WO2024116195A1

WO2024116195A1 - Oral liquid formulation comprising dapagliflozin or its pharmaceutically acceptable salt thereof

Info

Publication number: WO2024116195A1
Application number: PCT/IN2023/051086
Authority: WO
Inventors: Girish Shantilal Achliya; Piyush Kishor Mundada; Sanjaykumar D. POPTANI; Axaykumar G. SANGANI
Original assignee: Syri Research Private Limited
Priority date: 2022-11-28
Filing date: 2023-11-23
Publication date: 2024-06-06

Abstract

The present invention relates to an oral liquid formulation comprising Dapagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, process for the preparation of said liquid formulation and its application for the treatment of type 2 diabetes mellitus, adults with heart failure and chronic kidney disease.

Description

Oral liquid formulation comprising Dapagliflozin or its pharmaceutically acceptable salt thereof

Field of the Invention

The present invention relates to liquid formulation comprising Dapagliflozin or its pharmaceutically acceptable salt thereof. The present invention more particularly related to oral liquid formulation comprising Dapagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, process for the preparation of said liquid formulation and its application for the treatment of type 2 diabetes mellitus.

Background of the Invention

Diabetes refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose or hyperglycemia in the fasting state or after administration of glucose during an oral glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Therefore patients with Type 2 diabetes mellitus are at especially increased risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, therapeutical control of glucose homeostasis, lipid metabolism and hypertension are critically important in the clinical management and treatment of diabetes mellitus.

There are two generally recognized forms of diabetes. In type 1 diabetes, or insulindependent diabetes mellitus (IDDM), patients produce little or no insulin, the hormone which regulates glucose utilization. In type 2 diabetes, or noninsulin dependent diabetes mellitus (NIDDM), patients often have plasma insulin levels that are the same or even elevated compared to nondiabetic subjects; however, these patients have developed a resistance to the insulin stimulating effect on glucose and lipid metabolism in the main insulin- sensitive tissues, which are muscle, liver and adipose tissues, and the plasma insulin levels, while elevated, are insufficient to overcome the pronounced insulin resistance.

Insulin resistance is not primarily due to a diminished number of insulin receptors but to a post-insulin receptor binding defect that is not yet understood. This resistance to insulin responsiveness results in insufficient insulin activation of glucose uptake, oxidation and storage in muscle and inadequate insulin repression of lipolysis in adipose tissue and of glucose production and secretion in the liver.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are the latest class of anti-hyperglycemic agents to receive FDA approval. SGLT2 inhibitors function through a novel mechanism of reducing renal tubular glucose reabsorption, producing a reduction in blood glucose without stimulating insulin release. Other benefits may include favorable effects on blood pressure and weight.

Dapagliflozin is a drug belonging to the sodium-glucose cotransporter 2 (SGLT2) inhibitors class is an oral Type 2 diabetes medication. Dapagliflozin is currently administered in the form of oral film-coated tablets 5 and 10 mg (e.g., Farxiga [US], Forxiga [EP]) as immediate release tablets, containing the active substance Dapagliflozin propanediol. Dapagliflozin propanediol is a solvate containing 1:1:1 ratio of the Dapagliflozin, (S)-(+)-l,2-propanediol, and water. Its IUPAC name is (2S)-propane-l,2-diol (2S,3R,4R,5S,6R)-2-{4-chloro-3-[(4- ethoxyphenyl) methyl ]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol hydrate. It is a chiral molecule with five stereogenic centers and single polymorphic form observed. Its structural formula is as follows:

Dapagliflozin is a highly potent (Ki: 0.55 nM), selective and reversible inhibitor of SGLT2.

Forxiga is indicated in adults and children aged 10 years and above for the treatment of insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise as monotherapy when metformin is considered inappropriate due to intolerance, In addition to other medicinal products for the treatment of type 2 diabetes. Forxiga is indicated in adults for the treatment of symptomatic chronic heart failure. Forxiga is indicated in adults for the treatment of chronic kidney disease. The patent EP1224195B1 covers SGLT2 inhibiting compounds, generically Dapagliflozin or a pharmaceutically acceptable salt, and their application in the treatment of diabetes and related diseases.

The patent EP1506211B1 specifically claims the use of Dapagliflozin or a pharmaceutically acceptable salt, a stereoisomer thereof, or a prodrug ester thereof for the treatment of type II diabetes, either alone or in combination with another antidiabetic agent.

The patent EP2069374B1 relates to a crystalline solvate of Dapagliflozin with water and (S)- propylene glycol as SGLT2 inhibitors for the treatment of diabetes.

The patent EP2139494B1 claims an immediate release pharmaceutical formulation in the form of capsules or a tablet containing the stock granulation comprising Dapagliflozin propylene glycol hydrate, bulking agents, binders, disintegrants optionally glidants and/or anti-adherents; and optionally lubricants.

The patent WO2015128853 Al claims a pharmaceutical composition comprising a solid dispersion of Dapagliflozin and one or more pharmaceutically acceptable excipients. The solid dispersion comprises Dapagliflozin and a carrier, wherein the Dapagliflozin is dispersed or dissolved in the carrier. The invention also includes different processes for the preparation of said pharmaceutical composition and a method of treating diabetes by administering said pharmaceutical composition.

The present invention relates to a liquid formulation comprising Dapagliflozin, an antidiabetic agent, addressing the limitations associated with solid dosage forms, including difficulties in swallowing, especially for patient groups such as pediatrics and geriatrics, leading to poor patient compliance.

When formulating liquid formulation involves challenges in ensuring the stability of the solution or suspension throughout its shelf life, as inaccurate dosing may result in sub- therapeutic or toxic effects. In the context of treating type 2 diabetes mellitus, the rapid onset of action is desirable, making it preferable to administer in a liquid formulation with improved organoleptic properties over solid oral dosage forms. The inventors of the present invention surprisingly found that the liquid formulation comprising Dapagliflozin or its pharmaceutically acceptable salts thereof is safe and offers a valuable solution to swallowing difficulty in geriatric patients by enabling easy administration, enhancing patient compliance, offering a faster onset of action, improved drug solubility and acceptable stability of product.

Summary of the Invention

In one aspect, the present invention discloses a liquid formulation comprising Dapagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient.

In one aspect, the present invention discloses a liquid formulation comprising Dapagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein the liquid formulation is suitable for oral administration.

In one aspect, the present invention discloses a liquid formulation comprising Dapagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein Dapagliflozin or its pharmaceutically acceptable salt thereof is present at a concentration of 0.1 to 20% w/v in the liquid formulation.

In one aspect, the present invention discloses a liquid formulation comprising Dapagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein the formulation is stable for at least one month under storage conditions of 25°C/60% RH, 30°C/65% RH, 40°C/75% RH, and/or 2-8°C.

In one aspect, the present invention discloses a liquid formulation comprising Dapagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein the liquid formulation is in the form of suspension, solution or the like and any combination thereof.

In one aspect, the present invention discloses a liquid formulation comprising Dapagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein the Dapagliflozin or its pharmaceutically acceptable salt thereof has a particle size distribution D(90) less than about 200pm, preferably less than about 100pm, more preferably less than about 20pm, or can be used in a micronized form.

In one aspect, the present invention discloses a liquid formulation comprising Dapagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein the liquid formulation has a pH ranging from about 5 to about 8.

In another aspect, the present invention provides a liquid formulation comprising: a) 0.1-20% w/v of Dapagliflozin or its pharmaceutically acceptable salt thereof; b) 0.01-3% w/v of a preservative; c) 0.01-10% w/v of a viscosity enhancer or viscosity enhancing agent; and d) one or more pharmaceutically acceptable excipient, wherein the liquid formulation has a pH ranging from about 5 to about 8.

In another aspect, the present invention provides a liquid formulation comprising: a) 0.1-20% w/v of Dapagliflozin or its pharmaceutically acceptable salt thereof; b) 0.01-3% w/v of a preservative; c) 0.01-20% w/v of a solubilizer or solubilizing agent; and d) one or more pharmaceutically acceptable excipient, wherein the liquid formulation has a pH ranging from about 5 to about 8.

In another aspect, the present invention provides a process for the preparation of a liquid formulation, comprising: a) adding preservative into vehicle and mixing using suitable mixer to get clear solution; b) adding viscosity enhancer into above solution and mixing using suitable mixer to get clear solution; c) adding sweetener into above solution and mixing using suitable mixer to get clear solution; d) separately, dispersing Dapagliflozin or its pharmaceutically acceptable salt thereof into wetting agent and mixing using suitable mixer to get white to off-white suspension; e) separately, adding and dissolving buffer into vehicle and adding into step d) and mixing using suitable mixer to get suspension; and f) making up the volume with vehicle and mixing using suitable mixer to get homogeneous suspension. In another aspect, the present invention provides a process for the preparation of a liquid formulation, comprising: a) adding solubilizing agent into vehicle and mixing using suitable mixer to get clear solution; b) adding Dapagliflozin or its pharmaceutically acceptable salt thereof into above solution and mixing using suitable mixer to get clear solution; c) adding preservative into above solution and mixing using suitable mixer to get clear solution; d) adding sweetener into above solution and mixing using suitable mixer to get clear solution; e) adding viscosity enhancer/co-solvent and flavour into above solution and mixing using suitable mixer to get clear solution; f) separately, adding and dissolving buffer into vehicle and adding into step e) and mixing using suitable mixer to get clear solution; and g) making up the volume with vehicle and mixing using suitable mixer to get clear solution.

In another aspect, the present invention discloses a method of using a liquid formulation comprising Dapagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient for the treatment of type 2 diabetes, adults with heart failure and chronic kidney disease.

Detailed Description of the Invention

The term “Dapagliflozin” as used herein is not limited to the Dapagliflozin, but includes its solvates, hydrates, solvate-hydrate and polymorphic form including amorphous form. For example “Dapagliflozin” means Dapagliflozin propanediol hydrate.

The term “therapeutically effective amount” is defined to mean the amount or quantity of the active drug (e.g. Dapagliflozin or a pharmaceutical acceptable salt thereof), which is sufficient to elicit an appreciable biological response when administered to the patient.

The term “formulation” or “composition” or “pharmaceutical composition” or “dosage form” or “liquid formulation” or “liquid pharmaceutical composition” as used herein synonymously include dosage forms such as solution, suspension and the like. The term “excipient” or “excipients” or “ingredient” means a pharmacologically inactive component that are useful in preparing a liquid formulation which are generally safe, nontoxic and are acceptable for human pharmaceutical use. Reference to an excipient includes both one and more than one such excipient.

As used herein, the terms “stable” or “stability” encompass any characteristic of the liquid formulation which may be affected by storage conditions including, without limitation, potency, total impurities, degradation products, specific optical rotation, optical purity, appearance, viscosity and colour and clarity. The storage conditions which may affect stability include, for example, duration of storage, temperature, humidity, and/or light exposure.

The present invention relates to a liquid formulation comprising Dapagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient.

The present invention relates to a liquid formulation comprising Dapagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein the liquid formulation is suitable for oral administration.

The present invention relates to a liquid formulation comprising Dapagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein the liquid formulation is in the form of solution, suspension or the like and any combination thereof.

The one or more pharmaceutically acceptable excipient which are selected from the group consisting of preservatives, viscosity enhancer or viscosity enhancing agent, solubilizer or solubilizing agent, sweetener or sweetening agent, wetting agents, co-solvent, buffers or buffering agent, flavor or flavours, vehicle, suspending agents, antifoaming agents, taste masking agents, antioxidants, chelating agents, stabilizers, colorants and any other excipient known to the art for making formulations.

The present invention relates to a liquid formulation comprising Dapagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein the formulation is stable for at least one month under storage conditions of 25°C/60% RH, 30°C/65% RH, 40°C/75% RH, and/or 2-8°C.

The present invention relates to a liquid formulation comprising Dapagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein the Dapagliflozin or its pharmaceutically acceptable salt thereof has a particle size distribution D(90) less than about 200pm, preferably less than about 100pm, more preferably less than about 20pm, or can be used in a micronized form.

The present invention relates to a liquid formulation comprising Dapagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein the liquid formulation has a pH ranging from about 5 to about 8 with a particularly preferred range of about 6 to about 7.5.

The amount of Dapagliflozin or its pharmaceutically acceptable salt thereof according to the invention may be present at concentration from 0.01 to 30% w/v, and preferably from 0.05 to 25% w/v and more particularly from 0.1 to 20% w/v with respect to total volume of the liquid formulation.

Pharmaceutically acceptable excipient(s) are the components that are added to the liquid formulation other than the active ingredient Dapagliflozin or pharmaceutically acceptable salt thereof. Excipient may be added to facilitate manufacture, enhance stability, enhance product characteristics, enhance patient acceptability etc.

The examples of preservatives according to the present invention include but not limited to group comprising parabens (parahydroxybenzoate) such as methyl parahydroxybenzoate (methyl paraben), propyl parahydroxybenzoate (propyl paraben), butyl parahydroxybenzoate (butyl paraben) and their salts such as sodium methyl parahydroxybenzoate (Sodium MHB), sodium propyl parahydroxybenzoate (Sodium PHB), sorbic acid, sodium sorbate, potassium sorbate, calcium sorbate, benzoic acid, sodium benzoate, potassium benzoate, calcium benzoate, methyl hydroxybenzoate, ethyl para-hydroxybenzoate, sodium ethyl parahydroxybenzoate, sodium metabisulphite, chlorhexidine, diazolidinyl urea, sodium citrate, butylated hydroxyl toluene (BHT), butylated hydroxyl anisole (BHA), tocopherol, ethylenediamine tetraacetic acid, propyl gallate, quaternary compounds, e.g. benzalkonium chloride and cetylpyridinium chloride, phenyl ethyl alcohol and combinations thereof. The preferred preservative is sodium methyl parahydroxybenzoate (Sodium MHB). The preservative is present in an amount of about 0.001 % w/v to about 5% w/v of the liquid formulation. Particularly, the preservative is present in an amount of about 0.01 % w/v to about 3% w/v of the liquid formulation.

The examples of viscosity enhancer or viscosity enhancing agents according to the present invention include but not limited to group comprising of glycerol or glycerin, polyethylene glycol, polyethylene oxide, dextrin, liquid maltitol, liquid sorbitol, cellulose derivatives such as hydroxy ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methylcellulose, carboxymethyl cellulose and its salts/derivatives e.g., carboxymethyl cellulose sodium (carmellose sodium), microcrystalline cellulose, and co-processed spray dried forms of microcrystalline cellulose and carboxymethyl cellulose sodium, carbomers, gums such as xanthan gum, locust bean gum, tragacanth gum, arabinogalactan gum, agar gum, gellan gum, guar gum, apricot gum, karaya gum, sterculia gum, acacia gum, gum arabic, and carrageenan; pectin; propylene glycol alginate, dextran; gelatin; polyethylene glycols; pectin, alginates, alginic derivatives, alginic acid, sodium alginate, starches, chitosan, poloxamers, non-ionic poloxamers, polyvinylpyrrolidone (povidone), copovidone, polyvinyl compounds such as polyvinyl acetate, polyvinyl alcohol, and polyvinyl pyrrolidone; sugar alcohols, colloidal silica; maltodextrin, starch; and mixtures thereof. The preferred viscosity enhancer or viscosity enhancing agents are carbo xymethyl cellulose sodium (carmellose sodium) and glycerol. The viscosity enhancer or viscosity enhancing agents are present in an amount of about 0.001 to about 20% w/v of the liquid formulation. Particularly, the viscosity enhancer or viscosity enhancing agents are present in an amount of about 0.01% to about 15% w/v of the liquid formulation. More particularly, the viscosity enhancer or viscosity enhancing agents are present in an amount of about 0.1% to about 10% w/v of the liquid formulation. The examples of solubilizers or solubilizing agent according to the present invention include but not limited to group comprising glycol, acetone, alcohol (ethanol), benzyl alcohol, benzyl benzoate, butylene glycol, dibutyl phthalate, sorbitol, poloxamer, polysorbates, polyoxyethylene fatty acid esters, sodium lauryl sulphate, diethyl phthalate, dimethyl phthalate, dimethyl sulfoxide, dimethylacetamide, glycofurol, glycerin, isopropyl alcohol, isopropyl myristate, isopropyl palmitate, propylene glycol, polyethylene glycol such as PEG- 400, propylene carbonate, pyrrolidone, triacetin, triethyl citrate and triolein, the cyclodextrin includes a-cyclodextrin, P-cyclodextrin, 6-cyclodextrin, y-cyclodextrin, or combinations thereof, the cyclodextrin preferably includes either a substituted or non-substituted P- cyclodextrin. Examples of substituted cyclodextrins include hydroxypropyl-P-cyclodextrin (HP-P-CD) and sulfobutylether-P-cyclodextrin (SBE-P-CD), and the like. Particularly, the solubilizers or solubilizing agent are present in an amount of about 0.1% to about 30% w/v of the liquid formulation. More particularly, the solubilizers or solubilizing agent are present in an amount of about 1% to about 20% w/v of the liquid formulation. The preferred solubilizers or solubilizing agent is hydroxypropyl-P-cyclodextrin (HP-P-CD) is used in an amount of about 1% to about 8% w/v of the liquid formulation.

The examples of sweeteners according to the present invention include but not limited to group comprising glucose, maltose, aspartame, mannitol, sorbitol, xylitol, acesulfame, neotame, stevia, dextrose, saccharin, saccharin sodium, fructose, ribose, high fructose corn syrup, maltodextrin, sucralose, sucrose, mannose, glycerol or glycerin and mixture thereof. The preferred sweetener is sucralose. Preferably, sweeteners is present in an amount of from about 0.01 to about 5% w/v, more preferably from about 0.1 to 3% w/v with respect to total volume of the liquid formulation.

The examples of wetting agent according to the present invention include but not limited to group comprising propylene glycol, ethanol, glycerol, polyethylene glycols (PEGs), polysorbates (polysorbate 20 (Tween 20), polysorbate 80, tween 80)), sodium lauryl sulfate (SLS), poloxamers, sorbitan monolaurate (Span 20), and the like. The preferred wetting agents are propylene glycol and glycerol. The examples of co-solvent according to the present invention include but not limited to group comprising ethanol (ethyl alcohol), propylene glycol, polyethylene glycol (PEG), glycerin, sorbitol, water and the like. The preferred cosolvent is propylene glycol.

The examples of buffers/pH adjuster according to the present invention include but not limited to group comprising of sodium dihydrogen phosphate, sodium dihydrogen phosphate dihydrate, sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium glucomate, aluminum hydroxide, citric acid, sodium citrate, sodium tartrate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogenphosphate, dipotassium hydrogenphosphate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate, and other calcium salts and the like. The preferred buffers/pH adjuster is sodium dihydrogen phosphate dihydrate.

The examples of flavour or flavoring agents according to the present invention include but not limited to group comprising mix fruit, cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leave oil, oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil, vanilla, citrus oil lemon, orange, grape, lime and grapefruit apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and so forth. Flavors which have been found to be particularly useful include commercially available mix fruit, strawberry, orange, grape, cherry, vanilla, mint and citrus flavors and mixtures thereof.

The examples of vehicle/solvent according to the present invention include but not limited to group comprising of water, alcohol include ethyl alcohol (ethanol), glycerol or glycerin, propylene glycol, polyethylene glycol, syrup, oils include olive oil, peanut oil, soy bean oil, corn oil, mineral oil, castor oil, sesame oil, cottonseed oil, acetylated glycerides, ethyl oleate, mineral oil, fatty acid esters, mono- or di-fatty acid esters of polyethylene glycols, or glyceryl mono-oleate and combinations or mixtures thereof.

The examples of colorant according to the present invention include but not limited to group comprising of caramel colorant, red colorant Indigo yellow, quinoline yellow, quinizarine green, FD&C Blue #1 aluminum lake, FD&C blue #2, other FD&C blue colors, titanium dioxide, iron oxide, and/or combinations thereof.

The storage conditions used in the present invention are 25°C/60% RH and/or 30°C/65% RH and/or 40°C/75% and/or 2-8°C. The ‘storage condition of 25°C/60% RH’ means storage at a temperature of 25 °C and 60% relative humidity. Likewise the ‘storage condition of 30°C/65% RH’ means storage at a temperature of 30°C and 65% relative humidity, the ‘storage condition of 40°C/75% RH’ means storage at a temperature of 40°C and 75% relative humidity. The ‘storage condition of 2- 8 °C’ means storage at a temperature of 2 to 8°C.

In preferred embodiment of the present invention, the liquid formulation is stable for at least two months, preferably for at least three months, preferably for at least four months, more preferably for at least five months under storage condition of 25°C/60% RH. In another embodiment of the present invention, the liquid formulation is stable for at least six months under storage condition of 25°C/60% RH.

In preferred embodiment of the present invention, the liquid formulation is stable for at least two months, preferably for at least three months, preferably for at least four months, more preferably for at least five months under storage condition of 30°C/65% RH. In another embodiment of the present invention, the liquid formulation is stable for at least six months under storage condition of 30°C/65% RH.

In preferred embodiment of the present invention, the liquid formulation is stable for at least two months, preferably for at least three months, preferably for at least four months, more preferably for at least five months under storage condition of 40°C/75% RH. In another embodiment of the present invention, the liquid formulation is stable for at least six months under storage condition of 40°C/75% RH.

In preferred embodiment of the present invention, the liquid formulation is stable for at least two months, preferably for at least three months, preferably for at least four months, more preferably for at least five months under storage condition of 2- 8 °C. In another embodiment of the present invention, the liquid formulation is stable for at least six months under storage condition of 2- 8 °C. In preferred embodiment, an invention provides a liquid formulation comprising: a) 0.1-20% w/v of Dapagliflozin or its pharmaceutically acceptable salt thereof; b) 0.01-3% w/v of a preservative; c) 0.01-10% w/v of a viscosity enhancer or viscosity enhancing agent; and d) one or more pharmaceutically acceptable excipient, wherein the liquid formulation has a pH ranging from about 5 to about 8.

In preferred embodiment, an invention provides a liquid formulation comprising: a) 0.1-20% w/v of Dapagliflozin or its pharmaceutically acceptable salt thereof; b) 0.01-3% w/v of a preservative; c) 0.01-20% w/v of a solubilizer or solubilizing agent; and d) one or more pharmaceutically acceptable excipient, wherein the liquid formulation has a pH ranging from about 5 to about 8.

In preferred embodiment, an invention provides a process for the preparation of a liquid formulation, comprising: a) adding preservative into vehicle and mixing using suitable mixer to get clear solution; b) adding viscosity enhancer into above solution and mixing using suitable mixer to get clear solution; c) adding sweetener into above solution and mixing using suitable mixer to get clear solution; d) separately, dispersing Dapagliflozin or its pharmaceutically acceptable salt thereof into wetting agent and mixing using suitable mixer to get white to off-white suspension; e) separately, adding and dissolving buffer into vehicle and adding into step d) and mixing using mixer to get suspension; and f) making up the volume with vehicle and mixing using suitable mixer to get clear homogeneous suspension.

In preferred embodiment, an invention provides a process for the preparation of a liquid formulation, comprising: a) adding solubilizing agent into vehicle and mixing using suitable mixer to get clear solution; b) adding Dapagliflozin or its pharmaceutically acceptable salt thereof into above solution and mixing using suitable mixer to get clear solution; c) adding preservative into above solution and mixing using suitable mixer to get clear solution; d) adding sweetener into above solution and mixing using suitable mixer to get clear solution; e) adding viscosity enhancer/co-solvent and flavor into above solution and mixing using suitable mixer to get clear solution; f) separately, adding and dissolving buffer into vehicle and adding into step e) and mixing using suitable mixer to get solution; and g) making up the volume with vehicle and mixing using suitable mixer to get clear solution.

In preferred embodiment, of the present invention is a method of using liquid formulation for the treatment of type 2 diabetes, adults with heart failure and chronic kidney disease.

The liquid formulation can be conveniently packaged in various pharmaceutically acceptable containers, such as bottles, depending on the required dosage form.

The liquid formulation of the present invention is safe and offers a valuable solution to swallowing difficulty in geriatric patients by enabling easy administration, enhancing patient compliance, offering a faster onset of action, improved drug solubility and acceptable stability of product.

The following examples serve to illustrate the embodiments of the present invention. However, they do not intend to limit the scope of the present invention.

EXAMPLES

Example 1 & 2 - Dapagliflozin 10mg/5ml Oral Suspension:

Manufacturing Process: a) Sodium methyl parahydroxy benzoate was added to 50% of the total batch volume of water and mixed for 10 minutes using a suitable mixer at a speed of 1500-2000 RPM to get a clear solution; b) carmellose sodium was added to the above solution and mixed for 20 minutes using a suitable mixer at a speed of 1500-2000 RPM to get a clear solution; c) sucralose was added to the above solution and mixed for 10 minutes using a suitable mixer at a speed of 1500-2000 RPM to get a clear solution; d) Dapagliflozin was separately dispersed in propylene glycol/glycerol and mixed into the above solution for 10 minutes using a suitable mixer at a speed of 1500-2000 RPM to obtain a white to off-white suspension; e) sodium dihydrogen phosphate dihydrate was separately added and dissolved in 5% of the total batch volume of water, then added into step d) and mixed for 10 minutes using a suitable mixer at a speed of 1500-2000 RPM to obtain a suspension; and f) the volume was adjusted with purified water and mixed for 20 minutes using a suitable mixer at a speed of 1500-2000 RPM to get a homogeneous suspension.

Example 3 - Dapagliflozin 10mg/5ml Oral Solution

Manufacturing Process: a) Hydroxypropyl beta-cyclodextrin was added to 50% of the total batch volume of water and mixed for 60 minutes using a suitable mixer at a speed of 1500-2000 RPM to obtain a get, clear solution; b) Dapagliflozin was added to the above solution and mixed for 15 minutes using a suitable mixer at a speed of 1500-2000 RPM to obtain a get clear solution; c) the above solution was mixed with sodium methyl parahydroxybenzoate for 10 minutes using a suitable mixer at a speed of 1500-2000 RPM to achieve a clear solution; d) sucralose was added to the above solution and mixed for 10 minutes using a suitable mixer at a speed of 1500-2000 RPM to obtain a clear solution; e) glycerol, propylene glycol, and flavor were added to the above solution and mixed for 10 minutes using a suitable mixer at a speed of 1500-2000 RPM to obtain a clear solution; f) separately, sodium dihydrogen phosphate dihydrate was added and dissolved in 5% of the total batch volume of water, and then added into step e) and mixed for 10 minutes using a suitable mixer at a speed of 1500-2000 RPM to obtain a clear, solution; and g) the volume was adjusted with purified water and mixed for 15 minutes using a suitable mixer at a speed of 2000-2500 RPM to obtain a clear solution.

Stability data for Example 1:

Stability data of suspension formulation from example 1, packed in glass bottle is shown below.

Stability data for Example 2:

Stability data of suspension formulation from example 2, packed in glass bottle is shown below.

Claims

Claims:

1. An oral liquid formulation comprising Dapagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein Dapagliflozin or its pharmaceutically acceptable salt thereof is present at a concentration of 0.1 to 20% w/v in the liquid formulation.

2. The liquid formulation according to claim 1, wherein the liquid formulation is in the form of suspension or solution or the like and any combination thereof.

3. The liquid formulation according to claim 2, wherein the liquid formulation is in the form of a suspension.

4. The liquid formulation according to claim 2, wherein the liquid formulation is in the form of a solution.

5. The liquid formulation according to claim 1, wherein the liquid formulation has a pH ranging from about 5 to about 8.

6. The liquid formulation according to claim 5, wherein the liquid formulation has a pH in range of about 6 to about 7.5.

7. The liquid formulation according to claim 1, wherein the formulation is stable for at least one month under storage conditions of 25°C/60% RH, 30°C/65% RH, 40°C/75% RH, and/or 2-8°C.

8. The liquid formulation according to claim 1, wherein one or more pharmaceutically acceptable excipient is selected from the group consisting of preservatives, viscosity enhancer or viscosity enhancing agent, solubilizer or solubilizing agent, sweetener or sweetening agent, wetting agents, cosolvent, buffers or buffering agent, flavor or flavours, vehicle, suspending agents, antifoaming agents, taste masking agents, antioxidants, chelating agents, stabilizers, and colorants.

9. A liquid formulation comprising: a) 0.1-20% w/v of Dapagliflozin or its pharmaceutically acceptable salt thereof; b) 0.01-3% w/v of a preservative; c) 0.01-10% w/v of a viscosity enhancer or viscosity enhancing agent; and d) one or more pharmaceutically acceptable excipient.

10. A liquid formulation comprising: a) 0.1-20% w/v of Dapagliflozin or its pharmaceutically acceptable salt thereof; b) 0.01-3% w/v of a preservative; c) 0.01-20% w/v of a solubilizer or solubilizing agent; and d) one or more pharmaceutically acceptable excipient.

11. An oral suspension formulation comprising: a) 0.1-20% w/v of Dapagliflozin or its pharmaceutically acceptable salt thereof; b) 0.01-3% w/v of a preservative; c) 0.01-10% w/v of a viscosity enhancer or viscosity enhancing agent; and d) one or more pharmaceutically acceptable excipient, wherein the formulation has a pH ranging from about 5 to about 8.

12. An oral solution formulation comprising: a) 0.1-20% w/v of Dapagliflozin or its pharmaceutically acceptable salt thereof; b) 0.01-3% w/v of a preservative; c) 0.01-20% w/v of a solubilizer or solubilizing agent; and d) one or more pharmaceutically acceptable excipient, wherein the formulation has a pH ranging from about 5 to about 8.

13. The liquid formulation according to claims 8, 9 and 11, wherein the viscosity enhancer or viscosity enhancing agents are selected from the group consisting of cellulose derivatives, methylcellulose, hydroxypropylmethyl cellulose, ethylcellulose, hydroxypropylcellulose, hydroxy ethylcellulose, sodium carboxymethylcellulose, cellulose ethers, glycerol, from gums, xanthan gum, guar gum, tragacanth gum, acacia gum, gellan gums, poloxamers, nonionic poloxamers, polyvinylpyrrolidone (povidone), copovidone, alginic derivatives, alginic acid, sodium alginate, carbomer, liquid sorbitol, liquid maltitol, polyethylene glycol, polyethylene oxide, and combinations thereof.

14. The liquid formulation according to claim 13, wherein the viscosity enhancer or viscosity enhancing agents is preferably sodium carbo xymethylcellulose, used in an amount ranging from about 0.01% to about 10% w/v of the liquid formulation.

15. The liquid formulation according to claims 8, 10 and 12, wherein the solubilizer or solubilizing agent is selected from the group consisting of polyethylene glycol (PEG), propylene glycol, poloxamer, polysorbates, alcohol (ethanol), sorbitol, sodium lauryl sulfates, cyclodextrin or its derivatives, a-cyclodextrin, P-cyclodextrin, 6-cyclodextrin, y-cyclodextrin, and hydroxypropyl- P-cyclodextrin (HP-P-CD), and combinations thereof, wherein hydroxypropyl-P-cyclodextrin (HP-P-CD) is more preferably used in an amount ranging from about 1% to about 8% w/v of the liquid formulation.

16. The liquid formulation according to claim 15, wherein the solubilizer or solubilizing agent is preferably hydroxypropyl-P-cyclodextrin (HP-P-CD), used in an amount ranging from about 1% to about 8% w/v of the liquid formulation.

17. The liquid formulation according to claim 8, wherein the preservative is selected from the group consisting of methyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxy benzoate, and their salts such as sodium methyl parahydroxybenzoate (Sodium MHB), sorbic acid, sodium sorbate, potassium sorbate, calcium sorbate, benzoic acid, sodium benzoate, potassium benzoate, sodium citrate, butylated hydroxyl toluene (BHT), butylated hydroxyl anisole (BHA), and combinations thereof.

18. A process for the preparation of an oral liquid formulation, comprising: a) adding preservative into vehicle and mixing using suitable mixer to get clear solution; b) adding viscosity enhancer into above solution and mixing using suitable mixer to get clear solution; c) adding sweetener into above solution and mixing using suitable mixer to get clear solution; d) separately, dispersing Dapagliflozin or its pharmaceutically acceptable salt thereof into solvent or cosolvent/viscosity enhancer and mixing using suitable mixer to get white to off- white suspension; e) separately, adding and dissolving buffer into vehicle and adding into step d) and mixing using mixer to get suspension; and f) making up the volume with vehicle and mixing using suitable mixer to get clear homogeneous suspension.

19. A process for the preparation of an oral liquid formulation, comprising: a) adding solubilizing agent into vehicle and mixing using suitable mixer to get clear solution; b) adding Dapagliflozin or its pharmaceutically acceptable salt thereof into above solution and mixing using suitable mixer to get clear solution; c) adding preservative into above solution and mixing using suitable mixer to get clear solution; d) adding sweetener into above solution and mixing using suitable mixer to get clear solution; e) adding solvent or cosolvent/viscosity enhancer and flavor into above solution and mixing using suitable mixer to get clear solution; f) separately, adding and dissolving buffer into vehicle and adding into step e) and mixing using suitable mixer to get solution; and g) making up the volume with vehicle and mixing using suitable mixer to get clear solution.

20. The method of using the liquid formulation according to claim 1, wherein said liquid formulation comprising Dapagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient is used for the treatment of type 2 diabetes, adults with heart failure and chronic kidney disease.