Extended-release compositions comprising empagliflozin and metformin

Abstract

The present invention relates extended-release tablet compositions comprising empagliflozin or pharmaceutically acceptable salt thereof, metformin or pharmaceutically acceptable salt thereof.

Description

[0001]DESCRIPTION EXTENDED-RELEASE COMPOSITIONS COMPRISING EMPAGLIFLOZIN AND METFORMIN Field of Invention 5 The present invention relates extended-release tablet compositions comprising empagliflozin or pharmaceutically acceptable salt thereof, metformin or pharmaceutically acceptable salt thereof. Background of the Invention 10 Vitamin B complex supplements are widely used to address deficiencies and promote overall health. The B vitamins play crucial roles in energy production, brain function, and cell metabolism. Despite their importance, many individuals do not get sufficient amounts of these vitamins from their diets alone, leading to the need for supplementation. Type 2 diabetes is a rapidly growing condition that significantly reduces life expectancy 15 due to its high incidence of complications. The disease is the leading cause of adult-onset vision loss, kidney failure, primarily due to diabetes-related microvascular complications. Moreover, individuals with type 2 diabetes face a two to five-fold higher risk of developing cardiovascular diseases. Drugs are often employed as first- or second-line therapies, either as monotherapy or in combination with other treatments, whether as an initial or 20 add-on strategy. Empagliflozin is an inhibitor of sodium-glucose co-transporter type 2 (SGLT-2) and is therefore used to treat type 2 diabetes. It is currently approved for the treatment of type 2 diabetes and improvement of blood sugar control. The chemical name of empagliflozin (lS)-l,5-anhydro-l-(4-chloro-3-{4-[(3S)- tetrahydrofuran-3-yloxy]benzyl}phenyl)-D- 25 glucitol and its chemical structure is shown below. Empagliflozin Metformin is a biguanide class medication and is therefore used to treat type 2 diabetes. It is currently approved for the treatment of type 2 diabetes and improvement of blood sugar control. The chemical name of metformin is 1,1-Dimethylbiguanide hydrochloride and its chemical structure is shown below. 5 Metformin Extended-release (XR) tablets offer a significant advantage over immediate-release (IR) 10 tablets, especially in terms of improving patient compliance and ensuring more stable blood levels of the medication. Unlike IR tablets, which require multiple doses throughout the day, XR tablets are designed to release the active ingredient gradually over an extended period, often allowing for just one daily dose. This not only simplifies the dosing regimen but also reduces the risk of missed doses. Additionally, XR formulations can 15 minimize the peaks and troughs in drug concentration that are common with IR tablets, leading to fewer side effects and more consistent therapeutic effects. For patients requiring long-term treatment, XR tablets provide a more convenient, effective, and well- tolerated option. In view of the foregoing, there is a need to improve stability and high patient compliance 20 in extended-release tablet compositions comprising empagliflozin or pharmaceutically acceptable salt thereof, metformin, one or more matrix agent and one or more pharmaceutically acceptable excipients. The present invention provides a solution to these problems by providing novel compositions comprising empagliflozin or pharmaceutically acceptable salt thereof, metformin or pharmaceutically acceptable salt 25 thereof, one or more matrix agent and one or more pharmaceutically acceptable excipients. These solutions will be described in detail. Brief Description of the Invention The present invention provides a pharmaceutical composition of extended-release tablet 30 comprising empagliflozin or pharmaceutically acceptable salt thereof, metformin or pharmaceutically acceptable salt thereof, hydroxypropyl methylcellulose as a matrix agent and at least one pharmaceutically acceptable excipients, characterized in that the particle size distribution of the empagliflozin or a pharmaceutically acceptable salt thereof is d (90) ≤ 5 µm. 5 The extended-release tablet composition of the present invention comprises below: ^ 0.20% - 2.00% by weight empagliflozin or pharmaceutically acceptable salt thereof, ^ 60.00% - 75.00% by weight metformin or pharmaceutically acceptable salt 10 thereof, ^ 15.00% - 25.00% by weight matrix agent, ^ 0.50% - 1.0% by weight glidant, ^ 2.00% - 5.00% by weight binder, ^ 0.50% - 1.0% by weight lubricant, 15 ^ 5.00% - 15.00% by weight film coating. The extended-release tablet composition of the present invention comprises below: ^ 0.20% - 2.00% by weight Empagliflozin, ^ 60.00% - 75.00% by weight metformin hydrochloride, 20 ^ 18.00% - 22.00% by weight hydroxypropyl methylcellulose (HPMC) K100M SR ^ 0.50% - 1.00% by weight colloidal silicon dioxide, ^ 2.00% - 5.00% by weight povidone, ^ 0.50% - 1.00% by weight magnesium stearate, ^ 5.00% - 15.00% by weight film coating. 25 In other aspect of the present invention a process for preparing an extended-release tablet composition can be comprises below steps: a. Preparing extended-release metformin or pharmaceutically acceptable salt thereof core tablets, 30 i. Mixing metformin hydrochloride and half portion of povidone of total amount of povidone, ii. Dispersing the rest amount of povidone in pure water and adding to step i iii. Sieving and drying granules, iv. Sieving and mixing granules with colloidal silicon dioxide and HPMC K100M SR, v. Adding and mixing magnesium stearate with step iv mix, 5 vi. Producing extended-release metformin hydrochloride core tablets, b. Coating step a core tablets with colorless barrier coating c. Micronized empagliflozin or pharmaceutically acceptable salt thereof mixed with pure water, d. Coating step a core tablets with step b mix, 10 e. Coating step c tablets with coloring and polishing coating agents. Detailed Description of the Invention The aspects and disclosures according to the present invention, in particular the extended-release tablet compositions, methods and uses, refer to extended-release tablet 15 compositions comprising empagliflozin or pharmaceutically acceptable salt thereof, metformin or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. An extended-release tablet composition comprising empagliflozin or pharmaceutically acceptable salt thereof, metformin or pharmaceutically acceptable salt thereof, one or 20 more matrix agents and one or more pharmaceutically acceptable excipient, wherein the matrix agent is hydroxypropyl methylcellulose, characterized in that the particle size distribution of the empagliflozin or a pharmaceutically acceptable salt thereof is d (90) ≤ 5 µm. Excipients used in a formulation may adversely affect physicochemical and 25 pharmacokinetic properties. These excipients can interact with the active ingredient. For this reason, while developing the formulation, the substances to be used in addition to the active substance must be carefully and consciously selected. Preferably, the present invention relates to the extended-release tablet compositions comprising empagliflozin, metformin and one or more pharmaceutically acceptable 30 excipient, wherein the excipients are selected from the group including, but are not limited to diluents, lubricants, glidants, binders, disintegrants, antioxidants, solubility increasing agents, preservatives, buffering agents, solvents, flavoring agent, stabilizers, sweetening agent, mixtures thereof. and other materials known to one of ordinary skill in the art and the mixtures thereof. In one embodiment of the present invention, metformin or pharmaceutically acceptable salt thereof can be metformin hydrochloride. 5 The value d90 refers to the 90% value of the distribution measured using a laser diffractometer. For the purposes of the present invention, the d90 value denotes the particle size below which 90% of the quantity of particles is found based on the distribution. In other words, in The D90 describes the diameter where ninety percent of the distribution has a smaller particle size and ten percent has a larger particle size. 10 One can determine the average particle size of a solid from a knowledge of its surface area per unit weight and its density. In one embodiment of the present invention, empagliflozin or pharmaceutically acceptable salt thereof has d (90) ≤ 5 µm. In one embodiment of the present invention, empagliflozin or pharmaceutically 15 acceptable salt thereof has d (90) particle size between 1 µm and 5 µm. According to one embodiment of the present invention, the amount of empagliflozin or pharmaceutically acceptable salt thereof is present between 0.10% and 25.0% by weight in the total composition. Preferably, the amount of Empagliflozin is between 0.20% and 2.00%. 20 Lubricants are important excipients in tablet compositions, primarily used to reduce friction during the tablet manufacturing process. They help prevent the tablet blend from sticking to the equipment, ensuring a smooth and efficient production process. Lubricants improve the flow of the tablet mixture through the machinery, enhancing the uniformity and consistency of the final product. 25 Commonly used lubricants in tablet compositions include magnesium stearate, stearic acid, talc, sodium stearyl fumarate, colloidal silicon dioxide, and polyethylene glycol (PEG). In preferred embodiment in the present invention amount of lubricant can be between 0.5-1.0% (w / w). In preferred embodiment in present invention lubricant can be magnesium stearate. In 30 preferred embodiment present invention amount of lubricant can be between 0.5-1.0% (w / w). In tablet compositions, glidants are used to improve the flow properties of powders and granules during the manufacturing processes. These substances are added to formulations to ensure that mixtures flow freely and consistently during tablet or capsule production, preventing blockages and irregular distributions. Glidants are particularly important in formulations with high doses of active ingredients, which often have poor flow properties. In a preferred embodiment of the present invention, the amount of 5 glidant can be between 0.5-1.0% (w / w). Examples of glidants include colloidal silicon dioxide, talc, magnesium stearate, microcrystalline cellulose, stearic acid, calcium silicate, dicalcium phosphate, glyceryl behenate, precipitated silica, and corn starch. These substances help achieve more homogeneous mixtures during pharmaceutical manufacturing, enhancing the quality and 10 effectiveness of the final product In a preferred embodiment, the glidant in the present invention compositions can be colloidal silicon dioxide. In a preferred embodiment of the present invention, the amount of colloidal silicon dioxide can be between 0.5-1.0% (w / w). Examples of binders include polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), 15 hydroxypropyl methylcellulose (HPMC), starch, microcrystalline cellulose, methylcellulose, gelatin, acacia gum, and carboxymethyl cellulose (CMC). These substances help in holding the ingredients together in a tablet or granule, improving the cohesion and mechanical strength of the final product. In a preferred embodiment, the binder in the present invention compositions can be 20 povidone. In a preferred embodiment of the present invention, the amount of hydroxypropyl cellulose can be between 2.0-5.0% (w / w). Examples of matrix agents used in extended-release formulations include hydroxypropyl methylcellulose (HPMC), HPMC K100M SR, ethyl cellulose, polyethylene oxide (PEO), carbopol, xanthan gum, polyvinyl alcohol (PVA), glyceryl behenate, hydrogenated castor 25 oil, and sodium alginate. These substances help control the release of the active pharmaceutical ingredient over time, ensuring consistent drug delivery and prolonged therapeutic effect. In a preferred embodiment, the matrix agent in the present invention compositions can be hydroxypropyl methylcellulose (HPMC). 30 Hydroxypropyl Methylcellulose (HPMC) K100M SR is commonly used as a matrix-forming agent in the formulation of extended-release (ER) tablets. Its primary function is to control the drug release rate over an extended period, ensuring a sustained therapeutic effect. The "K100M" grade indicates a very high viscosity of the polymer, which is crucial for forming a robust gel matrix in aqueous environments. This high viscosity helps in controlling the drug release rate effectively. Ensures a steady drug release profile, which can enhance patient compliance by reducing dosing frequency. Achieving the desired release profile may require precise control over the amount of HPMC K100M used and 5 the tablet's overall formulation. In a preferred embodiment of the present invention, the amount of hydroxypropyl methylcellulose can be between 15.0-25.0% (w / w). The inventors surprisingly have found that the extended-release tablet compositions comprising empagliflozin or pharmaceutically acceptable salt thereof, metformin or 10 pharmaceutically acceptable salt thereof, one or more matrix agent and one or more pharmaceutically acceptable excipient improves chemical physical stability, content uniformity and increase patient compliance for tablet compositions. Additionally, using d(90) ≤ 5 µm value of empagliflozin and specific matrix agent in the formulation gives satisfied results according to content uniformity. We completed 15 comparison studies about unmicronized (d90 ≥ 10 µm) and micronized (d(90) ≤ 5 µm) empagliflozin using a specific matrix agent in the formulation under the same process steps. According to these studies, we have found that the composition using d(90) ≤ 5 µm value of empagliflozin and specific matrix agent in the formulation gives successful results for content uniformity. 20 In further embodiment tablet compositions in present invention can be comprise coating. The extended-release tablet composition of the present invention comprises below: ^ 0.20% - 2.00% by weight Empagliflozin or pharmaceutically acceptable salt thereof, 25 ^ 60.00% - 75.00% by weight metformin or pharmaceutically acceptable salt thereof, ^ 15.00% - 25.00% by weight matrix agent ^ 0.50% - 1.0% by weight glidant, ^ 2.00% - 5.00% by weight binder, 30 ^ 0.50% - 1.0% by weight lubricant, ^ 5.00% - 15.00% by weight film coating. The extended-release tablet composition of the present invention comprises below: ^ 0.20% - 2.00% by weight Empagliflozin, ^ 60.00% - 75.00% by weight metformin hydrochloride, ^ 18.00% - 22.00% by weight hydroxypropyl methylcellulose (HPMC) K100M SR ^ 0.50% - 1.00% by weight colloidal silicon dioxide, 5 ^ 2.00% - 5.00% by weight povidone, ^ 0.50% - 1.00% by weight magnesium stearate, ^ 5.00% - 15.00% by weight film coating. In other aspect of the present invention a process for preparing an extended-release 10 tablet composition can be comprises below steps: a. Preparing extended-release metformin or pharmaceutically acceptable salt thereof core tablets, i. Mixing metformin hydrochloride and half portion of binder of total amount of binder, 15 ii. Dispersing the rest amount of binder in pure water and adding to step i, iii. Sieving and drying granules, iv. Sieving and mixing granules with glidant and matrix agent, v. Adding and mixing lubricant with step iv mix, 20 vi. Producing extended-release metformin hydrochloride core tablets, b. Coating step a core tablets with colorless barrier coating, c. Micronized empagliflozin or pharmaceutically acceptable salt thereof mixed with pure water, d. Coating step a core tablets with step b mix, 25 e. Coating step c tablets with coloring and polishing coating agents. In other aspect of the present invention a wet granulation process for preparing an extended-release tablet composition can be comprises below steps: a. Preparing extended-release metformin or pharmaceutically acceptable salt 30 thereof core tablets, i. Mixing metformin hydrochloride and half portion of povidone of total amount of povidone, ii. Dispersing the rest amount of povidone in pure water and adding to step i, iii. Sieving and drying granules, iv. Sieving and mixing granules with colloidal silicon dioxide and HPMC 5 K100M SR, v. Adding and mixing magnesium stearate with step iv mix, vi. Producing extended-release metformin hydrochloride core tablets, b. Coating step a core tablets with colorless barrier coating c. Micronized empagliflozin or pharmaceutically acceptable salt thereof mixed 10 with pure water, d. Coating step a core tablets with step b mix, e. Coating step c tablets with coloring and polishing coating agents. In preferred aspect of the present invention a process for preparing an extended-release 15 tablet composition can be comprises below steps: a. Preparing extended-release metformin hydrochloride core tablets, i. Mixing metformin hydrochloride and half portion of binder of total amount of binder, ii. Dispersing the rest amount of binder in pure water and adding to 20 step i, iii. Sieving and drying granules, iv. Sieving and mixing granules with glidant and matrix agent, v. Adding and mixing lubricant with step iv mix, vi. Producing extended-release metformin hydrochloride core 25 tablets, b. Coating step a core tablets with colorless barrier coating c. Micronized empagliflozin mixed with pure water, d. Coating step a core tablets with step b mix, e. Coating step c tablets with coloring and polishing coating agents. 30 In preferred aspect of the present invention a wet granulation process for preparing an extended-release tablet composition can be comprises below steps: a. Preparing extended-release metformin hydrochloride core tablets, i. Mixing metformin hydrochloride and half portion of povidone of total amount of povidone, ii. Dispersing the rest amount of povidone in pure water and adding to step i, 5 iii. Sieving and drying granules, iv. Sieving and mixing granules with colloidal silicon dioxide and HPMC K100M SR, v. Adding and mixing magnesium stearate with step iv mix, vi. Producing extended-release metformin hydrochloride core 10 tablets, b. Coating step a core tablets with colorless barrier coating c. Micronized empagliflozin mixed with pure water, d. Coating step a core tablets with step b mix, e. Coating step c tablets with coloring and polishing coating agents. 15 In other aspect of a pharmaceutical composition of the present invention for use in use in the treatment of type 2 diabetes. Content uniformity Studies 20 The content uniformity results of the trials prepared with micronized empagliflozin (d (90)= 25 µm – Test1) and unmicronized empagliflozin (d (90) ≤ 5 µm – Test2) are as follows. Sample Test-1 Test-2 1 74,8 98,6 2 78,9 93,2 3 71,0 98,4 4 73,3 99,7 5 68,6 102,9 6 65,2 101,4 7 71,4 101,4 8 85,8 99,2 9 78,1 99,3 10 76,8 96,8 SD 5,9 2,7 Avg 74,4 99,1 Acceptance Criteria 38,2 6,5 The acceptance criteria should be less than 15, as can be seen from the table above, the results of test 2 gave acceptance criteria within the limit. 5 Dissolution Results Synjardy XR Time Product 25 / 1000 mg Test Product (min) Name tablet 0 0 0,0 0,0 60 1 54,8 54,4 120 2 66,3 66,3 240 3 77,5 78,5 360 4 84,3 86,2 480 5 88,7 91,5 600 6 93,3 94,7 720 7 95,8 97,2 F2 similarity 91,7 In pharmaceutical studies, particularly when comparing in vitro dissolution profiles of two formulations, an F2 value between 50 and 100 suggests that the profiles are similar. An F2 similarity value of 91.7 indicates a very high level of similarity between the 10 dissolution profiles of the formulations being compared. In test product, hydroxypropyl methylcellulose K100M SR used as a matrix agent. Hydroxypropyl methylcellulose K100M SR stands out as a cost-effective matrix agent compared to its counterparts on the market, which is another advantage it offers.

Claims

CLAIMS 1. A pharmaceutical composition of extended-release tablet comprising empagliflozin or pharmaceutically acceptable salt thereof, metformin or pharmaceutically acceptable salt thereof, hydroxypropyl methylcellulose as a matrix agent and at least one 5 pharmaceutically acceptable excipients, characterized in that the particle size distribution of the empagliflozin or a pharmaceutically acceptable salt thereof is d (90) ≤ 5 µm.

2. The pharmaceutical composition according to claim 1, characterized in comprising ^ 0.20% - 2.00% by weight empagliflozin or pharmaceutically acceptable salt thereof, ^ 60.00% - 75.00% by weight metformin or pharmaceutically acceptable salt thereof, ^ 15.00% - 25.00% by weight hydroxypropyl methylcellulose ^ 0.50% - 1.0% by weight glidant, ^ 2.00% - 5.00% by weight binder, ^ 0.50% - 1.0% by weight lubricant, ^ 5.00% - 15.00% by weight film coating.

3. The pharmaceutical composition according to claim 2, characterized in comprising ^ 0.20% - 2.00% by weight Empagliflozin, ^ 60.00% - 75.00% by weight metformin hydrochloride, ^ 18.00% - 22.00% by weight hydroxypropyl methylcellulose ^ 0.50% - 1.00% by weight colloidal silicon dioxide, ^ 2.00% - 5.00% by weight povidone, ^ 0.50% - 1.00% by weight magnesium stearate, ^ 5.00% - 15.00% by weight film coating.

4. A process for preparing pharmaceutical composition according to claim 1, comprising the steps of: a. Preparing extended-release metformin hydrochloride core tablets, i. Mixing metformin hydrochloride and half portion of povidone of total amount of povidone,ii. Dispersing the rest amount of povidone in pure water and adding to step i, iii. Sieving and drying granules, iv. Sieving and mixing granules with colloidal silicon dioxide and 5 hydroxypropyl methylcellulose v. Adding and mixing magnesium stearate with step iv mix, vi. Producing extended-release metformin hydrochloride core tablets, b. Coating step a core tablets with colorless barrier coating c. Micronized empagliflozin mixed with pure water, d. Coating step a core tablets with step b mix, e. Coating step c tablets with coloring and polishing coating agents.

5. Pharmaceutical composition according to one of the claims of 1-4, characterized in that said hydroxypropyl methylcellulose is HPMC K100M SR.

Images