FIELD OF INVENTION

The present invention relates to a multi-layered tablet formulation with an immediate release layer comprising dapagliflozin or a pharmaceutically acceptable salt thereof and an extended release layer comprising metformin hydrochloride and at least one pharmaceutically acceptable excipient for use in the treatment of the Type 2 diabetes.

BACKGROUND OF THE INVENTION

Diabetes is a group of metabolic disorder in which is related with high glucose in plasma. Currently, there is three types of diabetes, such as type 1, type 2, and gestational diabetes. However, type 2 diabetes is known to be the most common form of the diabetes in both of the developed and developing counties.

Type 2 diabetes (non-insulin dependent diabetes, (NIDDM)) is a condition and is called as insulin resistance where the body produces insulin, but certain mechanisms prevent insulin from moving glucose into cells. Therefore, glucose level rises to the unsafe in the blood and which is called as hyperglycemia.

Sustained hyperglycemia leads to worsen insulin resistance contributes to dysfunction in the beta cells of the pancreas. Diabetic microvascular complications and macro-vascular complications is the directly result of the degree of the sustained hyperglycemia. Thus, Type 2 diabetes is characterized by hyperglycemia and an increased risk of microvascular and macro- vascular complications.

In normal healthy individuals, glucose in plasma is filtered by glomerulus in the kidney and is actively reabsorbed in the proximal tube. However, Sodium-glucose co-transporter-2 (SGLT2) reabsorbs nearly all glucose at this site. Thus, a selective inhibitor of the SGLT2 in the kidney is essential to help the body retain glucose for its energy requirements.

Dapagliflozin is a first-in class compound which is a highly selective and orally active inhibitor of the human sodium-dependent glucose co-transporter 2 (SGLT2), and also is the major transporter responsible for renal glucose reabsorption from the turbula lumen. It inhibits the renal reabsorption of glucose and promotes excretion of excess glucose in the urine, thus it improves glycemic control in patients with Type 2 diabetes and lower glucose level in plasma.

The chemical name of Dapagliflozin is (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4- ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5- triol. The empirical formula of Dapagliflozin is C21H25CIO6 and its relative molecular mass is 408.87 mg/mole as a free base and 502.98 mg/mole as propanediol monohydrate salt.

Dapagliflozin is a white to off-white powder, soluble in many polar organic solvents and non- hygroscopic.

Metformin is an oral anti-hyperglycemic agent which has been widely used for improving glycemic control in patients with Type 2 diabetes for decades by being alone or combined form with other anti-hyperglycemic medications. Metformin can also be of value in the treatment of obese or overweight diabetic patients or in patients with polycystic ovary syndrome.

Metformin can be taken in high doses in the range of 500 mg to 2500 mg per day and that requires twice or three times a day dosing. However, this type of administration may cause the changes in the blood concentration of the drug and that will trigger to expose the adverse reactions and resistance to the drug.

According to the literature knowledge, Metformin can be associated with the adverse effects such as gastrointestinal symptoms, particularly diarrhea and nausea. In addition to that, it is largely eliminated unchanged by the kidneys and it can cause to be contraindicated in patients with renal disease or renal impairment. Thus, conventional administration has to be redesigned in order to lowering the adverse effects by reducing the frequency of administration required.

Extended release formulations of Metformin have advantages over immediate release generates more uniform maintenance of blood plasma active drug concentrations and providing better patient compliance.

Thus, Bristol-Myers Squibb and AstraZeneca developed another fixed dose combination of Dapagliflozin and Metformin for the treatment of the Type 2 diabetes, wherein Metformin is presented in the extended release formulation and Dapagliflozin is presented in the immediate release formulation. The fixed dose was firstly commercially authorized the U.S. It is currently marketed under the trade name of XIGDUO XR in the strengths of 2.5 mg/1000 mg, 5 mg/500 mg, 5 mg/ 1000 mg, 10 mg/500 mg and 10 mg/ 1000 mg per tablet.

In the state of art there are many patents/patent applications which are summarized below. EP2498758 relates to a bilayer tablet formulation comprising; Metformin hydrochloride as extended release form, sodium carboxymethyl cellulose as a binder; hydroxypropyl methylcellulose as a release modifier; magnesium stearate as a lubricant; and optionally silicon dioxide or colloidal silicon dioxide as a glidant presented in the first layer; Dapagliflozin (S) propylene glycol hydrate, fillers including microcrystalline cellulose and one or two additional fillers, crospovidone, silicon dioxide, and magnesium stearate presented in the second layer; and also optionally presented a film coating that covers the first layer and the second layer.

EP3315124 relates to a bilayer tablet formulation comprising a first layer which is composed of Metformin hydrochloride extended release form in an amount of 500 mg or 1000 mg, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, and optionally silicon dioxide or colloidal silicon dioxide; a second layer having a total weight of 300 mg to 400 mg, wherein it is composed of Dapagliflozin (S) propylene glycol hydrate in an amount of 2.5 mg, 5.0 mg or 10.0 mg, lactose anhydrous, microcrystalline cellulose, crospovidone, silicon dioxide, magnesium stearate, and optionally at least one of pregelatinized starch, hydroxypropyl cellulose and mannitol; and optionally a film coating that covers the first layer and the second layer.

W02020009352 relates to pharmaceutical formulation comprising Metformin in the core and amorphous Dapagliflozin L-proline in the coating layer.

WO2013137839 relates to pharmaceutical formulation comprising extended-release Metformin hydrochloride in the core tablet and Dapagliflozin or pharmaceutically acceptable salts, solvates or hydrates thereof in the coating solution.

Many pharmaceutical compositions for pharmaceutical formulations comprising Dapagliflozin or one of its pharmaceutically acceptable salt thereof, in combination with Metformin hydrochloride are explained in the prior art documents stated above.

However, there is a need for a multi-layered tablet formulation composed of an immediate release layer comprising dapagliflozin or one of its pharmaceutically acceptable salt thereof and an extended-release layer comprising metformin hydrochloride and at least one pharmaceutically acceptable excipient that improves compressibility of the extended release layer. Summary of the Invention

The object of this invention is to provide a solid pharmaceutical formulation comprising therapeutically effective amounts of dapagliflozin or pharmaceutically acceptable salts thereof metformin hydrochloride as active ingredients which present different release profiles at individual layers.

The present invention relates to provide a solid pharmaceutical formulation that can be manufactured as multi-layered tablet dosage form.

Another object of the present invention is to develop a multi-layered tablet formulation comprising two formulation layers wherein one of them is immediate release layer, other one is extended release layer.

Dapagliflozin or a pharmaceutically acceptable salt is presented in the immediate release layer and metformin hydrochloride is presented in the extended release layer.

Another object of the present invention is to provide an extended release pharmaceutical formulation comprising Metformin hydrochloride manufactured by using wet granulation process.

Another object of the present invention is to provide an extended release pharmaceutical formulation comprising Metformin hydrochloride as an active ingredient and at least one release modifier, disintegrant, binder, lubricant, glidant and solvent as pharmaceutically acceptable excipient. Another object of the present invention relates to an extended-release formulation comprising Metformin hydrochloride manufactured by using wet granulation process comprising the steps of: a) Metformin hydrochloride, Microcrystalline cellulose and specified amount of the Hydroxypropyl Methylcellulose are screened through a proper sieve and transferred high -shear· mixer to stir, b) Povidone is dissolved in sufficient quantity of water and added to the powder blend prepared in Step a to perform granulation process, c) The granule prepared in Step b is dried in fluid bed dryer and shifted through a proper sieve, d) The rest of the Hydroxypropyl Methylcellulose amount and Colloidal Silicon Dioxide are screened through a proper sieve and added to the granules prepared in Step c and stirred, e) Magnesium stearate is screened through a proper sieve and added to the granules prepared in Step d and mixed to obtain a uniform final blend, f) Tablet compression is performed with the final blend in Step e.

Another object of the present invention is to provide a pharmaceutical formulation comprising dapagliflozin or a pharmaceutically acceptable salt thereof present in the immediate release layer and Metformin hydrochloride present in the extended release layer with povidone as binder and at least one pharmaceutically acceptable excipient wherein the hardness range of tablet obtained with extended release layer after compression is between 150 kP to 250 kP.

Detailed Description of the Invention

The present invention provides solid pharmaceutical formulation comprising dapagliflozin or a pharmaceutically acceptable salt in immediate release layer and metformin hydrochloride in extended-release layer.

The term an "immediate release" refers to dosage forms disintegrate rapidly after administration with enhancing rate of dissolution. Moreover, in the case of solid dosage it should dissolve or disintegrate in the stomach within a short period. It should present rapid dissolution and absorption of drug, which may produce rapid onset of action. Therefore, in the present invention the immediate release layer is designed by considering the general literature knowledge.

However, the term “extended-release” refers to dosage forms provide a longer duration of pharmacological response after administration of the dosage form than are ordinarily experienced after administration of a corresponding immediate release composition comprising the same drug in the same amount. Therefore, in the present invention is related to provide to form the extended release dosage form by using at least one pharmaceutically acceptable excipients.

The extended release layer comprising metformin hydrochloride as an active ingredient with at least one pharmaceutically acceptable excipient is manufactured by using wet granulation process. Metformin is widely drug prescribed for lowering blood glucose in patients with Type 2 diabetes for decades. However, upon the necessity of administration in high doses in the range of 500 mg to 2500 mg per day, taking twice daily or three times a day is required.

Especially, gastrointestinal adverse effects are typically associated with Metformin. The combination with Dapagliflozin or any other related active substance does not lead to increase in the incidence of these adverse effects, which also helps to avoid observing adverse effects by reducing the frequency of administration method. Therefore, extended release layer comprising Metformin is necessary to improve the quality of therapy in patient with the type 2 diabetes. In the present invention, the extended release layer comprising metformin hydrochloride and at least one binder to overcome poor compressibility character of metformin during manufacturing, because the amount of metformin is very high due to dose per dosage form as it is presented in a range of 65 to 75% by weight per extended-release layer formulation. Thus, the proper binder is critical for obtaining a uniform granule with good compressibility characteristics.

In the present invention, since the compressibility is very important hardness of the tablet after the compression process should also be optimized.

In the present invention, povidone is selected as a binder which is widely used in a variety of pharmaceutical formulations and it is primarily used in solid-dosage forms. Also, povidone solution prepared by dissolving it in a proper solvent is used as granulation solution in wet- granulation processes.

In a preferred embodiment of the present invention, the solvent may be selected from deionized water, methanol, ethanol, isopropyl alcohol, dichloromethane, acetone, ethyl acetate, dimethylsulfoxide and their mixtures thereof. Preferably, the solvent is deionized water. In a preferred embodiment of the present invention is to provide extended release layer comprising metformin hydrochloride with povidone by using wet granulation process provided for the manufacture of tablets with at least one release modifier, disintegrant, lubricant and glidant. The release modifier is responsible for retarding of the prepared formulation by forming a gelling form. In the present invention, the selected release modifier is independent of pH, thus its mechanism does not depend on the pH of the environment it encounters.

In the preferred embodiment of the present invention, the release modifier may include, but are not limited to, hydroxypropyl methylcellulose, polyvinyl alcohol (PVA), ethyl cellulose, methacrylic polymers, hydroxypropyl cellulose, starches, gums, cellulose ethers, protein derived materials, nylon, acrylic resins, polylactic acid, polyvinylchloride, polyvinylpyrrolidones, and cellulose acetate phthalate. Preferably, at least one release modifier is Hydroxypropyl methylcellulose. In the preferred embodiment of the present invention, the disintegrant may include, but are not limited to croscarmellose sodium, crospovidone, starch, potato starch, pregelatinized starch, corn starch, sodium starch glycolate, microcrystalline cellulose, low substituted hydroxypropyl cellulose and other known disintegrants. Preferably, the disintegrant is Microcrystalline cellulose. In the preferred embodiment of the present invention, the glidant may include, but are not limited to silicon dioxide, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc and other known glidant. Preferably, the glidant is Colloidal silicon dioxide.

In the preferred embodiment of the present invention, the lubricant may include, but are not limited to magnesium stearate, zinc stearate, calcium stearate, talc, camauba wax, stearic acid, sodium stearyl fumarate sodium laurel sulfate, glyceryl palmitostearate, and hydrogenated vegetable oils and fats, as well as other known lubricants. Preferably, the lubricant is Magnesium stearate.

In some embodiments of the present invention, a solid pharmaceutical formulations are compressed into a multi-layered tablet form. The embodiment in accordance with the present invention is designed with adjusted quantitative composition composed of pharmaceutically acceptable ingredients mentioned above by using wet granulation process. The embodiment identified as Example 1 is given in the Table- 1 below.

The proposed embodiment based on the invention with the amounts in w/w% of the extended- release layer composition are as stated below:

Table 1: Unit Formula of Example 1

Another object of the present invention relates to an extended release layer prepared by using wet granulation process providing the steps of: a) Metformin hydrochloride, Microcrystalline cellulose and specified amount of the Hydroxypropyl methylcellulose were screened through a proper sieve and transferred into high-shear mixer and stirred, b) Povidone was dissolved in sufficient quantity of water, then added to the prepared in Step a to perform granulation process, c) The granules prepared in Step b were dried in fluid bed dryer and screened through a proper sieve, d) The rest of the amount of Hydroxypropyl methylcellulose and Colloidal silicon dioxide were screened through a proper sieve and added to the granules prepared in Step c and stirred, e) Magnesium stearate was screened through a proper sieve and added to the granules prepared in Step d and stirred to obtain a uniform final blend, f) Tablet compression is performed with the final blend in Step e.

In the present invention, the flowability of final blend was good that leads tablet compression process to be achieved. Moreover, tablet compression was performed to get tablets having hardness values between 150 kP to 250 kP.

The prepared extended release layer was investigated for the determined qualitative and quantitative formulation of Example 1. The obtained tablets were subjected to dissolution test which is one of the important analytical tests to characterize tablet properties and to achieve proper dissolution release profile for the tablet dosage form of the present invention. The comparative dissolution results of Example 1 with different hardness values were shown in Table 2. Example- la has the minimum hardness value, Example- lb has the maximum hardness value.

The dissolution test was carried out in pH 6.8 phosphate buffer. Other conditions are defined as; volume of dissolution media is 1000 ml, temperature of study is 37°C±0.5, rotation speed is 100 rpm, USP apparatus is I (Basket).

Table 2: The results of dissolution test conducted with Example 1 According to the results presented above, tablet hardness range which is between 150 kP to 250 kP is optimized to get proper dissolution profile.

While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.