WO2025080212A1

WO2025080212A1 - Pharmaceutical composition of empagliflozin and metformin with improved dissolution profile

Info

Publication number: WO2025080212A1
Application number: PCT/TR2023/051105
Authority: WO
Inventors: Abdulhaluk SANCAK; Yunus SANCAK; Elif Zehra ATUKEREN; Hakan Gürpinar; Akif ERDOĞAN; Şeyhmus EMEN; Koray YILMAZ
Original assignee: Humanis Saglik AS
Current assignee: Humanis Saglik AS
Priority date: 2023-10-09
Filing date: 2023-10-09
Publication date: 2025-04-17
Anticipated expiration: 2026-04-09

Abstract

The present invention relates to a wet granulation process for preparing a pharmaceutical composition comprising Empagliflozin and Metformin or pharmaceutically acceptable salts thereof, its use in the treatment of high blood sugar levels caused by type 2 diabetes. The pharmaceutical composition comprises at least a glidant as pharmaceutical acceptable excipient, wherein the glidant is present both in an intra-granular and an extra-granular phase with a specific weight ratio and wherein an improved dissolution profile has been obtained.

Description

PHARMACEUTICAL COMPOSITION OF EMPAGLIFLOZIN AND METFORMIN WITH IMPROVED DISSOLUTION PROFILE

Field of the Invention

Background of the Invention

Diabetes, also known as diabetes mellitus, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes appears when the pancreas not producing enough insulin, or when the cells of the body not responding properly to the insulin produced. If not kept under control, diabetes leads to many health complications. Untreated or poorly treated diabetes causes round about 1.5 million deaths per year.

A widely accepted treatment has not been found yet for most cases of diabetes. The most common cure for type 1 diabetes is insulin replacement therapy (insulin injections). Antidiabetic medications such as metformin and semaglutide, as well as modifications on lifestyle, can be used for preventing or responding to type 2 diabetes. Generally gestational diabetes resolves shortly after delivery.

As of 2019, an estimated 463 million people had diabetes worldwide accounting for 8.8% of the adult population. Type 2 diabetes is the most common of all types of diabetes, accounting for approximately 90% of all diabetes cases. The prevalence of the disease continues to increase, especially in low- and middle-income nations. The global expenditure on diabetes- related healthcare is an estimated USD 760 billion a year.

The risk of long-term complications is high in all forms of diabetes. These complications generally develop after many years (10-20) but may be the first symptom for the people who have otherwise not received a diagnosis before that time.

The major long-term complications are related with the damage to blood vessels. Diabetes increases the risk of cardiovascular disease significantly and about 75% of deaths in people with diabetes are due to coronary artery disease. Stroke and peripheral artery disease are other macrovascular diseases. These complications pose also a great risk for severe COVID- 19 illness.

There are six subtypes of diabetes mellitus: type 1 diabetes, type 2 diabetes, hybrid forms of diabetes, hyperglycemia first detected during pregnancy, "unclassified diabetes", and "other specific types". "Hybrid forms of diabetes" comprise slowly evolving, immune-mediated diabetes of adults and ketosis-prone type 2 diabetes. "Hyperglycemia first detected during pregnancy" comprises gestational diabetes mellitus and diabetes mellitus in pregnancy (type 1 or type 2 diabetes first diagnosed during pregnancy). The "other specific types" are a group of a few dozen individual causes. Diabetes is a more variable disease than once thought and people may experience different combinations of these forms.

A characteristic feature of type 2 diabetes is insulin resistance, which may be combined with relatively reduced insulin secretion. The defective responsiveness of body tissues to insulin is believed to involve the insulin receptor. However, the specific defects are not known. Diabetes mellitus cases due to a known defect are evaluated separately. Type 2 diabetes is the most common type of diabetes mellitus accounting for approxmately 90 % of diabetes. Many people with type 2 diabetes have evidence of prediabetes (impaired fasting glucose and/or impaired glucose tolerance) before experiencing the criteria for type 2 diabetes. The progression of prediabetes to overt type 2 diabetes can be slowed or reversed by lifestyle changes or medications that improve insulin sensitivity or reduce the liver’s glucose production.

Empagliflozin is an inhibitor of sodium-glucose co-transporter-2 (SGLT2), which are primarily responsible for the reabsorption of glucose in the kidney. For the management of type 2 diabetes mellitus, it is used clinically as an adjunct to diet and exercise, often in combination with other drug therapies.

As the most recently approved of the “flozin” drugs, empagliflozin has the highest selectivity for SGLT2 over SGLT1 (approximately 2700-fold). Empagliflozin was further approved by the EMA in March 2022 and Health Canada in April 2022, making it the first and only approved treatment in Europe and Canada for adults with symptomatic chronic heart failure regardless of ejection fraction.

Scheme 1. Empagliflozin

Empagliflozin has a chemical name as (2S,3J?,4J?,5S,6J?)-2-[4-Chloro-3-[[4-[(3S)-oxolan-3-yl] oxyphenyl]methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol and its chemical structure is shown in the Scheme 1.

Metformin is a biguanide antihyperglycemic agent and first-line pharmacotherapy used in the management of type II diabetes. Since lowering blood glucose concentrations in type II diabetes without causing hypoglycemia, Metformin is considered an antihyperglycemic drug. It is commonly described as an “insulin sensitizer”, leading to a decrease in insulin resistance and a clinically significant reduction of plasma fasting insulin levels. Another significantly appeared profit of Metformin is modest weight loss, making it an effective choice for obese patients type II diabetes. Metformin was first approved in Canada in 1972, and received subsequent FDA approval in the US in 1995.

Metformin is used also for treating non-insulin-dependent diabetes mellitus (NIDDM) as a biguanide antihyperglycemic agent not responding to dietary modification. It improves glycemic control by decreasing hepatic glucose production, decreasing glucose absorption and increasing insulin-mediated glucose uptake.

Scheme 2. Metformin

Metformin has a chemical name as 3-(diaminomethyIidene)-l,l-dimethylguanidine and its chemical structure is shown in the Scheme 2.

Empagliflozin and Metformin combination is used with proper diet and exercise to treat high blood sugar levels caused by type 2 diabetes. The brand name of the medicine for this combination is Synjardy. It is also used to lower the risk of cardiovascular death in patients with type 2 diabetes and heart or blood vessel disease. Besides providing important contributions of Synjardy as an antidiabetic medication, there is a requirement to develop a simple, reproducible and cost-effective manufacturing process and a stable pharmaceutical composition comprising Empagliflozin and Metformin with an improved flowability, content uniformity and processability, while at the same time ensuring that the desired properties such as dissolution, stability, bioavailability are maintained and are comparable with respect to the Reference Product Synjardy.

An aim of the present invention to solve the problems of the prior art and is to provide an improved pharmaceutical composition comprising Empagliflozin and Metformin or pharmaceutically acceptable salts thereof, obtaining concurrently comparable and satisfactory dissolution rates.

The pharmaceutical composition according to the present invention has suitable physical and chemical properties with the active ingredient and also with excipients present in the composition. According to these properties, the composition is stable and reproducible as a result, without any unwanted interaction with the active ingredient, and it provides the requirements for desired functionality and cost effective preparation, as well as improved dissolution profde.

The present invention introduces a pharmaceutical composition comprising Empagliflozin and Metformin or pharmaceutically acceptable salts thereof, wherein the composition comprises at least a glidant as pharmaceutical acceptable excipient, wherein the glidant is present both in an intra- and an extra-granular phase with a specific weight ratio and wherein an improved dissolution profile has been obtained.

Figures

Figure 1. Comparative Dissolution Profiles of Synjardy 12,5 mg/1000 mg Film-Coated Tablet (Reference Product) and Empagliflozin and Metformin HC1 12,5 mg/1000 mg Film-Coated Tablet (Test Product) in Quality Control Medium (The dissolution profile of Empagliflozin as active ingredient, when colloidal anhydrous silica as glidant only in extra-granular phase).

Figure 2. Comparative Dissolution Profiles of Synjardy 12,5 mg/1000 mg Film-Coated Tablet (Reference Product) and EmpagliflozinandMetformin HC1 12,5 mg/1000 mg Film-Coated Tablet (Test Product) in Quality Control Medium (The dissolution profile of Metformin as active ingredient, when colloidal anhydrous silica as glidant only in extra-granular phase). Figure 3. Comparative Dissolution Profiles of Synjardy 12,5 mg/1000 mg Film-Coated Tablet (Reference Product) and Empagliflozin and Metformin HC1 12,5 mg/1000 mg Film-Coated Tablet (Test Product) in Quality Control Medium (The dissolution profile of Empagliflozin as active ingredient, when colloidal anhydrous silica as glidant is both in intra- and extra- granular phase).

Figure 4. Comparative Dissolution Profiles of Synjardy 12,5 mg/1000 mg Film-Coated Tablet (Reference Product) and Empagliflozin and Metformin HC1 12,5 mg/1000 mg Film-Coated Tablet (Test Product) in Quality Control Medium (The dissolution profile of Metformin as active ingredient, when colloidal anhydrous silica as glidant is both in intra- and extra- granular phase).

Summary of the Invention

The present invention relates to the preperation of pharmaceutical compositions comprising Empagliflozin and Metformin or pharmaceutically acceptable salts thereof, and also relevant excipients, for use in the treatment of high blood sugar levels caused by type 2 diabetes.

For preparing the film coated tablet compositions of this invention, an improved process by wet granulation method have been used. The inventive composition comprises at least a glidant as pharmaceutical acceptable excipient, wherein the glidant is present both in an intra- and an extra-granular phase with a specific weight ratio and wherein an improved dissolution profile has been obtained.

Detailed Description of the Invention

“Wet granulation” is the most widely used process of granulation in the pharmaceutical industry. Wet granulation process can be very simple or very complex depending on the characteristics of the powders and the available equipments.

Basicly, wet granulation method involves addition of a liquid solution (with or without binder) to powders, to form a wet mass or it forms granules by adding the powder together with an adhesive, instead of by compaction. Then, drying process starts and then sized to obtained granules with desired mesh. The granulate may then be tabletted /compressed, or other excipients may be added prior to tableting with suitable excipients.

The term "oral solid dosage form" as used herein denotes solid preparations (e.g. tablets, capsules) for oral administration each containing a single dose of one or more active substances. The term “treatment” or “treating” means any treatment of a disease or condition in a subject, such as a mammal, including: 1) preventing or protecting against the disease or condition, that is, causing the clinical symptoms not to develop; 2) inhibiting the disease or condition, that is, arresting or suppressing the development of clinical symptoms; and/or 3) relieving the disease or condition that is, causing the regression of clinical symptoms.

As used herein, “pharmaceutically acceptable salt” refers to a salt of a compound that does not abrogate the biological activity and properties ofthe compound. Pharmaceutical salts can be obtained by reaction of a compound disclosed herein with an acid or base.

The term “% by total weight” is used herein to mean the percentage by weight of each ingredient in an uncoated pharmaceutical composition, based on the total weight of the uncoated pharmaceutical composition. The pharmaceutical composition is preferably in a form of a tablet, either uncoated or coated tablet.

The present invention relates to a wet granulation process for preparing a pharmaceutical composition comprising Empagliflozin and Metformin or pharmaceutically acceptable salts thereof, and also relevant excipients, for use in the treatment of high blood sugar levels caused by type 2 diabetes.

Excipients used in a formulation may adversely affect physicochemical and pharmacokinetic properties. These excipients can interact with the active ingredient. For this reason, while developing the formulation, the substances to be used in addition to the active substance must be carefully and consciously selected.

Preferably, the present invention relates to the pharmaceutical composition comprising Empagliflozin and Metformin or pharmaceutically acceptable salts thereof, and also relevant excipients, wherein the excipients are selected from the group including, but are not limited to solvents, diluents, lubricants, fdlers, disintegrants, binders, surfactants, and other materials known to one of ordinary skill in the art and the mixtures thereof.

Lubricants can also be used in the process. Lubricants are used for preventing adhesion of the tablet material to the surfaces of the die and punches. This helps to reduce the wear and tear on the tableting equipment and to prevent the formation of tablet defects, such as cracks or chips.

Suitable lubricants according to the present invention are selected from a group including, but are not limited to, calcium stearate, magnesium stearate, mineral oil, stearic acid, fumaric acid, sodium stearylfumarate, zinc stearate and polyethylene glycol and other materials known to one of ordinary skill in the art and mixtures thereof. The preferred lubricant is magnesium stearate. Binders can also be used in the process. Binder excipients are formulated to act as an adhesive to literally “bind together” powders, granules and other dry ingredients to impart to the product the necessary mechanical strength. They can also give volume to low active dose tablets.

Suitable binders according to the present invention are selected from the group including, but are not limited to, microcrystalline cellulose, starches, lactose, sugar alcohols like mannitol, polymers like polyvinylpyrrolidone, polyethylene glycol, isomalt, hypromellose (hydroxypropyl methylcellulose) and other materials known to one of ordinary skill in the art and mixtures thereof. The preferred binder for the inventive composition is povidone (polyvinylpyrrolidone) .

Solvents can also be used in the process. Solvents are excipients used to enhance solubility, taste, anti-microbial effectiveness or stability, to reduce dose volume (such as oral, injections). Conversely, solvents can be used to optimize insolubility (if taste of an active pharmaceutical ingredient is an issue).

Suitable solvents can be selected from the group, but not limited to, ethanol, ethyl alcohol, polyethylene glycol, propylene glycol, isopropyl alcohol, distilled water and other materials known to one of ordinary skill in the art and mixtures thereof. The preferred solvent is purified water.

Glidants can also be used in the process. Glidants are substances that is added to a powder to improve its flowability.

Glidants can be selected from the group, but are not limited to, colloidal silicon dioxide, colloidal silica, cornstarch, talc, calcium silicate, magnesium silicate, magnesium trisilicate, amorphous silica, colloidal silicon, silicon hydrogel, powdered cellulose, silicon dioxide, talc, tribasic calcium phosphate and other materials known to one of ordinary skill in the art. The preferred glidant is colloidal anhydrous silica.

Disintegrants can also be used in the process. Disintegrants are used for disintegrating tablets into fine particles in gastric and intestinal fluid, so that the other components of the composition can be quickly dissolved and absorbed to have a desired effect. Most of these substances have good water absorption and expansion, so as to achieve the disintegration of tablets.

Surprisingly, it is found that an appropriate dissolution profile can be obtained without any disintegrant, according to a series of essays for manufacturing process. The factor that brings out this situation is increasing the amount of Povidone as binder and colloidal anhydrous silica as glidant. The composition can be prepared without need for any disintegrant. The present invention relates to the preperation of pharmaceutical composition comprising Empagliflozin and Metformin or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients, wherein preferably povidone is used as binder, colloidal anhydrous silica can be used as glidant, magnesium stearate can be used as lubricant, purified water can be used as solvent.

Preferably the pharmaceutical compositions of the present invention comprising Empagliflozin and Metformin or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients, are prepared by a wet granulation process.

Preferably, the present invention relates to the pharmaceutical compositions comprising Empagliflozin and Metformin or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients, wherein the composition has an intra-granular phase and an extra-granular phase.

Preferably, the pharmaceutical compositions comprising Empagliflozin and Metformin or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients, wherein Empagliflozin and Metformin as active ingredients, a certain amount of glidant, binder and solvent are in the intra-granular phase.

Preferably, the pharmaceutical compositions comprising Empagliflozin and Metformin or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients, wherein remaining amount of glidant and lubricant are in the extra-granular phase.

Preferably, the pharmaceutical compositions comprising Empagliflozin and Metformin or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients, wherein Empagliflozin and Metformin as active ingredients, a certain amount of colloidal anhydrous silica as glidant, povidone as binder and purified water as solvent are in the intra-granular phase.

Preferably, the pharmaceutical compositions comprising Empagliflozin and Metformin or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients, wherein remaining amount of colloidal anhydrous silica as glidant and magnesium stearate as lubricant are in the extra-granular phase.

Preferably, the present invention relates to the pharmaceutical compositions comprising Empagliflozin and Metformin or pharmaceutically acceptable salts thereof, wherein 50% of total weight of colloidal anhydrous silica as glidant is present in the intra-granular phase. Preferably, the present invention relates to the pharmaceutical compositions comprising Empagliflozin and Metformin or pharmaceutically acceptable salts thereof, wherein the ratio of colloidal anhydrous silica as glidant present in the intra-granular phase is from 0,1 to 1% by total weight, preferably from 0,2 to 0,6 % by total weight, even more preferably from 0,3 to 0,5 % by total weight.

Preferably, the present invention relates to the pharmaceutical compositions comprising Empagliflozin and Metformin or pharmaceutically acceptable salts thereof, wherein the ratio of povidone as binder present in the intra-granular phase is from 3,5 to 7% by total weight, preferably from 4,5 to 5,5% by total weight.

Preferably, the present invention relates to the pharmaceutical compositions comprising Empagliflozin and Metformin or pharmaceutically acceptable salts thereof, wherein the ratio of colloidal anhydrous silica as glidant present in the extra-granular phase is from 0,1 to 1% by total weight, preferably from 0,2 to 0,6 % by total weight, even more preferably from 0,3 to 0,5 % by total weight.

Preferably, the present invention relates to the pharmaceutical compositions comprising Empagliflozin and Metformin or pharmaceutically acceptable salts thereof, wherein the ratio of magnesium stearate as lubricant present in the extra-granular phase is from 0,2 to 0,8% by total weight, preferably from 0,35 to 0,65% by total weight.

In present invention it is surprisingly found that a better dissolution profile can be obtained, when colloidal anhydrous silica as glidant is used both in intra- and in extra-granular phase, relative to the use of only in extra-granular phase. According to a series of essays for manufacturing process, the use of colloidal anhydrous silica in extra-granular phase is providing an improvement on flow process of the composition, and concurrently use of in intra-granular phase is providing an improvement on dissolution profile.

The process of the invention may comprise the steps below:

1) Mixing povidone with a sufficient amount of purified water and preparing a homogenous solution,

2) Sieving Empagliflozin and Metformin HC1,

3) Loading the substances from step 1 and 2 into high shear granulator and mixing at a certain speed,

4) Adding the granulation solution on to the mix from step 3 and keeping on mixing for preparing a homogenous solution, 5) Sieving the wet granules obtained after step 4,

6) Drying the granules from step 5,

7) Sieving the dried granules from step 6,

8) Sieving the colloidal anhydrous silica and mixing it with granules from step 7 homogenously,

9) Sieving the magnesium stearate and adding it to the mix from step 8 homogenously,

10) Tablet compressing,

11) Film coating of the tablets.

Preferably the pharmaceutical composition according to the present invention may be in the form of a tablet, capsule, caplet, film-coated tablet, enteric tablet, controlled-release tablet and any similar solid oral dosage forms. The preferred dosage form according to the present invention is film-coated tablet form. Commonly available coating materials may be used for coating of tablets.

The embodiment examples for inventive pharmaceutical film-coated tablet composition are given as detailed in Table 1 and Table 2 below. These examples are not limiting the scope of the present invention and is to be considered according to the foregoing detailed description. Any other modifications of the composition or production methods are possible if they are implemented in line with maintaining the stability of the composition and the dissolution profile of the active substance.

Example 1 is related to the case of adding all colloidal anhydrous silica as glidant only to extra- granular phase and Example 2 is related to the case of adding colloidal anhydrous silica as glidant to both of intra- and extra-granular phase. Also the dissolution profiles of these examples are given below for the comparison of two different cases and so for putting forward the improvement, when adding colloidal anhydrous silica as glidant to both of intra- and extra- granular phase. The process flows related to the Examples are also given below each table.

Table 1: Example 1 for the Composition of Empagliflozin (12,5 mg) and Metformin (1000 mg)

- Film Coated Tablet (Colloidal anhydrous silica as glidant is only in extra-granular phase)

Process flow for Preparing of Example 1 is summarized as below: a) Mixing povidone with a sufficient amount of purified water and preparing a homogenous solution, b) Sieving Empagliflozin and Metformin HC1, c) Loading the substances from step b into high shear granulator and mixing at a certain speed, d) Adding the granulation solution on to the mix from step c and keeping on mixing for preparing a homogenous solution, e) Sieving the wet granules obtained after step d, f) Drying the granules from step e, g) Sieving the dried granules from step f, h) Sieving the colloidal anhydrous silica and mixing it with granules from step g homogenously, i) Sieving the magnesium stearate and adding it to the mix from step h homogenously, j) Tablet compressing, k) Film coating of the tablets. Table 2: Example 2 for the Composition of Empagliflozin (12,5 mg) and Metformin (1000 mg)

- Film Coated Tablet (Colloidal anhydrous silica is in both intra- and extra-granular phases)

Process flow for Preparing of Example 2 is summarized as below: a) Mixing povidone with a sufficient amount of purified water and preparing a homogenous solution, b) Sieving Empagliflozin, Metformin HC1 and a certain amount of colloidal anhydrous silica, c) Loading the substances from step b into high shear granulator and mixing at a certain speed, d) Adding the granulation solution on to the mix from step c and keeping on mixing for preparing a homogenous solution, e) Sieving the wet granules obtained after step d, f) Drying the granules from step e, g) Sieving the dried granules from step f, h) Sieving the colloidal anhydrous silica and mixing it with granules from step g homogenously, i) Sieving the magnesium stearate and adding it to the mix from step h homogenously, j) Tablet compressing, k) Film coating of the tablets. Dissolution Tests

Dissolution test values for pharmaceutical compositions are one of the essential parameters for process development and solid dosage manufacturing. General properties of relevant batches are shown in Table 3.

Table 3: Summary of Batches used in In Vitro Dissolution Tests

In the dissolution analysis for comparison of Synjardy 12,5 mg/1000 mg Film Coated Tablet (FCT) (Reference Product) and the Test Product obtained in the scope of the 1st Example (Colloidal anhydrous silica as glidant is only in extra-granular phase), quality control medium is used. It is shown in Figure 1 that Empagliflozin release of Test Product is found not to be satisfactory and not compatible with Synjardy 12,5 mg/1000 mg FCT (Reference Product).

In the dissolution analysis for comparison of Synjardy 12,5 mg/1000 mg Film Coated Tablet (FCT) (Reference Product) and the Test Product obtained in the scope of the 1st Example (Colloidal anhydrous silica as glidant is only in extra-granular phase), quality control medium is used. It is shown in Figure 2 that Metformin release of Test Product is found not to be satisfactory and not compatible with Synjardy 12,5 mg/1000 mg FCT (Reference Product).

In the dissolution analysis for comparison of Synjardy 12,5 mg/1000 mg Film Coated Tablet (FCT) (Reference Product) and the Test Product obtained in the scope of the 2nd Example (Colloidal anhydrous silica as glidant is both in intra- and extra-granular phase), quality control medium is used. It is shown in Figure 3 that Empagliflozin release of Test Product is found to be satisfactory and compatible with Synjardy 12,5 mg/1000 mg FCT (Reference Product). In the dissolution analysis for comparison of Synjardy 12,5 mg/1000 mg Film Coated Tablet (FCT) (Reference Product) and the Test Product obtained in the scope of the 2nd Example (Colloidal anhydrous silica as glidant is both in intra- and extra-granular phase), quality control medium is used. It is shown in Figure 4 that Metformin release of Test Product is found to be satisfactory and compatible with Synjardy 12,5 mg/1000 mg FCT (Reference Product).

In conclusion, it is observed that the release of both active ingredients is delayed, when colloidal anhydrous silica as glidant is added only to extra-granular phase. However, as it is clearly stated on dissolution profiles, the release of both active ingredients of the combination has improved and compatible with reference product, when colloidal anhydrous silica as glidant is added both to intra- and extra-granular phase.

Claims

1. A pharmaceutical composition comprising Empagliflozin and Metformin or pharmaceutically acceptable salts thereof, where glidant is both in intra-granular phase and extra-granular phase.

2. A pharmaceutical composition according to Claim 1, characterized in that 50% of total weight of glidant is in intra-granular phase.

3. A pharmaceutical composition according to Claim 1, characterized in comprising colloidal anhydrous silica as glidant both in intra-granular phase and in extra-granular phase.

4. A pharmaceutical composition according to Claim 1, characterized in further comprising Povidone as binder in intra-granular phase.

5. A pharmaceutical composition according to Claim 1 or 2, characterized in further comprising Magnesium stearate as lubricant in extra-granular phase.

6. A pharmaceutical composition according to any one of the previous claims, wherein Purified Water is used as solvent.

7. A pharmaceutical composition according to any one of the previous claims, wherein the amount of povidone as binder is preferably 3,5 to 7%, more preferably 4,5 to 5,5% by total weight.

8. A pharmaceutical composition according to any one of the previous claims, wherein the amount of colloidal anhydrous silica as glidant in intra-granular phase is preferably 0, 1 tol%, more preferably 0,2 to 0,6%, even more preferably 0,3 to 0,5% by total weight.

9. A pharmaceutical composition according to any one of the previous claims, wherein the amount of magnesium stearate as lubricant is preferably 0,2 to 0,8%, more preferably 0,35 to 0,5% by total tablet weight.

10. A process for preparing a pharmaceutical composition according to any one of the previous claims, wherein

- % 50 of colloidal anhydrous silica as a glidant, Povidon as a binder, and purified water as a solvent are used in the intra-granular phase, and

- % 50 of colloidal anhydrous silica as a glidant and magnesium stearate as a lubricant are used in the extra-granular phase.

11. Process according to any one of the previous claims, wherein the process comprising the steps of: a) Mixing povidone with purified water to prepare a homogenous solution, b) Sieving Empagliflozin, Metformin HC1 and colloidal anhydrous silica, c) Loading the substances from step b into high shear granulator and mixing a d) Adding the granulation solution on to the mix from step c and keeping on mixing for preparing a homogenous solution, e) Sieving the wet granules obtained after step d, f) Drying the granules from step e, g) Sieving the dried granules from step f, h) Sieving the colloidal anhydrous silica and mixing it with granules from step g homogenously, i) Sieving the magnesium stearate and adding it to the mix from step h homogenously, j) Tablet compressing, k) Film coating of the tablets.

12. A pharmaceutical composition according to any one of the previous claims, for use in the treatment of high blood sugar levels caused by type 2 diabetes.