WO2013077819A1

WO2013077819A1 - Pharmaceutical formulations comprising nateglinide

Info

Publication number: WO2013077819A1
Application number: PCT/TR2012/000150
Authority: WO
Inventors: Mahmut Bilgic
Original assignee: Mahmut Bilgic
Priority date: 2011-11-23
Filing date: 2012-09-24
Publication date: 2013-05-30

Abstract

The present invention relates to pharmaceutical formulations comprising nateglinide that will be used in the treatment of type 2 diabetes (non-insulin dependent) diabetes mellitus where hyperglycaemia cannot be taken under control with diet and exercise.

Description

PHARMACEUTICAL FORMULATIONS COMPRISING NATEGLINIDE

The present invention relates to pharmaceutical formulations comprising nateglinide that will be used in the treatment of type 2 diabetes (non-insulin dependent), diabetes mellitus where hyperglycaemia cannot be taken under control with diet and exercise. Nateglinide was first disclosed in the application numbered EP0196222 (Bl). It is explained in the said document that nateglinide is effective in the treatment of diabetes as a hypoglycaemic agent.

On the market, nateglinide can be found in tablet or film coated tablet forms of 60 mg, 120 mg, 180 mg. Nateglinide has low solubility in water. Thus, it takes long to disperse in body for formulations comprising this active substance. However, nateglinide should affect in a short time after it is taken in order to lower the blood sugar level expeditiously which increases especially after meals. To this respect, the formulations comprising nateglinide should disperse in a short time.

On the other hand, concerning its structure, nateglinide is an amino acid derivative. These types of molecules cause formation of various side products by reacting with some excipients that are essentially used in pharmaceutical technology. As a result of this, formulations turn yellow and have a bad appearance; besides, the level of active substance in the formulation decreases as a result of degradation and that influences the effectiveness of the treatment.

In the studies he has carried out to develop pharmaceutical formulations comprising nateglinide, the inventor has found out that using lactose as diluent in the formulations in order for the pharmaceutical formulation to have the desired disintegration characteristics can provide the desired disintegration characteristics. However, it has been seen in the accelerated stability tests that the tablets prepared using this formulation turn yellow and this agent is incompatible with the active substance as the active substance level in the formulation decreases. During the studies conducted upon this, the inventors have surprisingly seen that tablets produced with formulations obtained in the case that lactose monohydrate is used in the range of 40-70%, preferably in the range of 50-60% in proportion to the weight of the unit dosage form disintegrate in a short time, for example in less than 5 minutes and no yellowing is observed in the accelerated stability tests and there is no decrease in the level of active substance amount.

In this respect, the present invention relates to nateglinide formulations comprising lactose monohydrate in the range of 40-70% by weight in proportion to the weight of the unit dosage form. In another aspect, the present invention relates to nateglinide formulations comprising lactose monohydrate in the range of 50-60% by weight in proportion to the weight of the unit dosage form.

Although some documents in the prior art indicates that there is no incompatibility between lactose and nateglinide, the inventors have found out in the studies they have carried out that the amount and type of lactose used plays an important role in the problem of incompatibility between nateglinide and lactose. According to this, they have seen that no incompatibility is observed and the dosage forms produced with the obtained formulation show the desired disintegration characteristic in the case that lactose is used in monohydrate form and in the range of 40-70% by weight in proportion to the weight of the unit dosage form.

In the prior art, it is explained that use of low substituted hydroxypropyl cellulose plays an important role in preparation of formulations comprising nateglinide, but the inventors have developed stabile nateglinide formulations that can disintegrate in a short time without using hydroxypropyl cellulose and/or low substituted hydroxypropyl cellulose in the event that lactose monohydrate is used in the range of 40-70% in the formulations they have developed.

In another aspect, the present invention relates to pharmaceutical nateglinide formulations comprising lactose monohydrate in the range of 40-70% wherein no hydroxypropyl cellulose and/or low substituted hydroxypropyl cellulose is used.

The inventors have surprisingly seen that no yellowing is observed in the pharmaceutical formulations of nateglinide comprising lactose monohydrate in the range of 40-70% wherein no hydroxypropyl cellulose is used and the tablet dosage forms generated with these formulations disintegrate in a short time.

The formulations prepared according to the invention can be in various dosage forms that are suitable for oral administration such as tablet, film tablet, prolonged release tablet, modified release tablet, capsule, dry powder for preparing suspension, effervescent tablet, effervescent granule, orodispersible tablet, chewable tablet, sachet forms. The formulations of the invention are preferably in tablet or film coated tablet form, more preferably film coated tablet form.

Nateglinide formulations of the invention comprise at least one pharmaceutically acceptable excipient along with lactose monohydrate in the range of 40-70%. At least one pharmaceutically acceptable excipient which can be used in nateglinide formulations of the invention along with lactose monohydrate in the range of 40-70% can be selected from a group comprising disintegrant, binder, lubricant, aroma agent, diluent, effervescent acid, effervescent base, glidant. The binder that can be used in nateglinide formulations of the invention along with lactose monohydrate in the range of 40-70% can be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, maltodextrin, methyl cellulose, povidone, starch. The lubricant that can be used in nateglinide formulations of the invention along with lactose monohydrate in the range of 40-70% can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid and zinc stearate.

The diluent that can be used in nateglinide formulations of the invention along with lactose monohydrate in the range of 40-70% can be selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, lactose monohydrate, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc and xylitol. The flavouring agent that can be used in nateglinide formulations of the invention along with lactose monohydrate in the range of 40-70% can be selected from flavours such as menthol, lemon, orange, vanillin, strawberry, raspberry, caramel and so forth.

The glidant that can be used in nateglinide formulations of the invention along with lactose monohydrate in the range of 40-70% can be selected from a group comprising tribasic calcium phosphate, colloidal silicone dioxide, magnesium silicate, magnesium trisilicate and talc.

The effervescent acid that can be used in nateglinide formulations of the invention along with lactose monohydrate in the range of 40-70% can be selected from a group comprising organic acids such as malic acid, citric acid, tartaric acid and fumaric acid.

The effervescent base that can be used in nateglinide formulations of the invention along with lactose monohydrate in the range of 40-70% can be selected from a group comprising agents such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate.

The disintegrant used in nateglinide formulations of the invention along with lactose monohydrate in the range of 40-70% can be selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, microcrystalline cellulose, methyl cellulose, chitosan, starch and sodium starch glycolate.

Preferably, the combination of at least two disintegrant substances selected from the abovementioned disintegrant group is used in the formulation of the invention. More preferably, a disintegrant combination comprising croscarmellose sodium and another disintegrant is used.

During their studies, the inventors have found that in the case that the ratio of lactose monohydrate and croscarmellose sodium to each other is in a certain range, not only the tablets can be pressed under a lower pressure but also it is provided that the obtained formulation can disintegrate in a short time.

According to this, another characteristic of the present invention is that the ratio of lactose to croscarmellose sodium used in formulations comprising nateglinide is in the range of 20: 1 and 35: 1.

Formulations of the invention comprise nateglinide in the range of 5-35%, preferably 10-30% more preferably 15-30% by weight in proportion to the weight of the unit dosage amount.

Nateglinide in the formulations of the invention can be in crystalline or amorphous form and/or in form of its hydrates, solvates or a combination thereof.

Formulation can be produced by using the techniques present in the prior art such as dry blending, wet granulation, etc. separately or successively in combination.

Formulations of the invention are prepared preferably by wet granulation method and the obtained formulation is filled into capsules or sachets optionally or can be compressed in tablet form and in the event that it is compressed in tablet form, it can optionally be coated with film coating agents, for example; sugar-based coating agents, water-soluble film coating agents, enteric coating agents or release-modifier coating agents.

More preferably, nateglinide and at least one excipient are granulated and the obtained granules are mixed with at least one other excipient. The obtained formulation is compressed in form of tablet and coated with film coating agent.

As sugar-based coating agent, saccharose can be used alone or optionally along with one of the agents such as talc, calcium carbonate, calcium phosphate, calcium sulphate, gelatine, gum arabic, polyvinylpyrrolidone and pullulan or a combination thereof.

Water-soluble film coating agent can be selected from cellulose derivatives such as hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose; synthetic polymers such as polyvinyl acetal diethyl amino acetate, aminoalkyl methacrylate copolymers and polyvinylpyrrolidone; and polysaccharides such as pullulan or a combination thereof. Enteric coating agents can be selected from cellulose derivatives such as hydroxypropyl methyl cellulose ftalat, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate ftalat; acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S; and natural substances such as shellac or combinations thereof.

Delayed-release coating agents can be selected from cellulose derivatives such as ethyl cellulose; acrylic acid derivatives such as amino alkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer emulsion or combinations thereof.

Pharmaceutical compositions of the present invention comprising nateglinide can comprise a second active substance in addition to nateglinide. Said second active substance can be selected from a group comprising meglitinides, alpha-glucosidase inhibitors, sulphonylureas, tiazolidinediones, biguanides and dipeptidyl peptidase-4 inhibitors.

From another aspect, said second active substance can be selected from a group comprising repaglinide from meglitinide group; acarbose which is an alpha glucosidase inhibitor; acetohexamide, glibenclamide, glibornuride, gliclazide, gliquidone, glimepiride, glipizide, chlorpropamide, tolbutamide from sulphonylurea group; pioglitazone, rosiglitazone, rivoglitazone, rosiglitazone maleate, pioglitazone hydrochloride, troglitazone from tiazolidinedion group; phenformin, metformin or a pharmaceutically acceptable salt thereof such as metformin hydrochloride from biguanide group; sitagliptin, vildagliptin, saxagliptin, saxagliptin hydrochloride, sitagliptin phosphate, sitagliptin phosphate monohydrate agents which are dipeptidyl peptidase-4 inhibitors. The second active substance that can be used in the formulations of the invention is preferably metformin, more preferably metformin hydrochloride.

Optionally, the second active substance can be used in the same formulation with nateglinide formulations as well as combined with nateglinide formulation of the invention after used in different formulations. In other words, nateglinide and the second active substance can be prepared to be in two separate formulations. The said formulations can be combined in one dosage form or can be in independent but the same or different dosage forms as a treatment package.

In the event that the two active substances are in different dosage forms, the formulations comprising the second active substance can be in any one of the dosage forms suitable for oral administration, for instance tablet, film tablet, prolonged release tablet, modified release tablet, capsule, dry powder for suspension preparation, effervescent tablet, effervescent granule, orodispersible tablet, chewable tablet and sachet form. EXAMPLES

EXAMPLE 1: Formulation and Process for Preparation of Nateglinide Film Tablet

The active substance nateglinide and lactose monohydrate are granulated by wet-granulation method and mixed with other excipients and croscarmellose sodium; the obtained formulation is compressed in tablet form and coated with film coating agents.

EXAMPLE 2: Formulation and Process for Preparation of Treatment Package Comprising Nateglinide and Metformin

These formulations are indicated for the treatment of type 2 diabetes (non-insulin dependent) diabetes mellitus where hyperglycaemia cannot be taken under control with diet and exercise. It can be used alone or with another oral anti-diabetic substance which has a complementary effect mechanism to its own; as seen in the example, with metformin.

Claims

1. A formulation comprising nateglinid characterized in that said formulation comprises lactose monohydrate in the range of 40-70%.

2. The formulation according to claim I, characterized in that said formulation comprises lactose monohydrate in the range of 50-60%.

3. The formulation according to claims 1 and 2, characterized in that said formulation is in one of the forms of tablet, film tablet, prolonged release tablet, modified release tablet, capsule, dry powder for suspension preparation, effervescent tablet, effervescent granule, orodispersible tablet, chewable tablet and sachet that are suitable for oral administration.

4. The formulation according to claims 1-3, characterized in that said formulation is in film coated tablet form.

5. The formulation according to claims 1-4, characterized in that said formulation comprises at least one excipient selected from excipients such as disintegrant, binder, lubricant, flavoring agent, diluent, effervescent acid, effervescent base, glidant in addition to nateglinide and lactose monohydrate.

6. The formulation according to claim 5, characterized in that said formulation comprises a binder selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, maltodextrin, methyl cellulose, povidone and starch.

7. The formulation according to claim 5, characterized in that said formulation comprises a diluent selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, lactose monohydrate, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc and xylitol.

8. The formulation according to claim 5, characterized in that said formulation comprises a lubricant selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid and zinc stearate.

9. The formulation according to claim 5, characterized in that said formulation comprises a disintegrant selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, microcrystalline cellulose, methyl cellulose, chitosan, starch and sodium starch glycolate.

10. The formulation according to claim 9, characterized in that the disintegrant comprised in said formulation is a combination of croscarmellose sodium and another disintegrant.

1 1. The formulation according to claims 1-5, 9 and 10, characterized in that the ratio of lactose monohydrate: croscarmellose sodium is in the range of 20: 1 and 35: 1.

12. The formulation according to any preceding claims, characterized in that said formulation comprises nateglinide in the range of 5-35% by weight in proportion to total amount of the unit dosage.

13. The formulation according to any preceding claims, characterized in that said formulation comprises nateglinide in the range of 10-30% by weight in proportion to total amount of the unit dosage.

14. The formulation according to any preceding claims, characterized in that said formulation comprises nateglinide in the range of 15-30% by weight in proportion to total amount of the unit dosage.

15. A method for production of a formulation claimed in any preceding claims, characterized in that said method comprises the steps of granulating nateglinide and at least one excipient, and mixing the obtained granules with at least one other excipient.

16. The formulation according to claims 1 -14, characterized in that said formulation comprises a second active substance selected from a group comprising meglitinides, alpha-glucosidase inhibitors, sulphonylureas, tiazolidinediones, biguanides, and dipeptidyl peptidase-4 inhibitors in addition to nateglinide.

17. The formulation according to claims 1-14 and 16, characterized in that said formulation comprises a second active substance selected from a group comprising repaglinide from meglitinide group, an alpha-glucosidase inhibitor acarbose; acetohexamide, glibenclamide, glibornuride, gliclazide, gliquidone, glimepiride, glipizide, chlorpropamide, tolbutamide from sulphonylurea group; pioglitazone, rosiglitazone, rivoglitazone, rosiglitazone maleate, pioglitazone hydrochloride, troglitazone from tiazolidinedion group; phenformin, metformin or a pharmaceutically acceptable salt thereof, for example metformin hydrochloride, from biguanide group; dipeptidyl peptidase-4 inhibitors sitagliptin, vildagliptin, saxagliptin, saxagliptin hydrochloride, sitagliptin phosphate, sitagliptin phosphate monohydrate agents.

18. The formulation according to claims 1-14, 16, 17, characterized in that said formulation comprises metformin hydrochloride as the second active substance.

19. The formulation according to claims 1-14, 16-18, characterized in that the second active substance and nateglinide are used in the same formulation.

20. The formulation according to claims 1-14, 16-18, characterized in that the second active substance and nateglinide are used in different formulations.

21. The formulation according to claim 20, characterized in that different formulations comprising nateglinide and the second active substance separately are combined in one dosage form.

22. The formulation according to claim 21, characterized in that different formulations comprising nateglinide and the second active substance separately are combined in the same or different but independent dosage forms.

23. The formulation according to claim 22, characterized in that the formulations comprising the second active substance are in any one of the forms of tablet, film tablet, prolonged release tablet, modified release tablet, capsule, dry powder for suspension preparation, effervescent tablet, effervescent granule, orodispersible tablet, chewable tablet or sachet forms that are suitable for oral administration.