Field of the Invention

The present invention relates to a sachet formulation comprising metformin, dapagliflozin and at least one pharmaceutically acceptable excipient.

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.

Dapagliflozin is a sodium-glucose cotransporter 2 inhibitor (SGLT2) indicated in the treatment of diabetes mellitus, in particular type 2 diabetes. It prevents reabsorption of at least 90% of the glucose in the kidney and facilitates elimination of the glucose through the urine.

Dapagliflozin, also known as (1 S)-1 ,5-Anhydro-1 -C-[4-chloro-3-[(4-ethoxyphenyl)methyl] phenyl]-D-glucitol, is represented by the structure of Formula I.

Formula I

Metformin is antidiabetics having an orally-administrated biguanide structure. 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 is 1 ,1 -dimethyl biguanide, has the following chemical structure of Formula II.

Formula II

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.

IN2012DN4094A application discloses an immediate release pharmaceutical formulation which includes a tablet or capsule formulation comprising metformin and the dapagliflozin or its propylene glycol hydrate.

CN109528706A application discloses a medicine composition for treatment of diabetes, which includes dapagliflozin and metformin hydrochloride according to mass ratio of 1 :50 to 1 :200. In the method, by control the amount of both the metformin hydrochloride amount and the dapagliflozin, mixing uniformity of the two active components is guaranteed, and flowability and tabletability of the particles are ensured.

Tablet and capsule forms comprising metformin and dapagliflozin are known in the prior art. But, the compressibility of metformin is poor, and how to obtain a tablet or a capsule having an acceptable mechanical strength is an important problem in formulation development.

There is thus still a need for a formulation comprising metformin and dapagliflozin that provides pharmacotechnical properties such as flowability, compressibility and homogeneity. In the present invention, the formulation is present in the form of a sachet, also the formulation provides desired dissolution profile. The formulation has been developed by using standard techniques which is simple and cost-effective method. Detailed Description of the Invention

The main object of the present invention is to provide a sachet formulation comprising metformin, dapagliflozin and at least one pharmaceutically acceptable excipient.

Another object of the present invention is to provide pharmacotechnical properties such as flowability and homogeneity and the desired dissolution profile.

Another object of the present invention is to provide a sachet formulation comprising metformin and dapagliflozin for increasing patient compliance.

The term "metformin" as used throughout the specification refers to not only metformin, 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.

The metformin can present in the invention as metformin free base or metformin hydrochloride.

The term "dapagliflozin" as used throughout the specification refers to not only dapagliflozin, 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.

In terms of physical properties, the compressibility of metformin is poor, and how to obtain a tablet or a capsule having an acceptable mechanical strength is an important problem in formulation development.

It has been surprisingly found that using a sachet formulation comprising metformin and dapagliflozin ensures the desired dissolution profile and high physically and chemically stability provides. The sachet formulations with a good solubility result in a homogenous mixture.

Also, concerning oral administration, sachet formulations have become an issue with increasing importance in terms of patient compliance as compared to conventional solid dosage forms such as capsules and tablets. This issue is more important in terms of patients having difficulty in swallowing. For these reasons, sachet formulations are one of the advantageous routes for administering the drugs comprising metformin and dapagliflozin and provide a higher patient compliance along with recommended pharmaceutical therapies. The term “sachet” will refer to an envelope or bag for a granulate, while “granulate” refers to particles, granulate or spheronised particles. The sachets require no special shaping or molding operations. Thus, the compaction, compression or tamping steps used with other dosage forms are not needed.

According to one embodiment of the invention, a sachet formulation comprises metformin, dapagliflozin and at least one pharmaceutically acceptable excipient.

According to one embodiment of the invention, the amount of metformin is 10.0% to 20.0% by weight of the total formulation.

According to one embodiment of the invention, the amount of dapagliflozin is 0.05% to 5.0% or 0.05% to 2.0% or 0.05% to 1.0% by weight of the total formulation.

According to one embodiment of the invention, at least one pharmaceutically acceptable excipient is selected from the group comprising fillers, pH adjusters, flavouring agent, aromas or mixtures.

Suitable fillers are selected from the group comprising mannitol, microcrystalline cellulose, sorbitol, sucrose, inorganic salts, calcium salts, spray-dried lactose, calcium silicate, polysaccharides, dextrose, sodium chloride, dextrates, lactitol, sugar pellet, lactose monohydrate, starch, maltodextrin, dibasic calcium phosphate, sucrose-maltodextrin mixtures, xylitol, trehalose, heavy magnesium carbonate, isomalt or mixtures thereof.

According to one embodiment of the invention, the amount of the fillers is 5.0% to 60.0% by weight of the total formulation. The amount of the fillers is 8.0% to 50.0% or 10.0% to 40.0% or 12.0% to 35.0% by weight of the total formulation.

According to one embodiment of the invention, the filler is mannitol.

Suitable pH adjusters are selected from the group comprising citric acid, sodium bicarbonate, aluminum potassium sulfate, anhydrous disodium hydrogen phosphate, potassium carbonate, anhydrous sodium dihydrogen phosphate, dibasic potassium sulfate, calcium carbonate, nicotinic acid, dilute hydrochloric acid, glacial acetic acid, lactic acid, maleic acid, monobasic potassium phosphate, phosphoric acid, adipic acid, sodium acetate, sodium carbonate, sodium citrate, sodium dihydrogen phosphate dihydrate, tartaric acid, tribasic sodium phosphate or mixtures thereof.

According to one embodiment of the invention, the amount of the pH adjusters is 4.0% to 80.0% by weight of the total formulation. The amount of the pH adjusters is 5.0% to 70.0% or 5.0% to 60.0% or 5.0% to 50.0% or 5.0% to 40.0% or 5.0% to 30.0% or 5.0% to 20.0% or 5.0% to 10.0% by weight of the total formulation.

According to one embodiment of the invention, the pH adjuster is citric acid or sodium bicarbonate or mixtures thereof.

Suitable flavourings are selected from the group comprising sucralose, sugar alcohols, sugars, liquid glucose, sucrose, saccharine sodium, xylitol, sorbitol, erythritol or mixtures thereof.

According to one embodiment of the invention, the amount of the flavourings is 0.1% to 10.0% by weight of the total formulation. The amount of the flavourings is 0.1% to 5.0% or 1 .0% to 3.0% by weight of the total formulation.

According to one embodiment of the invention, the flavouring is sucralose.

Suitable aromas are selected from the group comprising menthol, peppermint, cinnamon, chocolate, vanillin, fruit essences, cherry, orange, strawberry, grape, black currant, raspberry, banana, red fruits, wild berries, cardamom, anise, ethyl vanillin or mixtures thereof.

According to one embodiment of the invention, the amount of the aromas is 0.1% to 10.0% by weight of the total formulation. The amount of the aromas is 0.1% to 5.0% or 1.0% to 3.0% by weight of the total formulation.

When flavourings or aromas are used in the formulation, it is observed that the use of the formulation for the patient is very easy.

The pharmaceutical composition of the present invention may be prepared, using standard techniques and manufacturing processes well known in the art, such as direct compression, wet or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion/spheronization, slugging, spray drying and solvent evaporation.

Furthermore, the sachet formulation is obtained by using a wet granulation method therefore, a simple and low-cost production method was employed.

The sachet formulation can be used for treatment on the diabetes type II. Example 1 : The sachet formulation comprising metformin and dapagliflozin

The sachet content is adjusted so that the sachet weight is 4-5 grams.

Process for example 1 : The process for the preparation of the sachet formulation comprises the following steps: a) Granulating dapagliflozin, metformin and at least one filler with alcohol or alcohol/water, b) Then, drying and sieving, c) Then, adding pH adjusters, at least one flavouring and aromas and mixing, d) Filling the mixture into sachets under low humidity conditions.

Example 2: The sachet formulation comprising metformin and dapagliflozin

The sachet content is adjusted so that the sachet weight is 4-5 grams.

Process for example 2: The process for the preparation of the sachet formulation comprises the following steps: a) Granulating dapagliflozin, metformin and mannitol with alcohol or alcohol/water, b) Then, drying and sieving, c) Then, adding sodium bicarbonate, citric acid, sucralose, aroma and mixing, d) Filling the mixture into sachets under low humidity conditions.