Pharmaceutical Composition Containing Fixed Dose Combination Of
Voglibose With Metformin
Field of the Invention
The present invention relates to a pharmaceutical composition containing fixed dose combination of voglibose with metformin and process for the preparation thereof. The compositions are useful for the improvement of glycemic control in adult patients of Type II diabetes mellitus which is not achieved on therapy with voglibose or metformin alone.
In general terms, diabetes mellitus is broadly classified into two types, namely, Type I (Insulin Dependent) and Type II (Non-Insulin Dependent). In Type I diabetes, the beta cells in the pancreas, probably through an auto-immune reaction, cease producing insulin into the bloodstream of the person.
In Type II diabetes, the beta cells of the pancreas continue to produce insulin but, some or all of the insulin may fail to bind to the body's cell receptors and/or internalization or uptake of insulin in the cells is reduced.
The initial treatment of Type II diabetes involves diet control and exercise. Only after this has been shown to be inadequate oral antidiabetic drugs are used, and that only to complement the effect of diet and not replace it. Monotherapy with an oral antidiabetic can be effective treatment for many years. However, the efficacy can decrease with time. Thus to maintain glycaemic control as the disease progresses, there is a need for a combination of oral antidiabetic drugs. There are different classes of oral antidiabetic drugs available such as sulfonylureas, meglitinides, biguanides, thiazolidinediones, alpha-glucosidase inhibitors.
Sulfonylureas appear to stimulate the pancreas and increase the production of insulin from the beta cells in the pancreas. Unfortunately, there are potential unfavorable side effects from the use of sulfonylureas. Therefore, the less a patient is required to use a sulfonylurea, the fewer side effects are likely to be experienced by that patient.
Biguanides control the blood glucose by inhibiting hepatic glucose production, reducing intestinal absorption of glucose and enhancing peripheral glucose uptake. Biguanides lower both basal and post-prandial plasma glucose and thus improve glucose tolerance in patients.
Alpha-glucosidase inhibitors are saccharides that help in controlling Type II diabetes by selectively inhibiting alpha-glucosidase in the enteric canal, delaying the digestion and
absorption of carbohydrate, thereby suppressing sharp increase in post-prandial plasma glucose.
Metformin is an oral antidiabetic drug from the biguanide class. Chemically metformin is known as N, N-dimethylimidodicarbonimidic diamide. It is the first-line drug for the treatment of Type II diabetes and is considered as the 'gold' standard therapy in Type II diabetic patients who are overweight. Metformin is commercially available as immediate release and extended release tablets.
Voglibose is an alpha-glucosidase inhibitor and is chemically known as (1S,2S,3R,4S,5S)-5-(1,3-dihydroxypropan-2-ylamino)-1-(hydroxymethyl)cyclohexane-1,2,3,4-tetrol. Voglibose is often used in combination with sulfonylureas to control blood glucose levels. Voglibose is commercially available as 0.2 & 0.3 mg tablets.
There is a need of polypharmacy in the majority of patients with Type II diabetes in order to achieve target glycemic control. Metformin is often prescribed in combination with rosiglitazone (Avandamet®) and is also available in fixed dose combination with pioglitazone (Actoplus®), sulfonylureas-glipizide (Metaglip®) and glibenclamide (Glucovance®), dipeptidyl peptidase-4-inhibitor-sitagliptin (Janumet®) and meglitinide-repaglinide (PrandiMet®).
An evaluation of the medical patient population with Type II diabetes indicates that compliance with metformin monotherapy is higher than that associated with metformin dual therapy. Compliance can be promoted by the use of a single dosage unit combining two different classes of antidiabetic agents.
A combination therapy of alpha-glucosidase inhibitor with biguanide has been found to improve symptoms of diabetes since both agents act by different but complementary mechanism. Biguanide is prescribed in combination with alpha-glucosidase inhibitor and this combination is found to be more effective in lowering blood glucose levels than either biguanide or alpha-glucosidase inhibitor alone in Type II diabetes.
There are tablet dosage forms of metformin alone and voglibose alone available commercially. However, no such formulation is available that contains voglibose in an amount of from 0.20mg to 0.30mg in combination with metformin in an amount of from 500mg to 1000mg in a fixed dose combination.
Further, voglibose is a low dose drug having active compound in the range of 0.2-0.3 mg per tablet while metformin is a high dose drug having active compound in the range of 500-1000 mg per tablet. Thus when formulating a fixed dose combination of voglibose with metformin,
this difference in drug quantities could lead to poor content uniformity. Efficient mixing and acceptable blend and content uniformity are difficult to obtain for low dosage forms. The choice of excipients and the process for the preparation is important in order to ensure good content uniformity of the pharmaceutically active compound. Failure to maintain the uniformity of the drug content, eg., if uniformity is not strictly assured may result in an unforeseen accident of overdose or end up delivering a subtherapeutic dose. In view of above constraints, it would be a challenge to formulate both voglibose and metformin in a single dosage form.
PCT application No. 02/04024 discloses a pharmaceutical composition containing one or more insulin sensitizers together with an antidiabetic agent. The antidiabetic agents as per the invention include an alpha-glucosidase inhibitor, a biguanide and the like etc. The insulin sensitizers as per the invention include rosiglitazone, pioglitazone, metformin, trioglitazone, and the like.
PCT application No. 01/32158 discloses a low dose pharmaceutical composition which includes a combination of metformin and at least one other antidiabetic agent such as sulfonyl urea, a glucosidase inhibitor, a thiazolidinedione, an insulin sensitizer and the like. This patent application discloses that metformin will be employed in the weight ratio to the glucosidase inhibitor in the range from about 0.01:1 to about 100:1, preferably from about 0.5: 1 to about 50:1.
None of these applications disclose a pharmaceutical composition containing fixed dose combination of voglibose with metformin comprising voglibose in an amount of from 0.20mg to 0.30 mg and metformin in an amount of from 500mg to 1000mg.
The combination of voglibose with metformin provides a synergistic effect as compared to the monotherapy. Though voglibose and metformin are widely used individually, there is still a need for a fixed dose combination of voglibose with metformin, which will be economical, safer, effective and will have better patient compliance.
Thus the present invention relates to a pharmaceutical composition containing fixed dose combination of voglibose with metformin and the process for its preparation. The compositions are useful for the improvement of glycemic control in adult patients of Type II diabetes mellitus, and shall offer additional benefit compared to each monotherapy leading to increased efficacy and improved patient compliance.
Summary Of the Invention
According to one embodiment there is provided a pharmaceutical composition containing fixed dose combination of voglibose with metformin comprising voglibose in an amount of from 0.20mg to 0.30 mg and metformin in an amount of from 500mg to 1000mg, wherein the content uniformity values of Voglibose in the composition is between 85% to 115% of the average content, when measured as per test described in Indian Pharmacopoeia.
According to another embodiment there is provided a tablet containing fixed dose combination of voglibose with metformin, comprising voglibose in an amount of 0.2mg, metformin in an amount of 500mg and one or more pharmaceutically acceptable excipients, wherein the content uniformity values of Voglibose in the composition is between 85% to 115% of the average content, when measured as per test described in Indian Pharmacopoeia.
According to another embodiment, there is provided a process for the preparation of a tablet containing fixed dose combination of voglibose with metformin, the process comprising the steps of: a) granulating metformin and one or more pharmaceutically acceptable excipients to obtain granules, b) mixing voglibose and one or more pharmaceutically acceptable excipinets geometrically followed by granulation to obtain granules, and, c) mixing the granules obtained by step (a) and (b) and compressing to obtain tablet.
According to another embodiment, there is provided a process for the preparation of a tablet containing fixed dose combination of voglibose with metformin, the process comprising the steps of: a) mixing metformin, voglibose and one or more pharmaceutically acceptable excipients geometrically to obtain a blend, and, b) granulating the blend of step (a) using water to obtain granules, followed by compression into tablet.
According to another embodiment, there is provided a process for the preparation of a tablet containing fixed dose combination of voglibose with metformin, the process comprising the steps of: a) mixing metformin, voglibose and one or more pharmaceutically acceptable excipients geometrically to obtain a blend, b) dissolving one or more binders in water to obtain a solution, and, c) granulating the blend of step (a) using the solution of step (b) to obtain granules, followed by compression into tablet.
According to another embodiment, there is provided a process for the preparation of a tablet, the process comprising the steps of: a) blending metformin and one or more
pharmaceutical^ acceptable excipients to obtain a blend, b) dissolving voglibose in water to obtain a solution, and, c) granulating the blend of step (a) with the solution of step (b) to obtain granules, followed by compression into tablet.
According to another embodiment, there is provided a process for the preparation of a tablet, the process comprising the steps of: a) blending metformin and one or more pharmaceutical^ acceptable excipients to obtain a blend, b) dissolving voglibose and one or more binders in water to obtain a solution, and, c) granulating the blend of step (a) with the solution of step (b) to obtain granules, followed by compression into tablet.
Detailed Description of the Invention
The term "voglibose" as used herein refers to voglibose free base.
The term "metformin" refers to metformin or pharmaceutically acceptable salts thereof. For example, metformin hydrochloride may be used.
The "fixed dose combination" of the present invention comprises voglibose in an amount ranging from 0.2 to 0.3 mg; and metformin in an amount ranging from 500 to1000 mg.
The "composition" of the present invention may be in the form of tablets or capsules. The tablets may be uncoated tablets, coated tablets or bilayered tablets.
According to one embodiment the compositions of the present invention have good content uniformity. The content uniformity value of voglibose in the composition is between 85% to 115% of the average content when measured as per the test described in the Indian Pharmacopoeia. The Indian Pharmacopoeia (IP) states the following for content uniformity of tablets 'the preparation complies with the test if each individual content is 85 to 115 per cent of the average content. The preparation fails to comply with the test if more than one individual content is outside the limits of 75 to 125 percent of the average content.
The"pharmaceutical^ acceptable excipients" may be selected from one or more of binders, diluents, disintegrants and lubricants/glidants.
Suitable binders may be selected from one or more of starches such as corn starch, pregelatinized starch and maize starch; cellulose derivatives such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose and methylcellulose; gums such as xanthan gum, gum acacia and tragacanth; water-soluble vinylpyrrolidone polymers such as polyvinylpyrrolidone
and copolymer of vinylpyrrolidone vinyl acetate; sugars such as sorbitol, mannitol and mixtures thereof.
Suitable diluents may be selected from one or more of sugars such as dextrose, glucose and lactose; sugar alcohols such as sorbitol, xylitol and mannitol; cellulose derivatives such as powdered cellulose and microcrystalline cellulose; starches such as corn starch, pregelatinized starch, maize starch and mixtures thereof.
Suitable disintegrants may be selected from one or more of sodium starch glycolate, croscarmellose sodium, crospovidone, corn starch and mixtures thereof.
The lubricant/glidants may be selected from the one or more of magnesium stearate, talc, sodium stearyl fumarate, colloidal silicon dioxide and mixtures thereof.
The composition may be prepared by conventional processes known to a person skilled in the art. All the ingredients may be mixed to obtain a blend or the blend may be granulated further (by dry granulation or wet granulation) to obtain granules. One method of ensuring good content uniformity during blending of a low dose drug in a dosage form is by using geometric dilution.
"Geometric dilution" is a pharmaceutical term which is normally applied to the extemporaneous method of efficiently combining two unequal amounts of a powdered substance to form a homogenous mixture. The concept of geometric dilution centers on the successive addition and blending of equal quantities of materials.
For example, in the extemporaneous blending of 1 gram of substance A with 20 grams of substance B. the most efficient method to insure a homogenous blend of powders would be to initially blend about 1 gram of substance A with about 1 gram of substance B. After this combination is thoroughly triturated (blended), then about 2 grams of substance B would be added to the A-B mixture. Then 4 more grams of substance B would be added and so forth. This successive addition and blending of equal quantities is an efficient method to arrive at a homogenous mixture.
The blend/granules may be compressed into tablets using suitable toolings. Further, the granules may be compressed to obtain bilayered tablets. Alternatively, the granules can be filled into capsules.
The following non-limiting examples illustrate the pharmaceutical composition containing fixed dose combination of voglibose with metformin disclosed in various embodiments of the specification.
(TABLE REMOVED)
Metformin Granules
1. Metformin hydrochloride was milled through multimill using 0.5mm sieve & mixed
with sodium starch glycolate to obtain a blend.
2. Povidone was dissolved in hot purified water and to this maize starch slurry was
added to obtain a paste.
3. The blend of step 1 was granulated in rapid mixer granulator using the paste of step
2 to obtain granules.
4. The granules of step 3 were dried in fluid bed dryer and sized through multimill.
5. Colloidal anhydrous silica and magnesium stearate were mixed with the granules of
step 4 to obtain lubricated granules.
Voglibose Granules
6. Voglibose and intragranular starch (20%) were mixed geometrically to obtain a blend.
7. Remaining intragranular starch (80%), magnesium stearate and lactose were mixed
geometrically to obtain a blend.
8. Hydroxypropyl cellulose was dissolved in purified water to obtain a solution.
9. The blend of step 6 and 7 was mixed and granulated in rapid mixer granulator using
solution of step 8 to obtain granules.
10. The granules obtained in step 9 were dried at 55-60°C and sifted through # 25 BSS
sieve.
11. Extra granular starch, hydroxypropyl cellulose and magnesium stearate were mixed
with the granules of step 10 to obtain lubricated granules.
Compression
12. The lubricated granules of step 5 and 11 were compressed to obtain tablet using
approved tooling.
(TABLE REMOVED)
1. Voglibose and microcrystalline cellulose were mixed geometrically to obtain a blend.
2. The blend of step 1 was mixed with metformin hydrochloride geometrically to obtain a final blend.
3. Povidone was dissolved in purified water to obtain a solution.
4. The final blend of step 2 was granulated in rapid mixer granulator using solution of step 3 to obtain granules.
5. The granules of step 4 were dried in fluid bed dryer and sifted through #22 sieve.
6. Microcrystalline cellulose, sodium starch glycollate and magnesium stearate were
mixed with the granules of step 5 to obtain lubricated granules which were
compressed to obtain tablet.
(TABLE REMOVED)
1. Metformin hydrochloride was mixed with microcrystalline cellulose to obtain a blend.
2. Voglibose and povidone was dissolved in purified water to obtain a solution.
3. The blend of step 1 was granulated in rapid mixer granulator using solution of step2to obtain granules.
4. The granules of step 3 were dried in fluid bed dryer and sifted through #22 BSS
sieve.
5. Microcrystalline cellulose, sodium starch glycollate and magnesium stearate wereallmixed with the granules of step 4 to obtain lubricated granules which werecompressed to obtain tablet.
Assay, Dissolution Profile and Content Uniformity of Example 2 & Example 3 are given
below:
Table 1: Assay for Example 2 & Example 3:
(TABLE REMOVED)
Dissolution Profile:
For voglibose : Dissolution profile as measured in USP type II dissolution apparatus at 150 rpm in 100ml distilled water.
For Metformin: Dissolution profile as measured in USP type II dissolution apparatus at 50rpm in 900ml of 6.8 Phosphate buffer.
(TABLE REMOVED)
The content Uniformity of Voglibose in the tablets prepared as per the details given in Example 2 & 3 was tested as per the method specified for content uniformity testing in the Indian Pharmacopoeia (IP). The results of this testing showed that the content uniformity of these tablets were well within the specified limits. (Table 3)
(TABLE REMOVED)
As per IP tablets comply with the test if each individual content is 85 to 115 per cent of the average content. The preparation fails to comply with the test if more than one individual content is outside the limits of 75 to 125 per cent of the average content.

WE CLAIM:
1. A pharmaceutical composition containing fixed dose combination of voglibose with metformin comprising voglibose in an amount of from 0.20 mg to 0.30mg and metformin in an amount of from 500mg to 1000mg, wherein the content uniformity values of Voglibose in the composition is between 85% to 115% of the average content, when measured as per test described in Indian Pharmacopoeia.
2. The pharmaceutical composition according to claim 1, in the form of a tablet, wherein the tablet comprises: voglibose in an amount of 0.20 mg, metformin in an amount of 500mg and one or more pharmaceutically acceptable excipinets.
3. The pharmaceutical composition according to claim 2, wherein the pharmaceutically acceptable excipients are selected from one or more of binders, diluents, disintegrants and lubricants, wherein the binders are selected from one or more of starches selected from corn starch, pregelatinized starch and maize starch; cellulose derivatives selected from hydroxypropylmethyl cellulose, hydroxypropyl cellulose and methylcellulose; gums selected from xanthan gum, gum acacia and tragacanth; water-soluble vinylpyrrolidone polymers selected from polyvinylpyrrolidone and copolymer of vinylpyrrolidone vinyl acetate; and sugars selected from sorbitol and mannitol; wherein the diluents are selected from one or more of sugars selected from dextrose, glucose and lactose; sugar alcohol selected from sorbitol, xylitol and mannitol; cellulose derivatives selected from powdered cellulose and microcrystalline cellulose and starches selected from corn starch, pregelatinized starch and maize starch; wherein disintegrants are selected from one or more of sodium starch glycolate, croscarmellose sodium, crospovidone and corn starch; and wherein the lubricants are selected from one or more of magnesium stearate, talc, sodium stearyl fumarate and colloidal silicon dioxide.
4. The process for the preparation of the pharmaceutical composition according to claim 2, wherein the process comprises the steps of:

a) granulating metformin and one or more pharmaceutically acceptable excipients to obtain granules,
b) mixing voglibose and one or more pharmaceutically acceptable excipients followed by granulation to obtain granules, and,
c) mixing the granules obtained by step (a) and (b) and compressing to obtain tablet.
5. The process for the preparation of the pharmaceutical composition according to claim 4, wherein the voglibose and the pharmaceutically acceptable excipients in step (b) are mixed geometrically.
6. The process for the preparation of the pharmaceutical composition according to claim 2, wherein the process comprises the steps of: a) mixing metformin, voglibose and one or more pharmaceutically acceptable excipients geometrically to obtain a blend, and, b) granulating the blend of step (a) using water to obtain granules, followed by compression into tablet.
7. The process for the preparation of the pharmaceutical composition according to claim 2, wherein the process comprises the steps of: a) blending metformin and one or more pharmaceutically acceptable excipients to obtain a blend, and, b) dissolving voglibose in water to obtain a solution, and, c) granulating the blend of step (a) with the solution of step (b) to obtain granules, followed by compression into tablet.
8. The process for the preparation of the pharmaceutical composition according to any of the claims 6 or 7, wherein the water in step (b) further comprises of one or more binders.
9. The process for the preparation of pharmaceutical composition according to claim 8, wherein the binders are selected from one or more of starches selected from corn starch, pregelatinized starch and maize starch; cellulose derivatives selected from hydroxypropylmethyl cellulose, hydroxypropyl cellulose and methylcellulose; gums selected from xanthan gum, gum acacia and tragacanth; water-soluble vinylpyrrolidone polymers selected from polyvinylpyrrolidone and copolymer of vinylpyrrolidone vinyl acetate; and sugars selected from sorbitol and mannitol.
10. 10. A pharmaceutical composition containing fixed dose combination of voglibose with metformin and process of preparation thereof substantially described and exemplified herein.