WO2013081563A2

WO2013081563A2 - Stable tablet formulations

Info

Publication number: WO2013081563A2
Application number: PCT/TR2012/000175
Authority: WO
Inventors: Mahmut Bilgic
Original assignee: Mahmut Bilgic
Priority date: 2011-10-24
Filing date: 2012-10-19
Publication date: 2013-06-06
Also published as: WO2013081563A3

Abstract

The present invention relates to voglibose tablet formulations comprising at least one pharmaceutically acceptable diluent.

Description

STABLE TABLET FORMULATIONS

Background of the Invention Known with the chemical name of (lS,2S,3R,4S,5S)-5-(l,3-dihydroxyipropan-2-ylamino)-l-( hydroxymethyl) cyclohexane- 1 ,2,3,4- tetraol, voglibose is an alpha-glucosidase inhibitor used in the treatment of hyperglycaemia and diseases caused by hyperglycaemia (Formula I).

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Formula (I). Voglibose Voglibose tablet formulations marketed under the commercial name BASEN^® are used in the treatment of postprandial hyperglycaemia in non-insulin dependent diabetes patients (Type II diabetes).

Various patent applications related to formulations comprising voglibose are available in the prior art. The patent application numbered WO2006/03201 1 mentions that when alpha-glucosidase inhibitors including voglibose are used singly, they cause some side effects in gastrointestinal tract such as flatulence and abdominal pain. According to said patent, this problem is solved by use of alpha-glucosidase inhibitors in combination with another active agent in the formulations. The patent application numbered WO2000/006126, on the other hand, relates to fast soluble pharmaceutical dosage forms comprising an active agent selected from the group comprising voglibose which do not leave a feeling of roughness in the mouth. The characteristic feature of the water soluble formulations is to comprise a sugar and hydroxypropyl cellulose comprising hydroxypropyl group less than 7% by weight. The sugar comprised in the formulations of the present invention is given as sugars such as sucrose; starch sugars such as glucose, maltose, fructose; lactose; all types of honey; and sugar alcohols such as sorbitol, mannitol, xylitol.

In the patent application numbered WO/1999/029327, the effect of an alpha-glucosidase inhibitor in preventing transition from impaired glucose tolerance to diabetes is disclosed. The dosage form in the scope of the patent is tablet and it is basically as follows: o Voglibose

o Corn starch

o Hydroxypropyl cellulose

o Magnesium stearate

o Lactose

The studies conducted in the scope of the present invention have shown that some sugar derivative excipients used in voglibose tablet formulations have an important effect on stability of the formulation. According to this, sugars such as lactose, maltose, fructose and/or glucose comprised in voglibose tablet formulations cause degradation of the formulations by yellowing in a shorter time than expected under storage conditions.

In the case that formulations do not comprise these sugars, some problems are observed in tableting characteristics of the formulations. Formulations produced by using these sugars do not have sufficient hardness value even when they are compressed into tablets under high pressure. Tablets which do not have sufficient hardness value are subjected to breakage- crumble in blister packages and they disintegrate. This is an undesired result in terms of pharmaceutical technology.

The documents existing in the prior art do not mention these problems of the pharmaceutical formulations comprising voglibose and therefore they do not offer a solution.

Accordingly, the object of the present invention is to provide a pharmaceutical tablet formulation which can be used in order to prepare stable tablets having sufficient hardness value and can also remain undegraded for a long time under storage conditions.

This object has surprising been realized by selection of the type of the diluent comprised in the formulations. Detailed Description of the Invention

The present invention relates to new and improved voglibose tablet formulations which can remain stable under storage conditions and have superior tableting characteristics.

One characteristic feature of the tablet formulations of the present invention is that said formulations comprise voglibose, at least one pharmaceutically acceptable diluent and at least another excipient.

Another characteristic feature of the tablet formulations of the present invention is that the diluent comprised in the formulations is selected from a group excluding lactose, maltose, fructose and/or glucose or hydrates and/or anhydrates thereof. The inventor has achieved to develop more stable formulations having superior tableting characteristics by using at least one diluent selected from a group comprising calcium carbonate, calcium sulphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, cellulose, propyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, carboxymethyl cellulose, microcrystalline cellulose, magnesium carbonate, magnesium oxide, sucrose, trehalose, starch or combinations thereof in the formulations.

The formulations produced by this way can remain undegraded under storage conditions for longer time than the formulations comprising said diluents existing in the prior art and referred herein. For the tests to be implemented in the scope of the present invention, the tablets produced according to the formulation of the present invention and as the reference product, the tablets in the patent numbered WO/1999/029327 and produced according to the formulation comprising lactose were used.

For comparative stability assay, both products were kept under accelerated stability conditions (40 ± 2 °C and 70 ± 5 % relative humidity) for 6 weeks.

According to the results obtained, although total impurity amount in the reference product is 0.5% by weight, total impurity amount in the tablet formulations produced according to the formulation of the present invention is less than 0.01% by weight at the end of 6 weeks. This result has surprisingly shows that the reference product could not remain stable as much as the tablet formulations produced in the scope of the present invention under accelerated stability conditions and lactose used as the diluent in the formulations caused a significant decrease in the stability of the formulations. High stability of the tablets produced according to the formulation of the present invention has been achieved by use of at least one pharmaceutically acceptable diluent selected from a group excluding lactose, maltose, fructose and/or glucose in the formulations.

Another advantage of the tablets produced according to the formulations of the present invention is that said tablet formulations have improved tableting characteristics. Tablet formulations prepared according to the present invention and the reference tablet formulations were compressed in tablet form under 10- 40 kN, preferably under 10-30 kN pressure; hardness values of the tablets were measured right after tablet compression and 24 hours after by Heberlein hardness tester and finally, average hardness value of 10 tablets were measured. According to the results obtained, average hardness value of the tablet formulations produced according to the present invention is minimum 4 kP. According to this, one characteristic feature of the tablet formulations of the present invention is that tablet hardness value is minimum 4 kP, preferably in the range of 4 to 15 kP, more preferably in the range of 6 to 10 kP when they are compressed in tablet form. On the other hand, average hardness value of the reference tablet formulations is less than 4 kP.

Consequently, it has been seen that selection of the type of the diluent comprised in the formulations also affects tablet hardness of the end product positively.

One characteristic feature of the formulations of the present invention is to comprise at least one diluent selected from a group comprising calcium carbonate, calcium sulphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, cellulose, propyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, carboxymethyl cellulose, microcrystalline cellulose, magnesium carbonate, magnesium oxide, sucrose, trehalose, starch or combinations thereof. Another characteristic feature of the formulations of the present invention is that said formulations comprise at least two different diluents selected from the group given.

Another characteristic feature of the formulations of the present invention is that the diluent composition comprised in the formulations is composed of starch and another cellulose derivative diluent.

Another characteristic feature of the formulations according to the present invention is that cellulose derivative diluents are selected from a group comprising cellulose, propyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, carboxymethyl cellulose, microcrystalline cellulose or combinations thereof.

The cellulose derivative diluent used in the formulations of the present invention is comprised in the formulations minimum at 20% by weight, preferably in the range of 20% to 60% by weight, more preferably in the range of 20% to 50% by weight.

The formulations of the present invention comprise starch minimum at 50% by weight, preferably in the range of 50 to 90% by weight, more preferably in the range of 50 to 80% by weight in addition to the cellulose derivative diluent.

The cellulose derivative diluent that can be used in the formulations of the present invention is preferably microcrystalline cellulose.

Another characteristic feature of the formulations of the present invention is that said formulations comprise at least one other pharmaceutically acceptable excipient in addition to voglibose and diluents.

The formulations of the present invention comprise voglibose in the range of 0.01 to 5% by weight, preferably in the range of 0.05 to 2% by weight, more preferably in the range of 0.05 to 1% by weight. The formulations of the present invention comprise voglibose in the range of 0.01 to 5 mg, preferably in the range of 0.05 to 3 mg, more preferably in the range of 0.1 to 2 mg per unit dosage form.

The excipients that can be used in the formulations of the present invention can be selected from disintegrants, effervescent acids, effervescent bases, binders, lubricants, flavouring agents, sweeteners, colouring agents, pH regulating agents, anti adhesive agents or combinations thereof.

The excipient composition preferred for the tablet formulations of the present invention is composed of at least one binder, at least one anti-adhesive agent and at least one lubricant. The disintegrants that can be used in the formulations of the present invention can be selected from starches such as potato starch, corn starch, wheat starch, pregelatinized starch, sodium starch glycolate; cellulose derivatives such as carboxymethyl cellulose sodium or microcrystalline cellulose; polyvinylpyrrolidone; crospovidone; alginic acid and its salts; chyles such as xhantan gum or veegum; ion-exchange resins or a combination thereof. The effervescent acids that can be used in the formulations of the present invention can be selected from a group comprising acetic acid, citric acid, lactic acid, malic acid, phosphoric acid, propionic acid, tartaric acid or combinations thereof.

The effervescent bases that can be used in the formulations of the present invention can be selected from a group comprising potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, sodium hydrogen citrate or combinations thereof.

The binders that can be used in the formulations of the present invention can be selected from starches such as potato starch, corn starch, wheat starch; sugars such as sucrose, glucose, dextrose, lactose, maltodextrin; natural and synthetic gums; gelatine; cellulose derivatives such as microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose; polyvinylpyrrolidone(povidone); polyethylene glycol (PEG); waxes; calcium carbonate; calcium phosphate; alcohols such as sorbitol, xylitol, mannitol and water or a combination thereof. The formulations of the present invention comprise at least one pharmaceutically acceptable binder minimum at 5% by weight, preferably in the range of 5 to 15% by weight, more preferably in the range of 5 to 10% by weight.

The lubricants that can be used in the formulations of the present invention can be selected from metallic stearates (such as magnesium stearate, calcium stearate, aluminium stearate), fatty acid esters (such as sodium stearyl fumarate), fatty acids (such as stearic acid), fatty alcohols, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oil, leucine, polyethylene glycols (PEG), metallic lauryl sulphates (such as sodium lauryl sulphate, magnesium lauryl sulphate), sodium chloride, sodium benzoate, sodium acetate and talc.

The anti-adhesive agents that can be used in the formulations of the present invention can be selected from silicon dioxide, magnesium trisilicate, cellulose powder, starch, talc, tribasic calcium phosphate, metallic stearates, calcium silicate and metallic lauryl sulphates.

The flavouring agents that can be used in the formulations of the present invention can be selected from natural aroma oils (such as peppermint oil, oil of wintergreen, clove bud oil, parsley oil, eucalyptus oil, lemon oil, orange oil), menthol, menthane, anethole, methyl salicylate, eucalyptol, cinnamon, 1- methyl acetate, sage, eugenol, oxanon, alpha-irisone, marjoram, lemon, orange, blackberry, propenyl guaetol acetyl, cinnamon, vanilla, timole, linalool, cinnamaldehyde glycerol acetal, N-substituted p-menthane-3-carboxamide, 3,1- methoxy propane 1.2-diol or a combination thereof.

The sweeteners that can be used in the formulations of the present invention can be selected from sucralose, sucrose, fructose, glucose, galactose, xylose, dextrose, laevulose, lactose, maltose, maltodextrin, mannitol, maltitol, maltol, sorbitol, xylitol, erythritol, lactitol, isomalt, corn syrup, saccharin, saccharin salts, acesulfame potassium, aspartame, D-tryptophane, monoammonium glycyrrhizinate, neohesperidine dihydrochalcone, thaumatin, neotame, alitame, stevioside and cyclamates or a combination thereof. One characteristic feature of the formulations of the present invention is that at least one pharmaceutically acceptable lubricant and anti-adhesive agent are used in the formulations in the ratio of 1 : 1.

The formulations of the present invention can be produced by a method existing in the prior art. Wet granulation, dry granulation, dry blending can be listed among these production methods.

However, the production method preferred in order to provide sufficient tablet hardness in the tablet formulations comprising voglibose is dry blending.

According to said method; voglibose, at least two different pharmaceutically acceptable diluents and optionally other excipients are dry blended and sieved. The mixture sieved is treated initially with at least one pharmaceutically acceptable anti-adhesive agent and then at least one lubricant. The mixture sieved this way is compressed in tablet form and tablets are put into use after they are boxed.

The tablet formulations produced in the scope of the present invention can optionally be coated in order to provide various release characteristics, for instance fast release, sustained release, slow release or they are coated with film coating.

One characteristic feature of this method that shall be used in production of the tablet formulations of the present invention is to blend voglibose and at least two different pharmaceutically acceptable diluents together.

Another characteristic feature of this method that shall be used in production of the tablet formulations of the present invention is that the formulations prepared are compressed in tablet form under 40- 90 kN, preferably 50-80 kN of pressure.

The formulations of the present invention can optionally be combined with a second active agent. Dosage forms can be taken separately, simultaneously or sequentially; though, they can also be taken by combining voglibose with the said other active agent or agents in a single dosage form for combined treatment.

An anti-diabetic active agent, preferably an anti-diabetic active agent from the group of biguanides can be used as the second active agent in the formulations of the present invention. The active agent form the group of biguanides is preferably metformin and/or a pharmaceutically acceptable salt thereof. The formulations of the present invention are used in the treatment of postprandial hyperglycaemia in non-insulin dependent diabetes patients (Type II diabetes).

The examples of the formulations of the present invention are given below. Yet, the formulations of the present invention are not limited to these examples. EXAMPLE 1: Tablet formulation comprising voglibose and its production method

The production method to be followed for voglibose tablet formulations to be produced according the formulation given above is as follows:

1. Voglibose, microcrystalline cellulose, starch and binder are mixed and sieved,

2. Anti-adhesive agent is added into the mixture sieved and they are mixed together,

3. Lubricant is added into the final mixture and mixed finally,

4. The mixture is compressed in tablet form.

Claims

1. A tablet formulation comprising voglibose as the active agent, at least one pharmaceutically acceptable diluent and at least one other excipient, characterized in that at least one diluent comprised in the formulations is selected from a group excluding lactose, maltose, fructose and/or glucose or hydrates and/or anhydrates thereof.

2. The tablet formulation according to claim 1, characterized in that at least one pharmaceutically acceptable diluent is selected from a group comprising calcium carbonate, calcium sulphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, cellulose, propyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, carboxymethyl cellulose, microcrystalline cellulose, magnesium carbonate, magnesium oxide, sucrose, trehalose, starch or combinations thereof in the formulations.

3. The tablet formulation according to any preceding claims, characterized in that said formulations comprise at least two different diluents.

4. The tablet formulation according to claim 3, characterized in that diluent composition comprised in the formulations is composed of starch and another cellulose derivative diluent.

5. The tablet formulation according to claim 4, characterized in that said formulation comprises a cellulose derivative diluent minimum at 20% by weight.

6. The tablet formulation according to claim 5, characterized in that said tablet formulation comprises a cellulose derivative diluent in the range of 20% to 60% by weight.

7. The tablet formulation according to claim 6, characterized in that said formulation comprises a cellulose derivative diluent in the range of 20% to 50% by weight.

8. The tablet formulation according to claim 4, characterized in that said formulation comprises starch minimum at 50% by weight.

9. The tablet formulation according to claim 8, characterized in that said formulation comprises starch in the range of 50% to 90% by weight.

10. The tablet formulation according to claim 9, characterized in that said formulation comprises starch in the range of 50 to 80% by weight.

11. The tablet formulation according to claim 4, characterized in that said cellulose derivative diluents are selected from a group comprising cellulose, propyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, carboxymethyl cellulose, microcrystalline cellulose or combinations thereof.

12. The tablet formulation according to claim 11, characterized in that said cellulose derivative diluent is microcrystalline cellulose.

13. The tablet formulation according to claim 1, characterized in that pharmaceutically acceptable excipients are selected from disintegrants, effervescent acids, effervescent bases, binders, lubricants, flavouring agent, sweeteners, colouring agents, pH regulators, anti-adhesive agents or combinations thereof.

14. The tablet formulation according to any preceding claims, characterized in that said formulation is produced by any methods of wet granulation, dry granulation or dry blending.

15. The production method according to claim 14, characterized in that said method is dry blending.

16. The tablet formulation according to any preceding claims, characterized in that said formulation is used in the treatment of postprandial hyperglycaemia in non-insulin dependent diabetes patients.