Immediate-release compositions comprising empagliflozin and metformin

Abstract

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

Description

[0001] DESCRIPTION

[0002] IMMEDIATE-RELEASE COMPOSITIONS COMPRISING EMPAGLIFLOZIN AND METFORMIN

[0003] Field of Invention

[0004] 5 The present invention relates to immediate-release tablet compositions comprising empagliflozin or pharmaceutically acceptable salt thereof, metformin or pharmaceutically acceptable salt thereof.

[0005] Background of the Invention

[0006] 10 Type 2 diabetes is a rapidly growing condition that significantly reduces life expectancy 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, 15 either as monotherapy or in combination with other treatments, whether as an initial or add-on strategy.

[0007] 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 20 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- glucitol and its chemical structure is shown below.

[0008]

[0009] 25 Empagliflozin

[0010] 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

[0011] 1 sugar control. The chemical name of metformin is 1,1-Dimethylbiguanide hydrochloride and its chemical structure is shown below.

[0012]

[0013] 5 Metformin

[0014] Immediate-release (IR) tablets have distinct advantages over extended-release (XR) tablets, particularly in terms of flexibility and immediate therapeutic effect. Unlike XR tablets, which release the active ingredient gradually over an extended period, IR tablets 10 are designed to deliver the medication quickly, providing rapid relief of symptoms. This is especially beneficial in situations where prompt treatment is necessary. Additionally, IR formulations allow for more precise control of dosing, as they can be taken multiple times throughout the day, enabling adjustments based on the patient's immediate needs. For patients who require quick onset of action or who may need to adjust their dosage 15 frequently, IR tablets offer a more responsive and adaptable treatment option.

[0015] In view of the foregoing, there is a need to improve content uniformity, improve stability and high patient compliance in immediate-release tablet compositions comprising empagliflozin or pharmaceutically acceptable salt thereof, metformin colloidal silicon 20 dioxide as a glidant and one or more pharmaceutically acceptable excipients wherein the colloidal silicon dioxide is present in both the inner phase and the outer phase. The present invention provides a solution to these problems by providing novel compositions comprising empagliflozin or pharmaceutically acceptable salt thereof, metformin colloidal silicon dioxide as a glidant and one or more pharmaceutically acceptable 25 excipients wherein the colloidal silicon dioxide is present in both the inner phase and the outer phase. These solutions will be described in detail.

[0016] Brief Description of the Invention

[0017] The present invention provides an immediate-release tablet composition comprising 30 empagliflozin or pharmaceutically acceptable salt thereof, metformin or pharmaceutically

[0018] 2 acceptable salt thereof, colloidal silicon dioxide as a glidant and one or more pharmaceutically acceptable excipient,

[0019] characterized in that colloidal silicon dioxide is present in both the inner phase and the outer phase wherein the particle size distribution of the empagliflozin or a 5 pharmaceutically acceptable salt thereof is d (90) ≤ 5 µm.

[0020] The immediate-release tablet composition of the present invention comprises below:

[0021] ^ 0.20% - 2.00% by weight Empagliflozin or pharmaceutically acceptable salt thereof,

[0022] 10 ^ 80.00% - 95.00% by weight metformin or pharmaceutically acceptable salt thereof,

[0023] ^ 0.25% - 1.0% by weight colloidal silicon dioxide as a glidant, ^ 3.00% - 7.00% by weight binder,

[0024] ^ 0.25% - 1.0% by weight lubricant.

[0025] 15

[0026] The immediate-release tablet composition of the present invention comprises below:

[0027] ^ 0.20% - 2.00% by weight Empagliflozin,

[0028] ^ 80.00% - 95.00% by weight metformin hydrochloride,

[0029] ^ 0.25% - 1.0% by weight colloidal silicon dioxide,

[0030] 20 ^ 3.00% - 7.00% by weight povidone,

[0031] ^ 0.25% - 1.0% by weight magnesium stearate.

[0032] In other aspect of the present invention a process for preparing an immediate-release tablet composition can be comprises below steps:

[0033] 25 a. Preparing mix comprising a binder and pure water,

[0034] b. Adding and sieving Empagliflozin or pharmaceutically acceptable salt thereof and metformin or pharmaceutically acceptable salt thereof, a binder and half portion of colloidal silicon dioxide to step a,

[0035] c. Performing wet granulation,

[0036] 30 d. Wet sieving to the granules,

[0037] e. Adding granules to fluid bed dryer

[0038] f. Sieving dried granules,

[0039] 3 g. Sieving other half portion of colloidal silicon dioxide, adding onto dried granules from step f,

[0040] h. Adding and sieving a lubricant with step g,

[0041] i. Compressing tablets,

[0042] 5 j. Coating tablets with coating materials.

[0043] In other aspect of a pharmaceutical composition of the present invention for use in use in the treatment of type 2 diabetes.

[0044] 10 Detailed Description of the Invention

[0045] The aspects and disclosures according to the present invention, in particular the immediate-release tablet compositions, methods and uses, refer to immediate-release tablet compositions comprising empagliflozin or pharmaceutically acceptable salt thereof, metformin or pharmaceutically acceptable salt thereof and one or more 15 pharmaceutically acceptable excipients.

[0046] An immediate-release tablet composition comprising empagliflozin or pharmaceutically acceptable salt thereof, metformin or pharmaceutically acceptable salt thereof, colloidal silicon dioxide as a glidant and one or more pharmaceutically acceptable excipient, 20 characterized in that colloidal silicon dioxide is present in both inner phase and outer phase wherein the particle size distribution of the empagliflozin or a pharmaceutically acceptable salt thereof is d (90) ≤ 5 µm.

[0047] The present invention provides an immediate-release tablet composition comprising 25 empagliflozin or pharmaceutically acceptable salt thereof, metformin colloidal silicon dioxide as a glidant and one or more pharmaceutically acceptable excipient, characterized in that colloidal silicon dioxide is present in both the inner phase and the outer phase wherein the particle size distribution of the empagliflozin or a pharmaceutically acceptable salt thereof is d (90) ≤ 5 µm.

[0048] 30 In a tablet composition, the inner phase refers to the core of the tablet, which typically comprises the active pharmaceutical ingredient and may also include excipients that help in controlling the release or stability of the drug.

[0049] 4 The outer phase (or coating) is the external part of the tablet, often designed to protect the inner phase from environmental factors, enhance the tablet's appearance, or control the release profile of the drug (e.g., delayed, immediate or sustained release).

[0050] 5 A glidant is an excipient added to a tablet formulation to improve the flow properties of powder mixtures. It reduces friction between particles, making them easier to process.

[0051] ^In the inner phase, glidants help ensure uniform filling of the tablet die during manufacturing, promoting consistent weight and content of the inner core.

[0052] ^ In the outer phase, glidants can aid in the smooth application of the coating 10 materials, ensuring an even distribution and preventing clumping or unevenness during the coating process.

[0053] Excipients used in a formulation may adversely affect physicochemical and pharmacokinetic properties. These excipients can interact with the active ingredient. For 15 this reason, while developing the formulation, the substances to be used in addition to the active substance must be carefully and consciously selected.

[0054] Preferably, the present invention relates to the immediate-release tablet compositions comprising empagliflozin or pharmaceutically acceptable salt thereof, metformin 20 colloidal silicon dioxide as a glidant and one or more pharmaceutically acceptable excipient, characterized in that colloidal silicon dioxide is present in both the inner phase and the outer phase wherein the particle size distribution of the empagliflozin or a pharmaceutically acceptable salt thereof is d (90) ≤ 5 µm the excipients are selected from the group including, but are not limited to diluents, lubricants, glidants, binders, 25 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.

[0055] In one embodiment of the present invention, metformin or pharmaceutically acceptable 30 salt thereof can be metformin hydrochloride.

[0056] 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

[0057] 5 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. One can determine the average particle size of a solid from a knowledge of its surface area 5 per unit weight and its density.

[0058] In one embodiment of the present invention, empagliflozin or pharmaceutically acceptable salt thereof has d (90) ≤ 5 µm.

[0059] 10 In one embodiment of the present invention, empagliflozin or pharmaceutically acceptable salt thereof has d (90) particle size between 1 µm and 5 µm.

[0060] 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 15 in the total composition. Preferably, the amount of Empagliflozin is between 0.20% and 2.00%.

[0061] Lubricants are important excipients in tablet compositions, primarily used to reduce friction during the tablet manufacturing process. They help prevent the tablet blend from 20 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.

[0062] Commonly used lubricants in tablet compositions include magnesium stearate, stearic 25 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 0.25-1.0% (w / w).

[0063] In preferred embodiment in present invention lubricant can be magnesium stearate. In 30 preferred embodiment present invention amount of lubricant can be between 0.25-1.0% (w / w).

[0064] In tablet compositions, glidants are used to improve the flow properties of powders and granules during the manufacturing processes. These substances are added to 35 formulations to ensure that mixtures flow freely and consistently during tablet or capsule production, preventing blockages and irregular distributions. Glidants are particularly

[0065] 6 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 glidant can be between 0.25-1.0% (w / w).

[0066] 5 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 0.25-1.0% (w / w).

[0067] The inventors surprisingly have found that the immediate-release tablet compositions 10 comprising empagliflozin or pharmaceutically acceptable salt thereof, metformin or pharmaceutically acceptable salt thereof, colloidal silicon dioxide as a glidant and one or more pharmaceutically acceptable excipient wherein colloidal silicon dioxide is present in both the inner phase and the outer phase wherein the particle size distribution of the empagliflozin or a pharmaceutically acceptable salt thereof is d (90) ≤ 5 µm improves 15 chemical physical stability, content uniformity and increase patient compliance for immediate-release tablet compositions.

[0068] The inventors found that use of colloidal silicon dioxide in both the inner and outer phases of a tablet formulation offers several benefits, particularly for content uniformity.

[0069] 20

[0070] ^ In the inner phase, colloidal silicon dioxide acts as a glidant, improving the flowability of the powder blend. This ensures a more consistent and even distribution of the active pharmaceutical ingredient (API) during tablet compression, reducing the risk of segregation and improving uniformity in the 25 final dosage form.

[0071] ^In the outer phase (typically the coating), its inclusion can aid in ensuring smooth application of the coating materials and further maintain consistency in the distribution of the API within the tablet.

[0072] ^ By enhancing the flow properties and preventing segregation in both phases, 30 colloidal silicon dioxide plays a key role in achieving better content uniformity across all tablets.

[0073] Examples of binders include polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), starch, microcrystalline cellulose, 35 methylcellulose, gelatin, acacia gum, and carboxymethyl cellulose (CMC). These

[0074] 7 substances help in holding the ingredients together in a tablet or granule, improving the cohesion and mechanical strength of the final product.

[0075] In a preferred embodiment, the binder in the present invention compositions can be 5 povidone. In a preferred embodiment of the present invention, the amount of hydroxypropyl cellulose can be between 3.0-7.0% (w / w).

[0076] In further embodiment tablet compositions in present invention can be comprise coating.

[0077] 10 The immediate-release tablet composition of the present invention comprises below:

[0078] ^ 0.20% - 2.00% by weight Empagliflozin or pharmaceutically acceptable salt thereof,

[0079] ^ 80.00% - 95.00% by weight metformin or pharmaceutically acceptable salt thereof,

[0080] 15 ^ 0.25% - 1.0% by weight colloidal silicon dioxide as a glidant,

[0081] ^ 3.00% - 7.00% by weight binder,

[0082] ^ 0.25% - 1.0% by weight lubricant.

[0083] The immediate-release tablet composition of the present invention comprises below: 20 ^ 0.20% - 2.00% by weight Empagliflozin,

[0084] ^ 80.00% - 95.00% by weight metformin hydrochloride,

[0085] ^ 0.25% - 1.0% by weight colloidal silicon dioxide,

[0086] ^ 3.00% - 7.00% by weight povidone,

[0087] ^ 0.25% - 1.0% by weight magnesium stearate.

[0088] 25

[0089] In other aspect of the present invention a process for preparing an immediate-release tablet composition can be comprises below steps:

[0090] 30 a. Preparing mix comprising a binder and pure water,

[0091] b. Adding and sieving Empagliflozin or pharmaceutically acceptable salt thereof and metformin or pharmaceutically acceptable salt thereof, a binder and half portion of colloidal silicon dioxide to step a,

[0092] c. Performing wet granulation,

[0093] 8 d. Wet sieving to the granules,

[0094] e. Adding granules to fluid bed dryer

[0095] f. Sieving dried granules,

[0096] g. Sieving other half portion of colloidal silicon dioxide, adding onto dried granules 5 from step f,

[0097] h. Adding and sieving a lubricant with step g,

[0098] i. Compressing tablets,

[0099] j. Coating tablets with coating materials.

[0100] 10 In another aspect of the immediate-release tablet composition of the present invention comprises below:

[0101] Table 1: Pharmaceutical composition comprising Metformin HCl and Empagliflozin and relevant excipients

[0102] Function Amount

[0103] (w / w %)

[0104] Inner Phase

[0105] Metformin HCl Active ingredient 80.00 - 95.00 Empagliflozin Active ingredient 0.20 - 2.00

[0106] Povidone (K30) Binder 3.00 - 7.00

[0107] Silica, Colloidal AN Glidant 0.25 - 1.0

[0108] Outer Phase

[0109] Silica, Colloidal AN Glidant 0.25 - 1.0

[0110] Magnesium Stearate Lubricant 0.25% - 1.0%

[0111] 15 In another aspect of the present invention a process for preparing an immediate-release tablet composition can be comprises below steps:

[0112] a. Inner Phase

[0113] i. preparing mix comprising a binder and pure water,

[0114] ii. Adding and sieving Empagliflozin or pharmaceutically acceptable salt 20 thereof and metformin or pharmaceutically acceptable salt thereof, a binder and half portion of colloidal silicon dioxide to step a,

[0115] iii. Performing wet granulation,

[0116] iv. Wet sieving to the granules,

[0117] v. Adding granules to fluid bed dryer

[0118] 25 vi. Sieving dried granules,

[0119] 9 b. Outer Phase

[0120] i. Sieving other half portion of colloidal silicon dioxide, adding onto dried granules from step f,

[0121] ii. Adding and sieving a lubricant with step g,

[0122] 5 iii. Compressing tablets,

[0123] iv. Coating tablets with coating materials.

[0124] In other aspect of a pharmaceutical composition of the present invention for use in use in the treatment of type 2 diabetes.

[0125] 10

[0126] Content uniformity Studies

[0127] The content uniformity results of the trials prepared with a pharmaceutical composition comprising empagliflozin or pharmaceutically acceptable salt thereof, metformin or pharmaceutically acceptable salt thereof, colloidal silicon dioxide both inner phase and 15 outer phase (Test1) and colloidal silicon dioxide only outer phase (Test2) are as follows.

[0128] and one or more pharmaceutically acceptable excipient wherein the particle size distribution of the empagliflozin or a pharmaceutically acceptable salt thereof is d (90) ≤ 5 µm.

[0129] Sample Test-1 Test-2

[0130] 1 %98 %88

[0131] 2 %97 %89

[0132] 3 %98 %89

[0133] 4 %96 %94

[0134] 5 %97 %94

[0135] 6 %98 %94

[0136] 7 %97 %88

[0137] 8 %97 %88

[0138] 9 %95 %88

[0139] 10 %99 %99

[0140] Avg %97 %91

[0141] SD 0,01 3,9

[0142] %RSD 1,2 4,2

[0143] 20

[0144] Test 1 has provided more favorable values compared to Test 2. The use of colloidal silicon dioxide in both the inner and outer phases has improved and contributed to better content uniformity.

[0145] 10

Claims

CLAIMS1. A pharmaceutical composition of immediate-release tablet comprising empagliflozin or pharmaceutically acceptable salt thereof, metformin or pharmaceutically acceptable salt thereof, colloidal silicon dioxide as a glidant and one or more 5 pharmaceutically acceptable excipient,characterized in that colloidal silicon dioxide is present in both inner phase and outer phase wherein the particle size distribution of the empagliflozin or a pharmaceutically acceptable salt thereof is d (90) ≤ 5 µm.10 2. The immediate-release tablet according to claim 1, characterized in comprising ^ 0.20% - 2.00% by weight Empagliflozin or pharmaceutically acceptable salt thereof,^ 80.00% - 95.00% by weight metformin or pharmaceutically acceptable salt thereof,15 ^ 0.25% - 1.0% by weight colloidal silicon dioxide as a glidant,^ 3.00% - 7.00% by weight binder,^ 0.25% - 1.0% by weight lubricant,3. The immediate-release tablet according to claim 2, characterized in comprising 20 ^ 0.20% - 2.00% by weight Empagliflozin,^ 80.00% - 95.00% by weight metformin hydrochloride,^ 0.25% - 1.00% by weight colloidal silicon dioxide,^ 3.00% - 7.00% by weight povidone,^ 0.25% - 1.00% by weight magnesium stearate,254. A process for preparing immediate-release tablet according to claim 1, comprising the steps of:a. Preparing mix comprising a binder and pure water,b. Adding and sieving Empagliflozin or pharmaceutically acceptable salt thereof 30 and metformin or pharmaceutically acceptable salt thereof, a binder and half portion of colloidal silicon dioxide to step a,c. Performing wet granulation,d. Wet sieving to the granules,11e. Adding granules to fluid bed dryerf. Sieving dried granulesg. Sieving other half portion of colloidal silicon dioxide, adding onto dried granules of step f,5 h. Adding and sieving a lubricant with step g,i. Compressing tabletj. Coating tablet with coating materials.

5. The immediate-release tablet according any one of claims 1-3 for use in treatment of 10 type 2 diabetes.12

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