WO2024096838A1

WO2024096838A1 - A pharmaceutical composition comprising solid dispersion of empagliflozin

Info

Publication number: WO2024096838A1
Application number: PCT/TR2023/051217
Authority: WO
Inventors: Manas Ranjan Mund; Mesut GUNDAR; Emre Erol ALDENIZ; Udaya Kumar DUDE
Original assignee: Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi
Priority date: 2022-11-01
Filing date: 2023-10-30
Publication date: 2024-05-10

Abstract

The present invention relates to a pharmaceutical composition comprising i) a solid dispersion consisting of Empagliflozin, silicon dioxide and a surfactant and ii) at least one more pharmaceutically acceptable excipient. The said pharmaceutical composition has desirable pharmacokinetic characteristics, 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 hyperglycaemia.

Description

A PHARMACEUTICAL COMPOSITION COMPRISING SOLID DISPERSION OF EMPAGLIFLOZIN

FIELD OF THE INVENTION

The present invention relates to a pharmaceutical composition comprising i) a solid dispersion consisting of Empagliflozin, silicon dioxide and a surfactant ii) at least one more pharmaceutically acceptable excipient. The said pharmaceutical composition 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 hyperglycaemia.

BACKGROUND OF THE INVENTION

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

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 as mono Empagliflozin, in combination with metformin, in combination with linagliptin and in combination with linagliptin and metformin by Boehringer Ingelheim. These marketed products are approved in the form of film coated tablet. These tablets contain Empagliflozin in the strengths of 5 mg, 10 mg, 12.5 mg, 25 mg.

Firstly, Empagliflozin is marketed under the brand name Jardiance® in Europe since 2014.

Jardiance® is indicated for the treatment of adults with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise

- as monotherapy when metformin is considered inappropriate due to intolerance

- in addition to other medicinal products for the treatment of diabetes.

Jardiance is indicated in adults for the treatment of symptomatic chronic heart failure.

According to European Public Assessment Report (EPAR), Empagliflozin is a white to yellowish non-hygroscopic crystalline solid, very slightly soluble in water (pH 1 -7.4), slightly soluble in acetonitrile and ethanol, sparingly soluble in methanol, and practically insoluble in toluene. It is very slightly soluble in aqueous media between pH 1-7.5 but has low intestinal permeability and thus it is classified as BCS Class III compound based on Biopharmaceutical Classification System. According to EPAR, particle size was not found to be critical for dissolution, but since coarser API dissolves slightly more slowly and therefore the drug substance is milled and particle size is tightly controlled.

This latter characteristic i.e. low permeability is the factor limiting oral bioavailability of many such kind of compounds. To address such problem, numerous techniques are known in the art such as particle size reduction, nanosuspension technology, using surfactant, salt formation, pH adjustment, hydrotrophy, solid dispersion, etc. Solid dispersion is one of the techniques explored in the art to improve the dissolution and bioavailability of compound like Empagliflozin.

At the same time, while exploring solid dispersion technique, it is important to understand that alteration in polymorphic form of the compound also affect important pharmaceutical parameters such as storage, stability, compressibility, density and dissolution rates (important in determining bioavailability). It is known that crystalline solids normally require a significant amount of energy for dissolution due to their highly organized lattice like structures. For example, the energy required for a drug molecule to escape from a crystal is more than from an amorphous or a non-crystalline form. That may be the reason that why amorphous forms in a number of drugs exhibit different dissolution characteristics and, in some cases, different bioavailability patterns as compared to the crystalline form (Econno T., Chem. Pharm. Bull., 1990; 38: 2003-2007).

An amorphous form generally has better solubility and bioavailability than corresponding crystalline form of the same compound and that may be the reason, in particular cases, to use amorphous form of the said compound while targeting to obtain a formulation with better stability, solubility and compressibility etc.

Many attempts have been made in the art to improve the solubility of Empagliflozin and one of them is preparing an amorphous form. However, amorphous Empagliflozin alone is highly unstable and recrystallizes virtually immediately, which poses a great challenge while developing a composition with amorphous form of Empagliflozin.

WO 2005/092877 discloses glucopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture.

WO 2006/117359 A1 (EP 1888552 B1 ) discloses stable a crystalline form of Empagliflozin and a pharmaceutical composition or medicament comprising the crystalline form. Additional crystalline forms of Empagliflozin are disclosed in WO 2006/117360 A1 (EP 1888551 B1 ) and WO 2011/039107A1 (EP 2483286 B1). In particular, the said patent discloses the crystalline Form-I and Form-ll and process for preparation thereof.

WO 2016169534 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.

CN 111214450 B disclosed solid dispersion comprising Empagliflozin, a carrier material and other pharmaceutically acceptable auxiliary materials, and is characterized in that the carrier material consists of poloxamer and mannitol and a preparation process thereof.

KR 10-2330597 B1 covers a pharmaceutical formulation comprising amorphous Empagliflozin or a hydrate thereof and polycarbophil or optionally containing one or more excipients selected from the group consisting of magnesium alumino metasilicate or nonporous colloidal silica.

WO 2021123165 A1 provides solid pharmaceutical dosage forms and methods for making the same, wherein the pharmaceutical dosage forms comprise Empagliflozin in the form of an amorphous solid solution with at least one polymer wherein the at least one polymer is selected from the group consisting of polyvinylpyrrolidone, vinyl pyrrolidone-vinyl acetate copolymer, cellulose ether, dextrin, gum arabicum, pullulan, poly(meth)acrylate, and mixtures thereof.

IN 201711026696 discloses a pharmaceutical composition comprising amorphous Empagliflozin along with one or more pharmaceutically acceptable excipients.

IN 201741011748 discloses solid dispersion of Empagliflozin and processes for the preparation of the same wherein solid dispersion comprises HPMC, Co-povidone, HPC and prepared by hot-melt extrusion method. CN 106880595 A discloses solid dispersion of amorphous Empagliflozin and its preparation method. The solid dispersion comprises amorphous Empagliflozin and at least one of the pharmaceutically acceptable excipients.

CN 106692069 A discloses solid dispersion comprising Empagliflozin, povidone and lubricant wherein lubricant is selected from talc, magnesium stearate, silicon dioxide, sodium stearyl fumarate, and sodium lauryl sulfate.

WO 2016051368 discloses a solid dispersion of amorphous Empagliflozin and a cyclodextrin.

WO 2017203457 A1 discloses amorphous solid dispersion of Empagliflozin and one or more pharmaceutically acceptable carrier wherein the carrier is HPMC phthalate, methyl cellulose, ethyl cellulose, Soluplus®, hydroxypropyl cellulose, L-hydroxypropyl cellulose, HPMC, HPMC-As, Eudragit® E-100, microcrystalline cellulose.

IN 4964/CHE/2014 discloses amorphous solid dispersion of Empagliflozin with polyvinyl pyrrolidinone.

There still exist a need for pharmaceutical compositions comprising Empagliflozin, which are physically and chemically stable, have improved dissolution profile and are prepared by an economically viable process, which is also suitable on a commercial scale.

The inventors of the present invention have surprisingly found that a pharmaceutical composition comprising solid dispersion consisting of Empagliflozin, silicon dioxide and a surfactant not only provides storage stable composition but also provides a composition with similar dissolution profile when compared to the reference product Jardiance® tablet. OBJECT OF THE INVENTION

A main object of the present invention is to provide a pharmaceutical composition comprising a stable solid dispersion of Empagliflozin.

Another object of the present invention is to provide a pharmaceutical composition comprising a solid dispersion consisting of Empagliflozin, silicon dioxide and a surfactant.

Yet another object of the present invention is to provide a pharmaceutical composition comprising a solid dispersion consisting of an amorphous Empagliflozin, silicon dioxide and a surfactant.

Yet another object of the present invention is to provide a pharmaceutical composition comprising i) a solid dispersion consisting of Empagliflozin, silicon dioxide and a surfactant, and ii) at least one more pharmaceutically acceptable excipient.

Yet another object of the present invention is to provide a pharmaceutical composition comprising i) a solid dispersion consisting of an amorphous Empagliflozin, silicon dioxide and a surfactant, and ii) at least one more pharmaceutically acceptable excipient.

Yet another object of the present invention is to provide a pharmaceutical composition comprising i) a solid dispersion consisting of an amorphous Empagliflozin, silicon dioxide and a surfactant, and ii) at least one more pharmaceutically acceptable excipient, wherein said pharmaceutical composition is tablet.

Yet another object of the present invention is to provide a pharmaceutical composition comprising above mentioned solid dispersion of Empagliflozin, Metformin and at least one pharmaceutically acceptable excipient. Yet another object of the present invention is to provide a pharmaceutical composition comprising above mentioned solid dispersion of Empagliflozin, Linagliptin and at least one pharmaceutically acceptable excipient.

Yet another object of the present invention is to provide a pharmaceutical composition comprising above mentioned solid dispersion of Empagliflozin, which remains stable during manufacturing and stability.

Yet another object of the present invention is to provide a pharmaceutical composition above mentioned solid dispersion of Empagliflozin, which overcomes the problems of the prior art.

Yet another object of the invention is to provide a commercially scalable, cost effective, environment friendly and robust process for the preparation of a pharmaceutical composition comprising above mentioned solid dispersion of Empagliflozin.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a pharmaceutical composition comprising: i) a solid dispersion consisting of Empagliflozin, silicon dioxide and a surfactant, and ii) at least one more pharmaceutically acceptable excipient.

In another aspect, the present invention provides a pharmaceutical composition comprising: i) a solid dispersion consisting of an amorphous Empagliflozin, silicon dioxide and a surfactant, and ii) at least one more pharmaceutically acceptable excipient.

In another aspect, the present invention provides a pharmaceutical composition comprising: i) a solid dispersion consisting of Empagliflozin, silicon dioxide and a surfactant, and ii) at least one more pharmaceutically acceptable excipient, wherein Empagliflozin is in amount of about from 1 wt% to 20 wt% based on the total weight of the composition.

In another aspect, the present invention provides a pharmaceutical composition comprising: i) a solid dispersion consisting of Empagliflozin, silicon dioxide and a surfactant, and ii) at least one more pharmaceutically acceptable excipient, wherein silicon dioxide is in amount of about from 1 wt% to 15 wt% based on the total weight of the composition.

In another aspect, the present invention provides a pharmaceutical composition comprising: i) a solid dispersion consisting of Empagliflozin, silicon dioxide and a surfactant, and ii) at least one more pharmaceutically acceptable excipient, wherein a surfactant is in amount of about from 0.5 wt% to 10 wt% based on the total weight of the composition.

In another aspect, the present invention provides a pharmaceutical composition comprising: i) a solid dispersion consisting of Empagliflozin, silicon dioxide and a surfactant, and ii) at least one more pharmaceutically acceptable excipient, wherein silicon dioxide is in amount of about from 1 wt% to 15 wt% and a surfactant is in amount of about from 0.5 wt% to 10 wt% based on the total weight of the composition.

In another aspect, the present invention provides a pharmaceutical composition comprising: i) a solid dispersion consisting of Empagliflozin, silicon dioxide and a surfactant, and ii) at least one more pharmaceutically acceptable excipient, wherein Empagliflozin is in amount of about from 1 wt% to 20 wt% and silicon dioxide is in amount of about from 1 wt% to 15 wt% based on the total weight of the composition.

In another aspect, the present invention provides a pharmaceutical composition comprising: i) a solid dispersion consisting of Empagliflozin, silicon dioxide and a surfactant, and ii) at least one more pharmaceutically acceptable excipient, wherein Empagliflozin is in amount of about from 1 wt% to 20 wt% and a surfactant is in amount of about from 0.5 wt% to 10 wt% based on the total weight of the composition.

In another aspect, the present invention provides a pharmaceutical composition comprising: i) a solid dispersion consisting of Empagliflozin, silicon dioxide and a surfactant, and ii) at least one more pharmaceutically acceptable excipient, wherein Empagliflozin is in amount of about from 1 wt% to 20 wt%, silicon dioxide is in amount of about from 1 wt% to 15 wt% and a surfactant is in amount of about from 0.5 wt% to 10 wt% based on the total weight of the composition.

In another aspect, the present invention provides a tablet composition comprising: i) a solid dispersion consisting of Empagliflozin, silicon dioxide and a surfactant, and ii) at least one more pharmaceutically acceptable excipient, wherein Empagliflozin is in amount of about from 1 wt% to 20 wt% and silicon dioxide is in amount of about from 1 wt% to 15 wt% and a surfactant is in amount of about from 0.5 wt% to 10 wt% based on the total weight of the composition.

In another aspect, the present invention provides a tablet composition comprising: i) a solid dispersion consisting of an amorphous Empagliflozin, silicon dioxide and a surfactant, and ii) at least one more pharmaceutically acceptable excipient, wherein Empagliflozin is in amount of about from 1 wt% to 20 wt% and silicon dioxide is in amount of about from 1 wt% to 15 wt% and a surfactant is in amount of about from 0.5 wt% to 10 wt% based on the total weight of the composition.

In another aspect, the present invention provides a tablet comprising: a) 1 wt% to 20 wt% of Empagliflozin, b) 1 wt% to 15 wt% of silicon dioxide, c) 30 wt% to 80 wt% of one or more of diluents, d) 0.5 wt% to 10 wt% of one or more surfactant, e) 1 wt% to 20 wt% of one or more of disintegrants, f) 1 wt% to 15 wt% of one or more binders, and g) 0.1 wt% to 5 wt% of one or more lubricant based on the total weight of the composition.

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 3 months at 40°C and 75% relative humidity (RH).

In another aspect, the present invention provides a pharmaceutical composition comprising solid dispersion of Empagliflozin as mentioned herein above, which is prepared by solvent evaporation.

In another aspect, the present invention discloses a use of such pharmaceutical composition as medicament in the treatment of hyperglycemia.

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. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 : XRPD pattern of solid dispersion of Empagliflozin, silicon dioxide and a surfactant prepared according to Example 1.

Figure-2: An overlay of XRPD patterns of Empagliflozin composition (prepared according to Example-2) before (as numbered 3) and after (as numbered 2) storage at 40° C/75% RH for 3 months & placebo (as numbered 1).

DETAILED DESCRIPTION OF THE PRESENT INVENTION

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

The term % used in this specification means the percentage by weight unless otherwise stipulated.

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.

The term “composition” as used in the present invention means pharmaceutical composition includes, without limitation, capsule, tablet, caplet, powder, pellet, granules liquid dispersion, bead, solution, suspension, emulsion etc.

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. The term "solid dispersion" refers to a system in a solid state comprising at least two components, wherein one component is dispersed throughout the other component or components. The term "solid dispersion" as used herein, refers to stable solid dispersions comprising amorphous drug substance and carrier like silicon dioxide. Further the term "solid dispersion" as used herein also refers to stable solid dispersions comprising amorphous drug substance and carrier like silicon dioxide with or without another adsorbent/absorbent. By "amorphous drug substance," it is meant that the amorphous solid contains drug substance in a substantially amorphous solid state form i.e. at least about 80% of the drug substance in the dispersion is in an amorphous form. More preferably at least about 90% and most preferably at least about 95% of the drug substance in the dispersion is in amorphous form.

The term "stable" or "stability" means that the pharmaceutical dosage form is physically and chemically stable, whereas "chemically stable" means that the pharmaceutical dosage form when stored at 40 °C and 75 % relative humidity for 3 or 6 months, each of the degradation impurity and total impurities remain within ICH limit. The term "physically stable" as used herein means that X-ray powder diffraction pattern (XRPD) of the pharmaceutical dosage form according to the invention when stored at 40 °C and 75 % relative humidity for 1 or 3 months in a closed vial does not exhibit detectable X-ray diffractions characteristic of the crystalline form of Empagliflozin.

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 J-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 .

In general embodiment, a present invention provides a pharmaceutical composition comprising: i) a solid dispersion consisting of Empagliflozin, silicon dioxide and a surfactant, and ii) at least one more pharmaceutically acceptable excipient.

In one embodiment, a present invention provides a pharmaceutical composition comprising: i) a solid dispersion consisting of an amorphous Empagliflozin, silicon dioxide and a surfactant, and ii) at least one more pharmaceutically acceptable excipient.

In one embodiment, a composition of the present invention comprises active ingredient Empagliflozin in the amount from 1 wt% to 20 wt% based on the total weight of the composition.

In one embodiment, a composition of the present invention comprises silicon dioxide in amount from 1 wt% to 15 wt% based on the total weight of the composition.

In one embodiment, a composition of the present invention comprises a surfactant in amount from 0.5 wt% to 10 wt% based on the total weight of the composition. In one embodiment, a composition of the present invention comprises solid dispersion consisting of Empagliflozin, silicon dioxide and a surfactant in amount from 5 wt% to 20 wt% based on the total weight of the composition.

In another embodiment, a pharmaceutical composition 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 pharmaceutical excipient can be selected from excipient can be selected from diluent, binder, disintegrant, surfactant and lubricant.

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. Preferably, diluent is microcrystalline cellulose and lactose monohydrate.

The amount of diluent is preferably from about 30 wt% to about 80 wt%, more preferably from about 50 wt% to about 80 wt% based on the total weight of the pharmaceutical composition.

Disintegrant includes, but are not limited to, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, Crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, starch, pregelatinized starch, sodium alginate and mixtures thereof.

The amount of the disintegrant is preferably from 1 wt% to about 20 wt%, more preferably from 1 wt% to 15 wt% based on the total weight of the pharmaceutical composition. Binder includes, but are not limited to, carrageenan, hydroxyethyl cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose (L-HPC), hydroxypropyl methylcellulose, carbomers, carboxymethylcellulose sodium, dextrin, dextran, ethyl cellulose, methylcellulose, shellac, zein, gelatin, polymethacrylates, polyvinyl pyrrolidone, pregelatinized starch, pullulan, gums, synthetic resins and mixtures thereof.

The amount of the binder is preferably from about 1 wt% to 15 wt%, more preferably from about 1 wt% to about 10 wt% based on the total weight of the pharmaceutical composition.

Surfactant includes, but are not limited to, poloxamer, polysorbates, d-alpha tocopheryl glycol 1000 succinate, polyoxy-35-castor oil, polyoxy-40-hydrogenated castor oil, labrosol, propylene glycol and mixtures thereof.

The amount of the surfactant is preferably from about 0.5 wt% to 10 wt%, more preferably from about 0.5 wt% to about 5 wt% based on the total weight of the pharmaceutical composition.

Lubricant 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, corn starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc, waxes, DL-leucine, sodium lauryl sulfate, magnesium lauryl sulfate, and mixtures thereof.

The amount of one or more lubricant is preferably from about 0.1 wt% to 5 wt%, more preferably from about 0.2 wt% to about 3 wt% based on the total weight of the pharmaceutical composition.

The pharmaceutical composition includes, but are not limited to, capsules powder, tablet, minitablet, micro-tablet, granule, or pellet, pill, lozenge, solution, suspension, emulsion and the like wherein the composition can be further film coated. Preferably, the pharmaceutical composition is in the form of a tablet. Most preferably, the pharmaceutical composition is in the form of a film coated tablet.

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 filmforming 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 filmforming polymers which are known in the 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.

Release of the pharmaceutical composition includes, but are not limited to, immediate release, extended release, sustained release, zero order release and the like. Preferably, the pharmaceutical composition has immediate release.

In one embodiment, a process to obtain solid dispersion of the present invention includes, but is not limited to, solvent evaporation method, fusion method, kneading method, melting method, spray drying method, co-grinding method, lyophilization technique, hot melt extrusion, melt agglomeration, supercritical fluid (SCF) technology and the like.

In one embodiment, the solid dispersion of the present invention is prepared by dissolving Empagliflozin in a suitable solvent with a surfactant and sprayed onto silicon dioxide particles via the use of suitable technology like fluid bed technology. Suitable solvent used for dissolving Empagliflozin includes, but is not limited to, purified water, ethanol, methanol, isopropanol, acetone, N, N-dimethylformamide etc.

The pharmaceutical composition of the present invention can be obtained by using known conventional methods i.e. granulation or direct compression. The process to obtain granulate includes, but is not limited to, wet granulation, fluid bed granulation, spray drying, or dry granulation, slugging, roller compaction.

The pharmaceutical composition in accordance with the present invention may be used as a medicament. The pharmaceutical composition typically may be used in the treatment of hyperglycemia.

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.

Examples:

Example 1 : Preparation of solid dispersion of Empagliflozin, silicon dioxide and a surfactant

Empagliflozin (25 mg) was dissolved in N, N-dimethyl formamide (35 mg). Polysorbate 80 (8 mg) was added into obtained solution of Empagliflozin. Silicon dioxide (31.50) was loaded to granulator and obtained solution of Empagliflozin and polysorbate 80 was added to the granulator and mixed. The obtained mixture was dried till the residual solvent content found to be within the acceptable limit to get the solid dispersion of Empagliflozin, silicon dioxide and polysorbate 80 (64.50 mg). XRPD pattern is depicted in Fig.-1. Example 2: A pharmaceutical composition comprising solid dispersion of

Empagliflozin, silicon dioxide and polysorbate 80

Table-1

Process For The Preparation:

1. Microcrystalline cellulose, lactose monohydrate, hydroxypropyl cellulose and croscarmellose sodium were sieved through a suitable mesh size.

2. Solid dispersion obtained as per Example-1 and blend obtained in step-1 were added into the container and mixed.

3. Magnesium stearate was sieved through a suitable mesh and added into the container at step-2 and mixed.

4. The obtained blend in step-3 was compressed into tablet.

Example 3: Dissolution Data of Example 2 at pH 6.8 phosphate buffer 900 ml 50 rpm with USP apparatus II at 37°C Table-2

Dissolution of test products of Example-2 and reference product Jardiance® 25 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 that f2 is more than 50, which establishes sameness or equivalence both products i.e. test products (of Example-2) and reference product in terms of its dissolution and performance.

Example 4: Stability Result of Empagliflozin Composition prepared according to Example 2

The tablets prepared in Example-2, were placed in PVC/ aluminum blisters, and stored for 3 months under conditions of 40°C/75% RH. XRPD pattern of Empagliflozin composition (of Example-2) were checked before (as numbered 3) and after (as numbered 2) the storage along with its placebo (as numbered 1 ), which were depicted in Figure-2. It is evident from the given Figure-2 that amorphous Empagliflozin remained stable i.e. in amorphous form even after 3 months under conditions of 40°C/75% RH.

Claims

Claims:

1. A pharmaceutical composition comprising: a) a solid dispersion consisting of Empagliflozin, silicon dioxide and a surfactant, and b) at least one more pharmaceutically acceptable excipient.

2. The pharmaceutical composition according to claim 1 , wherein solid dispersion consisting of an amorphous Empagliflozin, silicon dioxide and a surfactant.

3. The pharmaceutical composition according to claim 1, wherein Empagliflozin is present in an amount from 1.0 % to 20 % by weight based on the total weight of the composition.

4. The pharmaceutical composition according to claim 1 , wherein silicon dioxide is present in an amount from 1.0 % to 15 % by weight based on the total weight of the composition.

5. The pharmaceutical composition according to claim 1, wherein a surfactant is present in an amount from 0.5 wt% to 10 wt% by weight based on the total weight of the composition.

6. The pharmaceutical composition according to claim 1 or claim 5, wherein a surfactant is polysorbate 80.

7. The pharmaceutical composition according to claim 1 , wherein at least one more pharmaceutically acceptable excipient is selected from the group comprising of diluent, binder, disintegrant and lubricant.

8. The pharmaceutical composition according to claim 7, wherein diluent 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. The pharmaceutical composition according to claim 7 or claim 8, wherein diluent is microcrystalline cellulose and lactose monohydrate. The pharmaceutical composition according to claim 7, wherein binder is selected from carrageenan, hydroxyethyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose (L-HPC), hydroxypropyl methylcellulose, carbomers, carboxymethylcellulose sodium, dextrin, dextran, ethyl cellulose, methylcellulose, shellac, zein, gelatin, polymethacrylates, polyvinyl pyrrolidone, pregelatinized starch, pullulan, gums, synthetic resins and mixture thereof. The pharmaceutical composition according to claim 7 or 10, wherein binder is hydroxypropyl cellulose or low-substituted hydroxypropyl cellulose. The pharmaceutical composition according to claim 7, wherein disintegrant is selected from sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, starch, pregelatinized starch, sodium alginate and mixtures thereof. The pharmaceutical composition according to claim 7 or claim 12, wherein disintegrant is croscarmellose sodium. The pharmaceutical composition according to claim 7, wherein lubricant is selected from magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyethylene glycols, corn starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc, waxes, DL-leucine, sodium lauryl sulfate, magnesium lauryl sulfate and mixtures thereof. The pharmaceutical composition according to claim 1 , wherein the pharmaceutical composition is selected from capsule, tablet, caplet, powder, pellet, granule, liquid dispersion, bead, solution, suspension and emulsion. The pharmaceutical composition according to claim 1 or claim 15, wherein pharmaceutical composition is tablet. The pharmaceutical composition according to any of claim 1 to 16 remains stable for 3 months at 40 °C and 75 % RH. A pharmaceutical composition according to any of claim 1 to claim 17 further contains one or more additional active substance. A pharmaceutical composition according to any of claim 1 to claim 18 is useful in the treatment of hyperglycemia.