WO2018034627A1

WO2018034627A1 - Pharmaceutical composition of antidiabetic tablet

Info

Publication number: WO2018034627A1
Application number: PCT/TR2016/050293
Authority: WO
Inventors: Hatice Öncel; Yilmaz Çapan; Onur PINARBAŞLI; Sibel AKANSEL; Nagehan SARRAÇOĞLU
Original assignee: Ilko Ilac Sanayi ve Ticaret AS
Current assignee: Ilko Ilac Sanayi ve Ticaret AS
Priority date: 2016-08-18
Filing date: 2016-08-18
Publication date: 2018-02-22
Anticipated expiration: 2019-02-18

Abstract

The present invention relates to the pharmaceutical fixed dose combination tablet comprising repaglinide and metformin by having specific criteria of particle size distribution and tapped density of repaglinide and metformin granules with an improved mixing process. The present invention also provides an effective method of producing the said tablet in terms of cost and time.

Description

DESCRIPTION

PHARMACEUTICAL COMPOSmON OF ANTIDIABETIC TABLET

Technical field: The present invention relates to a pharmaceutical fixed dose combination tablet comprising repaglinide and metformin or a salt thereof and a method of producing said tablet by using a mixing process with optimal ratio of particle size distribution and tapped density of repaglinide and metformin granules.

Prior Art: Metformin HCI is an oral antihyperglycemic drug used in the treatment of non-insulin dependent diabetes mellitus (NIDDM). It is described in US 3,174,901 is a long-acting biguanide antidiabetic. The Ν, Ν-dimethylimidocarbonimidic diamide hydrochloride, corresponding chemical name, and it is not chemically or pharmacologically related to any other class of oral antihyperglycemic agents. The structural formula is represented below:

Metformin HCI is a white to off-white crystalline compound with a molecular formula of C₄H N₅ · HCI and molecular weight of 165.63 g/mol. It is freely soluble in water and relatively incompressible. Therefore the additional processing is necessary because of the ineffectiveness of direct compression techniques. This problem can be overcomed by wet granulation which contains binders or other materials that have high binding capacity; or by increasing the residual moisture in blend prior to compression.

Repaglinide is a short-acting oral hypoglycemic agent structurally unrelated to the sulphonylurea drugs which is disclosed in European patent application No. 0 589 874. It lowers blood glucose levels acutely by stimulating the release of insulin from the pancreas, an effect which depends on functioning beta cells in the pancreatic islets. The chemical name is (S)-2-Ethoxy-4-[2-[[3-methyl-1 -[2-(1 -piperidinyl)phenyl]butyl]amino]-2- oxoethyl]benzoic acid witha structural formula shown below:

Repaglinide is a white to off-white powder with needle shape crystals with a molecular formula of C2 H36N2O4 and molecular weight of 452.586 g/mol. It is slightly soluble in aqueous acid, very slightly soluble in aqueous base and freely soluble in ethanol and methanol. It is an acid-base ampholyte, with two protonation sites of which pKa values are pKal (acid) 3.9 and pKa2 (amine) 6.0.

Diabetes is characterised by an impaired glucose metabolism manifesting itself among other things by an elevated blood glucose level in the diabetic patients. Underlying defects lead to a classification of diabetes into two major groups: Type 1 diabetes, or insulin demanding diabetes mellitus (IDDM), which arises when patients lack β-cells producing insulin in their pancreatic glands, and type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), which occurs in patients with an impaired β-cell function besides a range of other abnormalities.

In WO 2008037807 A1 , combination therapy of repaglinide with metformin is described as having superior glycemic control compared with repaglinide or metformin monotherapy in patients with type 2 diabetes whose glycemia had not been well controlled on metformin alone. The use of repaglin ide along with metformin has been demonstrated to be synergistic in rats in controlling N IDD M related symptoms when compared with the use of either of the compounds alone. Combination of repaglinide and metformin is marketed under the trademark PRANDIMET® to NovoNordisk. It is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are already treated with a meglitinide and metformin HCI or who have inadequate glycemic control on a meglitinide alone or metformin HCI alone.

European patent EP101 1673 B1 describes a pharmaceutical combination comprising repaglinide and metformin, said combination drug that shows the fast dissolution and immediate release drug release profile combined with adequate stability. Wherein repaglinide granulate is obtained by a spray drying process or by using the active triturate, which is a mixture of repaglinide spray drying granulate and microcrystalline cellulose. EP101 1673 B1 patent indicates that the solubility problem of repaglinide could be overcomed by this method. Moreover, content uniformity problem of repaglinide could be solved by the co-granulation of repaglinide active triturate and metformin with the fluidized bed granulation technique.

US2010/0029721 A1 discloses an invention which is related to a method for preparation of a pharmaceutical composition of repaglinide in combination with metformin in unit dosage form comprising (a) preparing a repaglinide pre-formulation granulate comprising repaglinide having a pH independent dissolution profile; (b) drying the repaglinide pre- formulation granulate to a relative humidity of less than about 25%; (c) mixing the repaglinide pre-formulation granu late from (b) with metformin or a salt thereof and optionally one or more pharmaceutically acceptable excipients; and (d) processing the mixture of (c) into the unit dosage form . In this invention, repaglinide triturate and metfomin granulate was mixed with excipients in a number of mixing steps and suitable mixers namely diffusive double cone mixer.

As can be understood from the previous patents, chemical compounds of repaglinide and metformin are difficult to handle in pharmaceutical process. Therefore, there is still a need for developing pharmaceutical compositions which incorporate repaglinide and metformin methods for preparing such compositions with time and cost effective process without the active ingredient release properties being affected.

Description of the Invention: The aim of present invention is to develop a tablet formulation with pharmaceutical composition of repaglinide and metformin or a salt thereof for oral intake.The present invention leads to develop a tablet formulation having specific criteria of particle size distribution and tapped density of repaglinide and metformin granules with an improved mixing process to overcome content uniformity problem of repaglinide. The developed formulation should have fast dissolution profile and high stability of the said active ingredients. In addition, it is also an aim of the present invention to provide a process to prepare such pharmaceutical compositions, particularly tablets, which can be applied at an industrial level with low cost in energy and effective in time plus does not make the active ingredient subject to aggressive formulation conditions that can entail stability loss. Moreover, the present invention enables a bioequivalence product with commercially available repaglinide - metformin combination that marketed under the trade name of Prandimet® 2mg-500mg Film Coated Tablets. Metformin could be used as salt form such as hydrochloride, acetate, maleate, fumarate, succinate etc. A detailed description of the different salts of metformin is described in the literature and is available in U.S. Pat. No. 6,031 ,004. In the present invention, metformin is metformin hydrochloride. In the tablet formulation, there are some technical problems to be overcome. Such as, metformin hydrochloride is more than 75% w/w and repaglinide is less than 0.5% w/w of the composition which causes content uniformity problems. Another problem is bad flow property of metformin which causes compressibility problems.

The term 'mixing' is used in its normal meaning and will encompass any conventional mixing process.

Furthermore, in the current invention, the dosage form formulation has an immediate release formulation property. The term "immediate release formulation" as used herein is defined as a formulation showing a release of the active substance(s) that is not deliberately modified by a special formulation design and/or manufacturing method. In one aspect of the unit dosage form formulation according to the invention is 85% or more of the drug(s) is released within 1 5 minutes tested under mild dissolution test conditions (<50 rpm/paddle) of 0.1 N HCI.

The authors of the present invention found that the method for preparing repaglinide and metformin granulates which enables fast dissolution profile, ease of flow property and stability without spray drying and co-granulating methods in use.

It is a particular challenge to a pharmaceutical scientist to develop the type of formulation as described one active substance, with the low-dose and low-solubility of repaglinide, is being uniformly dispersed in another active substance, the high-dose and highly water- soluble metformin or a salt thereof, where both active substances are eventually released at the desired rate.

It is highly crucial to develop a mixing method given the reasons stated above. And it is also precious to develop such a method with using conventional mixing procedure without any special mixing equipment such as diffusive double cone mixer.

The main criteria in mixing procedure of pharmaceutical composition comprising metformin and repaglinide is the particle size ratio between metformin and repaglinide granules.

According to the main criteria which is about particle size distribution, the particle size distribution (d90) of metformin granule is between of 300-800 μιη , preferably 350-450 μιη and particle size distribution(d90) of repaglinide granule is between of 150-400 μιη , preferably 250-350 μιη determined by the method of laser diffraction in a dry dispersion system in the present invention (Malvern Mastersizer-2000, single narrow mode, sample refractive index: 1 .50, vibration rate:30%, obscuration: 0.5%-5.0%).

Criteria of particle size ratio between metformin and repaglinide granules is described below:

i) Particle size distribution (d90) of metformin granule is less than or equal to three times of particle size distribution (d90) of repaglinide granule,

ii) Particle size distribution (d50) of metformin granule is less than or equal to three times of particle size distribution (d50) of repaglinide granule

iii) Particle size distribution (d1 0) of metformin granule is less than or equal to three times of particle size distribution (d10) of repaglinide granule. Particle size distribution test is applied by laser diffraction in a dry dispersion system (Malvern Mastersizer-2000, single narrow mode). Laser diffraction enables to measure particle size distributions by measuring the angular variation by scattering light intensity as a laser beam passes through a dispersed particulate sample. Large particles scatter light at small angles relative to the laser beam and small particles scatter light at large angles. The angular scattering intensity data is then analyzed to calculate the size of the particles responsible for creating the scattering pattern, using the Mie theory of light scattering. The particle size is reported as a volume equivalent sphere diameter.

A common approach to define the distribution width is to cite three values on the x-axis as d10, d50 and d90. The d50, named as median, has been defined as the diameter where 50 percent of the distribution lies below this value. Similarly, d90 has been defined as 90 percent of the distribution lies below, and 10 percent of the population lies below the d10.

The particle size has a profound influence on almost every step in tablet manufacturing, including mixing, granulation, compression, and coating (Shekunov BY, Chattopadhyay P, Tong HH, Chow AH., Particle size analysis in pharmaceutics: principles, methods and applications. Pharm Res. 2007 Feb;24(2):203-27). Besides the manufacturability of tablets, the dissolution rate, which is proportional to surface area of drugs, is largely dependent on particle size distribution of drug particles.

As the additional criteria, tapped density of the metformin granule may be less than or equal to two times of the tapped density of repaglinide granule. In the present invention, metformin granule has a tapped density between 0.4 and 0.8 g/m L, and repaglinide granule has a tapped density between of 0.3 and 0.6 g/MI measured by USP Method 2 (Erweka SVM-102 tapped density tester, stroke height 3.0 mm , 100 strokes/min) .

Criteria of tapped density ratio between metformin and repaglinide granules is described below:

i) Tapped density of metformin granule is less than or equal to two times of tapped density of repaglinide granule.

In USP tapped density is defined as an increased bulk density attained after mechanically tapping a container containing the powder sample. Tapped density is obtained by mechanically tapping a graduated measuring cylinder or vessel containing a powder sample. After observing the initial powder volume or weight, the measuring cylinder or vessel is mechanically tapped, and volume or weight readings are taken until little further volume or weight change is observed.

In the present invention, Erweka SVM-102 tapped density tester is used for measuring tapped density. It has been designed to measure tapped volume and tapped density of powders, granules and similar products. It is available for holding one or two glass cylinders and works according USP method.

In the present invention, the tapped density measurents are applied as follows: A measuring cylinder is weighed on a top pan balance (2 place). Approximately 50 g powder is introduced into the measuring cylinder, and the weight is recorded. The measuring cylinder containing the powder is attached to a jolting volumeter. The jolting volumeter is set to tap 100 times. During each tap, the measuring cylinder is raised and allowed to fall a set distance. After the 100 taps, the volume of the powder is measured. The tapping is repeated and the new volume measured. The tapping process is continued until the powder will settle to its limits. The tapped density is calculated as the weight of the powder divided by the final tap volume (g/m L). The procedure is performed three times (with new powder each time) for each measured powder, and the mean tapped density calculated from those three final tapped volume values. Particle size ratio and tapped density ratio between repaglinide and metformin granule has not been considered anywhere to overcome the content uniformity problem of repaglinide in repaglinide - metformin tablet. By using these criterions with developed mixing procedure explained below, the content uniformity problem has been overcome properly. In the present invention, repaglinide and metformin granules are manufactured separately with fluidized bed spray granulation method. In this method; repaglinide, suitable surfactant, pH agent and binder is dissolved in the mixture of ethanol and water. Obtained solution is sprayed onto microcrystalline cellulose and microcrystalline cellulose covered with repaglinide. Poloxamer, meglumine (N-methylglucamine) and polyvinylpyrrolidone (PVP K-25) are preferred as surfactant, pH agent and binder, respectively.

Metformin is granulated with water solution of suitable binders and fillers according to fluidized bed spray granulation method. Polyvinylpyrrolidone (PVP K-25), sorbitol and polyethylene glycol 6000 are preferred as binder and filler. After ensured all criteria of particle size distribution and tapped density of granules mentioned above, repaglinide granules, metformin granules and other excipients should be mixed as written below and shown in Figurel .

Repaglinide and metform in granule are mixed. Obtained blend mixed with disintegrants, fillers. Polacrilin potassium and microcrystalline cellulose (Avicel PH1 02) is preferred as disintegrant and filler. Then, the final blend is obtained by adding lubricants.

In the preferred embodiments of this invention, the solid dosage form is a tablet preferably a film coated tablet. The amount of repaglinide is 0.5 - 10 mg, preferably 0.5 - 2 mg and metformin is 100 - 3000 mg, preferably 200 - 1000 mg respectively.

The tablet composition according to present invention generally comprises 5 to 95 wt.%, preferably 60 to 80 wt.%, of active ingredients; 1 to 10 wt.%, preferably 3 to 5 wt.%., of wet granulation binder; 0 to 80 wt.%, preferably 5 to 15 wt.%, of filler and 0 to 30 wt.%, preferably 1 to 10 wt.%, of disintegrant.

Examples of suitable diluents include, but are not limited to one or more of lactose, lactose monohydrate, mannitol, sucrose, maltodextrin, dextrin, maltitol, sorbitol, xylitol, powdered cellulose, cellulose gum , microcrystalline cellulose, starch, calcium phosphate, or metal carbonate.

Examples of suitable binders include, but are not limited to one or more of starch, gums, pregelatinized starch, polyvinylpyrrolidone (PVP), copovidone, cellulose derivatives, such as hydroxypropylmethylcellulose, hydroxypropylcellulose, and carboxymethylcellulose and their salts.

Examples of suitable lubricants include, but are not limited to one or more of talc, magnesium stearate, calcium stearate, polyethylene glycol, hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate. Examples of suitable disintegrants include, but are not limited to one or more of starch, croscarmellose sodium , cross povidone, sodium starch glycolate and polacrilin potassium .

Examples of suitable surfactants include, but are not limited to one or more of poloxamers or pluronics, polyethylene glycols, polyethylene glycol monostearate, polysorbates, sodium lauryl sulphate, and polyethoxylated and hydrogenated castor oil.

Examples of suitable pH adjusters include, but are not limited to one or more of alkali metal salts, e.g. alkali metal hydroxides such as NaOH and KOH, NaHC0₃, KHC0₃, Na₂C0₃, K₂C0₃, Na₂HP0₄, K₂HP0₄,basic amino acids such as arginine, lysine and meglumine (N-methyl-D-glucamine). Repaglinide- Metformin HCI Film Coated Tablet is prepared according to the unit formula below:

Table 1. Unit formula of Repaglinide- Metformin HCI Film Coated Tablet

Example 1. Repaglinide-Metformin HCI Film Coated Tablet formulations are representatives of the preferred compositions of the present invention. Example 1 is prepared according to the unit formula below:

Mixing Procedure: Repaglinide, polyvinyl pyrrolidone, N-methylglucamine and poloxamer 188 are solved in etanol-water mixture. This solution is sprayed onto microcrystalline cellulose and therefore repaglinide granules are obtained by spray granulation.

Metformin is granulated with the water solution of sorbitol, polyethylene glycol 6000 and polyvinyl pyrrolidone and therefore metformin granule is obtained by spray granulation method. And then, repaglinide and metformin granules are mixed. Obtained blend is mixed with polacrilin potassium , microcrystalline cellulose. Then, the final blend is obtained by adding magnesium stearate. Final blend is pressed into tablets and tablets are film coated. Content uniformity of repaglinide is problematic as mentioned reasons above. The invention is further clarified by testing content uniformity with two examples, namely Example 1 A and Example 1 B. Same unit formula (written in Example 1 ) and same mixing procedure are used with different particle size distribution ratio and tapped density ratio of repaglinide and metformin granules.

Example 1 A: Unit formula and mixing procedure written in Example 1 are used with repaglinide and metformin granules.

The results of particle size distribution for used active substances, repaglinide and metformin, were measured by the method of laser diffraction in a dry dispersion system (Malvern Mastersizer-2000, single narrow mode, sample refractive index: 1.50, vibration rate:30%, obscuration: 0.5%-5.0%) are given below.

Metformin HCI (M) 284,130 μιη 426,203 μιη 890,568 μιη Repaglinide (R) 39,929 μιη 92,846 μιη 282,179 μιη Ratio (M/R) 7,12 4,59 3,15

The results of tapped density for used active substances, repaglinide and metformin, measured by USP Method 2 (Erweka SVM- 102 tapped density tester, stroke height 3.0 mm , 100 strokes/min) are given below.

Tapped density (g/mL)

Metformin HCI (M) 0,92 Repaglinide (R) 0,42 Ratio (M/R) 2,19 Example 1 B: Unit formula and mixing procedure written in Example 1 are used with repaglinide and metform in granules.

The results of particle size distribution for used active substances, repaglinide and metformin, were measured by the method of laser diffraction in a dry dispersion system (Malvern Mastersizer-2000, single narrow mode, sample refractive index: 1 .50, vibration rate:30%, obscuration: 0.5%-5.0%) are given below.

Tapped density (g/mL)

Metformin HCI (M) 0,57

Repaglinide (R) 0,42

Ratio (M/R) 1 ,36

Results: Example 1 A is not ensured particle size distribution criteria and tapped density criteria; particle size (d90) of metformin granule is 3.2 times to repaglinide granule and tapped density of metformin granule is 2.19 times to repaglinide granule. Example 1 B is ensured both criteria of particle size distribution and tapped density of granules. Example 1 A procedure gives unsuitable content uniformity results which are given in Table 2. In the present invention, applying this mixing procedure with ensured both criteria of particle size distribution and tapped density of granules (Example 1 B) develops a surprising effect on content uniformity. In a further embodiment, the relative standard deviation of the content uniformity is less than 2.0% as can be seen in Table 3 for tablets prepared by developed mixing procedure with ensured both criteria of mean particle size distribution and tapped density of granules (Example 1 B). Table 2. Results of Example 1 A (Content Uniformity of Repaglinid and Weight Uniformity of Metformin HCI)

Sample Kcpaglinidc <<< ) Metformin HCl (%)

1 127.5 100.5

2 120.6 101.6

3 116.5 100.9

4 124.3 102.1

5 117.3 99.6

6 119.6 99.5

7 118.7 102.6

8 120.5 100.8

9 128.5 99.9

10 127.6 102.4

Average 122.1 101.0

SD 4.50 1.15

RSD % 3.68 1.13

Table 3. Results of Example 1 B (Content Uniformity of Repaglinid and Weight Uniformity of Metformin HCI)

Sample Uepagliniflc l ' c ) Metformin HCI (%)

1 102.1 99.3

2 100.6 102.4

3 101.4 101.0

4 101.5 102.6

5 100.2 101.3

6 101.9 100.8

7 99.8 99.7

8 102.4 102.6

9 101.0 101.3

10 100.7 101.4

Averag< ϊ 1012 1012

SE ► 0.8 1.1

RSD <¾ ^■> 0.8 1.1

As can be obviously seen in the results, ensuring both criteria of mean particle size and tapped density of repaglinide and metformin granules highly affect the content uniformity of the repaglinide, but not affect the metformin weight uniformity results . After producing tablets having proper content uniformity results , other pharmaceutical tests are applied to show tablets have fast dissolution profile, product stability of said active ingredients and bioequivalence to commercially available repaglinide and metformin combination formulation marketed under the trade name of Prandimet® 2 mg-500 mg Film Coated Tablets.

In one aspect of the invention, the unit dosage form formulation releases each active substance from the unit-dose formulation at a rate similar to or faster than that of marketed product in individual form (Prandimet® 2 mg-500 mg Film Coated Tablets, Novo Nordisk). In order to determine the tablets similarity the dissolution profile of the unit dosage form formulation may be compared according to the invention and the individual products as described in the similarity test (f2-test) (25 Aug. 1997. Dissolution Testing of Immediate Release Solid Oral Products. Guidance for Industry). The dissolution profile of the unit dose formulation according to the invention may be measured in several aqueous buffer solutions in the pH range of 3-7.5. Dissolution of repaglinide is strongly pH-dependant. The pH- value of 5.0 is the most sensitive level for performing dissolution tests. Dissolution data of the present invention prepared according to Example 1 B is given in Table 4 with pH 5.0, Paddle, citric acid-phosphate buffer, 900 imL, 50 rpm condition which is registered to FDA for Repaglinide-Metformin tablet. In addition, the formulation of the present invention show a dissolution profile substantially similar to that of the product marketed under the trade name Prandimet® 2 mg-500 mg Film Coated Tablets. Table 4. Dissolution data of Repaglinide-Metformin HCI 2 mg/500 mg Film Coated Tablet of Example 1 B in dissolution medium pH 5.0, Paddle, citric acid-phosphate buffer, 900 imL, 50 rpm

Bioequivalence means the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives become available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.

In-vivo study was conducted in healthy human volunteers to asses bioequivalence of Example 1 B Repaglinide- Metformin 2mg-500mg Film Coated Tablet of the invention with that of Prandimet® 2mg-500mg Film Coated Tablets. Table 5 and Table 6 provides summary of pharmacokinetic parameters under fast conditions of Repaglinide - Metformin HCIFilm Coated Tablet formulation prepared by Example 1 against Prandimet® 2 mg - 500 mg Film Coated Tablets.

The composition of the invention exhibits bioequivalence to commercially available repaglinide and metformin combination formulation marketed under the trade name Prandimet® 2mg-500mg Film Coated Tablets.

Table 5. Pharmacokinetic parameters of repaglinide for composition of the present invention prepared by Example 1 B against Prandimet® 2 mg - 500 mg Film Coated Tablets.

Table 6. Pharmacokinetic parameters of Metformin HCI for composition of the present invention prepared by Example 1 B against Prandimet® 2 mg - 500 mg Film Coated Tablets.

In a further aspect of the invention, the unit dosage form of formulation according to the invention is physically and chemcally stable. Stability of the tablets can be measured at accelerated as well as at long term storage conditions for periods of several weeks. Experiments can be performed at different temperatures and humidities . The oral pharmaceutical compositions of the present invention which are prepared according to Example 1 B were subjected to accelerated stability studies at 40 ±2°C, 75±5 % RH conditions. Repaglinide- Metformin HCI Film Coated Tablets are stable according to assay, dissolution and related substances at 40 ±2°C, 75±5 % RH conditions for 6 months. This procedure can be applied at an industrial level with low energy costs and time effectively with respect to other methods used in Repaglinide-Metformin Tablet production. In a further embodiment, there are less mixing steps and sieving steps with respect to other procedures and also for the mixing step a conventional mixer which is known as cubic mixer is used. In production method developed by Novo Nordisk, a suitable mixer namely diffusive double cone mixer is used with a number of mixing and sieving steps in order to ensure the content uniformity of repaglinide. The present invention gets an edge over Novo Nordisk production method by lowering the production steps with low energy costs and time efficiency.

REPAGLINIDE GRANULE

METFORMIN GRANULE

DISINTEGRANTS FILLERS

Figure 1 : Flow sheet of process

Claims

CLAIMS . A pharmaceutical tablet composition comprising repaglinide in combination with metformin or a salt thereof, wherein repaglinide and metformin is granulated with solution of suitable binders and fillers by fluidized bed spray granulation method separately, wherein repaglinide and metformin granules characterized as,

i) metformin granule has particle size distribution (d90) between 300 - 800 μιη, and ii) repaglinid granule has particle size distribution (d90) between 150 - 400 μιη , and iii) particle size distribution (d90) of metformin granule is less than or equal to three times of particle size distribution (d90) of repaglinide granule.

2. A pharmaceutical tablet according to claim 1 , wherein particle size distribution (d90) of metformin granule is between 350 - 450 μιη .

3. A pharmaceutical tablet according to claim 1 , wherein particle size distribution (d90) of repaglinid granule is between 250 - 350 μιη .

4. A pharmaceutical tablet according to claim 1 , wherein tapped density of metformin granule is less than or equal to two times of tapped density of repaglinide granule.

5. A pharmaceutical tablet according to claim 4, wherein metformin granule has a tapped density between of 0.4 and 0.8 g/mL.

6. A pharmaceutical tablet according to claim 4 or 5, wherein repaglinide granule has a tapped density between of 0.3 and 0.6 g/m L.

7. A pharmaceutical tablet according to claim 1 , wherein the binder for the preparation of repaglinide or metformin granule is selected from the group consisting of starch, gums, pregelatinized starch, polyvinyl pyrrolidone (PVP), copovidone, cellulose derivatives, such as hydroxypropylmethylcellulose, hydroxypropylcellulose, and carboxymethylcellulose and their salts.

8. A pharmaceutical tablet according to claim 1 , wherein the diluent for the preparation of repaglinide or metformin granule is selected from the group consisting of lactose, lactose monohydrate, mannitol, sucrose, maltodextrin, dextrin, maltitol, sorbitol, xylitol, powdered cellulose, cellulose gum , microcrystalline cellulose, starch, cabium phosphate, or metal carbonate.

9. A pharmaceutical tablet according to claim 1 , wherein the disintegrant is selected from the group consisting of starch, croscarmellose sodium, crosspovidone, sodium starch glycolate and polacrilin potassium.

10. A pharmaceutical tablet according to claim 1 , wherein the lubricant is selected from the group consisting of talc, magnesium stearate, calcium stearate, polyethylene glycol, hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate.

1 1 . A pharmaceutical tablet according to claim 1 , the process for preparing a pharmaceutical tablet comprising the steps of:

a) Repaglinide and metformin is granulated with solution of suitable binders and fillers by fluid ized bed spray granulation method separately,

b) Obtained repaglinide and metformin granules in step a) are mixed,

c) Obtained blend in step b) is mixed with disintegrant and filler,

d) The final blend is obtained by adding lubricant to obtained blend in step c), e) The final blend obtained in step d) is compressed to tablet form ,

f) Optionally obtained tablet in step e) is coated by film .

12. The process according to claim 1 1 , Repaglinide is granulated with etanol-water solution of poloxamer, meglumine (N-methylglucamine) and polyvinylpyrrolidone (PVP K-25).

13. The process according to claim 1 1 , Metformin is granulated with water solution of Polyvinylpyrrolidone (PVP K-25), sorbitol and polyethylene glycol 6000.

14. A pharmaceutical tablet according to claim 1 , wherein it comprises;

a) 60 to 80 wt.% of active ingredients as repaglinide and metformin,

b) 3 to 5 wt.% of wet granulation binder as polyvinylpyrollidone.

c) 5 to 15 wt.%, of diluents as m ic roc rystal line cellulose and sorbitol.

d) 1 to 10 wt.%, of disintegrant as polacrilin potassium .

15. The pharmaceutical tablet according to any of the previous claims, wherein it comprises 0.5 mg to 2 mg of repaglinide and 500 mg to 1000 mg of metformin.