight is reached.

[0096] Example 2: Empagliflozin’s Dissolution Data of Example-1

[0097] Table-2

[0098] (** = More than 85% drug release at 15 minutes for both reference and test product. Therefore, f2 calculation is not necessary.)

[0099] Empagliflozin’s dissolution of test products of Example-1 and reference product Synjardy® 1000 mg / 12,5 mg were performed using standard USP apparatus II, paddles, at 50 rpm in 900 ml at pH=6.8. The drug release was determined by using an HPLC method. From the above dissolution data given in table-2, it is evident when f2 is more than 50 or more than 85% of drug released within 15 minutes establishes sameness or equivalence of both products i.e. test products (of Example-1) and reference product in terms of its dissolution and performance. Example 3: Metformin’s Dissolution Data of Example 1

[0100] Table-3

[0101] (** = More than 85% drug release at 15 minutes for both reference and test product. Therefore, f2 calculation is not necessary.)

[0102] Metformin’s dissolution of test products of Example-1 and reference product Synjardy® 1000 mg / 12,5 mg were performed using standard USP apparatus II, paddles, at 50 rpm in 900 ml at pH=6.8. The drug release was determined by using an HPLC method. From the above dissolution data given in table-3, it is evident that f2 is more than 50 or more than 85% of drug released within 15 minutes establishes sameness or equivalence of both products i.e. test products (of Example-1) and reference product in terms of its dissolution and performance.

[0103] Example 4: Stability Result of Empagliflozin & Metformin composition prepared according to Example 1

[0104] The tablets prepared in Example-1 , were placed in PVC / aluminum blisters, and stored for 1 month under conditions of 40°C / 75% RH. 1 month stability result is presented herein below table-4.

[0105] Table-4

Claims

Claims1. An immediate release monolithic tablet comprising: a. granules comprising Metformin or its pharmaceutically acceptable salt, hydroxypropyl methylcellulose and at least one more pharmaceutically acceptable excipient, and b. powder mixture consisting essentially of Empagliflozin or its pharmaceutically acceptable salts, low substituted hydroxypropyl cellulose and at least one diluent, wherein said immediate release monolithic tablet doesn’t comprise copovidone.

2. An immediate release monolithic tablet according to claim 1 , wherein Metformin or its pharmaceutically acceptable salt is present in an amount about from 40 % to 90 % by weight based on the total weight of the tablet.

3. An immediate release monolithic tablet according to claim 1 , wherein hydroxypropyl methylcellulose is present in an amount about from 2 % to 10 % by weight based on the total weight of the tablet.

4. An immediate release monolithic tablet according to claim 1 , wherein at least one more pharmaceutically acceptable excipient present in granules of Metformin or its pharmaceutically acceptable salt is selected from the group consisting of diluent, disintegrant, lubricant and glidant.

5. An immediate release monolithic tablet according to claim 1 , wherein at least one more pharmaceutically acceptable excipient present in granules of Metformin or its pharmaceutically acceptable salt is pregelatinized starch in an amount about from 0.1 % to 10 % by weight based on the total weight of the tablet.

6. An immediate release monolithic tablet according to claim 1 , whereinEmpagliflozin or its pharmaceutically acceptable salt is present in crystalline or amorphous form.

7. An immediate release monolithic tablet according to claim 1 , whereinEmpagliflozin or its pharmaceutically acceptable salt is present in an amount about from 0.1 % to 8 % by weight based on the total weight of the tablet.

8. An immediate release monolithic tablet according to claim 1 , wherein low substituted hydroxypropyl cellulose is present in an amount about from 0.05 % to 5 % by weight based on the total weight of the tablet.

9. An immediate release monolithic tablet according to claim 1 , wherein at least one diluent present in powder mixture of Empagliflozin or its pharmaceutically acceptable salt is selected from lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, pregelatinized starch, dextrates, dextran, dextrin, dextrose, maltodextrin, calcium carbonate, dibasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, and mixtures thereof.

10. An immediate release monolithic tablet according to claim 9, wherein said at least one diluent is microcrystalline cellulose or pregelatinized starch or mixtures thereof.

11. An immediate release monolithic tablet according to claim 9, wherein said at least one diluent is present in an amount about from 1 % to 20 % by weight based on the total weight of the tablet.

12. An immediate release monolithic tablet according to claim 1 , said powder mixture of Empagliflozin or its pharmaceutically acceptable salt is obtained by simple mixing process.

13. An immediate release monolithic tablet according to any of claim 1 to claim 12 further contains one or more additional therapeutic agent.

14. An immediate release monolithic tablet according to any of claim 1 to 13 is useful in the treatment of diabetes.

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