A stable ready to use suspension of empagliflozin

Abstract

The present invention relates to a stable ready to use suspension of empagliflozin Particularly, the present invention relates to a stable, taste-masked, ready to use suspension of empagliflozin and the process for preparing it. The present invention also relates to a method for treating patients with diabetes, type 1 or type 2 by administering a stable, taste-masked, ready-to-use suspension comprising empagliflozin and pharmaceutically acceptable excipients.

Description

[0001] A Stable Ready To Use Suspension of Empagliflozin

[0002] Technical Field

[0003] The present invention relates to a stable ready to use suspension of empagliflozin. Particularly, the present invention relates to a stable, taste-masked, ready to use suspension of empagliflozin and the process for preparing it. The present invention also relates to a use of empagliflozin for treating, preventing, protecting against and / or delaying the progression of chronic kidney disease in patients, for example patients with prediabetes, type 1 or type 2 diabetes mellitus.

[0004] Background & Prior Art

[0005] Empagliflozin is a sodium glucose co -transporter-2 (SGLT-2) inhibitor. SGLT2 co-transporters are responsible for reabsorption of glucose from the glomerular filtrate in the kidney. The glucuretic effect resulting from SGLT2 inhibition reduces renal absorption and lowers the renal threshold for glucose, resulting in increased glucose excretion. Additionally, it contributes to reduced hyperglycaemia, assists weight loss, and reduces blood pressure.

[0006] Empagliflozin is an inhibitor of the sodium glucose co-transporter-2 (SGLT-2). Empagliflozin is known chemically as (1S)-1, 5-anhydro-l-(4-chloro-3-{4-[(3S) - tetrahydrofuran-3-yloxy) benzyl} phenyl)-D-glucitol / also known as D-Glucitol, 1, 5-anhydro-l-C-. [4-chloro-3-[[4-[[(3S)-tetrahydro- 3-furanyl) oxy] phenyl) methyl] phenyl]- (IS). Its empirical formula is C23H27CI07 and the molecular weight is 450.91. The chemical structure of empagliflozin is as follows:

[0007] Formula I Empagliflozin is a sodium glucose co-transporter-2 (SGLT-2) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes. SGLT2 co- transporters are responsible for reabsorption of glucose from the glomerular filtrate in the kidney. The glucuretic effect resulting from SGLT2 inhibition reduces renal absorption and lowers the renal threshold for glucose, therefore resulting in increased glucose excretion. Additionally, it contributes to reduced hyperglycaemia and also assists weight loss and blood pressure reduction.

[0008] Empagliflozin is a white to yellowish non-hygroscopic crystalline solid, very slightly soluble in water (pH 1-7.4), slightly soluble in acetonitrile and ethanol, sparingly soluble in methanol, and practically insoluble in toluene.

[0009] Empagliflozin is available on the market in the form of a free base and is sold under trade name Jardiance®, as an oral tablet in 10 mg and 25 mg strengths. Further it is available on the market as a combination product with Metformin and a combination product with Linagliptin.

[0010] EP1730131 discloses Empagliflozin, process for production thereof, its use and pharmaceutical composition thereof. The composition of a tablet is disclosed that comprises active ingredient in admixture with non-toxic pharmaceutically acceptable excipients, such as lactose, com starch, polyvinylpyrrolidone, magnesium stearate.

[0011] EP1888551 and EP1888552 disclose specific crystalline forms of Empagliflozin, methods for production thereof and synthesis of Empagliflozin.

[0012] The most common dosage forms currently employed for oral administration of active substances are tablets and capsules. However, in recent years awareness of the drawbacks of using these dosage forms has increased. Thus, tablets and capsules are generally less suitable for administering of an active substance to pediatric and geriatric patients for whom tablets or capsules are difficult to ingest, or the large dosages necessitate the administration of several tablets or capsules at a time, resulting in impaired patient compliance. In such situations, oral liquid dosage forms are the preferred choice. However, these dosage forms usually lead to perceptible exposure of the active drug ingredient to the taste buds, which is a very serious problem when the drug has an unpleasant or bitter taste.

[0013] The unpleasant or bitter taste of the drugs, which are orally administered, is disadvantageous in several aspects. Taste is an important parameter governing the compliance. The disagreeable and unpleasant taste of drugs causes difficulties in swallowing or causes patients to avoid their medication, thereby resulting in low patient compliance. Thus, taste-masking technologies are considered important and are developed by many researchers.

[0014] Another problem associated with an active to be formulated in a liquid dosage form is its low solubility which further affects the dissolution, potency of the drug and onset time, the potency and onset time depends on the dissolution rate of the drug.

[0015] Liquid dosage forms may be formulated as powders or granules to be reconstituted before administration, powders or granules to be admixed with a liquid in a container such as a glass before administration, thereby overcoming the difficulties involved in administering an active substance in tablet or capsule form. However, with such formulation other problems arise, especially when the active substance in question is not dissolved in the liquid, but is present in particulate form. In such cases, the particles tend to sink to the bottom of the glass and stay there even when the contents of the glass are stirred before the glass is upended for ingestion of the liquid or to adhere to the sides of the glass when the liquid is ingested. In this way a certain amount of the active substance will remain in the glass giving rise to an unacceptable variation in the dosage of the active substance actually ingested by those to whom it is administered in this form. Furthermore, such granules or particles often have an unpleasant feel in the mouth as they typically have an irregular shape which makes them feel gritty, and they also tend to adhere to oral mucosa after the liquid carrier has been washed down. Such a dosage form therefore also tends to lead to reduced patient compliance. The granules / powder for suspension have many disadvantages such as reduced patient compliance and further there are chances for dose variation and stability problems.

[0016] In light of the above disadvantages, still there is a need to develop suspension for SGLT2 inhibitors, especially empagliflozin which can overcome the above disadvantages. Specifically empagliflozin has limited solubility in water due to its positive log P values, which typically influences the bioavailability in the body of a patient or makes it difficult to find adequate solvents to get the substance dissolved in a liquid formulation before administering it into the body of a patient.

[0017] So, considering bitter taste of empagliflozin, its limited solubility in water, and with an objective to avoid use of polar solvents and or solubilizers and or surfactants, it is desired to design an aqueous oral liquid suspension dosage.

[0018] We have now found that empagliflozin can be formulated in the form of ready-to- use suspension, with an improved taste and stability by careful manipulation of the taste masking agent, flavouring agent, sweetening agent and particle size. Such formulations are envisaged to fulfil the existing need of patient friendly dosage forms especially for the pediatric and geriatric patient populations. Further, this ready-to-use suspension has many advantages over the reconstituted granules for suspension that it has improved patient compliance, improved stability and there is no dose variation while administration of ready-to-use suspension.

[0019] Ob ject of the Invention:

[0020] An object of the present invention is to provide a stable, taste-masked, ready-to- use suspension comprising SGLT2 inhibitor and one or more pharmaceutically acceptable excipients.

[0021] An object of the present invention is to provide a stable, taste-masked, ready-to- use suspension comprising empagliflozin and one or more pharmaceutically acceptable excipients. An object of the present invention is to provide a stable, taste-masked, ready-to- use suspension comprising empagliflozin, taste masking agent, and one or more pharmaceutically acceptable excipients.

[0022] Another object of the present invention is to provide a stable, taste-masked, ready- to-use suspension of empagliflozin with improved taste having high patient compliance.

[0023] Another object of the present invention is to provide a stable, taste-masked, ready- to-use suspension of empagliflozin which is devoid of sugar.

[0024] Another object of the invention is to provide a stable, taste-masked ready-to-use suspension comprising empagliflozin having a particle size such that dgois not more than 50 pm (microns).

[0025] Yet another object of the invention is to provide a process for preparing a stable, taste-masked, ready-to-use suspension, comprising empagliflozin and one or more pharmaceutically acceptable additives.

[0026] Detailed Description of the Invention:

[0027] Unless otherwise defined, all terms used in disclosing the invention, including technical and scientific terms, have the meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0028] It should be understood that the detailed description and specific examples are intended for purposes of illustration only and are not intended to limit the scope of the invention. Numerous changes, substitutions, and modifications may be made without departing from the scope of the present invention.

[0029] According to one aspect the present invention provides an oral, stable, pharmaceutical ready-to-use suspension of empagliflozin. The suspension dosage form is capable of masking the bitter taste of the drug and also provides the drug in a suitable form to take thereby providing patient compliance, especially for children and the elderly. In one embodiment, the present invention provides a stable, taste-masked, ready- to-use aqueous suspension comprising empagliflozin, and pharmaceutically acceptable excipients.

[0030] In one embodiment, the present invention provides a stable, taste-masked, ready- to-use suspension comprising empagliflozin, taste masking agent, and pharmaceutically acceptable excipients.

[0031] In one embodiment, the present invention provides a stable, taste-masked, ready- to-use suspension comprising empagliflozin, taste masking agent, preservative and pharmaceutically acceptable excipients.

[0032] In one embodiment, the present invention provides a stable, taste-masked, ready- to-use preservative free suspension comprising empagliflozin, taste masking agent, and pharmaceutically acceptable excipients.

[0033] According to one embodiment, the present invention provides a stable, taste- masked, ready-to-use suspension comprising of:

[0034] 7.0 % to 13 % (w / v) empagliflozin,

[0035] 0.25 % to 25 % (w / v) taste masking agent,

[0036] 0.1 % to 10 % (w / v) viscosity enhancing agent,

[0037] 0.1 % to 2 % (w / v) suspending agent,

[0038] 0.02 % to 0.5 % (w / v) preservative,

[0039] 1 % to 50 % (w / v) emollient,

[0040] 1 % to 10 % (w / v) sweetening agent,

[0041] 0.2 % to 5 % (w / v) flavoring agent.

[0042] According to one embodiment, the present invention provides a stable, taste- masked, ready-to-use suspension comprising of:

[0043] 7.0 % to 13 % (w / v) empagliflozin,

[0044] 0.25% to 25 % (w / v) polacrilin potassium,

[0045] 0.1% to 10% (w / v) xanthan gum,

[0046] 0.1% to 2% (w / v) sodium carboxymethyl cellulose, 0.02 % to 0.5% (w / v) preservative agent selected from sodium benzoate, sodium methyl paraben, sodium propyl paraben, potassium sorbate, and sorbic acid,

[0047] 1 % to 50 % (w / v) glycerine,

[0048] 1% to 10 % (w / v) sweetening agent selected from sucralose, aspartame, acesulfame K, and saccharine sodium,

[0049] 0.2 % to 5 % (w / v) flavouring agent selected from peppermint and orange flavour.

[0050] According to one embodiment, the present invention provides a stable, taste- masked, ready-to-use suspension comprising of:

[0051] 7.0 % to 13 % (w / v) empagliflozin,

[0052] 0.25 % to 25 % (w / v) taste masking agent,

[0053] 0.1 % to 10 % (w / v) viscosity enhancing agent,

[0054] 0.1 % to 2 % (w / v) suspending agent,

[0055] 0.02 % to 0.5 % (w / v) preservative,

[0056] 1 % to 10 % (w / v) sweetening agent,

[0057] 0.2 % to 5 % (w / v) flavoring agent.

[0058] According to one embodiment, the present invention provides a stable, taste- masked, ready-to-use suspension comprising of:

[0059] 7.0 % to 13 % (w / v) empagliflozin,

[0060] 0.25% to 25 % (w / v) polacrilin potassium,

[0061] 0.1% to 10% (w / v) xanthan gum,

[0062] 0.1% to 2% (w / v) sodium carboxymethyl cellulose,

[0063] 0.02 % to 0.5% (w / v) preservative agent selected from sodium benzoate, sodium methyl paraben, sodium propyl paraben, potassium sorbate, and sorbic acid,

[0064] 1% to 10 % (w / v) sweetening agent selected from sucralose, aspartame, acesulfame K, and saccharine sodium,

[0065] 0.2 % to 5 % (w / v) flavouring agent selected from peppermint and orange flavour.

[0066] According to one embodiment, the present invention provides a stable, taste- masked, ready-to-use suspension comprising of:

[0067] 0.50 % (w / v) empagliflozin, 1 % (w / v) polacriclin potassium,

[0068] 0.5 % (w / v) xanthan gum,

[0069] 1.25 % (w / v) sodium carboxy methyl cellulose,

[0070] 0.20 % (w / v) sodium methyl paraben,

[0071] 5 % (w / v) glycerine,

[0072] 0.5 % (w / v) sucralose, and,

[0073] 0.25 % (w / v) peppermint flavour, wherein the composition has pH in the range of 4.5 to 7, and viscosity is in the range of 200 cps to about 1200 cps, and, wherein the empagliflozin and polacrilin potassium are in the ratio of 1: 0.5 to 1: 50.

[0074] According to one embodiment, the present invention provides a stable, taste- masked, ready-to-use suspension comprising of:

[0075] 0.50 % (w / v) empagliflozin,

[0076] 1 % (w / v) polacriclin potassium,

[0077] 0.5 % (w / v) xanthan gum,

[0078] 1.25 % (w / v) sodium carboxy methyl cellulose,

[0079] 0.20 % (w / v) sodium methyl paraben,

[0080] 0.5 % (w / v) sucralose, and,

[0081] 0.25 % (w / v) peppermint flavour, wherein the composition has pH in the range of 4.5 to 7, and viscosity is in the range of 200 cps to about 1200 cps, and, wherein the empagliflozin and polacrilin potassium are in the ratio of 1: 0.5 to 1: 50

[0082] According to one embodiment, the dgo of the empagliflozin dispersed or suspended in the stable, taste-masked, ready-to-use suspension of the present invention is in the range of 5 to 50pm (microns).

[0083] According to one embodiment, the dgo of the empagliflozin dispersed or suspended in the stable, taste-masked, ready-to-use suspension of the present invention is in the range of 5 to 30pm (microns). According to one embodiment, the dgo of the empagliflozin dispersed or suspended in the stable, taste-masked, ready-to-use suspension of the present invention is not more than 20pm (microns).

[0084] According to one embodiment, the dgo of the empagliflozin dispersed or suspended in the stable, taste-masked, ready-to-use suspension of the present invention is about 10pm (microns).

[0085] According to one embodiment, the stable, taste-masked, ready-to-use suspension of the present invention contains empagliflozin and polacrilin potassium in the ratio of 1: 0.5 to 1: 50.

[0086] According to one embodiment, the stable, taste-masked, ready-to-use suspension of the present invention contains empagliflozin and polacrilin potassium in the ratio of 1: 0.5 to 1: 10.

[0087] According to one embodiment, the stable, taste-masked, ready-to-use suspension of the present invention contains empagliflozin and polacrilin potassium in the ratio of 1: 1 to 1: 5.

[0088] According to one embodiment, the stable, taste-masked, ready-to-use suspension of the present invention contains empagliflozin and polacrilin potassium in the ratio of 1: 2.

[0089] The present invention further contains one or more pharmaceutically acceptable excipients selected from the group comprising but not limited to taste masking agents, preservatives, viscosity enhancing agents, suspending agent, flavouring agents, sweetening agents, pH adjusting agent(s), taste enhancing agent(s), emollient and mixtures thereof.

[0090] Taste masking agents used in the present invention include but not limited to polacrilin or its potassium salt. Resins have been primarily used to mask taste and control liquid drug delivery systems. Many studies addressed the use of ion exchange resins for taste masking. However, few investigations have been reported on poorly water-soluble drugs. In order to improve the solubility, it is widely used as a disintegrating and taste masking agent in oral dosage formulations.

[0091] Viscosity enhancing agent used in the present invention include but not limited to xanthan gum, guar gum, sodium carboxy methyl cellulose, hydroxyl ethyl cellulose, hydroxyl propyl methyl cellulose, silicon dioxide, aluminium magnesium silicate, among others, or their mixtures.

[0092] Flavoring agent(s) used in the invention is meant to impart a pleasant flavor and / or odor to a pharmaceutical composition. Suitable flavoring agents include but not limited to strawberry, raspberry, orange, banana, chocolate, vanilla, mixed berry, berry, apple, lemon, peppermint, tutti-frutti, orange, pineapple or apricot; among many others or in any of their mixtures.

[0093] Sweetening agents(s), used in the present invention include but not limited to sodium or calcium saccharin, sucralose, aspartame, acesulfame potassium, sodium or potassium cyclamate, neo hesperidin dihydrochalcone, thaumatin and their mixtures, among others.

[0094] Preservative agents(s), used in the present invention include but not limited to sorbic acid, sodium sorbate, potassium sorbate, calcium sorbate, benzoic acid sodium benzoate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, sodium metabisulfite, sodium acetate, methylparaben, ethyl paraben, propylparaben, butylparaben, butylparaben sodium, sodium benzoate, potassium benzoate, among others, or their mixtures.

[0095] Suspending agent(s) used in the present invention include but not limited to aluminium magnesium silicate, Carboxymethylcellulose sodium, alginic acid, sodium alginate, potassium alginate, carrageenan, guar gum, gellan gum, acacia gum, gum tragacanth , dextrin pectin , gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, methylcellulose, microcrystalline cellulose, povidone, maltodextrin, pectin, Pregelatinised starch, polycarbophil, carbomers , colloidal anhydrous silica , aluminum and magnesium silicate among others, or in their mixtures. pH adjusting agent(s)used in the present invention include but not limited to potassium acetate, sodium acetate, acetic acid, adipic acid, boric acid, citric acid, hydrochloric acid, fumaric acid, malic acid, nitric acid, propionic acid, succinic acid, sulfuric acid, tartaric acid, potassium bicarbonate, sodium phosphate monobasic, sodium phosphate dibasic, sodium bicarbonate, ammonium carbonate, sodium carbonate, potassium citrate, sodium citrate dihydrate, diethanolamine, ammonium phosphate, potassium phosphate, sodium phosphate, sodium glycolate, ammonium hydroxide, sodium hydroxide, sodium lactate or sodium propionate, among others, or their mixtures.

[0096] Preferably, the pH of the suspension is in range of about 2 about 8. Most preferably the pH of suspension is in range from about 4.5 to about 7.

[0097] Emollient used in the present invention is glycerine. The use of glycerine is optional.

[0098] The water used for the suspension is typically purified water for pharmaceutical use, available commercially, commonly obtained by distillation, ion exchange or any other suitable method from potable water.

[0099] It is desired that in the present invention, the viscosity of the suspension should not be so high that pumping and handling would be difficult in industrial practice, but high enough to confer upon the suspension stability to settling of suspended particles for a reasonable period of time. The viscosity of the suspension should be such that it provides a pourable consistency to the suspension. The suspension of the present invention has a viscosity in the range of about 200 cps to about 1200 cps.

[0100] According to one embodiment, the suspension of the present invention has a viscosity in the range of about 200 cps to about 600 cps. According to one aspect the present invention provides an oral, stable, pharmaceutical ready-to-use suspension of SGLT2 inhibitors selected from empagliflozin, dapagliflozin and canagliflozin. The suspension dosage form is capable of masking the taste of the drug and also provides the drug in a suitable form to take thereby providing patient compliance, especially for children and the elderly.

[0101] According to one embodiment, the present invention provides a stable, taste- masked, ready-to-use aqueous suspension comprising SGLT2 inhibitor, taste masking agent and pharmaceutically acceptable excipients.

[0102] According to one embodiment, the present invention provides a stable, taste- masked, ready-to-use aqueous suspension comprising at least one SGLT2 inhibitor, polacrilin and / or its potassium salt as taste masking agent and pharmaceutically acceptable excipients.

[0103] The term “empagliflozin” as used is the invention is meant to cover empagliflozin in the form of freebase or its pharmaceutically acceptable salt(s), hydrate(s), solvate(s) and physiologically functional derivative(s) and precursors thereof. The term also includes all polymorphic forms or mixtures thereof.

[0104] Empagliflozin may be used as a single active agent, or may be combined with other active agents, vitamins, minerals, dietary supplements, etc.

[0105] According to another aspect, the present invention provides a process to prepare a stable, taste-masked, ready-to-use suspension comprising empagliflozin, taste masking agent and pharmaceutically acceptable excipients.

[0106] In one embodiment, the present invention provides a process to prepare a stable, taste-masked, ready-to-use suspension comprising empagliflozin, comprises of following steps: a) Preparing a homogenous dispersion comprising of taste masking agent in water. b) Addition of SGLT2 inhibitor to step (a) dispersion under constant stirring for minimum three hours. c) Preparing a uniform dispersion comprising of glycerin and at least one viscosity enhancing agent. d) Mixing of step (b) and step (c) dispersion. e) Addition of sweetening agent, flavoring agent and one or more pH adjusting agent under homogenization to step (d). f) Addition of preservative to step (e) under homogenization. g) Adjusting volume with purified water.

[0107] In one embodiment, the present invention provides a process to prepare a stable, taste-masked, ready-to-use suspension comprising empagliflozin, comprises of following steps: a) Preparing a homogenous dispersion comprising of Polacrilin or its potassium salt in water. b) Addition of empagliflozin to step (a) dispersion under constant stirring for minimum three hours. c) Preparing a uniform dispersion comprising of glycerin and at least one viscosity enhancing agent. d) Mixing of step (b) and step (c) dispersion. e) Addition of sucralose, peppermint flavor and citric acid and sodium citrate under homogenization to step (d). f) Addition of sodium methyl paraben to step (e) under homogenization. g) Adjusting volume with purified water.

[0108] In one embodiment, the present invention provides a process to prepare a stable, taste-masked, ready-to-use suspension comprising empagliflozin, comprises of following steps: a) Preparing a homogenous dispersion comprising of taste masking agent in water. b) Addition of SGLT2 inhibitor to step (a) dispersion under constant stirring for minimum three hours. c) Addition of at least one viscosity enhancing agent and or suspending agent slowly to step (b) to form uniform dispersion. d) Mixing of step (c) dispersion. e) Addition of sweetening agent, flavoring agent and one or more pH adjusting agent under homogenization to step (d). f) Addition of preservative to step (e) under homogenization. g) Adjusting volume with purified water.

[0109] In one embodiment, the present invention provides a process to prepare a stable, taste-masked, ready-to-use suspension comprising empagliflozin, comprises of following steps: a) Preparing a homogenous dispersion comprising of Polacrilin or its potassium salt in water. b) Addition of empagliflozin to step (a) dispersion under constant stirring for minimum three hours. c) Addition of at least one viscosity enhancing agent and or suspending agent to step (b) to form uniform dispersion. d) Mixing of step (c) dispersion. e) Addition of sucralose, peppermint flavor and citric acid and sodium citrate under homogenization to step (d). f) Addition of sodium methyl paraben to step (e) under homogenization. g) Adjusting volume with purified water.

[0110] According to another aspect, the present invention provides a method for treating patients with diabetes, type 1 or type 2 by administering a stable, taste-masked, ready-to-use suspension comprising empagliflozin and pharmaceutically acceptable excipients.

[0111] In one embodiment, the present invention provides a method for treating, patients with diabetes, type 1 or type 2 by administering a stable, taste-masked, ready-to- use suspension comprising empagliflozin, taste masking agent and pharmaceutically acceptable excipients.

[0112] In one embodiment, , the present invention provides a method for treating, patients with diabetes, type 1 or type 2 by administering a stable, taste-masked, ready-to-use suspension comprising empagliflozin, taste masking agent, preservative and pharmaceutically acceptable excipients.

[0113] According to another aspect, the present invention provides a stable, taste- masked, ready-to-use suspension comprising empagliflozin and pharmaceutically acceptable excipients packaged in suitable bottle containers.

[0114] In one embodiment, the present invention provides a stable, taste-masked, ready- to-use aqueous suspension comprising empagliflozin and pharmaceutically acceptable excipients packaged in glass bottle containers.

[0115] In one embodiment, the present invention provides a stable, taste-masked, ready- to-use aqueous suspension comprising empagliflozin and pharmaceutically acceptable excipients packaged in amber glass bottle containers.

[0116] In one embodiment, the present invention provides a stable, taste-masked, ready- to-use aqueous suspension comprising empagliflozin and pharmaceutically acceptable excipients packaged in flexible plastic bottle containers.

[0117] In one embodiment, the present invention provides a stable, taste-masked, ready- to-use aqueous suspension comprising empagliflozin and pharmaceutically acceptable excipients, packaged in 100ml to 300 ml bottle containers.

[0118] The following examples are illustrative of the present invention, and the examples should not be considered as limiting the scope of this invention in any way, as these examples and other equivalents thereof will become apparent to those versed in the art, in the light of the present disclosure, and the accompanying claims.

[0119] Example 1

[0120] Manufacturing Process: a) Purified water was dispensed into a stainless-steel vessel to which dispensed quantity of Polacrilin potassium was added under continuous stirring / homogenization to form uniform dispersion. b) Dispensed quantity of Empagliflozin was added to the above step a) dispersion with continuous stirring / homogenization and continued for minimum 180 minutes to ensure empagliflozin: resin complex formation and bitter taste masking of API. c) Sodium carboxy methyl cellulose and xanthan gum were added to step b) to form uniform dispersion. d) Continue stirring / homogenization to form uniform dispersion. e) Methyl paraben was added into above step d) dispersion with continuous stirring / homogenization. f) Citric acid and Sodium citrate were added into above step e) with continuous stirring / homogenization. g) Sucralose and peppermint flavour was added into above dispersion respectively with continuous stirring / homogenization. h) pH of suspension was checked to ensure within desired range. i) Volume of suspension was adjusted by using purified water. Example 2

[0121] Manufacturing Process: a) Purified water was dispensed into a stainless-steel vessel to which dispensed quantity of Polacrilin / Polacrilin potassium was added under continuous stirring / homogenization to form uniform dispersion. b) Dispensed quantity of Empagliflozin was added to the above step a) dispersion with continuous stirring / homogenization and continued for minimum 180 minutes to ensure empagliflozin: resin complex formation and bitter taste masking of API. c) In another stainless-steel vessel weighed quantity of glycerine was taken to which sodium carboxy methyl cellulose and xanthan gum were added to form uniform dispersion. d) The dispersion of step b) and step c) were mixed with continuous stirring / homogenization. e) Methyl paraben was added into above step d) dispersion with continuous stirring / homogenization. f) Citric acid and Sodium citrate were added into above step e) with continuous stirring / homogenization. g) Sucralose and peppermint flavour was added into above dispersion respectively with continuous stirring / homogenization. h) pH of suspension was checked to ensure within desired range. i) Volume of suspension was adjusted by using purified water.

[0122] Example 3

[0123] Manufacturing Process: a) Purified water was dispensed into a stainless-steel vessel to which dispensed quantity of Polacrilin potassium was added under continuous stirring / homogenization to form uniform dispersion. b) Dispensed quantity of Empagliflozin was added to the above step a) dispersion with continuous stirring / homogenization and continued for minimum 180 minutes to ensure empagliflozin: resin complex formation and bitter taste masking of API. c) Weighed quantity of sodium hydroxyl ethyl cellulose and xanthan gum were added to step (b) and mixed to form uniform dispersion. d) The dispersion of step b) and step c) were mixed with continuous stirring / homogenization. e) Sorbic acid and potassium sorbate were added into above step d) dispersion with continuous stirring / homogenization. f) Citric acid and Sodium citrate were added into above step e) with continuous stirring / homogenization. g) Acesulfame potassium and orange flavour were added into above dispersion respectively with continuous stirring / homogenization. h) pH of suspension was checked to ensure within desired range. i) Volume of suspension was adjusted by using purified water. Example 4 Manufacturing Process: a) Purified water was dispensed into a stainless-steel vessel to which dispensed quantity of Polacrilin / Polacrilin potassium was added under continuous stirring / homogenization to form uniform dispersion. b) Dispensed quantity of Empagliflozin was added to the above step a) dispersion with continuous stirring / homogenization and continued for minimum 180 minutes to ensure empagliflozin: resin complex formation and bitter taste masking of API. c) In another stainless-steel vessel weighed quantity of glycerine was taken to which sodium hydroxyl ethyl cellulose and xanthan gum were added to form uniform dispersion. d) The dispersion of step b) and step c) were mixed with continuous stirring / homogenization. e) Propyl paraben was added into above step d) dispersion with continuous stirring / homogenization. f) Citric acid and Sodium citrate were added into above step e) with continuous stirring / homogenization. g) Aspartame and orange flavour were added into above dispersion respectively with continuous stirring / homogenization. h) pH of suspension was checked to ensure within desired range. i) Volume of suspension was adjusted by using purified water. Example 5

[0124] Manufacturing Process: a) Purified water was dispensed into a stainless-steel vessel to which dispensed quantity of Polacrilin / Polacrilin potassium was added under continuous stirring / homogenization to form uniform dispersion. b) Dispensed quantity of Empagliflozin was added to the above step a) dispersion with continuous stirring / homogenization and continued for minimum 180 minutes to ensure empagliflozin: resin complex formation and bitter taste masking of API. c) In another stainless-steel vessel weighed quantity of glycerine was taken to which sodium hydroxyl propyl ethyl cellulose and xanthan gum were added to form uniform dispersion. d) The dispersion of step b) and step c) were mixed with continuous stirring / homogenization. e) Methyl paraben and propyl paraben were added into above step d) dispersion with continuous stirring / homogenization. f) Citric acid and Sodium citrate were added into above step e) with continuous stirring / homogenization. g) Sucralose and peppermint flavour were added into above dispersion respectively with continuous stirring / homogenization. h) pH of suspension was checked to ensure within desired range. i) Volume of suspension was adjusted by using purified water.

[0125] Example 6

[0126] Manufacturing Process: a) Purified water was dispensed into a stainless-steel vessel to which dispensed quantity of Polacrilin potassium was added under continuous stirring / homogenization to form uniform dispersion. b) Dispensed quantity of Empagliflozin was added to the above step a) dispersion with continuous stirring / homogenization and continued for minimum 180 minutes to ensure empagliflozin: resin complex formation and bitter taste masking of API. c) In another stainless-steel vessel weighed quantity of glycerine was taken to which sodium carboxy methyl cellulose and xanthan gum were added to form uniform dispersion. d) The dispersion of step b) and step c) were mixed with continuous stirring / homogenization. e) Methyl paraben was added into above step d) dispersion with continuous stirring / homogenization. f) Citric acid and Sodium citrate were added into above step e) with continuous stirring / homogenization. g) Sucralose and peppermint flavour were added into above dispersion respectively with continuous stirring / homogenization. h) pH of suspension was checked to ensure within desired range. i) Volume of suspension was adjusted by using purified water.

[0127] Example 7 Manufacturing Process: a) Purified water was dispensed into a stainless-steel vessel to which dispensed quantity of Polacrilin potassium was added under continuous stirring / homogenization to form uniform dispersion. b) Dispensed quantity of Empagliflozin was added to the above step a) dispersion with continuous stirring / homogenization and continued for minimum 180 minutes to ensure empagliflozin: resin complex formation and bitter taste masking of API. c) Weighed quantity of sodium carboxy methyl cellulose and xanthan gum were added to step (b) and mixed to form uniform dispersion. d) The dispersion of step b) and step c) were mixed with continuous stirring / homogenization. e) Methyl paraben was added into above step d) dispersion with continuous stirring / homogenization. f) Citric acid and Sodium citrate were added into above step e) with continuous stirring / homogenization. g) Sucralose and peppermint flavour were added into above dispersion respectively with continuous stirring / homogenization. h) pH of suspension was checked to ensure within desired range. i) Volume of suspension was adjusted by using purified water.

[0128] Example 8 Manufacturing Process: a) Dispensed quantity of Empagliflozin was added to sufficient quantity of purified water and mixed continuously with stirrer / homogenizer. b) In another stainless-steel vessel weighed quantity of glycerine was taken to which sodium carboxy methyl cellulose and xanthan gum were added to form uniform dispersion. c) The dispersion of step b) was mixed with step a) under continuous stirring / homogenization. d) Methyl paraben was added into above step c) dispersion with continuous stirring / homogenization. e) Citric acid and Sodium citrate were added into above step d) with continuous stirring / homogenization. f) Sucralose and peppermint flavour were added into above dispersion respectively with continuous stirring / homogenization. g) pH of suspension was checked to ensure within desired range. h) Volume of suspension was adjusted by using purified water.

[0129] Taste Masking Evaluation Procedure: 1. Ten volunteers selected from the R&D staff available.

[0130] 2. All volunteers told about the objective of study, therapeutic class of drug product & possible side effects for drug product.

[0131] 3. 1 ml of each sample given to each volunteer for taste evaluation.

[0132] 4. After each sample evaluation each volunteer needs to rate for sweetness of sample with using below rating scale

[0133] Taste Masking Evaluation Details:

[0134] Stability Data of Example 1:

[0135] Stability Studies as per ICH guidelines have been performed for Example 1 at 40° C / 75% RH for initial, 1 month, 2 months and 3 months respectively and 25° C / 60% RH for 3months and 6 months respectively. As per the observations made, the composition of the present invention is stable under the conditions mentioned.

[0136] Based on physicochemical data of Example 1, it can be concluded that composition as per example 1 is having desired stability to achieve required product shelf life.

Claims

We Claim:

1. A stable, taste-masked, ready-to-use suspension comprising empagliflozin, taste masking agent, and pharmaceutically acceptable excipients.

2. The stable, taste-masked, ready-to-use suspension as claimed in claimed 1, wherein the taste masking agent is polacrilin and / or its acceptable salt.

3. The stable, taste-masked, ready-to-use suspension as claimed in claimed 1, wherein the pH of the suspension is in range of about 2 about 8.

4. The stable, taste-masked, ready-to-use suspension as claimed in claimed 1, wherein the ratio of Empagliflozin: Polacrilin potassium can be between 1 : 0.5 to 1: 50.

5. The stable, taste-masked, ready-to-use suspension as claimed in claimed 1, wherein one or more pharmaceutically acceptable excipients are selected from the group comprising of preservative(s), emollient(s), viscosity modifying agent(s), flavouring agent(s), sweetening agent(s), buffering agent(s) and mixtures thereof.

6. The stable, taste-masked, ready-to-use suspension as claimed in claimed 1, wherein the viscosity of the suspension is from about 200 cps to about 1200 cps.

7. The stable, taste-masked, ready-to-use suspension as claimed in claimed 1, wherein dgo of the empagliflozin is not more than 20 pm.

8. The stable, taste-masked, ready-to-use suspension as claimed in claimed 1, wherein the suspension is stable for 6 months under accelerated condition (40° C. / 75% RH).

9. A process to prepare stable, taste-masked, ready-to-use suspension of claim 1, comprises of the following steps: a) Preparing a homogenous dispersion comprising of Polacrilin or its potassium salt in water; b) Addition of empagliflozin to step (a) dispersion under constant stirring for minimum three hours;c) Preparing a uniform dispersion comprising of at least one viscosity enhancing agent; d) Mixing of step (b) and step (c) dispersion; e) Addition of sweetening agent, flavoring agent and buffering agent under homogenization to step (d); f) Addition of sodium methyl paraben to step (e) under homogenization; g) Adjusting volume with purified water;

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