Multi-layer pharmaceutical compositions comprising dapagliflozin and metformin

Abstract

The present invention relates to pharmaceutical compositions in multi-layer tablet form comprising dapagliflozin or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof as active substances.

Description

[0001] MULTI-LAYER PHARMACEUTICAL COMPOSITIONS COMPRISING DAPAGLIFLOZIN AND METFORMIN

[0002] Technical Field

[0003] The present invention relates to stable, high-dissolution-rate, multi-layer tablet-form oral pharmaceutical compositions comprising dapagliflozin or a pharmaceutically acceptable salt thereof as a sodium-glucose co-transporter type 2 (SGLT-2) inhibitor, and metformin or a pharmaceutically acceptable salt thereof, and to the manufacturing of the same.

[0004] State of the Art

[0005] Type 2 diabetes is a high-risk chronic disease characterized by relative insulin deficiency caused by pancreatic p-cell dysfunction and insulin resistance in target organs. Cardiovascular disease is the leading cause of morbidity and mortality associated with type 2 diabetes and requires intensive management of blood pressure, glucose, and lipid concentrations to minimize the risk of complications and disease progression. Therefore, it is essential to actively monitor blood glucose levels in order to properly manage the disease. For many years, various treatment methods have been designed for the treatment of this chronic disease.

[0006] Dapagliflozin is an antidiabetic drug included in the group of sodium-glucose co-transporter type 2 (SGLT-2) inhibitors, which reduces renal glucose reabsorption through the selective inhibition of renal SGLT2. Dapagliflozin increases glucose excretion and decreases blood glucose levels by blocking glucose reabsorption in the kidneys.

[0007] Dapagliflozin is used to improve glycemic control in adults with type 2 diabetes. Additional effects of dapagliflozin include the reduction of body weight and blood pressure, which may be beneficial in patients with Type 2 diabetes. Dapagliflozin is a useful medication that can be prescribed as a single treatment or alongside other antidiabetic drugs for patients who cannot tolerate metformin.

[0008] Dapagliflozin is a hygroscopic solid that is white or yellowish-white in color. It is freely soluble in methanol, ethanol, dimethyl sulfoxide, and N,N-dimethyl formamide, and practically insoluble in water.

[0009] FORXIGA Oral Tablets, comprising dapagliflozin, was approved by the EMA on November 11, 2011, and by the FDA on January 8, 2014, for 5 and 10 mg doses.

[0010] Its molecular weight is 408.87 g / mol and its chemical name is (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol. The chemical structure of dapagliflozin is shown in Formula 1 below.

[0011] ..Ci

[0012] , . , j i r j

[0013] "OH

[0014]

[0015] OH

[0016] Formula 1Metformin is an oral biguanide antidiabetic that is taken orally. Metformin is similar to phenformin, a biguanide drug that was withdrawn from the U.S. market in 1977 because of cases of lactic acidosis. However, metformin has a significantly lower risk of causing lactic acidosis. The effects of metformin are different from those of sulfonylureas and other antidiabetic medications. Compared with glibenclamide (glyburide) in type 2 diabetes, it was found to provide a similar level of glycemic control, but with a higher incidence of digestive complaints. Metformin has also been found useful in the treatment of polycystic ovary syndrome (PCOS); it lowers serum androgen levels, restores normal menstrual cycles and ovulation, and may increase pregnancy rates. Metformin HCI was selected as the first-line treatment based on its efficacy, safety and cost-effectiveness. The chemical name of metformin is "N,N-dimethylimidodicarbonimidic diamide", its empirical formula is C4H11N5 and its molecular weight is 129.16 g / mol.

[0017] Metformin is freely soluble in water, slightly soluble in ethanol, and practically insoluble in methylene chloride and acetone. Metformin is a white, crystalline powder. The chemical structure of metformin is shown in Formula 2 below.

[0018]

[0019] Metformin

[0020] Formula 2

[0021] Dapagliflozin was first disclosed in patent US 6515117 B2. The patent also disclosed the molecule itself, its salts, its use in treating type 1 and type 2 diabetes, its status as an SGLT-2 inhibitor and its combination with metformin.

[0022] Metformin as an active substance was first disclosed by Emil A. Werner and James Bell in the document J. Chem. Soc., 121, 1922, 1790-1794. Metformin hydrochloride was introduced in Europe in the 1950s, but was not approved by the FDA in the U.S. until November 1994. XIGDUCT oral film-coated tablets comprising dapagliflozin and metformin as active substances was approved by the EMA on January 16, 2014, for 5mg / 850mg and 5mg / 1000mg dosage combinations, and XIGDUO’ XR oral extended-release film-coated tablets was approved by the FDA on January 29, 2014, for 5mg / 500mg, 5mg / 1000mg, 10mg / 500mg, and lOmg / lOOOmg dosage combinations. In adults, it is indicated as an adjunct to diet and exercise to improve glycemic control in the treatment of inadequately controlled Type 2 diabetes. Patent EP2498758 Bl discloses a double-layer film-coated tablet composition comprising of a first extended-release layer comprising metformin hydrochloride and a second layer comprising dapagliflozin or dapagliflozin (S) propylene glycol hydrate.

[0023] Patent application EP3946344 Al discloses a triple-layer tablet composition comprising low-dose sitagliptin or a pharmaceutically acceptable salt or hydrate thereof, metformin or a pharmaceutically acceptable salt or hydrate thereof, and dapagliflozin or empagliflozin or pharmaceutically acceptable salts or hydrates thereof.

[0024] Patent application EP4051246 Al discloses a double-layer tablet composition comprisingdapagliflozin or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof in a rapid-release layer, and metformin or a pharmaceutically acceptable salt thereof in a second extended-release layer.

[0025] Patent EP2482806 Bl discloses a solid pharmaceutical composition comprising 5mg or 12.5mg dapagliflozin with 500mg, 850mg, or lOOOmg metformin hydrochloride and copovidone as a binder.

[0026] Detailed Description of the Invention

[0027] In the prior art, there is a need for stable pharmaceutical compositions with a long shelf life and an appropriate dissolution rate profile comprising dapagliflozin or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof.

[0028] As a result of their experiments, the present inventors have surprisingly discovered that when tablet compositions comprising dapagliflozin or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof as active substances are manufactured in the form of a multi-layer tablet, they have a similar or better dissolution rate profile, tablet hardness, friability, and stability properties compared to the reference product. The present invention relates to stable oral multi-layer tablet compositions comprising dapagliflozin or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof.

[0029] The present invention relates to triple-layer tablet compositions comprising dapagliflozin or a pharmaceutically acceptable salt thereof and metformin ora pharmaceutically acceptable salt thereof.

[0030] Specifically, the present invention relates to triple-layer tablet compositions comprising of a rapid-release layer comprising dapagliflozin or a pharmaceutically acceptable salt thereof and at least one or more extended-release layers comprising metformin or a pharmaceutically acceptable salt thereof.

[0031] More specifically, the present invention relates to a triple-layer tablet composition obtained by placing the rapid-release layer comprising dapagliflozin or a pharmaceutically acceptable salt thereof between two extended-release layers comprising metformin or a pharmaceutically acceptable salt thereof.

[0032] The "dapagliflozin" comprised in the multi-layer pharmaceutical compositions according to the present invention may be in the form of, but not limited to, dapagliflozin and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs, and various crystalline and amorphous forms. Preferably, the dapagliflozin used in the present invention is in its free base form and in amorphous form.

[0033] The "metformin" comprised in the multi-layered pharmaceutical composition according to the present invention may be in the form of, but not limited to, metformin and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptableprodrugs, and various crystalline and amorphous forms. Preferably, the metformin used in the present invention is in its hydrochloride salt form.

[0034] Multi-layer pharmaceutical compositions are pharmaceutical compositions formed by combining two or more tablet layers. These pharmaceutical compositions provide advantages such as separating incompatible active substances from each other and optimizing each layer according to its unique solubility and stability properties.

[0035] In cases where it is not sufficient on its own for the treatment of type 2 diabetes, metformin is used in combination with different active substances to increase the efficacy of the treatment. For this treatment method, called combined use, formulating the active substances together in a single dosage form rather than giving the patients two or more active substances separately in different dosage forms is a very commonly used pharmaceutical manufacturing technique. These combined pharmaceutical compositions also have their own disadvantages. The solubility differences of the active substances and the differences in their daily dosage amounts are among these disadvantages. Presenting metformin and dapagliflozin to the patient in a single conventional pharmaceutical composition may cause the rapid release of metformin due to its high solubility in water and prevent the patient from receiving the appropriate treatment.

[0036] The present inventors have observed that in double-layer compositions comprising dapagliflozin and metformin together in the state of the art, the layer comprising dapagliflozin is thinner than the layer comprising metformin, resulting in separation within the tablet. They have also observed that the tablets do not achieve homogeneous hardness values and, consequently, homogeneous release profiles are not observed in the compositions.

[0037] Therefore, there is a need for pharmaceutical compositions in the state of the art comprising dapagliflozin and metformin together, in which the solubility and stability properties of the active substances are not affected by each other.

[0038] In the compositions according to the present invention, the inventors have obtained pharmaceutical compositions with optimum and homogeneous release profiles without seeing inter-layer separation, by means of a rapid-release layer comprising dapagliflozin located between two extended-release layers comprising metformin hydrochloride.

[0039] The multi-layer compositions according to the present invention have allowed the preparation of compositions according to the solubility properties of the active substances by placing the active substances in different tablet layers, and have enabled patients to reach the appropriate treatment they need with these compositions.

[0040] A feature of a multi-layer pharmaceutical composition according to the present invention is that the composition is in the form of a triple-layer tablet.

[0041] The multi-layer pharmaceutical compositions according to the present invention may comprise at least one pharmaceutically acceptable excipient. Excipients used in a pharmaceutical composition may positively or negatively affect physicochemical and pharmacokinetic properties such as the solubility, absorption, and bioavailability of the active substance. Therefore, while the excipients accompanying an active substance are selected carefully and consciously during the development of a pharmaceutical composition, attention should also be paid to their proportions within the composition.At the same time, in pharmaceutical compositions comprising more than one active substance, the fact that the active substances are in different dose amounts and have different solubility properties may also positively or negatively affect physicochemical and pharmacokinetic properties such as the bioavailability of the pharmaceutical composition. For this reason, attention should be paid to the selection of manufacturing techniques to be used while developing the pharmaceutical composition.

[0042] The present inventors have surprisingly discovered that pharmaceutical compositions in multilayer tablet form comprising dapagliflozin or a pharmaceutically acceptable salt thereof and metformin ora pharmaceutically acceptable salt thereof as active substances, obtained bythe layers containing different ratios and different varieties of pharmaceutically acceptable excipients, have dissolution profiles and stability properties that are the same as or even better than the original product.

[0043] At least one pharmaceutically acceptable excipient that can be used in multi-layer pharmaceutical compositions according to the present invention may be selected from fillers, Disintegrants, lubricants, solvents, binders, glidants, controlled-release agents, film-coating agents, or combinations thereof.

[0044] The layer of the multi-layer pharmaceutical compositions according to the present invention comprising dapagliflozin or a pharmaceutically acceptable salt thereof may comprise at least one pharmaceutically acceptable excipient selected from fillers, Disintegrants, lubricants, solvents, film-coating agents, or combinations thereof.

[0045] The layers of the multi-layer pharmaceutical compositions according to the present invention comprising metformin or a pharmaceutically acceptable salt thereof may comprise at least one pharmaceutically acceptable excipient selected from binders, lubricants, solvents, glidants, controlled-release agents, film-coating agents, or combinations thereof.

[0046] The glidant that can be used in the layers of the multi-layer pharmaceutical compositions according to the present invention comprising metformin or a pharmaceutically acceptable salt thereof may be selected from colloidal silicon dioxide, starch, talc, or combinations thereof.

[0047] The filler that can be used in the layer of the multi-layer pharmaceutical compositions according to the present invention comprising dapagliflozin or a pharmaceutically acceptable salt thereof may be selected from microcrystalline cellulose, lactose, lactose monohydrate, starch, mannitol, dibasic calcium phosphate, tribasic calcium phosphate, trehalose, isomalt, pregelatinized starch, sodium carbonate, sodium bicarbonate, silicified microcrystalline cellulose, calcium carbonate, or combinations thereof.

[0048] The filler that can be used in the layer of the multi-layer pharmaceutical compositions according to the present invention comprising dapagliflozin or a pharmaceutically acceptable salt thereof may be a mixture of silicified microcrystalline cellulose and microcrystalline cellulose.

[0049] Glidants, in their simplest properties, ensure that particles within a powder or granule mass flow smoothly over each other. In the absence of glidants, insufficient fluidity of powders during the tablet compression process causes problems such as deterioration of tablet weight, homogeneity in terms of the amount of active substance comprised in the tablets, and productquality.

[0050] As a result of their experiments, the present inventors have surprisingly discovered that in the multi-layer pharmaceutical compositions according to the present invention, the problems that would be observed due to the lack of sufficient fluidity of the powders; because the layer comprising dapagliflozin and at least one pharmaceutically acceptable excipient does not comprise a glidant as an excipient; are prevented by the optimization of the ratio by weight of silicified microcrystalline cellulose to microcrystalline cellulose used as a filler.

[0051] In the multi-layer pharmaceutical compositions according to the present invention, the ratio by weight of silicified microcrystalline cellulose to microcrystalline cellulose that can be used as a filler in the layer comprising dapagliflozin or a pharmaceutically acceptable salt thereof is between 0.2 and 1.0. In the multi-layer pharmaceutical compositions according to the present invention, the ratio by weight of silicified microcrystalline cellulose to microcrystalline cellulose that can be used as a filler in the layer comprising dapagliflozin or a pharmaceutically acceptable salt thereof is preferably between 0.2 and 0.5. With the optimized silicified microcrystalline cellulose / microcrystalline cellulose ratio, the tablet is ensured to reach the desired fluidity and the problems that could be seen with the non-use of glidants are prevented.

[0052] The binder to be used in the layers comprising metformin or a pharmaceutically acceptable salt thereof of the multi-layer pharmaceutical compositions according to the present invention may be selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, low-substituted hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl acetate, pul I u Ian, agar, pregelatinized starch, alginate, sodium alginate, glycyrrhizin, polymethacrylates, poloxamer, polyacrylamide, aluminum hydroxide, polyethylene oxide, xylitol, sucrose acetate, or combinations thereof. The binder to be used in the layers comprising metformin or a pharmaceutically acceptable salt thereof of the multi-layer pharmaceutical compositions according to the present invention is preferably a cellulose derivative binder.

[0053] The Disintegrant to be used in the layer comprising dapagliflozin or a pharmaceutically acceptable salt thereof of the multi-layer pharmaceutical compositions according to the present invention may be selected from croscarmellose sodium, sodium starch glycolate, pregelatinized starch, microcrystalline cellulose, maltodextrin, or combinations thereof. The lubricant to be used in the multi-layer pharmaceutical compositions according to the present invention may be selected from magnesium stearate, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, fumaric acid, glyceryl palmitostearate, hydrogenated natural oils, zinc stearate, calcium stearate, silica, talc, stearic acid, polyethylene glycol, paraffin, or combinations thereof.

[0054] The solvent that can be used in the multi-layer pharmaceutical compositions according to the present invention may be purified water, propylene glycol, glycerin, ethanol, polyethylene glycol, or combinations thereof.

[0055] The pharmacokinetic properties of the active substance determine critical characteristics such as the dose range of the pharmaceutical composition, the mode of administration, the starting dose of the treatment, and the time to reach the concentration required for optimum treatment. It is very important to optimize these critical characteristics in pharmaceuticalcompositions so that patients can receive the most appropriate treatment. By optimizing the pharmaceutical compositions according to the release characteristics of the active substance, the most appropriate treatment conditions for patients can be provided. In the state of the art, it is known that pharmaceutical compositions manufactured using modified-release techniques such as rapid-release, extended-release, and sustained-release have positive effects such as increasing the clinical efficacy of the active substance, reducing undesirable effects, increasing patient compliance, and reducing treatment costs.

[0056] The high solubility of metformin in water causes it to dissolve faster than dapagliflozin when used in combination with dapagliflozin. This leads to a need for the use of pharmaceutical compositions that incorporate both rapid-release and extended-release properties of the active substances in the treatment of some patients. While rapid-release dapagliflozin instantly balances blood glucose levels, extended-release metformin maintains blood glucose levels in balance for a long period. In the state of the art, there are pharmaceutical compositions comprising dapagliflozin with a rapid-release profile and metformin with an extended-release profile.

[0057] In the multi-layer pharmaceutical compositions according to the present invention, the placement of a rapid-release dapagliflozin intermediate layer between two extended-release metformin hydrochloride layers prevents the separation of the dapagliflozin layer from the composition, while at the same time allowing for the preparation of multi-layer pharmaceutical compositions where the layers do not affect each other's dissolution profiles during dissolution, enabling patients to reach the appropriate treatment they need with these compositions.

[0058] The multi-layer pharmaceutical compositions according to the present invention are in the form of a double-layer or triple-layer tablet comprising dapagliflozin or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof, and the layers may be in immediate-release, extended-release, sustained-release dosage forms or combinations thereof.

[0059] In the multi-layer pharmaceutical compositions according to the present invention, the controlled-release agents used in the layers comprising metformin or a pharmaceutically acceptable salt thereof may be selected from glyceryl behenat, polymethacrylates (Eudragit), polyacrylic acid (carbomer), ethyl acetate, ethyl methacrylate copolymer, 40 ethyl cellulose, methyl cellulose, hypromellose phthalate, polydextrose, polyvinyl acetate phthalate, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, low-weight hydroxypropyl methylcellulose (methocel), hydroxyethyl cellulose, hydroxymethyl cellulose, gelatin, polyethylene oxide, polyhydroxy methylmethacrylate, sodium carboxymethylcellulose, carboxymethyl cellulose, sodyum alginate, alginic acid, polygalacturonic acid, acrylic acid polymer, agar, gum, nitrocellulose, methyl cellulose, glycerol, propylene glycol, phthalate esters, dibutyl sebacate, citrate esters, castor oil, or combinations thereof.In the multi-layer pharmaceutical compositions according to the present invention, the controlled-release agents used in the layers comprising metformin or a pharmaceutically acceptable salt thereof may be a combination of hydroxypropyl methyl cellulose and glyceryl behenate.

[0060] In the multi-layer pharmaceutical compositions according to the present invention, the ratio by weight of hydroxypropyl methylcellulose to glyceryl behenate, among the controlled-release agents used in the layer comprising metformin or a pharmaceutically acceptable salt thereof, may be in the range of 0.5 - 2.0. In the multi-layer pharmaceutical compositions according to the present invention, the ratio by weight of hydroxypropyl methyl cellulose to glyceryl behenate, among the controlled-release agents used in the layer comprising metformin or a pharmaceutically acceptable salt thereof, may preferably be in the range of 1.0 - 1.5.

[0061] In the multi-layer pharmaceutical compositions according to the present invention, the controlled-release agents used in the layers comprising metformin or a pharmaceutically acceptable salt thereof may be a combination of hydroxypropyl methyl cellulose and carbomer.

[0062] In the multi-layer pharmaceutical compositions according to the present invention, the ratio by weight of hydroxypropyl methyl cellulose to carbomer, among the controlled-release agents used in the layers comprising metformin or a pharmaceutically acceptable salt thereof, may be in the range of 5.0 - 7.0. In the multi-layer pharmaceutical compositions according to the present invention, the ratio by weight of hydroxypropyl methylcellulose to carbomer, among the controlled-release agents used in the layer comprising metformin or a pharmaceutically acceptable salt thereof, may preferably be in the range of 6.0 - 6.8.

[0063] In the compositions according to the present invention, it has been observed that with the ideal ratio achieved between the binder and controlled-release agents used in the extended-release metformin hydrochloride layers, good compression and flow properties are provided throughout the tablets, while dissolution profiles are positively affected for the user's needs with low friability and high hardness, and it does not prevent the dissolution of the dapagliflozin layer located between the metformin hydrochloride layers.

[0064] In the compositions according to the present invention, the ratio by weight of the binder used in the extended-release metformin hydrochloride layers to the controlled-release agent combination may be between 0.15-0.30.

[0065] In the compositions according to the present invention, the ratio by weight of the binder used in the extended-release metformin hydrochloride layers to the controlled-release agent combination may preferably be between 0.18-0.22.

[0066] The multi-layer pharmaceutical compositions according to the present invention may preferably comprise a film coating.

[0067] The film-coating agent that can be used in the multi-layer pharmaceutical compositions according to the present invention may be selected from polymethacrylates, hydroxypropyl methyl cellulose, triacetin, glycerol triacetin, talc, red iron dioxide, yellow iron dioxide, propylene glycol, lactose monohydrate, hydroxypropyl cellulose, polyvinyl alcohol, polyethylene glycol, polyvinyl alcohol-polyethylene glycol copolymer (Kollicoat® IR), ethyl cellulose dispersions (Surelease8), polyvinyl pyrrolidone, polyvinylpyrrolidone-vinyl acetatecopolymer (PVP-VA), all Opacify® varieties, pigments, dyes, titanium dioxide, macrogol, or combinations thereof.

[0068] The multi-layer pharmaceutical compositions according to the present invention may comprise 2.5 mg, 5 mg, or 10 mg of dapagliflozin or a pharmaceutically acceptable salt thereof.

[0069] The multi-layer pharmaceutical compositions according to the present invention may comprise 500 mg, 850 mg, or 1000 mg of metformin hydrochloride.

[0070] The multi-layer pharmaceutical compositions according to the present invention may comprise the following;

[0071] Dapagliflozin in the range of 0.1% - 1.2% by weight,

[0072] Metformin hydrochloride in the range of 40.0% - 70.0% by weight,

[0073] Filler in the range of 8.0% - 25.0% by weight,

[0074] Binder in the range of 2.0% - 6.0% by weight,

[0075] Disintegrant in the range of 0.3% - 1.2% by weight,

[0076] Lubricant in the range of 0.5% - 1.5% by weight,

[0077] Controlled-release agent in the range of 15.0% - 30.0% by weight,

[0078] Film-coating agent in the range of 1.5% - 3.0% by weight.

[0079] The multi-layer pharmaceutical compositions according to the present invention may comprise the following;

[0080] Dapagliflozin in the range of 0.1% - 1.2% by weight,

[0081] Metformin hydrochloride in the range of 40.0% - 70.0% by weight,

[0082] Filler in the range of 8.0% - 25.0% by weight,

[0083] Binder in the range of 2.0% - 6.0% by weight,

[0084] Disintegrant in the range of 0.3% - 1.2% by weight,

[0085] Lubricant in the range of 0.5% - 1.5% by weight,

[0086] Glidant in the range of 0.5% - 1.5% by weight,

[0087] Film-coating agent in the range of 1.5% - 3.0% by weight,

[0088] Controlled-release agent in the range of 15.0% - 30.0% by weight.

[0089] The multi-layer pharmaceutical compositions according to the present invention can be manufactured by one of the methods of wet granulation, dry granulation, fluid bed granulation, high-shear granulation, dry blending, direct compression, slugging, or combinations of these methods. Accordingly, the layers in the pharmaceutical compositions according to the present invention can be manufactured using the same or a different manufacturing technique.

[0090] The multi-layer pharmaceutical compositions according to the present invention can be manufactured by a manufacturing method comprising of the following steps;

[0091] a) First Metformin layer:

[0092] Metformin hydrochloride and a cellulose derivative binder are sieved through a sieve and taken into a fluid bed granulator,

[0093] Granulated with deionized water and then dried,

[0094] After drying, the resulting granules are milled and mixed with hydroxypropylmethyl cellulose and glyceryl behenate.

[0095] A lubricant is added to the resulting mixture to obtain the first metformin hydrochloride layer.

[0096] b) Dapagliflozin intermediate layer:

[0097] Dapagliflozin, silicified microcrystalline cellulose, and sodium starch glycolate are sieved and taken into a wet granulator,

[0098] Granulated with deionized water, the resulting granules are sieved and then dried, After drying, the resulting granules are milled, mixed by adding microcrystalline cellulose and sodium starch glycolate,

[0099] A lubricant is added to the resulting mixture to obtain the dapagliflozin intermediate layer.

[0100] c) Second metformin layer:

[0101] Metformin hydrochloride and a cellulose derivative binder are sieved through a sieve and taken into a fluid bed granulator,

[0102] Granulated with deionized water and then dried,

[0103] After drying, the resulting granules are milled and mixed with hydroxypropyl methyl cellulose and glyceryl behenate.

[0104] A lubricant is added to the resulting mixture to obtain the second metformin hydrochloride layer.

[0105] d) The granules obtained in steps (a), (b), and (c) are combined together so that layer (b) forms the intermediate layer, and are compressed into a triple-layer tablet, and the film coating process is applied using the prepared film coating solution.

[0106] The multi-layer pharmaceutical compositions according to the present invention can be manufactured by a manufacturing method comprising of the following steps;

[0107] a) First Metformin layer:

[0108] Metformin hydrochloride and a cellulose derivative binder are sieved through a sieve and taken into a fluid bed granulator,

[0109] Granulated with deionized water and then dried,

[0110] After drying, the resulting granules are milled and mixed with the addition of a glidant, hydroxypropyl methyl cellulose, and carbomer,

[0111] A lubricant is added to the resulting mixture to obtain the first metformin hydrochloride layer.

[0112] b) Dapagliflozin intermediate layer:

[0113] Dapagliflozin, silicified microcrystalline cellulose, and sodium starch glycolate are sieved and taken into a wet granulator,

[0114] Granulated with deionized water, the resulting granules are sieved and then dried, After drying, the resulting granules are milled and mixed with the addition of microcrystalline cellulose and sodium starch glycolate,

[0115] A lubricant is added to the resulting mixture to obtain the dapagliflozin intermediate layer.

[0116] c) Second metformin layer:

[0117] Metformin hydrochloride and a cellulose derivative binder are sieved through a sieve and taken into a fluid bed granulator,

[0118] Granulated with deionized water and then dried,

[0119] After drying, the resulting granules are milled and mixed with the addition of aglidant, hydroxypropyl methyl cellulose, and carbomer,

[0120] A lubricant is added to the resulting mixture to obtain the second metformin hydrochloride layer.

[0121] d) The granules obtained in steps (a), (b), and (c) are combined together so that layer (b) forms the intermediate layer, and are compressed into a triple-layer tablet, and the film coating process is applied using the prepared film coating solution.

[0122] The multi-layer pharmaceutical compositions according to the present invention are administered orally. The dosage form and route of administration of the multi-layer pharmaceutical compositions according to the present invention should be selected by a person skilled in the art, taking into account various factors such as weight, age, gender, and medical condition of the patient to be treated.

[0123] The multi-layer pharmaceutical compositions according to the present invention can be used to treatment type 2 diabetes.

[0124] Examples of multi-layer pharmaceutical compositions according to the present invention are given as follows for a clearer understanding of the subject matter of the invention and cannot be used in any way to limit the subject matter of the invention.

[0125] Examples

[0126] Example-1: Triple-Layer Tablet Composition Comprising Dapagliflozin and Metformin Hydrochloride:

[0127] First Metformin Layer Ratio by Weight (%) Metformin Hydrochloride 32.0 Cellulose Derivative Binder 2.1 Controlled-Release Agent (combination of Hydroxypropyl Methyl 9.7 Cellulose & Glyceryl Behenate)

[0128] Lubricant 0.3 Dapagliflozin Intermediate Layer

[0129] Dapagliflozin 0.3 Silicified Microcrystalline Cellulose 2.7 Microcrystalline Cellulose 6.0 Disintegrant 0.4 Lubricant 0.1 Second Metformin Layer

[0130] Metformin Hydrochloride 32.0 Cellulose Derivative Binder 2.1 Controlled-Release Agent (combination of Hydroxypropyl Methyl 9.7 Cellulose & Glyceryl Behenate)

[0131] Lubricant 0.3 Film Coating 2.3

[0132]

[0133] Total 100.0%Manufacturing method for Example-1:

[0134] a) First Metformin layer:

[0135] Metformin hydrochloride and a cellulose derivative binder are sieved through a sieve and taken into a fluid bed granulator,

[0136] Granulated with deionized water and then dried,

[0137] After drying, the resulting granules are milled and mixed with hydroxypropyl methyl cellulose and glyceryl behenate.

[0138] A lubricant is added to the resulting mixture to obtain the first metformin hydrochloride layer.

[0139] b) Dapagliflozin intermediate layer:

[0140] Dapagliflozin, silicified microcrystalline cellulose, and a Disintegrant are sieved and taken into a wet granulator,

[0141] Granulated with deionized water, the resulting granules are sieved and then dried, After drying, the resulting granules are milled, mixed by adding microcrystalline cellulose and a Disintegrant,

[0142] A lubricant is added to the resulting mixture to obtain the dapagliflozin intermediate layer.

[0143] c) Second metformin layer:

[0144] Metformin hydrochloride and a cellulose derivative binder are sieved through a sieve and taken into a fluid bed granulator,

[0145] Granulated with deionized water and then dried,

[0146] After drying, the resulting granules are milled and mixed with hydroxypropyl methyl cellulose and glyceryl behenate.

[0147] A lubricant is added to the resulting mixture to obtain the second metformin hydrochloride layer.

[0148] d) The granules obtained in steps (a), (b), and (c) are combined together so that layer (b) forms the intermediate layer, and are compressed into a triple-layer tablet, and the film coating process is applied using the prepared film coating solution.

[0149] Example-2: Triple-Layer Tablet Composition Comprising Dapagliflozin and Metformin Hydrochloride:

[0150] First Metformin Layer Ratio by Weight (%) Metformin Hydrochloride 30.3 Cellulose Derivative Binder 1.9 Controlled-Release Agent (combination of Hydroxypropyl Methyl 7.5 Cellulose & Glyceryl Behenate)

[0151] Lubricant 0.3 Dapagliflozin Intermediate Layer

[0152] Dapagliflozin 0.6 Silicified Microcrystalline Cellulose 4.0 Microcrystalline Cellulose 12.8 Disintegrant 0.5 Lubricant 0.2

[0153]

[0154] Second Metformin LayerMetformin Hydrochloride 30.3 Cellulose Derivative Binder 1.9 Controlled-Release Agent (combination of Hydroxypropyl Methyl 7.5 Cellulose & Glyceryl Behenate)

[0155] Lubricant 0.3 Film Coating 1.9

[0156]

[0157] Total 100.0% Manufacturing method for Example-2:

[0158] a) First Metformin layer:

[0159] Metformin hydrochloride and a cellulose derivative binder are sieved through a sieve and taken into a fluid bed granulator,

[0160] Granulated with deionized water and then dried,

[0161] After drying, the resulting granules are milled and mixed with hydroxypropyl methyl cellulose and glyceryl behenate.

[0162] A lubricant is added to the resulting mixture to obtain the first metformin hydrochloride layer.

[0163] b) Dapagliflozin intermediate layer:

[0164] Dapagliflozin, silicified microcrystalline cellulose, and a Disintegrant are sieved and taken into a wet granulator,

[0165] Granulated with deionized water, the resulting granules are sieved and then dried, After drying, the resulting granules are milled, mixed by adding microcrystalline cellulose and a Disintegrant,

[0166] A lubricant is added to the resulting mixture to obtain the dapagliflozin intermediate layer.

[0167] c) Second metformin layer:

[0168] Metformin hydrochloride and a cellulose derivative binder are sieved through a sieve and taken into a fluid bed granulator,

[0169] Granulated with deionized water and then dried,

[0170] After drying, the resulting granules are milled and mixed with hydroxypropyl methyl cellulose and glyceryl behenate,

[0171] A lubricant is added to the resulting mixture to obtain the second metformin hydrochloride layer.

[0172] d) The granules obtained in steps (a), (b), and (c) are combined together so that layer (b) forms the intermediate layer, and are compressed into a triple-layer tablet, and the film coating process is applied using the prepared film coating solution.Among the triple-layer pharmaceutical compositions according to the present invention, the first and second metformin hydrochloride layers are manufactured in extended-release tablet dosage form using a fluid bed granulator, while the intermediate layer comprising dapagliflozin is manufactured in immediate-release dosage form using the wet granulation manufacturing method. The hardness and friability tests and in vitro dissolution rate trials at a speed of 100 rpm in pH 6.8 phosphate buffer medium were conducted on the compositions of Example - 1 and Example - 2 obtained by combining the pharmaceutical compositions according to the present invention as triple-layer tablets. The results of the dissolution rate test of Example - 1 and Example - 2, provided in comparison with the hardness and friability test results of the reference product Xigduo® XR, are given in the table below.

[0173] Table-1: Dapagliflozin in vitro dissolution rate results of Example - 1 and Example - 2 compositions in pH 6.8 phosphate buffer medium at a speed of 100 rpm

[0174] pH 6.8 Phosphate Buffer, pH 6.8 Phosphate Buffer, Basket, Basket, 1000 rpm, 1000 ml 1000 rpm, 1000 ml DAPAGL FLOZIN DAPAGLIFLOZIN

[0175] Reference Reference

[0176] Example-1 Example-2 5 mg / 1000 mg 10 mg / 1000 mg

[0177] Time (min) Time (min)

[0178] 5 65.6 66.4 5 58.9 75.3

[0179] 10 91.6 83.4 10 91.5 85.9

[0180] 15 96.0 88.5 15 97.2 92.1 20 97.1 91.0 20 98.9 94.9 30 98.5 93.3 30 99.2 97.9

[0181]

[0182] 45 99.2 99.4 45 99.9 100.5 Table-2: Metformin Hydrochloride in vitro dissolution rate results of Example-1 and Example-2 compositions in pH 6.8 phosphate buffer medium at a speed of 100 rpm

[0183] pH 6.8 Phosphate Buffer, pH 6.8 Phosphate Buffer, Basket, 1000 rpm, 1000 ml Basket, 1000 rpm, 1000 ml Metformin Hydrochloride Metformin Hydrochloride Reference Reference

[0184] Example-1 Example-2 5 mg / 1000 mg 10 mg / 1000 mg

[0185] Time (min) Time (min)

[0186] 0.5 19.9 21.0 0.5 18.6 20.3

[0187] 1 31.3 32.7 1 30.1 31.9

[0188] 2 47.5 48.7 2 47.3 47.7

[0189] 3 59.8 61.6 3 59.9 61.1

[0190] 4 68.9 71.2 4 69.5 71.1

[0191] 6 81.5 84.4 6 82.9 84.5

[0192] 8 89.3 92.6 8 91.3 93.2

[0193] 10 93.6 97.2 10 96.1 97.4

[0194]

[0195] 12 95.9 99.4 12 98.4 99.4Table-3: Hardness and friability test results of Example-1 and Example-2 compositions In-Process Controls (core tb) Example-1 Example-2 Hardness (30-40 kp) 32 kp 33 kp

[0196]

[0197] Friability amount (max. 1.0%) 0.21% 0.22%

[0198] Example-3: Triple-Layer Tablet Composition Comprising Dapagliflozin and Metformin Hydrochloride:

[0199] First Metformin Layer Ratio by Weight (%) Metformin Hydrochloride 32.4 Cellulose Derivative Binder 1.7 Controlled-Release Agent (combination of Hydroxypropyl Methyl 9.2 Cellulose & Carbomer)

[0200] Glidant 0.3 Lubricant 0.4 Dapagliflozin Intermediate Layer

[0201] Dapagliflozin 0.3 Silicified Microcrystalline Cellulose 2.9 Microcrystalline Cellulose 6.4 Disintegrant 0.3 Lubricant 0.2 Second Metformin Layer

[0202] Metformin Hydrochloride 32.4 Cellulose Derivative Binder 1.7 Controlled-Release Agent (combination of Hydroxypropyl Methyl 9.2 Cellulose & Carbomer)

[0203] Glidant 0.3 Lubricant 0.4 Film Coating 1.9

[0204]

[0205] Total 100.0% Manufacturing method for Example-3:

[0206] a) First Metformin layer:

[0207] Metformin hydrochloride and a cellulose derivative binder are sieved through a sieve and taken into a fluid bed granulator,

[0208] Granulated with deionized water and then dried,

[0209] After drying, the resulting granules are milled and mixed with the addition of a glidant, hydroxypropyl methyl cellulose, and carbomer,

[0210] A lubricant is added to the resulting mixture to obtain the first metformin hydrochloride layer.

[0211] b) Dapagliflozin intermediate layer:

[0212] Dapagliflozin, silicified microcrystalline cellulose, and a Disintegrant are sieved and taken into a wet granulator,

[0213] Granulated with deionized water, the resulting granules are sieved and then dried,After drying, the resulting granules are milled, mixed by adding microcrystalline cellulose and a Disintegrant,

[0214] A lubricant is added to the resulting mixture to obtain the dapagliflozin intermediate layer.

[0215] c) Second metformin layer:

[0216] Metformin hydrochloride and a cellulose derivative binder are sieved through a sieve and taken into a fluid bed granulator,

[0217] Granulated with deionized water and then dried,

[0218] After drying, the resulting granules are milled and mixed with the addition of a glidant, hydroxypropyl methyl cellulose, and carbomer,

[0219] A lubricant is added to the resulting mixture to obtain the second metformin hydrochloride layer.

[0220] d) The granules obtained in steps (a), (b), and (c) are combined together so that layer (b) forms the intermediate layer, and are compressed into a triple-layer tablet, and the film coating process is applied using the prepared film coating solution.

[0221] Example-4: Triple-Layer Tablet Composition Comprising Dapagliflozin and Metformin Hydrochloride:

[0222] First Metformin Layer Ratio by Weight (%) Metformin Hydrochloride 30.0 Cellulose Derivative Binder 1.8 Controlled-Release Agent (combination of Hydroxypropyl Methyl 7.5 Cellulose & Carbomer)

[0223] Glidant 0.3 Lubricant 0.4 Dapagliflozin Intermediate Layer

[0224] Dapagliflozin 0.6 Silicified Microcrystalline Cellulose 5.1 Microcrystalline Cellulose 11.5 Disintegrant 0.6 Lubricant 0.3 Second Metformin Layer

[0225] Metformin Hydrochloride 30.0 Cellulose Derivative Binder 1.8 Controlled-Release Agent (combination of Hydroxypropyl Methyl 7.5 Cellulose & Carbomer)

[0226] Glidant 0.3 Lubricant 0.4 Film Coating 1.9

[0227]

[0228] Total 100.0%Manufacturing method for Example-4:

[0229] a) First Metformin layer:

[0230] Metformin hydrochloride and a cellulose derivative binder are sieved through a sieve and taken into a fluid bed granulator,

[0231] Granulated with deionized water and then dried,

[0232] After drying, the resulting granules are milled and mixed with the addition of a glidant, hydroxypropyl methyl cellulose, and carbomer,

[0233] A lubricant is added to the resulting mixture to obtain the first metformin hydrochloride layer.

[0234] b) Dapagliflozin intermediate layer:

[0235] Dapagliflozin, silicified microcrystalline cellulose, and a Disintegrant are sieved and taken into a wet granulator,

[0236] Granulated with deionized water, the resulting granules are sieved and then dried, After drying, the resulting granules are milled, mixed by adding microcrystalline cellulose and a Disintegrant,

[0237] A lubricant is added to the resulting mixture to obtain the dapagliflozin intermediate layer.

[0238] c) Second metformin layer:

[0239] Metformin hydrochloride and a cellulose derivative binder are sieved through a sieve and taken into a fluid bed granulator,

[0240] Granulated with deionized water and then dried,

[0241] After drying, the resulting granules are milled and mixed with the addition of a glidant, hydroxypropyl methyl cellulose, and carbomer,

[0242] A lubricant is added to the resulting mixture to obtain the second metformin hydrochloride layer.

[0243] d) The granules obtained in steps (a), (b), and (c) are combined together so that layer (b) forms the intermediate layer, and are compressed into a triple-layer tablet, and the film coating process is applied using the prepared film coating solution.

[0244] Among the triple-layer pharmaceutical compositions according to the present invention, the first and second metformin hydrochloride layers are manufactured in extended-release tablet dosage form using a fluid bed granulator and by changing the release agent combination according to Example - 1 and Example - 2, while the intermediate layer comprising dapagliflozin is manufactured in immediate-release dosage form using the wet granulation manufacturing method; the Example-3 and Example-4 compositions obtained by combining these compositions as triple-layer tablets were subjected to hardness and friability tests and in vitro dissolution rate trials at a speed of 100 rpm in pH 6.8 phosphate buffer medium. The hardness and friability test results of Example-3 and Example-4 and the dissolution rate test results provided in comparison with the reference product Xigduo’ XR are given in the table below.Table-4: Dapagliflozin in vitro dissolution rate results of Example-3 and Example-4 compositions in pH 6.8 phosphate buffer medium at a speed of 100 rpm

[0245] pH 6.8 Phosphate Buffer, pH 6.8 Phosphate Buffer, Basket, 1000 rpm, 1000 ml Basket, 1000 rpm, 1000 ml DAPAGL FLOZIN DAPAGLIFLOZIN

[0246] Reference Reference

[0247] Example-3 Example-4 5 mg / 1000 mg 10 mg / 1000 mg

[0248] Time (min) Time (min)

[0249] 5 65.6 62.8 5 58.9 61.7 10 91.6 81.3 10 91.5 83.2 15 96.0 88.3 15 97.2 91.1 20 97.1 93.6 20 98.9 94.2 30 98.5 97.2 30 99.2 99.3

[0250]

[0251] 45 99.2 99.2 45 99.9 100.7 Table-5: Metformin Hydrochloride in vitro dissolution rate results of Example-3 and Example-4 compositions in pH 6.8 phosphate buffer medium at a speed of 100 rpm

[0252] pH 6.8 Phosphate Buffer, pH 6.8 Phosphate Buffer, Basket, 1000 rpm, 1000 ml Basket, 1000 rpm, 1000 ml Metformin Hydrochloride Metformin Hydrochloride Reference Reference

[0253] Example-3 Example-4 5 mg / 1000 mg 10 mg / 1000 mg

[0254] Time (min) Time (min)

[0255] 0.5 19.9 23.2 0.5 18.6 20.1

[0256] 1 31.3 35.6 1 30.1 32.0

[0257] 2 47.5 51.8 2 47.3 47.3

[0258] 3 59.8 64.1 3 59.9 58.1

[0259] 4 68.9 73.0 4 69.5 68.2

[0260] 6 81.5 84.7 6 82.9 83.8

[0261] 8 89.3 92.0 8 91.3 88.2 10 93.6 96.5 10 96.1 96.7

[0262]

[0263] 12 95.9 99.3 12 98.4 99.2 Table-6: Hardness and friability test results of Example-3 and Example-4 compositions In-Process Controls (core tb) Example-3 Example-4 Hardness (30-40 kp) 34 kp 34 kp

[0264]

[0265] Friability amount (max. 1.0%) 0.90% 0.90%According to the in vitro dissolution tests performed, the multi-layer compositions according to the present invention show a similar and even better dissolution rate than the reference product.

[0266] Furthermore, it has been revealed that a stable product was obtained in accelerated stability studies conducted with the multi-layer compositions according to the present invention. Detailed stability information for Example-1, Example-2, Example-3, and Example-4 compositions obtained by combining the first and second metformin hydrochloride layers manufactured in extended-release tablet dosage form using a fluid bed granulator and the intermediate layer comprising dapagliflozin manufactured in immediate-release dosage form using the wet granulation manufacturing method as triple-layer tablets is as follows;

[0267] Table-7: Stability data of Example-1 composition:

[0268] Related Substances - Dapagliflozin

[0269] Reference Reference Reference

[0270] Xigduo’ XR Example- Xigduo8XR Example- Xigduo8XR Example- 5mg / 1000mg 1 5mg / 1000mg 1 5mg / 1000mg 1 70°C±2-C, 100% BN±5% 40°C±2-C, 75% BN±5% INITIAL ANALYSIS BN, 1 week BN, 1 month

[0271] Each Unknown 0.14% 0.06% BRL* BRL* BRL* BRL* Impurity 0.2%

[0272] Total Impurity 0.14% 0.06% BRL* BRL* BRL* BRL* 1.0%

[0273] Related Substances - Metformin Hydrochloride

[0274] Reference Reference Reference

[0275] Xigduo’ XR Example- Xigduo8XR Example- Xigduo8XR Example- 5mg / 1000mg 1 5mg / 1000mg 1 5mg / 1000mg 1 70°C±2-C, 100% BN±5% 40°C±2-C, 75% BN±5% INITIAL ANALYSIS BN, 1 week BN, 1 month

[0276] Each Unknown BRL* BRL* BRL* BRL* BRL* BRL* Impurity 0.2%

[0277] Total Impurity BRL* BRL* BRL* BRL* BRL* BRL*

[0278]

[0279] 1.0%

[0280] *BRL: Below reporting limit. (0.05%)Table-8: Stability data of Example-2 composition:

[0281] Related Substances - Dapagliflozin

[0282] Reference Reference Reference

[0283] Xigduo XR Example- Xigduo XR Example- Xigduo XR Example-2 lOmg / lOOOmg 2 lOmg / lOOOmg 2 lOmg / lOOOmg 70°C±29C, 100% BN±5% 40°C±29C, 75% BN±5% INITIAL ANALYSIS BN, 1 week BN, 1 month

[0284] Each Unknown 0.12% 0.05% BRL* BRL* BRL* BRL* Impurity 0.2%

[0285] Total Impurity 1.0% 0.12% 0.05% BRL* BRL* BRL* BRL* Related Substances - Metformin Hydroch oride

[0286] Reference Reference Reference

[0287] Xigduo XR Example- Xigduo XR Example- Xigduo XR Example-2 lOmg / lOOOmg 2 lOmg / lOOOmg 2 lOmg / lOOOmg 70°C±29C, 100% BN±5% 40°C±29C, 75% BN±5% INITIAL ANALYSIS BN BN,1 month

[0288] 1 week

[0289] Each Unknown BRL* BRL* BRL* BRL* BRL* BRL* Impurity 0.2%

[0290]

[0291] Total Impurity 1.0% BRL* BRL* BRL* BRL* BRL* BRL* *BRL: Below reporting limit. (0.05%)

[0292] Table-9: Stability data of Example-3 composition:

[0293] Related Substances - Dapagliflozin

[0294] Reference Reference Reference

[0295] Xigduo XR Example- Xigduo XR Example- Xigduo XR Example- 5mg / 1000mg 3 5mg / 1000mg 3 5mg / 1000mg 3 70°C±29C, 100% BN±5% 40°C±29C, 75% BN±5% INITIAL ANALYSIS BN, 1 week BN, 1 month

[0296] Each Unknown 0.14% 0.08% BRL* BRL* BRL* BRL* Impurity 0.2%

[0297] Total Impurity 1.0% 0.14% 0.08% BRL* BRL* BRL* BRL* Related Substances - Met ormin Hydroch oride

[0298] Reference Reference Reference

[0299] Xigduo XR Example- Xigduo XR Example- Xigduo XR Example- 5mg / 1000mg 3 5mg / 1000mg 3 5mg / 1000mg 3 70°C±29C, 100% BN±5% 40°C±29C, 75% BN±5% INITIAL ANALYSIS BN BN,1 month

[0300] 1 week

[0301] Each Unknown BRL* BRL* BRL* BRL* BRL* BRL* Impurity 0.2%

[0302]

[0303] Total Impurity 1.0% BRL* BRL* BRL* BRL* BRL* BRL* *BRL: Below reporting limit. (0.05%)Table- 10: Stability data of Example-4 composition:

[0304] Related Substances - Dapagliflozin

[0305] Reference Reference Reference Xigduo XR Example- Xigduo XR Example- Xigduo XR Example- lOmg / lOOOmg 4 lOmg / lOOOmg 4 lOmg / lOOOmg 4 70°C±2-C, 100% BN±5% 40°C±2-C, 75% BN±5% INITIAL ANALYSIS BN, 1 week BN, 1 month

[0306] Each 0.12% 0.07% BRL* BRL* BRL* BRL* Unknown

[0307] Impurity

[0308] 0.2%

[0309] Total 0.12% 0.07% BRL* BRL* BRL* BRL* Impurity

[0310] 1.0%

[0311] Related Substances - Metformin Hydroch oride

[0312] Reference Reference Reference Xigduo XR Example- Xigduo XR Example- Xigduo XR Example- lOmg / lOOOmg 4 lOmg / lOOOmg 4 lOmg / lOOOmg 4 70°C±2-C, 100% BN±5% 40°C±2-C, 75% BN±5% INITIAL ANALYSIS BN, 1 week BN, 1 month

[0313] Each BRL* BRL* BRL* BRL* BRL* BRL* Unknown

[0314] Impurity

[0315] 0.2%

[0316] Total BRL* BRL* BRL* BRL* BRL* BRL* Impurity

[0317]

[0318] 1.0%

[0319] *BRL: Below reporting limit. (0.05%)

Claims

CLAIMS1. A multi-layer tablet composition comprising dapagliflozin or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof as active substances, characterized in that an intermediate layer comprising dapagliflozin or a pharmaceutically acceptable salt thereof is located between two layers comprising metformin or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition according to Claim 1, characterized in that the dapagliflozin is in the form of one of its pharmaceutically acceptable salts, solvates, hydrates, enantiomers, derivatives, free base, polymorphs or prodrugs, and various crystalline and amorphous forms.

3. A pharmaceutical composition according to Claim 2, characterized in that the dapagliflozin is in its free base form and in amorphous form.

4. A pharmaceutical composition according to Claim 1, characterized in that the metformin is in the form of one of its pharmaceutically acceptable salts, solvates, hydrates, enantiomers, derivatives, free base, polymorphs or prodrugs, and various crystalline and amorphous forms.

5. A pharmaceutical composition according to Claim 4, characterized in that the metformin is in its hydrochloric acid salt form.

6. A pharmaceutical composition according to any one of the preceding claims, characterized in that the composition is in the form of a triple-layer tablet.

7. A pharmaceutical composition according to Claim 6, characterized in that the composition comprises a rapid-release intermediate layer comprising dapagliflozin or a pharmaceutically acceptable salt thereof located between two extended-release layers comprising metformin or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition according to any one of the preceding claims, characterized in that the composition is in the form of a film-coated tablet.

9. A pharmaceutical composition according to any one of the preceding claims, characterized in that the composition comprises at least one excipient selected from pharmaceutically acceptable fillers, disintegrants, lubricants, solvents, binders, glidants, controlled-release agents, film-coating agents, or combinations thereof.

10. A pharmaceutical composition according to any one of the preceding claims, characterized in that the layer comprising dapagliflozin or a pharmaceutically acceptable salt thereof comprises at least one excipient selected from pharmaceutically acceptable fillers, disintegrants, lubricants, solvents, film-coating agents, or combinations thereof.

11. A pharmaceutical composition according to Claim 10, characterized in that the filler that used in the layer comprising dapagliflozin or a pharmaceutically acceptable salt thereof is selected from microcrystalline cellulose, lactose, lactose monohidrate, starch, mannitol, dibasic calcium phosphate, tribasic calcium phosphate, trehalose, isomalt, pregelatinized starch, sodium carbonate, sodium bicarbonate, silicified microcrystalline cellulose, calcium carbonate, or combinations thereof.

12. A pharmaceutical composition according to Claim 11, characterized in that the filler used in the layer comprising dapagliflozin or a pharmaceutically acceptable salt thereof is a mixture of microcrystalline cellulose and silicified microcrystalline cellulose.

13. A pharmaceutical composition according to Claim 11 or Claim 12, characterized in that the ratio by weight of silicified microcrystalline cellulose to microcrystalline cellulose used as a filler in the layer comprising dapagliflozin or a pharmaceutically acceptable salt thereof is between 0.2 and 1.0.

14. A pharmaceutical composition according to Claim 13, characterized in that the ratio by weight of silicified microcrystalline cellulose to microcrystalline cellulose used as a filler in the layer comprising dapagliflozin or a pharmaceutically acceptable salt thereof is preferably between 0.2 and 0.5.

15. A pharmaceutical composition according to Claim 10, characterized in that the Disintegrant that can be used in the layer comprising dapagliflozin or a pharmaceutically acceptable salt thereof is selected from croscarmellose sodium, sodium starch glycolate, pregelatinized starch, microcrystalline cellulose, maltodextrin, or combinations thereof.

16. A pharmaceutical composition according to any one of the preceding claims, characterized in that the layer comprising metformin or a pharmaceutically acceptable salt thereof comprises at least one excipient selected from pharmaceutically acceptable binders, lubricants, solvents, glidants, controlled-release agents, film-coating agents, or combinations thereof.

17. A pharmaceutical composition according to Claim 16, characterized in that the glidant used in the layers comprising metformin or a pharmaceutically acceptable salt thereof is selected from colloidal silicon dioxide, starch, talc, or combinations thereof.

18. A pharmaceutical composition according to Claim 16, characterized in that the binder used in the layers comprising metformin or a pharmaceutically acceptable salt thereof is selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, low- substituted hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl acetate, pu Hu la n, agar, pregelatinized starch, alginate, sodium alginate, glycyrrhizin, polymethacrylates, poloxamer, polyacrylamide, aluminum hydroxide, polyethylene oxide, xylitol, sucrose acetate, or combinations thereof.

19. A pharmaceutical composition according to Claim 16, characterized in that the binder used in the layers comprising metformin or a pharmaceutically acceptable salt thereof is preferably a cellulose derivative binder.

20. A pharmaceutical composition according to Claim 16, characterized in that the controlled-release agent used in the layers comprising metformin or a pharmaceutically acceptable salt thereof is selected from glyceryl behenate, polymethacrylates (Eudragit), polyacrylic acid (carbomer), ethyl acetate, ethyl methacrylate copolymer, 40 ethyl cellulose, methyl cellulose, hypromellose phthalate, polydextrose, polyvinyl acetate phthalate, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, low-weight hydroxypropyl methylcellulose (methocel), hydroxyethyl cellulose, hydroxymethyl cellulose, gelatin, polyethylene oxide, polyhydroxy methylmethacrylate, sodium carboxymethylcellulose, carboxymethyl cellulose, sodium alginate, alginic acid, polygalacturonic acid, acrylic acidpolymer, agar, gum, nitrocellulose, methyl cellulose, glycerol, propylene glycol, phthalate esters, dibutyl sebacate, citrate esters, castor oil, or combinations thereof.

21. A pharmaceutical composition according to Claim 16 or Claim 20, characterized in that the controlled-release agent used in the layers comprising metformin or a pharmaceutically acceptable salt thereof is a combination of hydroxypropyl methyl cellulose and glyceryl behenate.

22. A pharmaceutical composition according to Claim 21, characterized in that the ratio by weight of hydroxypropyl methyl cellulose to glyceryl behenate that can be used in the layers comprising metformin or a pharmaceutically acceptable salt thereof is between 0.5-2.0.

23. A pharmaceutical composition according to Claim 21 or Claim 22, characterized in that the ratio by weight of hydroxypropyl methyl cellulose to glyceryl behenate used in the layers comprising metformin or a pharmaceutically acceptable salt thereof is preferably between 1.0-1.5.

24. A pharmaceutical composition according to Claim 16 or Claim 20, characterized in that the controlled-release agent used in the layers comprising metformin or a pharmaceutically acceptable salt thereof is a combination of hydroxypropyl methyl cellulose and polyacrylic acid (carbomer).

25. A pharmaceutical composition according to Claim 24, characterized in that the ratio by weight of hydroxypropyl methyl cellulose to polyacrylic acid (carbomer) used in the layers comprising metformin or a pharmaceutically acceptable salt thereof is between 5.0-7.0.

26. A pharmaceutical composition according to Claim 24 or Claim 25, characterized in that the ratio by weight of hydroxypropyl methyl cellulose to polyacrylic acid (carbomer) that can be used in the layers comprising metformin or a pharmaceutically acceptable salt thereof is preferably between 6.0-6.8.

27. A pharmaceutical composition according to any one of the preceding claims, characterized in that the ratio by weight of the binder used in the layers comprising metformin ora pharmaceutically acceptable salt thereof to the controlled-release agent combination is between 0.15 - 0.30.

28. A pharmaceutical composition according to Claim 27, characterized in that the ratio by weight of the binder used in the layers comprising metformin or a pharmaceutically acceptable salt thereof to the controlled-release agent combination is preferably between 0.18 - 0.22.

29. A pharmaceutical composition according to any one of the preceding claims, characterized in that the lubricant is selected from magnesium stearate, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, fumaric acid, glyceryl palmitostearate, hydrogenated natural oils, zinc stearate, calcium stearate, silica, talc, stearic acid, polyethylene glycol, paraffin, or combinations thereof.

30. A pharmaceutical composition according to any one of the preceding claims, characterized in that the solvent is selected from purified water, propylene glycol, glycerin, ethanol, polyethylene glycol, or combinations thereof.

31. A pharmaceutical composition according to any one of the preceding claims, characterized in that the layers are in the form of immediate-release, extended-release, sustained-release, or combinations thereof.

32. A pharmaceutical composition according to any one of the preceding claims, characterized in that the composition comprises a film coating.

33. A pharmaceutical composition according to any one of the preceding claims, characterized in that the film-coating agent that can be used in the composition is selected from polymethacrylates, hydroxypropyl methyl cellulose, triacetin, glycerol triacetin, talc, red iron dioxide, yellow iron dioxide, propylene glycol, lactose monohydrate, hydroxypropyl cellulose, polyvinyl alcohol, polyethylene glycol, polyvinyl alcohol-polyethylene glycol copolymer (Kollicoat® IR), ethyl cellulose dispersions (Surelease8), polyvinyl pyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer (PVP- VA), all Opadry8varieties, pigments, dyes, titanium dioxide, macrogol, or combinations thereof.

34. A pharmaceutical composition according to any one of the preceding claims, characterized in that the composition comprises 2.5 mg, 5 mg, or 10.0 mg of dapagliflozin.

35. A pharmaceutical composition according to any one of the preceding claims, characterized in that the composition comprises 500 mg, 850 mg, or 1000 mg of metformin hydrochloride.

36. A pharmaceutical composition according to any one of the preceding claims, characterized in that the composition comprises the following;Dapagliflozin in the range of 0.1% - 1.2% by weight,Metformin hydrochloride in the range of 40.0% - 70.0% by weight,Filler in the range of 8.0% - 25.0% by weight,Binder in the range of 2.0% - 6.0% by weight,Disintegrant in the range of 0.3% - 1.2% by weight,Lubricant in the range of 0.5% - 1.5% by weightControlled-release agent in the range of 15.0% - 30.0% by weight.,Film-coating agent in the range of 1.5% - 3.0% by weight,37. A pharmaceutical composition according to any one of the preceding claims, characterized in that the composition comprises the following;Dapagliflozin in the range of 0.1% - 1.2% by weight,Metformin hydrochloride in the range of 40.0% - 70.0% by weight,Filler in the range of 8.0% - 25.0% by weight,Binder in the range of 2.0% - 6.0% by weight,Disintegrant in the range of 0.3% - 1.2% by weight,Lubricant in the range of 0.5% - 1.5% by weight,Glidant in the range of 0.5% - 1.5% by weight,Film-coating agent in the range of 1.5% - 3.0% by weight,Controlled-release agent in the range of 15.0% - 30.0% by weight.

38. A pharmaceutical composition according to any one of the preceding claims, characterized in that the composition is manufactured by one of the methods of wet granulation, dry granulation, fluid bed granulation, high-shear granulation, dry blending, direct compression, slugging, or combinations of these methods.

39. A pharmaceutical composition according to any one of the preceding claims, characterized in that the layers in the composition can be manufactured using the same or different manufacturing techniques.

40. A manufacturing method forthe preparation of a pharmaceutical composition according to any one of the preceding claims, characterized in that it comprises the following process steps;a) First Metformin layer:- Metformin hydrochloride and a cellulose derivative binder are sieved through a sieve and taken into a fluid bed granulator,- Granulated with deionized water and then dried,- After drying, the resulting granules are milled and mixed with hydroxypropyl methyl cellulose and glyceryl behenate,- A lubricant is added to the resulting mixture to obtain the first metformin hydrochloride layer.b) Dapagliflozin intermediate layer:- Dapagliflozin, silicified microcrystalline cellulose, and sodium starch glycolate are sieved and taken into a wet granulator,- Granulated with deionized water, the resulting granules are sieved and then dried, - After drying, the resulting granules are milled and mixed with the addition of microcrystalline cellulose and sodium starch glycolate,- A lubricant is added to the resulting mixture to obtain the dapagliflozin intermediate layer.c) Second metformin layer:- Metformin hydrochloride and a cellulose derivative binder are sieved through a sieve and taken into a fluid bed granulator,- Granulated with deionized water and then dried,- After drying, the resulting granules are milled and mixed with hydroxypropyl methyl cellulose and glyceryl behenate.- A lubricant is added to the resulting mixture to obtain the second metformin hydrochloride layer.d) The granules obtained in steps (a), (b), and (c) are combined together so that layer (b) forms the intermediate layer, and are compressed into a triple-layer tablet, and the film coating process is applied using the prepared film coating solution.

41. A manufacturing method forthe preparation of a pharmaceutical composition according to any one of the preceding claims, characterized in that it comprises the following process steps;a) First Metformin layer:- Metformin hydrochloride and a cellulose derivative binder are sieved through a sieve and taken into a fluid bed granulator,- Granulated with deionized water and then dried,- After drying, the resulting granules are milled and mixed with the addition of a glidant, hydroxypropyl methyl cellulose, and carbomer,- A lubricant is added to the resulting mixture to obtain the first metformin hydrochloride layer.b) Dapagliflozin intermediate layer:- Dapagliflozin, silicified microcrystalline cellulose, and sodium starch glycolate are sieved and taken into a wet granulator,- Granulated with deionized water, the resulting granules are sieved and then dried, - After drying, the resulting granules are milled and mixed with the addition of microcrystalline cellulose and sodium starch glycolate,- A lubricant is added to the resulting mixture to obtain the dapagliflozin intermediate layer.c) Second metformin layer:- Metformin hydrochloride and a cellulose derivative binder are sieved through a sieve and taken into a fluid bed granulator,- Granulated with deionized water and then dried,- After drying, the resulting granules are milled and mixed with the addition of a glidant, hydroxypropyl methyl cellulose, and carbomer,- A lubricant is added to the resulting mixture to obtain the second metformin hydrochloride layer.d) The granules obtained in steps (a), (b), and (c) are combined together so that layer (b) forms the intermediate layer, and are compressed into a triple-layer tablet, and the film coating process is applied using the prepared film coating solution.

42. A pharmaceutical composition according to any one of the preceding claims for use in the treatment of type 2 diabetes.T1

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