WO2020013777A2

WO2020013777A2 - Tablet formulations comprising metformin and sitagliptin

Info

Publication number: WO2020013777A2
Application number: PCT/TR2019/050190
Authority: WO
Inventors: Ali Turkyilmaz; Seval Ataman
Original assignee: Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi
Priority date: 2018-04-27
Filing date: 2019-03-25
Publication date: 2020-01-16
Also published as: WO2020013777A3; EP3784672A4; EP3784672A2

Abstract

The present invention relates to a pharmaceutical tablet formulation comprising metformin and sitagliptin and at least one surfactant. Further the present invention provides a method for the preparation of said composition.

Description

TABLET FORMULATIONS COMPRISING METFORMIN AND SITAGLIPTIN

Field of the invention

Background of the invention

Diabetes mellitus is a group of disorders of carbohydrate metabolism in which the action of insulin is diminished or absent through altered secretion, decreased insulin activity or a combination of both factors. There are two main types of diabetes; Type 1 and Type 2:

Type 1 diabetes occurs because the insulin-producing cells of the pancreas (beta cells) are damaged. In Type 1 diabetes, the pancreas makes little or no insulin, so sugar cannot get into the body's cells for use as energy. People with Type 1 diabetes must use insulin injections to control their blood glucose.

In Type 2 diabetes, the pancreas makes insulin, but it either doesn't produce enough, or the insulin does not work properly. This diabetes occurs most often in people who are over 40 years old and overweight. Type 2 diabetes may sometimes be controlled with a combination of diet, weight management, and exercise. However, treatment also may include oral glucose-lowering medications or insulin injections.

Metformin is antidiabetics having an orally-administrated biguanide structure. Metformin hydrochloride is a white to off-white crystalline compound and it is freely soluble in water and practically insoluble in acetone, ether and chloroform. Oral doses of metformin are generally recommended in the range of 500 to 2500 mg a day and a single dose may vary from 250 to 1000 mg. It is used singly or in combination with sulfonylureas, alpha-glucosidase inhibitors, or insulin.

The chemical name of metformin hydrochloride is 1 ,1-dimethylbiguanide hydrochloride, has the following chemical structure of Formula I.

Formula I

Although metformin is effective at lowering blood glucose levels, its use is associated with gastrointestinal (Gl) adverse effects, particularly diarrhea and nausea. These adverse effects may limit the tolerated dose of metformin and cause patients to discontinue the therapy.

Sitagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It is an oral antihyperglycemic of the dipeptidyl peptidase-4 (DPP-4) inhibitor class. DPP-4 inhibitors work by blocking the action of DPP-4, an enzyme which destroys the hormone incretin. There are two types of incretin hormones found in the body, called glucagon-like peptide-1 (GLP-1) and glucose-dependent insulin tropic peptide (GIP). These hormones are naturally produced by the body in response to food intake. Their function is to help the body produce more insulin only when it is needed and reduce the amount of glucose being produced by the liver when it is not needed. Sitagliptin works by binding to DPP-4 and preventing it from breaking down the GLP-1 and GIP. This increases the levels of these hormones in the body and so increases their effect on controlling blood sugar.

The chemical name of sitagliptin is (3R)-3-amino-1-[3-(trifluoromethyl)-6,8-dihydro-5H- [1 ,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl) butan-1-one or (2R)-4-oxo-4- [3- (trifluoromethyl)-5,6-dihydro[1 ,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5trifluorophenyl) butan-2-amine) and its chemical structure is shown in the Formula II.

Formula II Sitagliptin is disclosed in the patent US 6699871. A crystal phosphate monohydrate form of sitagliptin is disclosed in the patent WO 2005003135.

DPP-4 inhibitors, especially sitagliptin have a novel mechanism of action and many studies are available which shows their efficacy and safety in therapies/medication are available. The single sitagliptin alone does not provide adequate glycemic control.

Sitagliptin increases plasma GLP-1 concentration and elevates cellular cAMP levels in pancreatic beta-cells leading to potentiate insulin secretion, whereas metformin improves glucose tolerance in patients with Type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents in that metformin decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Therefore, they both help to reduce blood glucose levels in different pathways in type 2 diabetes patients.

A tablet formulation for metformin and sitagliptin combination is commercially available under the trade name Janumet®. It contains either 500 or 1000 mg metformin, and 50 mg sitagliptin. Pharmaceutical compositions comprising fixed-dose combinations of immediate- release sitagliptin and metformin are disclosed in WO 2007/078726 patent application which published on July 12, 2007.

U.S. publication number 2012/0202820 discloses pharmaceutical compositions comprising sitagliptin and metformin in combination with a lubricant wherein the lubricant is polyethylene glycol or mixtures of polyethylene glycol with one or more other lubricants and comprises more than 10% by weight of the total weight of the composition.

Sitagliptin and metformin combination has incompatibility and stability problems due to interactions between drug substances. In the present invention, the tablet in which sitagliptin and metformin are in different compartments is formulated so as to overcome the problems. Thus, not only metformin and sitagliptin do not interact with each other, but also this provides easy and cost-effective process.

In the present invention, it has been surprisingly observed that an unexpected and also a synergistic therapeutic benefit can be obtained in the treatment of type-2 diabetes with a combination therapy comprising metformin and sitagliptin, while minimizing problem of incompatibility.

Therefore, there is still need for a pharmaceutical tablet formulation comprising metformin and sitagliptin that has desired stability and dissolution rate.

Detailed description of the Invention

The main object of the present invention is to avoid incompatibility problems between metformin and sitagliptin using the tablet having different compartments.

Another object of the present invention is to provide improved stability and desired dissolution rate in tablet formulation.

Another object of the present invention is to provide compressible property of metformin.

As used herein, the term "metformin" includes metformin and pharmaceutically acceptable salts thereof. The pharmaceutically acceptable salts include hydrochloride, hydrobromide, fumarate, malonate, malate, succinate, lactate, glycolate, maleate, citrate, and aspartate. The pharmaceutically acceptable salts of metformin may be present in hydrous or anhydrous forms. They may also be present in crystalline or amorphous forms. In this invention, preferably metformin hydrochloride is used.

As used herein, the term "sitagliptin" includes sitagliptin and pharmaceutically acceptable salts thereof. The pharmaceutically acceptable salts include hydrochloride, hydrobromide, phosphate, sulphate, mesylate, besylate, fumarate, malonate, malate, succinate, lactate, glycolate, maleate, citrate, and aspartate. The pharmaceutically acceptable salts of sitagliptin may be present in hydrous or anhydrous forms. The hydrate forms may be monohydrate or dihydrate forms. The pharmaceutically acceptable salts of sitagliptin may also be present in crystalline or amorphous forms. In this invention, preferably sitagliptin malate is used.

The term "compartment" used herein throughout the specification is used to intend a part of the dosage form comprising one or both of metformin and sitagliptin, and optionally together with pharmaceutical excipients. The part of the dosage form may be in the form of a layer or core or tablet. The forms may be formed by coating or compression. The term "core" as used herein refers to a compact mass having a definite geometric shape such as tablets, granules, pellets, capsules.

Sitagliptin and metformin combination has incompatibility and stability problems due to interactions between drug substances. Separating metformin and sitagliptin in such a way that their interaction is eliminated is an effective solution so as to overcome these problems.

In the present invention, the tablet is designed by placing these two drug substances in different compartments that solves the interaction problems. Furthermore, this is an easy and cost-effective process and this provides improvement in dissolution profile with using certain excipients.

According to one embodiment of the present invention, the pharmaceutical tablet formulation comprises sitagliptin, metformin and at least one surfactant, wherein the active agents are in different compartments.

According to one embodiment of the present invention, the compartments are in direct contact with each other or the compartments are separated by a coating layer. In each compartment, at least one type of active ingredient is contained.

According to one embodiment of the present invention, the first compartment comprises metformin. The second compartment comprises sitagliptin.

According to one embodiment of the present invention, the ratio of the first compartment to the second compartment is in the range of between 25:1 to 1 :25 by weight, preferably between 19:1 and 1 :19 by weight. This ratio provides desired dissolution profile of active agents and desired combination efficacy.

According to one embodiment of the present invention, the amount of metformin in total composition is between 45.0% and 82.0% or between 60.0% and 80.0% or between 45% and 76% or between 55.0% and 76.0%.

According to one embodiment of the present invention, the amount of sitagliptin in total composition is between 3.0% and 16.0% or between 3.0% and 12.0% or between 3.0% and 10.0%. Surfactants offer many advantages. One of these is the use of surfactants becomes inevitable to reduce the interfacial tension between the medium and the drug and to increase solubility of drugs so also, surfactants help to maintain stability in combination formulations. Suitable surfactants are selected from the group comprising polyoxyethylene sorbitan esters (polysorbate), sodium lauryl sulphate, propylene glycol, glyceryl oleate, tocopherol, ascorbyl palmitate, citric acid, polyethoxylated fatty acid esters, polyoxyethylene hydrogenated castor oil, sorbitan esters, docusate sodium, nonoxynol or mixtures thereof.

According to one embodiment of the present invention, the surfactants are present in the first compartment or the second compartment or both.

According to one embodiment of the present invention, the amounts of surfactants in the tablet is between 0.0001% and 10.0% or between 0.001 % and 7.0% or between 0.001 % and 2.0% by weight of the total composition.

According to one embodiment of the present invention, preferably the surfactant is polyoxyethylene sorbitan esters (polysorbate) or sodium lauryl sulphate or mixtures thereof.

According to one embodiment of the present invention, it is not necessary to use a disintegrant because each active ingredient is combined with suitable excipients that enable desired dissolution profile in each compartment. So, the formulation is free of disintegrant.

According to one embodiment of the present invention, said disintegrant is crospovidone or dibasic calcium phosphate or croscarmellose sodium or sodium starch glycolate or alginic acid or sodium alginate or calcium alginate.

One embodiment in this invention, the composition further comprises at least one pharmaceutically acceptable excipient which is selected from the group comprising fillers, binders, pore formers, lubricants, glidants, coating agents, coloring agents, solvents or mixtures thereof.

Suitable fillers or binders are selected from group comprising microcrystalline cellulose, polyvinylpyrrolidone, lactose monohydrate, starch, dibasic calcium phosphate, tribasic calcium phosphate, trehalose, isomalt, sodium carbonate, sodium bicarbonate, calcium carbonate, carboxymethyl cellulose, polydextrose, polyethylene oxide, hydroxypropyl methyl cellulose, methyl cellulose, polyethylene glycol or mixtures thereof. According to one embodiment of the present invention, the amount of fillers or binders in the tablet is between 1.0% and 40.0% or between 4.0% and 32.0% or between 1.0% and 10.0% by weight of the total composition.

According to one embodiment of the present invention, preferably the filler or binder is microcrystalline cellulose or polyvinylpyrrolidone or mixtures thereof.

According to one embodiment of the present invention, fillers or binders are present in the first compartment or the second compartment or both. Preferably, fillers or binders are present in the first compartment.

According to another embodiment of the present invention, the pore former may be used. When the coating has more pores, the speed of the drug release will consequently increase. Pore formers dissolve or disperse away without swelling and the pore formed by this way, provides improved drug release.

Suitable pore formers are selected from group comprising sodium chloride, talc, silicon dioxide, lactose, sucralose, copovidone, maltodextrin, xylitol, poloxamers, polydextrose or mixtures thereof.

According to one embodiment of the present invention, the amount of pore formers in the tablet is between 0.5% and 6.0%, preferably it is between 0.1% and 4.0% by weight of total composition.

According to one embodiment of the present invention, preferably, pore former is sodium chloride. It may be in the first compartment or the second compartment or both. Preferably sodium chloride is in the second compartment.

Suitable lubricants or glidants are selected from group comprising magnesium stearate, hydrophobic silicon dioxide, talc, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulphate, magnesium lauryl sulphate, fumaric acid, glyceryl palmitostearate, hydrogenated natural oils, zinc stearate, calcium stearate, silica, stearic acid, polyethylene glycol, paraffin or mixtures thereof.

According to one embodiment of the present invention, the amount of glidants in the tablet is between 0.1% and 5.0%, preferably it is between 0.2% and 4.0% by weight of total composition. According to one embodiment of the present invention, preferably the glidant is hydrophobic silicon dioxide.

According to one embodiment of the present invention, the amount of lubricants in the tablet is between 0.1% and 5.0%, preferably it is between 0.2% and 4.0% by weight of total composition.

The use of high amount lubricant in the pharmaceutical composition has achieved a surprising result as it is known that the advantage of their lubricating effect is often opposed by the disadvantage of hydrophobisation of the tablet and therefore a lengthening of the disintegration rate of the tablet, so that lubricants should be used in the lowest possible concentration in the combination.

According to one embodiment of the present invention, effective amount of lubricant is used in the tablet. Preferably the lubricant is magnesium stearate.

An embodiment of this present invention, the pharmaceutical combination is formulated as tablets comprising compressed tablets, coated or uncoated tablets, multilayer tablets, mini tablets, bilayer tablet, buccal tablets, sublingual tablets, inlay tablets, effervescent tablets, film-coated tablets, orally disintegrating tablets, gastric disintegrating tablets, chewable tablet, dispersing tablet, lozenges or pastilles.

According to another embodiment of the present invention, coating layers does not comprise an active pharmaceutical agent and typically will rapidly disperse or dissolves in water.

According to one embodiment of the present invention, coating layers comprise at least one coating agent.

According to one embodiment of the present invention, the amount of coating layers in the tablet is between 1.0% and 12.0%, preferably it is between 3.0% and 7.0% by weight of total composition.

Suitable coating agents are selected from the group comprising polyvinyl alcohol (PVA), titanium dioxide, polyethylene glycol (PEG), talc, candelilla wax, hydroxypropyl methylcellulose, polymethacrylates, triacetin, glycerol triacetin, hydroxypropyl cellulose, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat® IR), ethylcellulose dispersions (Surelease®), polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA), all kinds of Opadry®, macrogol, coloring agents or mixtures thereof.

Suitable coloring agents are selected from the group comprising ferric oxide, Food, Drug & Cosmetic (FD&C) dyes (such as; FD&C blue, FD&C green, FD&C red, FD&C yellow, FD&C lakes), ponceau, indigo Drug & Cosmetic (D&C) blue, indigotine FD&C blue, carmoisine indigotine (indigo Carmine); iron oxides (such as; iron oxide red, yellow, black), quinoline yellow, flaming red, carmine, carmoisine, sunset yellow or mixtures thereof.

Preferably, the coating agents are polyvinyl alcohol (PVA), titanium dioxide, polyethylene glycol (PEG), talc, candelilla wax or mixtures thereof.

Metformin is known to be very poorly compressible active substance for tableting process. As it is highly crystalline and has poor compaction properties, it is difficult to form tablets by direct compression or dry granulation. Metformin further, is a high dose drug that is hard to compress directly into tablets. On the other hand, it is known that conventional methods of dry granulation fail to provide a satisfactory solution to poor compaction properties of metformin. It has been found that desired stability and improved dissolution may be obtained when metformin and sitagliptin are formulated in wet granulation process.

Preferably, the tablet comprising metformin and sitagliptin are formed by wet granulation. The compartments then may be processed with compression or coating process.

In the present invention, wet granulation method is used for elimination of compressibility problems related to metformin.

During wet granulation process, solvents are used. Suitable solvents are selected from the group comprising pure water, isopropyl alcohol, propylene glycol, polyethylene glycol, glycerin, ethanol, or mixtures thereof.

According to one embodiment of the present invention, preferably the solvent is pure water or isopropyl alcohol or mixtures thereof.

The resulting formulation may also possess enhanced formulation robustness and stability.

According to one embodiment of the present invention, sitagliptin and metformin combination are stable. The combination does not show incompatibilities, degradation problems or extraction problems with certain excipients such as microcrystalline cellulose, polyvinylpyrrolidone, hydrophobic silicon dioxide, magnesium stearate, polyoxyethylene sorbitan esters, hydroxypropyl methyl cellulose, isopropyl alcohol, coating agents, pure water or mixtures thereof.

According to another embodiment of the present invention, sitagliptin and metformin combination are stable. The combination does not show significant incompatibilities, degradation problems or extraction problems with certain excipients such as polyvinylpyrrolidone, sodium lauryl sulphate, magnesium stearate, polyoxyethylene sorbitan esters, sodium chloride, coating agents, candelilla wax, pure water or mixtures thereof.

According to one embodiment of the present invention, compartments or coating layers may be coated or it may be compressed as a layer.

Example 1

q.s.: quantity sufficient A process for preparing the tablet in example 1 comprises the following steps:

First compartment

a) dissolving polyvinylpyrrolidone in pure water

b) granulating metformin and microcrystalline cellulose with polyvinylpyrrolidone solution c) drying and sieving the granules

d) mixing the granules with hydrophobic silicon dioxide

e) then, adding magnesium stearate and mixing

f) compressing the mixture to form core

Coating layer

g) mixing coating agents and pure water

h) coating with the mixture prepared at the step (g) as coating layer onto the core

Second compartment

i) preparing isopropyl alcohol:pure water mixture

j) adding hydroxypropyl methyl cellulose, polyoxyethylene sorbitan esters and sitagliptin k) coating with the mixture prepared at the step G) as second compartment onto the coating layer

Coating layer

L) mixing coating agents and pure water

m) coating with the mixture prepared at the step (I) as coating layer onto the second compartment

Example 2

q.s.: quantity sufficient A process for preparing the tablet in example 2 comprises the following steps:

First compartment

a) dissolving polyvinylpyrrolidone in pure water

b) granulating metformin and sodium lauryl sulphate with polyvinylpyrrolidone solution c) drying and sieving the granules

d) then, adding magnesium stearate and mixing

e) compressing the mixture to form core Coating layer

f) mixing coating agents and pure water

g) coating with the mixture prepared at the step (f) as coating layer onto the core

Second compartment

h) mixing and homogenizing polyoxyethylene sorbitan esters, sodium chloride and coating agents

i) adding sitagliptin and then mixing

j) coating with the mixture prepared at the step (i) as second compartment onto the coating layer

Coating layer

k) mixing coating agents and pure water

L) coating with the mixture prepared at the step (k) as coating layer onto the second compartment and polishing with candelilla wax.

Claims

1. A pharmaceutical tablet formulation comprising sitagliptin, metformin and at least one surfactant, wherein the active agents are in different compartments.

2. The pharmaceutical tablet formulation according to claim 1 , wherein the compartments are in direct contact with each other or the compartments are separated by a coating layer.

3. The pharmaceutical tablet formulation according to claim 2, wherein the first compartment comprising metformin and the second compartment comprising sitagliptin.

4. The pharmaceutical tablet formulation according to claim 3, wherein the ratio of the first compartment to the second compartment is in the range of between 25:1 and 1 :25 by weight.

5. The pharmaceutical tablet formulation according to claim 4, wherein the ratio of the first compartment to the second compartment is in the range of between 19:1 and 1 :19 by weight.

6. The pharmaceutical tablet formulation according to claim 3, wherein the amount of metformin in total composition is between 45.0% and 82.0%.

7. The pharmaceutical tablet formulation according to claim 3, wherein the amount of sitagliptin in total composition is between 3.0% and 16.0%.

8. The pharmaceutical tablet formulation according to claim 1 , wherein the surfactants are in the first compartment or in the second compartment or in both.

9. The pharmaceutical tablet formulation according to claim 8, wherein said surfactants are selected from the group comprising polyoxyethylene sorbitan esters, sodium lauryl sulphate, propylene glycol, glyceryl oleate, tocopherol, ascorbyl palmitate, citric acid, polyethoxylated fatty acid esters, polyoxyethylene hydrogenated castor oil, sorbitan esters, docusate sodium, nonoxynol or mixtures thereof.

10. The pharmaceutical tablet formulation according to claim 9, wherein the surfactant is polyoxyethylene sorbitan esters or sodium lauryl sulphate or mixtures thereof.

11. The pharmaceutical tablet formulation according to any preceding claims, wherein the formulation is free of disintegrant.

12. The pharmaceutical tablet formulation according to claim 11 , wherein said disintegrant is crospovidone or dibasic calcium phosphate or croscarmellose sodium or sodium starch glycolate or alginic acid or sodium alginate or calcium alginate.

13. The pharmaceutical tablet formulation according to any preceding claims, further comprising at least one pharmaceutically acceptable excipient which is selected from the group comprising fillers, binders, pore formers, lubricants, glidants, coating agents, coloring agents, solvents or mixtures thereof.

14. The pharmaceutical tablet formulation according to claim 13, wherein the amount of fillers or binders in the tablet is between 1.0% and 40.0% by weight of the total composition.

15. The pharmaceutical tablet formulation according to claim 13, wherein the fillers or binders are in the first compartment or in the second compartment or in both.

16. The pharmaceutical tablet formulation according to claim 15, wherein the fillers or binders are in the first compartment.

17. The pharmaceutical tablet formulation according to claim 14, wherein the fillers or binders are selected from group comprising microcrystalline cellulose, polyvinylpyrrolidone, lactose monohydrate, starch, dibasic calcium phosphate, tribasic calcium phosphate, trehalose, isomalt, sodium carbonate, sodium bicarbonate, calcium carbonate, carboxymethyl cellulose, polydextrose, polyethylene oxide, hydroxypropyl methyl cellulose, methyl cellulose, polyethylene glycol or mixtures thereof.

18. The pharmaceutical tablet formulation according to claim 17, wherein the filler or binder is microcrystalline cellulose or polyvinylpyrrolidone or mixtures thereof.

19. The pharmaceutical tablet formulation according to any preceding claims, wherein the tablet comprising;

- 45.0 - 76.0% by weight of metformin

- 3.0 - 10.0% by weight of sitagliptin

- 8.0 - 30.0% by weight of microcrystalline cellulose

- 3.0 - 10.0% by weight of polyvinylpyrrolidone - 0.1 - 3.0% by weight of hydrophobic silicon dioxide

- 0.1 - 3.0% by weight of magnesium stearate

- 0.001 - 2.0% by weight of polyoxyethylene sorbitan esters

- 0.01 - 3.0% by weight of hydroxypropyl methyl cellulose

- 0.8 - 6.0% by weight of coating agents of the total composition.

20. The pharmaceutical tablet formulation according to any preceding claims, wherein the tablet comprising;

- 60.0 - 80.0% by weight of metformin

- 3.0 - 12.0% by weight of sitagliptin

- 1.0 - 10.0% by weight of polyvinylpyrrolidone

- 1.0 - 10.0% by weight of sodium lauryl sulphate

- 0.1 - 3.0% by weight of magnesium stearate

- 0.1 - 3.0% by weight of polyoxyethylene sorbitan esters

- 0.1 - 4.0% by weight of sodium chloride

- 1.0 - 9.0% by weight of coating agents of the total composition.