Field of the Invention

The present invention relates to a pharmaceutical composition comprises a granulate comprising empagliflozin or salts thereof and linagliptin or salts or crystalline polymorph thereof, wherein the granulate is obtained by hot melt extrusion.

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 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.

Linagliptin is used for type 2 or non-insulin dependent diabetes. It is a selective, orally administered, xanthine based dipeptidyl peptidase-4 (DPP-4) inhibitor used as an adjunct to diet and exercise to improve glycemic control. 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 insulinotropic 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. Linagliptin 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 linagliptin is 8-[(3R)-3-aminopiperidin-1-yl]-7-but-2-yn-1-yl)-3-methyl-1- [(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-1H-purine-2, 6-dione and its chemical structure is shown in the Formula I.

Formula I

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-1 -yl)- 2-[4-((S)-tetrahydrofuran-3-yloxy)- benzylj-benzene and its chemical structure is shown in the Formula II.

Tablets of empagliflozin in combination with linagliptin for oral administration are currently being marketed in United States under the name Glyxambi® by Boehringer Ingelheim indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus and are available as single layer tablets in two dosage strengths i.e. 10 mg/5 mg and 25 mg/5 mg respectively.

US 2017/0312287 Patent publication describes pharmaceutical compositions of linagliptin, their preparation and their use in the treatment of type 1 diabetes mellitus and type 2 diabetes mellitus.

US 2010/0209506 Patent publication discloses single layered pharmaceutical compositions comprising combination of empagliflozin and linagliptin. In prior art, there are also several patents which disclose a pharmaceutical composition comprising empagliflozin or salts thereof and linagliptin or salts or crystalline polymorph thereof in oral pharmaceutical dosage forms.

There still remains a need in the art to provide an improved a pharmaceutical composition of a pharmaceutical composition comprising empagliflozin or salts thereof and linagliptin or salts or crystalline polymorph thereof having high solubility, dissolution rate and te desired content uniformity which is also obtained by using an effective process.

Detailed Description of the Invention

The main object of the present invention is to provide a pharmaceutical composition comprising empagliflozin or salts thereof and linagliptin or salts or crystalline polymorph thereof having the desired content uniformity and the desired dissolution profile by the help of selection of excipients using an effective process and bringing additional advantages to the relevant prior art.

The content uniformity of low dose drugs in dosage forms is very important for quality assurance. The advantages of the present invention are even more significant, as the problem of homogeneity is even more likely to occur when two active substances are incorporated in one final dosage form, especially when two actives is used very different regarding the amount. Improved content uniformity efficiently contributes to a marked increase in bioavailability. Improved content uniformity also favors to avoid toxicity in the otherwise possible event that the amount of drug substance would be too high.

Linagliptin is used small proportion that can lead to important problems during the process of the formulation. This causes the content uniformity problems and this causes dissolution problem. At this invention using hotmelt extrusion process provides homogeneity and content uniformity which would not lead to losses in the linagliptin or excipients during production.

According to one embodiment of the present invention, a pharmaceutical composition comprises granulates comprising empagliflozin or salts thereof and linagliptin or salts or crystalline polymorph thereof, wherein the granulates is obtained by hot melt extrusion.

According to another embodiment of the present invention, granules is obtained that at the end of the hot melt extrusion, extrudates form is converted to granules.

According to another embodiment of the present invention, a d (0.9) particle size of obtained extrudate using hot melt extrusion is less 250 pm, more preferably it is less 200 pm. The size of the extrudate provides surprisingly better solubility and stability. According to one embodiment of this invention, the total amount of empagliflozin or salts thereof is between 5.0% and 30.0% by weight of the total composition.

According to one embodiment of this invention, the total amount of empagliflozin or salts thereof is between 7.0% and 25.0% or 13.0% and 20.0% by weight of the total composition.

According to one embodiment of this invention, the total amount of linagliptin or salts or crystalline polymorph thereof is between 0.5% and 8.0% by weight of the total composition.

According to one embodiment of this invention, the total amount of linagliptin or salts or crystalline polymorph thereof is between 1.3% and 6.0% or 2.0% and 5.0% by weight of the total composition.

Empagliflozin have melting points in the range of about 145°C to 160°C. Preferably, melting points of empagliflozin is 153°C.

Linagliptin have melting points in the range of about 198°C to 206°C. Preferably, melting points of empagliflozin is 202°C.

According to one embodiment of the present invention, the granulates further comprises at least one filler.

Suitable fillers are selected from the group comprising polyvinylpyrrolidone, dibasic calcium phosphate, microcrystalline cellulose, lactose monohydrate, ammonium alginate, calcium carbonate, calcium phosphate, calcium phosphate dehydrate, neutral pellets, calcium sulfate, cellulose, cellulose acetate, compressible sugar, dextrates, dextrin, dextrose, ethylcellulose, fructose, glyceryl palmitostearate, lactose, mannitol, magnesium carbonate, magnesium oxide, maltodextrin, medium chain triglycerides, polydextrose, polymethacrylates, simethicone, sodium alginate, sodium chloride, sugar spheres, sulfobutylether betacyclodextrin, talc, tragacanth, trehalose, xylitol or mixtures thereof.

According to one embodiment of this invention, the filler is polyvinylpyrrolidone or dibasic calcium phosphate or mixtures thereof.

According to one embodiment of this invention, the amount of the filler is between 50.0% to 90.0% by weight of the total composition.

According to one embodiment of this invention, the amount of the filler is between 55.0% to 88.0% or 65.0% to 88.0% by weight of the total composition. According to one embodiment of this invention, the pharmaceutical composition comprises;

A. The amount of granulate is at least 95.0% by weight of the total composition and the granulate comprising;

- Empagliflozin or salts thereof

- Linagliptin or salts or crystalline polymorph thereof

- At least one filler

B. the amount of at least one pharmaceutically acceptable excipient is between 0.05% to 5.0% by weight of the total composition.

According to one embodiment of the present invention, the pharmaceutical composition comprises granulates and at least one pharmaceutically acceptable excipient which selected from the group comprising glidants, lubricants or mixtures thereof.

Suitable glidants are selected from the group comprising colloidal silicon dioxide, polyethylene glycol, triacetin, alpha tocopherol, docusate sodium, glyceryl monooleate, glyceryl monostearate, phospholipids, polyoxylglycerides, triethyl citrate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, butyl stearate, stearyl alcohol, propylene glycol, diethyl phthalate, dibutly phthalate, dioctyl phosphate, sodium lauryl sulphate, potassium cetylphosphate, ethylene glycol distearate, sodium dodecanoate, dioctyl sodium sulfosuccinate, sodium stearate, benzalkonium chlorides, polysorbates, poloxamers or mixtures thereof.

According to one embodiment of this invention, the glidant is colloidal silicon dioxide.

According to one embodiment of this invention, the amount of the glidant is between 0.05% to 3.0% by weight of the total composition.

Suitable lubricants are selected from group comprising magnesium stearate, stearic acid, calcium stearate, zinc stearate, sodium stearyl fumarate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, mineral oil, polyethylene glycol, sodium benzoate or mixtures thereof.

According to one embodiment of this invention, the lubricant is magnesium stearate.

According to one embodiment of this invention, the amount of the lubricant is between 0.02% to 2.0% by weight of the total composition. According to one embodiment of this invention, the pharmaceutical composition is in the form of capsule or tablet.

According to one embodiment of this invention, the pharmaceutical composition is formulated as tablets including compressed tablets, coated or uncoated tablets, multilayer tablets, mini tablets, bilayer tablet, buccal tablets, sublingual tablets, effervescent tablets, film-coated tablets, orally disintegrating tablets, chewable tablet, dispersing tablet, lozenges or pastilles.

According to one embodiment of this invention, the pharmaceutical composition is formulated as film coated tablet.

According to one embodiment of this invention, the pharmaceutical composition is formulated as capsule.

It has surprisingly been found that a pharmaceutical composition of excellent content uniformity, good flowability and showing improved dissolution can be obtained when the following steps are applied in hot melt extrusion, so it is observed that the desired dissolution profile, flowability, content uniformity.

A process for the preparation of the pharmaceutical composition comprises empagliflozin or salts thereof and linagliptin or salts or crystalline polymorph thereof comprising the following steps: a) Dry mixing empagliflozin, linagliptin and polyvinylpyrrolidone, b) Heating the mixture prepared at step(a) thereby forming an extrudate, c) Cooling the extrudate at step(b), d) Converting extrudates form to granules, e) Adding dibasic calcium phosphate and colloidal silicon dioxide and then mixing, f) Adding magnesium stearate and mixing, g) Then, optionally pressing to form tablet or filling capsules. Example 1 : A tablet or capsule prepared by hot melt extrusion

Example 2: A tablet prepared by hot melt extrusion Example 3: A tablet prepared by hot melt extrusion A process for example 1 or 2 or 3; a) Dry mixing empagliflozin, linagliptin and polyvinylpyrrolidone, b) Heating the mixture prepared at step(a) thereby forming an extrudate, c) Cooling the extrudate at step(b), d) Converting extrudates form to granules, e) Adding dibasic calcium phosphate and colloidal silicon dioxide and then mixing, f) Adding magnesium stearate and mixing, g) Then, optionally pressing to form tablet or filling capsules.