AN EFFERVESCENT TABLET COMPOSITION OF SITAGLIPTIN Field of the invention

The present invention relates to an effervescent tablet comprising sitagliptin or a pharmaceutically acceptable salt, solvate or polymorph thereof and at least one pharmaceutically acceptable excipient. Further, the present invention provides a method for the preparation of said tablet.

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.

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

Formula 1. Sitagliptin

The film-coated tablets of Sitagliptin named as Januvia ^® are being marketed by Merck in the USA. The Januvia ^® tablet contains 32.13, 64.25, or 128.5 mg of sitagliptin phosphate monohydrate, which is equivalent to 25, 50, or 100 mg, respectively, of free base.

Given that the greatest problem encountered with solid oral dosage forms of sitagliptin is the lower stability of the product due to its hygroscopic feature, there is still a need in the art for a solid oral dosage form that provides high stability and thus a long shelf life, without compromising its dissolution, disintegration and flowability features while having a safe composition for use in hypertensive and cardiac patients.

Detailed description of the Invention The main object of the present invention is to obtain a composition of sitagliptin which overcomes all the above-mentioned problems and brings additional advantages to the relevant prior art.

Another object of the present invention is to obtain a formulation by which the rapidly absorbed of sitagliptin and rapidly effective are enhanced. The term "sitagliptin" as used throughout the specification refers to not only sitagliptin, but also its other pharmaceutically acceptable salt, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof. Effervescent tablets break down quickly when they are dropped into water or another liquid. Effervescent tablets are uncoated tablets containing substances that react in the presence of water and give off carbon dioxide.

Effervescent compositions are an interesting dosage form offering some unique advantages such as administration of an Active Pharmaceutical Ingredient (API) in solution form and taste masking of the API. Patients benefited by the use of effervescent tablets are the geriatric population, pediatric-population and a large adult population with a gag reflex and/or swallowing difficulty.

Taking big tablets or capsules is difficult for the patients. Effervescent technology provides an alternative to them. Dissolving and break-down of standard tablets also takes additional time in the stomach. In effervescents, ingredients are distributed in the solution and they are not localized at a certain point.

According to this embodiment of the present invention, sitagliptin or a pharmaceutically acceptable salt, solvate or polymorph thereof is present in an effervescent tablet form, so it is to provide effective and easy use.

According to this embodiment of the present invention, an effervescent tablet comprises sitagliptin or a pharmaceutically acceptable salt, solvate or polymorph thereof and at least one pharmaceutically acceptable excipient.

According to this embodiment of the present invention, sitagliptin is present as sitagliptin malate form.

Surprisingly, using sitagliptin malate provides desired stability in the composition.

The formulation of the invention was designed without having to compromise on stability to achieve the rapidly absorbed and desired dissolution rate which was linked to the surprisingly coordinated effect of using sitagliptin malate as a source of sitagliptin and using the effervescent tablet form.

According to this embodiment of the present invention, the amount of sitagliptin malate is between 0.5% and 20.0% or between 0.5% and 10.0% or between 0.5% and 5.0% by weight of the total composition.

According to this embodiment of the present invention, the effervescent tablet comprises at least one pharmaceutically acceptable excipient which is selected from the group comprising subliming agents, diluents, gas generating agents, acid sources, flavoring agents, super- disintegrants, glidants, lubricants or mixtures thereof.

Suitable subliming agents are selected from the group comprising camphor, ammonium bicarbonate, thymol, menthol, vanillin or mixtures thereof. The subliming agents provide the porous structure in the tablet so, the disintegrating time of the effervescent tablet decreases.

According to this embodiment of the present invention, the amount of the subliming agent is between 0.1% and 40.0% by weight of the total composition.

According to this embodiment of the present invention, the subliming agent is camphor.

Suitable diluents are selected from the group comprising mannitol, starch, sorbitol, lactose, lactose monohydrate, dextrose, sucrose, fructose, maltose, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, microcrystalline cellulose or mixtures thereof.

According to this embodiment of the present invention, the amount of the diluent is between 5.0% and 60.0% or between 15.0% and 45.0% or between 20.0% and 35.0% by weight of the total composition.

According to this embodiment of the present invention, the diluent is mannitol.

Gas generating in effervescent tablets is obtained due to the presence of acid and base substances such as carbonates or bicarbonates that react rapidly in the presence of water and release C02 to provide a carbonated or sparkling liquid drink. Due to liberation of C02, the dissolution of API in water as well as taste masking of the API is achieved.

Suitable gas generating agents are selected from the group comprising sodium bicarbonate, aluminum potassium sulfate, anhydrous disodium hydrogen phosphate, potassium bicarbonate, anhydrous sodium dihydrogen phosphate, dibasic potassium sulfate, calcium carbonate, monobasic potassium phosphate, sodium acetate, sodium carbonate, sodium glycine carbonate sodium citrate, sodium dihydrogen phosphate dihydrate, tribasic sodium phosphate or mixtures thereof.

According to this embodiment of the present invention, the amount of the gas generating agent is between 2.0% and 40.0% or between 10.0% and 35.0% or between 20.0% and 30.0% by weight of the total composition. According to this embodiment of the present invention, the gas generating agent is sodium bicarbonate.

Suitable acid sources are selected from the group comprising citric acid, nicotinic acid, dilute hydrochloric acid, glacial acetic acid, malic acid, ascorbic acid, acetylsalicylic acid, lactic acid, maleic acid, acid, adipic acid, tartaric acid or mixtures thereof.

According to this embodiment of the present invention, the amount of the acid sources is between 2.0% and 40.0% or between 15.0% and 25.0% by weight of the total composition.

According to this embodiment of the present invention, the acid source is citric acid.

Suitable flavoring agents are selected from the group comprising menthol, peppermint, cinnamon, chocolate, vanillin or fruit essences such as cherry, orange, strawberry, grape, black currant, raspberry, banana, red fruits, wild berries or mixtures thereof. Also, taste masking agents can be used. For example; sodium bicarbonate-citric acid- lemon, sodium bicarbonate-citric acid- orange, sodium bicarbonate-citric acid-cherry or mixtures thereof.

According to this embodiment of the present invention, the amount of the flavoring is between 0.1% and 10.0% by weight of the total composition.

The selection of excipients has more importance to obtain the ideal disintegrating time during the shelf life. Especially, the choice of the disintegrant has a major role in the manufacture of the effervescent tablets. Therefore, the choice of a suitable disintegrant and an optimal use level are critical to ensure a high disintegration rate. Some disintegrants, also known as super-disintegrants, are particularly effective in inducing rapid tablet disintegration due to the combined effect of swelling and water absorption by the formulation.

Suitable super-disintegrants are selected from the group comprising crospovidone, croscarmellose sodium, low-substituted hydroxypropylcellulose, sodium starch glycolate mixtures thereof.

According to this embodiment of the present invention, the amount of the super-disintegrant is between 1.0% and 30.0% or between 8.0% and 20.0% by weight of the total composition.

According to this embodiment of the present invention, the super-disintegrant is crospovidone.

Suitable lubricants are selected from the group comprising sodium stearyl fumarate, magnesium stearate, calcium stearate, zinc stearate, wax, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, glyceryl palmito sulphate, sodium lauryl sulphate or mixtures thereof.

According to this embodiment of the present invention, the amount of the lubricants is between 0.05% and 2.0% by weight of the total composition.

According to this embodiment of the present invention, the lubricant is sodium stearyl fumarate.

Suitable glidants are selected from the group comprising colloidal silicon dioxide, talc, aluminum silicate, colloidal silica, calcium silicate, magnesium silicate, magnesium oxide, starch or mixtures thereof.

According to this embodiment of the present invention, the amount of the glidant is between 0.05% and 2.0% by weight of the total composition.

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

The effervescent tablet of the present invention can be prepared by using standard techniques and manufacturing processes well known in the art, such as direct compression, wet or dry granulation, sublimation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion, spheronization, slugging, spray drying.

According to this embodiment of the present invention, optionally the effervescent tablet of the present invention is prepared by direct compression or wet granulation or dry granulation or sublimation method. It has been found that when the tablet is prepared with these methods, the disintegration time of the effervescent tablet is shortened.

Example 1 : Effervescent tablet comprising sitagliptin malate

Example 2: Effervescent tablet comprising sitagliptin malate A process for preparing the effervescent tablet processed by direct compression in example 1 and example 2 comprises the following steps;

- Mixing sitagliptin malate, mannitol, sodium bicarbonate, citric acid, flavoring agent, crospovidone and colloidal silicon dioxide,

- Adding sodium stearyl fumarate and then mixing,

- Pressing to form effervescent tablet in low humidity conditions.

A process for preparing the effervescent tablet processed by wet granulation in example 1 and example 2 comprises the following steps;

- Mixing sitagliptin malate, mannitol, citric acid, flavoring agent and crospovidone, - Granulating the mixture with water,

- Then drying the granules and sieving the granules,

- Adding sodium bicarbonate and colloidal silicon dioxide and then mixing,

- Adding sodium stearyl fumarate and then mixing,

- Pressing to form effervescent tablet in low humidity conditions. Example 3: Effervescent tablet comprising sitagliptin malate

A process for preparing the effervescent tablet processed by sublimation methods in example 3 comprises the following steps;

- Mixing sitagliptin malate, camphor, mannitol, citric acid, flavoring agent and crospovidone,

- Granulating the mixture with water-alcohol mixture,

- Then, drying the granules with vacuum under a certain temperature for a period of time,

- Then, providing sublimation of camphor,

- Obtaining the granules and then sieving,

- Adding sodium bicarbonate and colloidal silicon dioxide then mixing,

- Adding sodium stearyl fumarate and then mixing,

- Pressing to form effervescent tablet in low humidity conditions.

A process for preparing the effervescent tablet processed by sublimation methods in example 3 comprises the following steps;

- Mixing sitagliptin malate, camphor, mannitol, sodium bicarbonate, citric acid, flavoring agent, colloidal silicon dioxide and crospovidone,

- Adding sodium stearyl fumarate and then mixing,

- Pressing to form tablet in low humidity conditions,

- Then, drying the tablets with vacuum under a certain temperature for a period of time,

- Then, providing sublimation of camphor,

- . Thus, effervescent tablets having pours are obtained by this method