WO2008062273A2

WO2008062273A2 - Solid oral dosage form having antidiabetic drug combination

Info

Publication number: WO2008062273A2
Application number: PCT/IB2007/003513
Authority: WO
Inventors: Indravadan Ambalal Modi; Ashok Omray; Kartik Y. Shah; Bakuleh Mafatlal Khamar
Original assignee: Cadila Pharmaceuticals Limited
Priority date: 2006-11-20
Filing date: 2007-11-16
Publication date: 2008-05-29
Also published as: WO2008062273A8; WO2008062273A3

Abstract

The present invention relates to solid oral dosage form for the treatment of non-insulin dependant type diabetes (diabetes of type II) using a combination of pharmaceutically acceptable salt of Metformin and Glibenclamide containing essentially surfactant and /or along with other excipients.

Description

SOLID ORAL DOSAGE FORM HAVING ANTIDIABETIC DRUG COMBINATION

FIELD OF INVENTION

The present invention relates to solid oral dosage form for the treatment of non-insulin dependant type diabetes (diabetes of type II) using a combination of oral hypoglycemic agents.

BACKGROUND OF THE INVENTION

Non-insulin dependant diabetes is a metabolic disorder characterized by hyperglycemia, which occurs due to insulin deficiency, insulin resistance and reduced glucose tolerance.

Monotherapy with an oral antidiabetic has been an effective way of treatment for diabetes for many years. Diet and physical exertion are unanimously recognized to be the foundation of the therapy of diabetes of type II, both of them lead to a reduction in insulin resistance and, in the long run, to an improvement in the pancreas secretive deficit. However, these provisions are insufficient and a pharmacological aid with oral hypoglycemic agents is necessary. There are two main families of oral hypoglycemic agents,- at present, available. Sulphonylureas, such as Glibenclamide, act by stimulating insulin release and are thus only effective with some residual pancreatic beta-cell activity. The biguanides, such as Metformin (expressed as the hydrochloride salt of Metformin), act by decreasing gluconeogenesis thereby increasing peripheral utilization of glucose, and as they require endogenous insulin they are only effective with some residual pancreatic islet cell activity. The use of sulphonylureas and biguanides in monotherapy, in most cases, allows obtaining an effective glycometabolic control for some years if an appropriate diet and behavioral regimen are kept. Nevertheless, the efficacy of the therapy with oral hypoglycemic agents can decrease with time.

The co-therapy plays a significant role in therapeutic, since it allows obtaining an effective metabolic control in the patients of diabetes of type II, where the therapy using either sulphonylureas or biguanides becomes ineffective.

Combined antidiabetic therapy with sulphonylureas and biguanides, having complementary mode of action, is now an acceptable form of the treatment for diabetes of type II with solid oral dosage form like tablets that ensures enhanced patient compliance. Such a combination of Metformin hydrochloride with Glibenclamide has been disclosed in PCT publication WO 97/17975 and Australian patent AU 199954179 B2 for the treatment of diabetes of type II with a defined ratio of the twc its, which is a requirement in order to obtain an optimum therapeutic effect. The Australian patent AUl 99954179B2 discloses that the solid oral form such as tablet contains a combination of Metformin hydrochloride and Glibenclamide in which the size of the Glibenclamide at most 10% of the particles are less than 2μm and at most 10% of the particles are greater than 60μm so that the Glibenclamide bioavailability is comparable to the Glibenclamide bioavailability obtained with a separate administration of Metformin hydrochloride and Glibenclamide. It also discloses, a solid oral dosage form comprising of the combination of Metformin hydrochloride and Glibenclamide in which the size of Glibenclamide wherein at most 25% of the particles are less than l lμm and at most 25% of the particles are greater than 46μm so that the Glibenclamide bioavailability is comparable to the Glibenclamide bioavailability obtained with a separate administration of Metformin hydrochloride and Glibenclamide.

In the present invention provides a pharmaceutical composition of Metformin hydrochloride and Glibenclamide pharmaceutically with acceptable surfactant provides the same dissolution profile and bioavailability obtained with a separate administration of Metformin hydrochloride and Glibenclamide.

However, the pharmaceutical composition of a solid oral dosage form, comprising Metformin hydrochloride and Glibenclamide demonstrates bioequivalence with reference product (Glucovance).

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides pharmaceutical composition of a solid oral dosage form containing oral hypoglycemic agents, Metformin hydrochloride and Glibenclamide, in diverse therapeutically recommended strengths. In the first combination, Metformin hydrochloride dose is 500mg and Glibenclamide dose is 5mg. In other combinations, doses are respectively: 500mg of Metformin hydrochloride and 2.5mg of Glibenclamide, 250mg of Metformin hydrochloride and 1.25mg of Glibenclamide. During the course of present study, the novel pharmaceutical composition of Metformin hydrochloride and Glibenclamide with surfactant is giving the desired dissolution profile and its bioavailability.

The excipient is used here are such agents as diluents, earners, binders, disintegrants, surfactants, glidants, lubricants and coating agents. Such materials are employed which do not adversely effect the processing set forth herein and which do not interfere with the stability of the resulting products.

The known diluents are the family of modified celluloses such as hydroxyethyl cellulose, hydroxypropyl cellulose, methylhydroxyethyl cellulose, methylhydroxypropyl cellulose, carboxymethyl cellulose and other cellulose derivatives such as starch and sodium starch glycolate, pregelatinised starch may also be employed. The diluents disclosed herein are not limited to illustrate as above. In another embodiment diluents of the present invention are preferably, lactose, saccharose, fructose, Sorbitol, Mannitol, calcium phosphate and calcium hydrogen phosphate. The more preferred diluent is microcrystalline cellulose wherein an amount of microcrystalline cellulose ranges from about 1.0 to 50.0%w/w per unit dose, preferably 3.0 to 20.0%w/w, and in particular from about 4.0 to 14.0%w/w. Any of the members of this family may be used in connection with the practice of one or more embodiments of the present invention. Other cellulose products those are similar in nature to microcrystalline cellulose may find utility herein, such a parenchymal cell cellulose.

The binder holds the components of the formulation together. The preferred binders include gelatin, alginates (sodium alginate), starch grades (pregelatinized or plain), hydroxypropylcellulose, and carboxymethylcellulose and their salts, lactose, and microcrystalline cellulose (Avicel). The illustrated binders are not limited to present invention. In preferred embodiment the binder used herein is hydroxypropyl methylcellulose, wherein an amount ranges from about 0.5 to about 20.0%w/w, preferably about 1.0 to about 10.0%w/w, and more preferably ranges from about 1.37 to about 5.0% w/w. It may in addition also be advantageous to add other conventional pharmaceutical auxiliary substances and carriers as binders.

The disintegrating agent enhances the conversion of a compact material into fine primary particles during dissolution. The preferred disintegrating agents are not limited to, starch (com starch), pectins, carboxymethyl cellulose, ultramyl pectin, bentonite, polyvinyl pyrrolidone (in the case of polyvinyl Pyrrolidone the filamentory macromolecules are crosslinked; it has a porous structure and a great swelling capacity). In a preferred embodiment the disintegrant is sodium starch glycolate and/or crosspovidone. The preferred disintegrant ranges in amount from about 0.5 to about 20.0 %w/w, preferably about 1.0 to about 10.0 %w/w and more preferably from about 3.0 %w/w to about 9.0 %w/w. Cellulose products such as microcrystalline cellulose (plain or coarse) may also find utility herein as most preferable disintegrant.

The surfactant enhances the wettability of poorly soluble drug at the diffusion layer, thereby improving the solubility. Different types of surfactants i.e. cationic, anionic and non- ionic forms the basis to improvement of solubility of poorly soluble drugs. Surfactants include in the present invention, but are not limited to, sodium lauryl sulphate, sodium lauryl sulfoacetate, sodium cocomonoglyceride sulphate, sodium sulphated monoglyceride, sodium N-lauroyl sarcosinate. In still another embodiment of the invention poloxamer(s) finds utility as well. In a preferred embodiment of the present invention, the surfactant is sodium lauryl sulphate. Sodium lauryl sulphate, an anionic surfactant, finds herein utility to show linear increase in solubility with increasing concentration. It has found to be an efficient solubiliser in a preferred embodiment of the present study and is characterized in amount from 0.1 to 2.0 %w/w, preferably 0.2 to 1.8 %w/w and in particular from about 0.3 % to 1.5 %w/w.

The lubricant acts as an additive to prevent the sticking of the formulation to tooling during the tabletting process. Lubricants illustrated herein are not limited to stearates, hydrogenated vegetable oils, and talc. The preferred lubricant is a stearate. In another embodiments more preferred, lubricant is magnesium stearate or glycerol monostearate which ranges in an amount from about 0.01 to about 10.0 %w/w per unit dose. The preferred range of lubricant is magnesium stearate and in an amount from about 0.2 to about 1.0 %w/w per unit dose.

The various components of the typical formulation are standardized invention. Microcrystalline cellulose of this example formulation serves as a diluent. Sodium starch glycolate and crosspovidone are internally crosslmked polymer and serves as a disintegrant. Binder is hydroxypropyl methylcellulose while sodium lauryl sulphate is a wetting agent. Magnesium stearate serves as a lubricant. The granulation solvent is purified water.

Table 1 shows the typical composition range of different excipients used in the present invention: TABLE 1

The preferred typical composition of drug product prepared using defined micronized and/or coarse particle size distribution of Glibenclamide is provided in the table 2, with ranges on components being provided:

Table: 2

* a commercially available film coat composition is used such as opadry.

The tablet according to the present invention may be obtained by a process comprising:

1. Forming granules by wet granulation of a mixture of Metformin hydrochloride and Glibenclamide.

2. Blending and lubrication of granules.

3. Tableting the blend thus obtained into tablets. The following text illustrate the processing methodology:

A tablet of Metformin hydrochloride and Glibenclamide has been prepared as follows:

Geometrically mix Metformin hydrochloride, Glibenclamide (micronized/ coarse), microcrystalline cellulose Plain, crosspovidone, sodium starch glycolate and sodium lauryl sulphate in granulator to produce the pre-mix. Granulating binder is prepared by mixing hydroxypropyl methylcellulose with purified water. The binder solution is added to the granulator and the wet mass is granulated. The granulated mass is emptied into a preheated fluidized bed dryer and the granules are dried until the moisture content is 2.5-3.5%w/w. Dried granulated mass is sifted through 16# sieve, while retention over milled through 2.0mm screen. Sized granules thus obtained are blended with extragranular ingredients like sodium starch glycolate, colloidal silicon dioxide, Avicel PH 200 and purified talc, followed by lubrication with magnesium stearate. The lubricated blend is compressed using a suitable tablet press. The tablets are film coated using suitable aqueous coat in a coating machine.

Example 1: Preparation of Metformin Hydrochloride and Glibenclamide stable pharmaceutical solid dosage form (Batch Size: 100000 Units) using the Glibenclamide in which the size of the Glibenclamide between about 0.2 micron to about 10 micron.

Geometrically mix Metformin hydrochloride 51.02 Kg, Glibenclamide 0.51 Kg, microcrystalline cellulose Plain 4.55 Kg, crosspovidone 2.0 Kg, sodium starch glycolate 1.5 Kg and sodium lauryl Sulphate 0.20 Kg in granulator to produce the pre-mix. Granulating binder is prepared by mixing hydroxypropyl methylcellulose 1.8 Kg with purified water. The binder solution is added to the granulator and the wet mass is granulated. The granulated mass is emptied into a preheated fluidized bed dryer and the granules are dried until the moisture content is 2.5-3.5%w/w. Dried granulated mass is sifted through 16# sieve, while retention over milled through 2.0mm screen. Sized granules thus obtained are blended with extragranular ingredients like sodium starch glycolate 1.25 Kg, colloidal silicon dioxide 1.0 Kg, Avicel PH 200 0.70 Kg and purified talc 0.30 Kg, followed by lubrication with magnesium stearate 0.20 Kg. The lubricated blend is compressed using a suitable tablet press. The tablets are film coated using suitable aqueous coat in a coating machine.

Example 2: Preparation of Metformin Hydrochloride and Glibenclamide stable pharmaceutical solid dosage form (Batch Size: 100000 Units) using the Glibenclamide in which the size of the Glibenclamide is between about 60 micron to about 100 micron.

Geometrically mix Metformin hydrochloride 51.02 Kg, Glibenclamide 0.51 Kg, microcrystalline cellulose Plain 3.9 Kg, crosspovidone 2.0 Kg, sodium starch glycolate 1.5 Kg and sodium lauryl Sulphate 0.80 Kg in granulator to produce the pre-mix. Granulating binder is prepared by mixing hydroxypropyl methylcellulose 1.8 Kg with purified water. The binder solution is added to the granulator and the wet mass is granulated. The granulated mass is emptied into a preheated fluidized bed dryer and the granules are dried until the moisture content is 2.5-3.5%w/w. Dried granulated mass is sifted through 16# sieve, while retention over milled through 2.0mm screen. Sized granules thus obtained are blended with extragranular ingredients like sodium starch glycolate 1.25 Kg, colloidal silicon dioxide 1.0 Kg, Avicel PH 200 0.70 Kg and purified talc 0.30 Kg, followed by lubrication with magnesium stearate 0.20 Kg. The lubricated blend is compressed using a suitable tablet press. The tablets are film coated using suitable aqueous coat in a coating machine. DETAIL DESCRIPTION OF DRAWING:

Figure Ia: Comparative Dissolution Profiling of Metformin 500 from Lot No.: 52151 and Batch No.: B165E6001 Figure Ib: Comparative Dissolution Profiling of Glibenclamide 5 from Lot No.: 52151 and Batch No.: B165E6001 Figure 2a: Comparative Dissolution Profiling of Metformin 500 from Lot No.: 52151 and Batch No.: 08/038/13 Figure 2b: Comparative Dissolution Profiling of Glibenclamide 5 from Lot No.: 52151 and Batch No.: 08/038/13 Figure 3 a: Plasma concentration curves (mean ± SEM) on log scale of Metformin hydrochloride in fixed dose formulation of Metformin hydrochloride 500 mg and Glibenclamide 5 mg Tablets of Cadila

Pharmaceuticals Limited, India and Glucovance Tablets, Alphapharm, Australia. Figure 3b: Plasma concentration curves (mean ± SEM) on log scale of Glibenclamide in fixeddose formulation of

Metformin hydrochloride500 mg and Glibenclamide 5 mg tablets of Cadila Pharmaceuticals Limited,

India and Glucovance Tablets, Alphapharm, Australia.

TABLE 3a

TABLE 3b

The study reveals that, the formulations under the study i.e., test products prepared with micronized and coarse Glibenclamide have been pharmaceutical equivalent with reference product which have followed the similar pattern in dissolution behaviour for Metformin hydrochloride 500mg and Glibenclamide 5mg Tablets.

Relative Bioavailability Study

Bioavailability refers to the degree to which the therapeutically active medicament becomes available in the body after administration. Typically, bioavailability is measured in patients who fasted overnight before being dosed with the test preparation. Plasma samples are then taken and analyzed for the plasma concentration of the parent compound and/ or its active metabolite. The data may be expressed as Cmax, the maximum amount of active ingredient found in the plasma, or as AUC, the area under the plasma concentration time curve. In-vivo bioavailability studies were performed, in particular, with tablets prepared using defined micronized particle size distrbution of Glibenclamide.

The test batch, Cadila Pharmaceuticals Limited, India was administered to healthy human subjects (n = 23) in comparison to reference batch marketed under the trade name Glucovance, Alphapharm, Australia.

Pharmacokinetic parameters (C_max, T_max, K_ei, ti_/2, AUC_0-t and AUC_0-∞) for both the drug products (i.e., Test and Reference) have been summarized for Metformin hydrochloride in Table 4a.

Pharmacokinetic parameters (C_max, T_max, K_e1, ty₂, AUC_0-t and AUCo-_∞) for both the drug products (i.e., Test and Reference) have been summarized for Glibenclamide in Table 4b.

Confidence Interval has been calculated on logarithmic transformed data of Metformin hydrochloride for pharmacokinetic parameters (C_max, AUC_0-t and AUC₀._∞) and shown in Table 5a.

Confidence Interval has been calculated on logarithmic transformed data of Glibenclamide for pharmacokinetic parameters (C_max, AUC_0-t and AUCo-_∞) and shown in Table 5b.

Table 6a represents descriptive statistical analysis of pharmacokinetic parameters (C_max, AUC_0-t and AUC_0-∞) for test and reference products of Metfonnin hydrochlorides 00 mg and Glibenclamide 5 mg Tablets for Metformin hydrochloride. The mean plasma concentration-time curve of Metformin hydrochloride after administration of Metformin hydrochlorides 00 mg and Glibenclamide 5 mg Tablets, Cadila Pharmaceuticals Limited, India and Glucovance (Metformin hydrochloride 500 mg and Glibenclamide 5 mg) Tablets, Alphapharm, Australia formulations has been shown in Figure 3a.

Table 6b represents descriptive statistical analysis of pharmacokinetic parameters (C_raax, AUC_0-t and AUC_0-00) for test and reference products of Metformin hydrochlorides 00 mg and Glibenclamide 5 mg Tablets for Glibenclamide. The mean plasma concentration-time curve of Glibenclamide after administration of Metformin hydrochlorides 00 mg and Glibenclamide 5 mg Tablets, Cadila Pharmaceuticals Limited, India and Glucovance (Metformin hydrochloride 500 mg and Glibenclamide 5 mg) Tablets, Alphapharm, Australia formulations has been shown in Figure 3b. TABLE 4: SUMMARY TABLE OF PHARMACOKINETIC PARAMETERS

Table: 4a

Metformin ( N = 23 )

Test product Reference product

C_max (ng/mL) 1360.820 ± 50.160 1450.907 ± 87.501

T_max (hr) 2.065 ± 0.173 1.870 ± 0.114 kd Chr^"1) 0.247 ± 0.008 0.271 ± 0.010 tin (hrs) 2.878 ± 0.092 2.627 ± 0.079

AUC_0-4 (ng*hr/mL) 7038.439 ± 312.086 7446.066 ± 397.569

AUC_0-OC (ng*hr/mL) 7292.360 ± 308.029 7661.862 ± 401.169

All values represent Mean ± SEM of 23 subjects

Table: 4b

Glibenclamide ( N = 23 )

Test product Reference product

C_max (ng/mL) 367.073 ± 29.258 390.828 ± 43.048

T_max (hr) 3.044 ± 0.154 3.022 ± 0.120 kei Chr ¹) 0.314 ± 0.036 0.288 ± 0.035 ti_/2 (hrs) 3.103 ± 0.482 4.138 ± 0.870

AUC_0-4 (ng*hr/mL) 1293.037 ± 97.967 1277.239 ± 117.197

AUC_0-0C (ng*hr/mL) 1378.082 ± 105.562 1379.204 ± 120.758

All values represent Mean ± SEM of 23 subjects.

TABLE 5: SUMMARY OF CONFIDENCE INTERVAL ON LOG

TRANSFORMED DATA

Table 5a: Metformin hydrochloride

Test Product Vs. Reference Product

Lower Limit Upper Limit v^ max 87.89

105.80

AUC_0-I 89.02 102.56

Table 5b: Glibenclamide

Test Product Vs. Reference Product

Lower Limit Upper Limit v^max 83.38 115.31

AUCo-t 95.07 113.08

TABLE 6: SUMMARY STATISTICS

Table 6a: Metformin hydrochloride 500 mg

Summary Statistics of Log-transformed Pharmacokinetic Parameters for Metformin hydrochloride in formulation of Metformin hydrochlorideSOO mg and Glibenclamide 5 mg Tablets (Test product) with that of Glucovance (Metformin hydrochloride 500 mg and Glucovance 5 mg) (Reference product) after single dose administration in healthy human subjects

Product/ '-'max AUCo_-4 AUC₀._∞

Statistics (ng/mL) (ng*hr/mL) (ng*hr/mL)

Test product

Geometric Mean 1340.616 6868.859 7133.298

C.V.(%) of Geometric Mean 17.85 23.70 22.48

N 23 23 23

Reference product

Geometric Mean 1392.270 7193.778 7413.558

CV. (%) Geometric Mean 30.77 28.34 27.60

N 23 23 23

Ratio of Least Square Mean

Test/ Reference 96.43 95.55 96.28

90% Confidence Interval (T/R)

Test / Reference

Lower Limit (%) 87.89 89.02 89.91

Upper Limit'(%) 105.80 102.56 103.11 p- Value TANOVAl

Form 0.5074 0.2813 0.3521

Period 0.5389 0.2849 0.2341

Sequence 0.7382 0.6837 0.7029

Power

Test / Reference 0.9877 0.9993 0.9996

CV (%) of Intrasubject Variability 18.4073 14.0006 13.5419 Table 6b: Glibenclamide 5 mg

Summary Statistics of Log-transformed Pharmacokinetic Parameters for Glibenclamide in formulation of Metformin hydrochloride500 mg and Glibenclamide 5 mg Tablets (Test product) with that of Glucovance (Metformin hydrochloride 500 mg and Glibenclamide 5 mg) (Reference product) after single dose administration in healthy human subjects

Product/ AUC_0-4 AUCo-_∞

Statistics (ng/mL) (ng*hr/mL) (ng*hr/mL)

Test product

Geometric Mean 342.489 1202.790 1280.791

CV. (%) of Geometric Mean 39.99 42.42 42.61

N 23 23 23

Reference product

Geometric Mean 349.209 1164.528 1261.680

CV. (%) Geometric Mean 50.08 46.96 46.62

N 23 23 23

Ratio of Least Square Mean

Test / Reference 98.05 103.68 101.72

90% Confidence interval (T/R)

Test / Reference

Lower Limit (%) 83.38 95.07 93.81 Upper Limit (%) 115.31 113.08 110.29 p-Value fANOVA]

Form 0.8368 0.4811 0.7206

Period 0.9592 0.0956 0.3378

Sequence 0.0389 0.0101 0.0438 Power

Test / Reference 0.7385 0.9934 0.9968

CV (%) of Intrasubject Variability 32.7295 17.2011 16.0238 The relative bioavailability of Metformin hydrochloride has been assessed by ratio of Cmax, AUC₀._t and AUCo-_∞ values. The ratios of Geometric Least Square Means of C_maX; AUC_0-t and AUCo-oo have been found to be 96.43%, 95.55% and 96.28% and 90% Confidence Interval of C_max, AUC₀._t and AUC_0-00 lies between 87.89% - 105.80%, 89.02% - 102.56 % and 89.91% - 103.11% for Metformin hydrochloride in fixed dose formulation of Metformin hydrochloride 500 mg and Glibenclamide 5 mg Tablet of Cadila Pharmaceuticals Limited, India with that of Glucovance (Metformin hydrochloride 500 mg and Glibenclamide 5 mg) Tablet of Alphapharm, Australia, respectively.

The relative bioavailability of Glibenclamide has been assessed by ratio of C_max, AUC_0-t and AUCo_-∞ values. The ratios of Geometric Least Square Means of C_maχ, AUCo-t and AUC_0-∞ have been found to be 98.05%, 103.68% and 101.72% and 90% Confidence Interval of C_max, AUC_0-1 and AUC_0-Oo lies between 83.38% - 115.31%, 95.07% - 113.08 % and 93.81% - 110.29% for Glibenclamide in fixed dose formulation of Metformin hydrochloride 500 mg and Glibenclamide 5 mg Tablet of Cadila Pharmaceuticals Limited, India with that of Glucovance (Metformin hydrochloride 500 mg and Glibenclamide 5 mg) Tablet of Alphapharm, Australia, respectively.

It has been monitored that the Metformin hydrochloride 500 mg and Glibenclamide 5 mg Tablets of Cadila Pharmaceuticals Limited, India has been bioequivalent in comparison with Glucovance of Alphapharm, Australia in terms of both rate and extent of absorption after single dose administration in healthy human subjects.

Both test and reference formulations have been found to be safe in both the periods during a course of the study.

The two formulations under the study i.e., test product prepared with micronized Glibenclamide (Batch No.: B165E6001) and reference product (Batch No.: 52151) have been bioequivalent and have followed the similar pattern in absorption, distribution and elimination phases for Metformin hydrochlorides 00 mg and Glibenclamide 5 mg Tablets.

The study reveals that, the formulations under the study i.e., test product prepared and reference product have been pharmaceutical as well as bioequivalent and have followed the similar pattern in dissolution behaviour and absorption, distribution, eliminaton phases for Metformin hydrochloride 500mg and Glibenclamide 5mg Tablets.

Claims

We claims,

1. A pharmaceutical dosage form comprising a combination of Metformin and Glibenclamide contains essentially surfactant and /or alongwith other excipients.

2. The excipients according to the claim 1 include diluents, binders, disintegrants, glidants, lubricants and coating agents.

3. The pharmaceutical composition containing Metformin hydrochloride and Glibenclamide consisting of the surfactants includes, but are not limited to, sodium lauryl sulphate, sodium lauryl sulfoacetate, sodium cocomonoglyceride sulphate, sodium sulphated monoglyceride, sodium N-lauroyl sarcosinate and poloxamer(s).

4. The pharmaceutical composition in claim 3, where in the said surfactant is sodium lauryl sulphate.

5. The pharmaceutical composition of the claim 4, wherein amount of sodium lauryl sulphate from about 0.1 to about 10.0 %w/w.

6. The pharmaceutical composition of the claim 4, wherein amount of sodium lauryl sulphate is preferably from about 0.2 to about 5.0 %w/w.

7. The pharmaceutical composition of the claim 4, wherein amount of sodium lauryl sulphate is more preferably from about 0.3 to about 1.5 %w/w.

8. The use of excipient according to claim 1, wherein the one or more diluent selected from, but is not limited to, the family of modified celluloses such as hydroxyethyl cellulose, hydroxypropyl cellulose, methylhydroxyethyl cellulose, methylhydroxypropyl cellulose, carboxymethyl cellulose, starch, sodium starch glycolate, crosspovidone, lactose, saccharose, fructose, sorbitol, mannitol, calcium phosphate, calcium hydrogen phosphate and microcrystalline cellulose.

9. The pharmaceutical composition in claim 8, where in the said diluent is microcrystalline cellulose.

10. The pharmaceutical composition of the claim 9, wherein amount of microcrystalline cellulose is from about 1.0 to about 50.0%w/w.

11. The pharmaceutical composition of the claim 9, wherein amount of microcrystalline cellulose is preferably form about 3.0 to about 20.0%w/w.

12. The pharmaceutical composition of the claim 9, wherein amount of microcrystalline cellulose is more preferably from about 4.0 to 14.0%w/w.

13. The pharmaceutical composition in claim 1, wherein the said binder includes, but are not limited to, gelatin, alginates, starch grades (pregelatinized or plain), hydroxypropylcellulose, and carboxymethylcellulose and their salt thereof.

14. The pharmaceutical composition according to claim 13, wherein the said binder is hydroxypropyl methylcellulose.

15. The pharmaceutical composition according to claim 14, wherein amount of hydroxypropyl methyl cellulose is from about 0.5 to about 20.0%w/w.

16. The pharmaceutical composition according to claim 14, wherein amount of hydroxypropyl methyl cellulose is preferably from about 1.0 to about 10.0%w/w.

17. The pharmaceutical composition according to claim 14, wherein amount of hydroxypropyl methyl cellulose is in particular from about 1.37 to about 5.0% w/w.

18. The pharmaceutical composition according to claim 1, wherein the disintegrant includes, but are not limited to, starch (corn starch), pectins, carboxymethyl cellulose, ultramyl pectin, bentonite and crosspovidone.

19. The pharmaceutical composition according to claim 18, the disintegrants are sodium starch glycolate and/ or crosspovidone.

20. The pharmaceutical composition according to claim 19, wherein amount of sodium starch glycolate and/ or crosspovidone is from about 0.5 to about 20.0%w/w.

21. The pharmaceutical composition according to claim 19, wherein amount of sodium starch glycolate and/ or crosspovidone is preferably from about 1.0 to about 10.0%w/w.

22. The pharmaceutical composition according to claim 19, wherein amount of sodium starch glycolate and/ or crosspovidone is in particular from about 3.0 to about 9.0% w/w.

23. The pharmaceutical composition according to claim 1, wherein the lubricant includes, but are not limited to, stearates, hydrogenated vegetable oils, and talc.

24. The pharmaceutical composition according to claim 23, the lubricant is in an amount from about 0.01 to from 10.0 %w/w.

25. A solid oral dosage form as claimed in any one of claims 1 to 24 in which Metformin is present as Metformin salt and the weight ratio of Metformin salt to Glbenclamide is 100/1 to 100/0.5.

26. A solid oral dosage form as claimed in claims 1 to 25 is in the form of a tablet.

27. A tablet as claimed in claim 26 which is obtained by a process comprising: a. forming granules by wet granulation of a mixture of Metformin and Glibenclamide; b. blending the granules with a tabletting aid; c. tabletting the blend thus obtained into tablets.

28. The pharmaceutical dosage form according to claim 1, where the dosage form giving the similar dissolution profile and bioavailability as Glucovance.