A formulation comprising empagliflozin and metformin hydrochloride

Abstract

The present invention relates to a film coated tablet comprising empagliflozin and metformin hydrochloride, wherein comprising at least two fillers and the amount of fillers is 10.0% to 60.0% by weight in the total composition, the tablet provides the desired stability and pharmacotechnical properties and the desired dissolution profile. The present invention also relates to a simple, rapid, cost effective, time-saving and industrially convenient method of preparing the tablet.

Description

[0001] A FORMULATION COMPRISING EMPAGLIFLOZIN AND METFORMIN HYDROCHLORIDE

[0002] Field of the Invention

[0003] The present invention relates to a film coated tablet comprising empagliflozin and metformin hydrochloride, wherein comprising at least two fillers and the amount of fillers is 10.0% to 60.0% by weight in the total composition, the tablet provides the desired stability and pharmacotechnical properties and the desired dissolution profile. The present invention also relates to a simple, rapid, cost effective, time-saving and industrially convenient method of preparing the tablet.

[0004] Background of the Invention

[0005] 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:

[0006] 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.

[0007] 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 overweighed. 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.

[0008] 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 500 to 850 mg. It is used singly or in combination with sulfonylureas, alpha-glucosidase inhibitors, or insulin.

[0009] The chemical name of metformin hydrochloride is 1,1-dimethylbiguanide hydrochloride, has the following chemical structure of Formula I.

[0010] Formula I

[0011] Empagliflozin is a known SGLT2 inhibitor that is described for the treatment or improvement in glycemic control in patients with type 2 diabetes mellitus. The chemical name of empagliflozin is 1 - chloro-4-(3-D-glucopyranos-l -yl)- 2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene and its chemical structure is shown in the Formula II.

[0012] Formula II

[0013] Combination product of empagliflozin and metformin hydrochloride is marketed under the trademark Synjardy®. The combination is to help control blood glucose in people with T2D. Empagliflozin, a sodium glucose co-transporter-2 (SGLT2) inhibitor, removes excess glucose through the urine by blocking glucose re-absorption in the kidney.

[0014] Active ingredients have some disadvantages in the formulation and process. The main problem encountered when preparing formulations comprising empagliflozin is low solubility, leading to difficulties with disintegration and dissolution times. Furthermore, metformin is a very poorly compressible active substance and metformin presents in high amounts in a composition. This causes some problems for examples; homogeneity, flowability and dissolution profile.

[0015] WO2011039337 (Al) application discloses pharmaceutical compositions comprising fixed dose combinations of a SGLT-2 inhibitor drug and a partner drug, processes for the preparation thereof, and their use to treat certain diseases.

[0016] CN104586834 (A) application discloses a pharmaceutical composition of empagliflozin and metformin, a preparation method and application thereof. The composition comprises the following components: i.) empagliflozin; ii.) metformin hydrochloride; and one or more fillers; one or more adhesives; one or more flow aids and one or more lubricants.

[0017] In the prior art, there are also several patents which disclose empagliflozin and metformin hydrochloride in oral pharmaceutical dosage forms. However, because of the dissolution problem of empagliflozin, and the poorly compressible of metformin, an effective formulation and method has not been disclosed.

[0018] There still remains a need in the art to provide an improved a film coated tablet comprising empagliflozin and metformin hydrochloride having high solubility, excellent pharmacomechanic properties and accordingly a high bioavailability and a long-term stability which is also obtained by using an effective process.

[0019] Detailed Description of the Invention

[0020] The main object of the present invention is to provide a film coated tablet comprising empagliflozin and metformin hydrochloride with having the desired level of dissolution rate and excellent physicochemical properties, such as flowability, compressibility, homogeneity, and content uniformity which overcomes the above-described problems in the prior art and have additive advantages over them.

[0021] Another object of the present invention is to provide a film coated tablet comprising empagliflozin and metformin hydrochloride with having high stability.

[0022] Another object of the present invention is to provide a process for preparing a film coated tablet comprising empagliflozin and metformin hydrochloride. The process is a simple, rapid, cost effective, time-saving, and industrially convenient method.

[0023] The main problem encountered when preparing formulations comprising empagliflozin is low solubility, leading to difficulties with disintegration and dissolution times. Furthermore, metformin is a very poorly compressible active substance and metformin presents in high amounts in a composition. This causes some problems for examples; homogeneity, flowability and dissolution profile. Therefore, the excipients and process steps used are very important. Especially the selection of fillers with a high percentage is very important.

[0024] According to an embodiment of the present invention, a film coated tablet comprises metformin hydrochloride and empagliflozin wherein comprising at least two fillers and the amount of fillers is 10.0% to 60.0% by weight in the total composition. The film coated tablet is obtained which shows the desired dissolution profile, and physicochemical properties, such as flowability, compressibility, homogeneity, and content uniformity.

[0025] Encountered while developing formulations is the flowability-problem and compressibility of metformin HCI, which makes the production difficult. It has been observed that this problem is overcome by using at least one filler.

[0026] Suitable fillers are selected from the group comprising microcrystalline cellulose, lactose, anhydrous lactose, starch, mannitol, calcium hydrogen phosphate dihydrate, dicalcium hydrogen phosphate anhydrate, calcium phosphate trihydrate, neutral pellets, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium chain triglycerides or mixtures thereof.

[0027] According to an embodiment of the present invention, the fillers are microcrystalline cellulose and lactose. The fillers provide flowability and compressibility of metformin HCI.

[0028] According to an embodiment of the present invention, the amount of fillers is 30.0% to 50.0% by weight in the total composition.

[0029] According to an embodiment of the present invention, the amount of microcrystalline cellulose is 5.0% to 30.0% by weight in the total composition.

[0030] According to an embodiment of the present invention, the amount of lactose is 5.0% to 30.0% by weight in the total composition.

[0031] According to an embodiment of the present invention, the film coated tablet comprises metformin hydrochloride and empagliflozin wherein comprising microcrystalline cellulose and lactose as filler and the amount of fillers is 10.0% to 60.0% by weight in the total composition.

[0032] According to an embodiment of the present invention, the film coated tablet further comprises at least one glidant / lubricant.

[0033] Suitable glidants / lubricants are selected from the group comprising anhydrous colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate, magnesium oxide, starch, silicone dioxide, talc, polyethylene glycol, stearic acid, aluminum silicate, magnesium silicate, colloidal silica or mixtures thereof.

[0034] According to an embodiment of the present invention, the glidant / lubricant is anhydrous colloidal silicon dioxide or magnesium stearate or mixtures thereof. These excipients provide the flowability of the powder mixture. According to an embodiment of the present invention, the amount of glidants / lubricants is 0.2% to 10.0% by weight in the total composition, the amount of glidants / lubricants used helps to provide the desired flowability and compressibility of tablet. Especially, the amount of anhydrous colloidal silicon dioxide used helps to provide the desired flowability and compressibility of tablet, the amount of anhydrous colloidal silicon dioxide is 0.1% to 5.0% by weight in each layer composition.

[0035] According to an embodiment of the present invention, the film coated tablet is coated with at least one film coating agent.

[0036] Suitable film coating agents are selected from the group comprising polymethacrylates, hydroxypropyl methylcellulose, lactose monohydrate, talc, hydroxypropyl cellulose, polyvinyl alcohol (PVA), polyethylene glycol (PEG), glycerin, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat® IR), ethylcellulose dispersions (Surelease®), polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA), iron oxide yellow, iron oxides, all kinds of Opadry®, pigments, dyes, titanium dioxide, coloring agent or mixtures thereof.

[0037] According to an embodiment of the present invention, the film coated tablet comprises; a) Metformin HCI b) Empagliflozin c) Microcrystalline cellulose d) Lactose e) Anhydrous colloidal silicon dioxide f) Magnesium stearate

[0038] The film coated tablet of the present invention may be prepared, using standard techniques and manufacturing processes well known in the art, such as direct compression or dry granulation or wet granulation.

[0039] According to one embodiment of the present invention, a process for the preparation of the film coated tablet comprises the following steps: a) Mixing Metformin HCI, empagliflozin, microcrystalline cellulose, lactose and anhydrous colloidal silicon dioxide, b) Sieving the mixture and then mixing, c) Adding magnesium stearate and then mixing, d) Compressing the mixture into the tablet, e) Coating the tablets with film coating agent. According to one embodiment of the present invention, a process for the preparation of the film coated tablet comprises the following steps: a) Mixing Metformin HCI, empagliflozin, microcrystalline cellulose and lactose, b) Granulating the mixture at step (b) with a solvent (preferably water), c) Sieving the wet granule, d) Drying the wet granules and sieving, e) Adding anhydrous colloidal silicon dioxide and magnesium stearate and then mixing, f) Compressing the mixture into the tablet, g) Coating the tablets with film coating agent.

[0040] According to this embodiment of the present invention, a solvent is used at wet granulation.

[0041] Suitable solvents are selected from the group comprising pure water, dichloromethane, 0.1N HCI, methanol, ethanol, isopropyl alcohol, benzyl alcohol, propylene glycol, polyethylene glycol, cyclomethicone or mixtures thereof. Preferably, the solvent is water.

[0042] In this present invention, a desired compressibility and a desired content uniformity of the film coated tablet is obtained and it has a simple and low-cost preparation process, in favor of industrial production.

[0043] Example 1: The tablet formulation

[0044] A process for example 1; a) Sieving metformin HCI through 2 mm, b) Mixing Metformin HCI, empagliflozin, microcrystalline cellulose, lactose and colloidal silicon dioxide, c) Sieving the mixture through 630 p and then mixing, d) Adding magnesium stearate and then mixing, e) Compressing the mixture into the tablet, f) Coating the tablets with film coating agent.

[0045] A process for example 1; a) Sieving metformin HCI through 2 mm, b) Mixing Metformin HCI, empagliflozin, microcrystalline cellulose and lactose, c) Granulating the mixture at step (b) with a solvent ( preferably water), d) Sieving the wet granule through 8 mm, e) Drying the wet granules at 50 °C and sieving through 1.5 mm, f) Adding anhydrous colloidal silicon dioxide and magnesium stearate and then mixing, g) Compressing the mixture into the tablet, h) Coating the tablets with film coating agent.

Claims

CLAIMS1) A film coated tablet comprises metformin hydrochloride and empagliflozin wherein comprising at least two fillers and the amount of fillers is 10.0% to 60.0% by weight in the total composition.2) The film coated tablet according to claim 1, wherein fillers are selected from the group comprising microcrystalline cellulose, lactose, anhydrous lactose, starch, mannitol, calcium hydrogen phosphate dihydrate, dicalcium hydrogen phosphate anhydrate, calcium phosphate trihydrate, neutral pellets, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium chain triglycerides or mixtures thereof.3) The film coated tablet according to claim 1, wherein the fillers are microcrystalline cellulose and lactose.4) The film coated tablet according to claim 3, wherein the amount of microcrystalline cellulose is 5.0% to 30.0% by weight in the total composition.5) The film coated tablet according to claim 3, wherein the amount of lactose is 5.0% to 30.0% by weight in the total composition.6) The film coated tablet according to claim 1, wherein the amount of fillers is 30.0% to 50.0% by weight in the total composition.7) The film coated tablet according to claim 1, wherein the film coated tablet further comprises at least one glidant / lubricant.8) The film coated tablet according to claim 7, wherein glidants / lubricants are selected from the group comprising anhydrous colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate, magnesium oxide, starch, silicone dioxide, talc, polyethylene glycol, stearic acid, aluminum silicate, magnesium silicate, colloidal silica or mixtures thereof.9) The film coated tablet according to claim 7, wherein the glidant / lubricant is anhydrous colloidal silicon dioxide or magnesium stearate or mixtures thereof.10) The film coated tablet according to claim 9, wherein the amount of glidants / lubricants is 0.2% to 10.0% by weight in the total composition.) The film coated tablet according to claim 1, wherein the film coated tablet is coated with at least one film coating agent. ) The film coated tablet according to claim 1, wherein the film coated tablet comprising; a) Metformin HCI b) Empagliflozin c) Microcrystalline cellulose d) Lactose e) Colloidal silicon dioxide f) Magnesium stearate ) a process for the preparation of the film coated tablet comprises the following steps: a) Mixing Metformin HCI, empagliflozin, microcrystalline cellulose, lactose and anhydrous colloidal silicon dioxide, b) Sieving the mixture and then mixing, c) Adding magnesium stearate and then mixing, d) Compressing the mixture into the tablet, e) Coating the tablets with film coating agent. ) A process for the preparation of the film coated tablet comprises the following steps: a) Mixing Metformin HCI, empagliflozin, microcrystalline cellulose and lactose, b) Granulating the mixture at step (b) with a solvent (preferably water), c) Sieving the wet granule, d) Drying the wet granules and sieving, e) Adding anhydrous colloidal silicon dioxide and magnesium stearate and then mixing, f) Compressing the mixture into the tablet, g) Coating the tablets with film coating agent.

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