WO2024116202A1 - Oral liquid formulation of canagliflozin or its pharmaceutically acceptable salt thereof - Google Patents

Abstract

The present invention relates to a liquid formulation comprising Canagliflozin or its pharmaceutically acceptable salt with one or more pharmaceutically acceptable excipient, its process for preparation and its application for the treatment of type 2 diabetes mellitus and associated cardiovascular and renal complications.

Description

Oral liquid formulation of Canagliflozin or its pharmaceutically acceptable salt thereof

Field of the Invention

The present invention relates to a liquid formulation comprising Canagliflozin or its pharmaceutically acceptable salt thereof. The present invention is more particularly related to an oral liquid formulation comprising Canagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient. This invention also related to a process for preparation of the liquid formulation and its application for the treatment of type 2 diabetes mellitus and associated cardiovascular and renal complications.

Background of the Invention

Type 2 diabetes mellitus (T2DM) is a chronic, progressive metabolic condition that is not fully understood. Hyperglycemia represents the primary characteristic of diabetes mellitus, which is a chronic, progressive, and inadequately understood metabolic disorder. Type 2 diabetes mellitus (T2DM), which encompasses a range of conditions, initially arising from tissue insulin resistance and gradually advances to a state characterized by the complete loss of secretory activity in the beta cells of the pancreas. It is believed to result from impaired insulin secretion, insulin resistance in tissues, or a combination of both factors.

Numerous treatment approaches for diabetes mellitus have been discovered and are well- established for the management of hyperglycemia. Common treatments include therapeutic agents such as sulfonylureas like glipizide, glyburide, gliclazide, and glimepiride; meglitinides like repaglinide and nateglinide; biguanides like metformin; thiazolidinediones such as rosiglitazone and pioglitazone; a-glucosidase inhibitors like acarbose, miglitol, and voglibose; and DPP-4 inhibitors like sitagliptin, saxagliptin, vildagliptin, linagliptin, alogliptin, or combinations thereof.

Since Diabetes mellitus is a chronic metabolic condition, patients typically require lifelong medication. This is often associated with the severe adverse effects of antidiabetic drugs. The spectrum of these undesired effects spans from minor issues such as gastric discomfort, nausea, diarrhoea, and weight gain to more severe, life-threatening conditions like cardiovascular complications and lactic acidosis. Therefore, there is a continual need for the development of novel antihyperglycemic agents that can provide improved control over blood sugar levels with minimal adverse effects. Sodium glucose co-transporter-2 (SGLT2) inhibitors are relatively new additions to the class of antidiabetic agents. The SGLT2 inhibitors are recognised for glycemic control and have reduced the risk of kidney disease for those with diabetes and can reduce the risk of being hospitalized or dying from heart failure.

Canagliflozin is the first sodium glucose co -transporter- 2 (SGLT 2) inhibitor is approved in USA and Europe under the brand name Invokana is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus, to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease and, to reduce the risk of end-stage kidney disease, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria. These drugs reduce plasma glucose (PG) levels by decreasing the renal threshold for glucose excretion (RTG) and inhibiting renal glucose reabsorption, leading to an increase in urinary glucose excretion (UGE).

The IUPAC name of canagliflozin hemihydrate is (lS)-l,5-anhydro-l-[3-[[5-(4- fluorophenyl)-2-thienyl] -methyl] -4-methylphenyl]-D-glucitol hemihydrate and has the following structure:

Canagliflozin hemihydrate is a white to off-white powder, practically insoluble in water and freely soluble in ethanol and non-hygroscopic. Canagliflozin exhibits stereoisomerism due to the presence of five chiral centres. Polymorphism has been observed for canagliflozin: the manufactured form I is a hemihydrate, and an unstable amorphous Form II.

The patent EP1651658B1 disclosed Canagliflozin or a pharmaceutically acceptable salt thereof generically and specifically and is useful in the treatment of diabetes mellitus or diabetic complications such as diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, and delayed wound healing.

The patent application W02008069327A1 disclosed a crystalline form of 1-(P-D- glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemihydrate useful as an inhibitor of sodium-dependent glucose transporter, to pharmaceutical compositions which include the compound and a pharmaceutically acceptable carrier and to pharmaceutical methods of treatment.

The patent IN385195B disclosed the process for preparation of stable solid formulation comprising Canagliflozin in an amount of about 40-60% w/w, one diluent in an amount of about 10-45% w/w, one disintegrant in an amount of about 1-20% w/w, and one or more pharmaceutically acceptable excipients.

The patent US10174010B2 (US20170145000A1) discloses Canagliflozin Monohydrate and its crystalline forms, preparation methods, pharmaceutical compositions and uses thereof. In addition, the disclosed oral suspension is characterized by strength of 50 mL/vial, with each vial containing 104 mg of either Canagliflozin Monohydrate Form HI or Canagliflozin Monohydrate Form HII.

The Canagliflozin is classified under the biopharmaceutics classification system (BCS) Class IV due to its characteristics of low solubility and low bioavailability. The formulation containing Canagliflozin faces considerable challenges in terms of solubility and bio availability due to its BCS Class IV designation. The low solubility of Canagliflozin create a hurdle to its efficient dissolution and subsequent absorption, while the associated low bio availability further complicates the development of formulations that can deliver this Canagliflozin effectively. In light of these challenges, the disclosed patent application addresses the critical need for innovative strategies aimed at improving the solubility and bio availability of Canagliflozin.

The oral liquid drug delivery system is always considered as simple, convenient and beneficial for the patient population like geriatrics, patients with dysphagia, self administrative and pain free alternative. Therefore, oral liquid formulation is preferred choice over various routes of administration. The inventor of the present invention provides solution over problems arising due to solid dosage form such as dose dumping and difficulty in adjustment of dose. The present invention provides flexibility in dosage options while ensuring a consistent and controlled concentration of the Canagliflozin for effective therapeutic use. The present invention also provides simple manufacturing process, enhance patient compliance, improving the solubility and enhancing the stability.

Summary of the Invention

The present invention provides a liquid formulation comprising Canagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient.

The present invention provides a liquid formulation comprising Canagliflozin 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 provides a liquid formulation comprising Canagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein Canagliflozin or its pharmaceutically acceptable salt thereof is present at a concentration of 0.5 to 10% w/v in the liquid formulation.

The present invention provides a liquid formulation comprising Canagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein the liquid formulation is in the form of suspension or solution or the like.

The present invention provides a liquid formulation comprising Canagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein the liquid formulation has a pH ranging from about 4 to about 8.

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

The present invention provides a liquid formulation comprising: a) 0.5-10% w/v of Canagliflozin or its pharmaceutically acceptable salt thereof; b) 0.015-3% w/v of a preservative; c) 0.1-10% w/v of a viscosity modifier; and d) one or more pharmaceutically acceptable excipient.

The present invention provides a liquid formulation comprising: a) 0.5-10% w/v of Canagliflozin or its pharmaceutically acceptable salt thereof; b) 0.015-3% w/v of a preservative; c) 0.1-10% w/v of a suspending agent; d) 0.1-10% w/v of a surface active agent; and e) one or more pharmaceutically acceptable excipient.

The present invention provides an oral suspension formulation comprising: a) 0.5-10% w/v of Canagliflozin or its pharmaceutically acceptable salt thereof; b) 0.015-3% w/v of a preservative; c) 0.1-10% w/v of a viscosity modifier; and d) one or more pharmaceutically acceptable excipient, wherein the formulation has a pH ranging from about 4 to about 8.

The present invention provides an oral suspension formulation comprising: a) 0.5-10% w/v of Canagliflozin or its pharmaceutically acceptable salt thereof; b) 0.015-3% w/v of a preservative; c) 0.1-10% w/v of a suspending agent; d) 0.1-10% w/v of a surface active agent; and e) one or more pharmaceutically acceptable excipient, wherein the formulation has a pH ranging from about 4 to about 8.

The present invention provides a process for the preparation of a liquid formulation, comprising: a) Separately soaking a viscosity modifier in a vehicle; b) separately dissolving a preservative in the vehicle at a desired temperature, getting a clear solution and subsequently cooling down the preservative-containing solution; c) adding and dispersing Canagliflozin or its pharmaceutically acceptable salt thereof into the step b) of above solution and mixing using a suitable mixer at the desired speed and time to obtain a homogeneous suspension; d) adding and mixing a sweetener and an antifoaming agent into the above suspension using a suitable mixer at the desired speed and time to obtain a suspension; e) adding and mixing the dispersion from step a) into the above suspension using a suitable mixer at the desired speed and time to get a suspension; f) adding a flavour into the above dispersion using a suitable mixer at the desired speed and time to get a homogeneous dispersion; g) adding a buffering agent into the above dispersion and mixing for a desired time, followed by checking the pH of the dispersion; and h) making up the volume with a vehicle and mixing for a desired time using a suitable mixer at the desired speed to get a homogeneous dispersion.

The present invention provides a process for the preparation of a liquid formulation, comprising: a) Separately dispersing a suspending agent in a vehicle using a suitable mixer; b) separately dissolving a preservative in the vehicle with heating to a desired temperature. After getting a clear solution, cooling down the preservative-containing solution; c) mixing the dispersion from step a) and the solution from step b) to get a homogeneous suspension; d) adding and dispersing Canagliflozin or its pharmaceutically acceptable salt thereof in a surfactant to get a homogeneous suspension; e) adding the dispersion from step d) into the suspension from step c) using a suitable mixer at the desired speed and time to get a suspension; f) adding and mixing a sweetener and an antifoaming agent into the above suspension using a suitable mixer at the desired speed and time to get a suspension; g) adding a flavour into the above dispersion using a suitable mixer at the desired speed and time to get a homogeneous dispersion; h) adding a buffering agent into the above dispersion and mixing for a desired time followed by checking the pH of the dispersion; i) making up the volume with a vehicle and mixing for a desired time using a suitable mixer at the desired speed to get a homogeneous dispersion; and j) passing the suspension through a colloidal mill for a desired time.

The present invention provides a liquid formulation comprising Canagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient is used for the treatment of type 2 diabetes mellitus and associated cardiovascular and renal complications.

Detailed Description of the Invention

The term “Canagliflozin” as used herein is not limited to the Canagliflozin, but includes its solvates, hydrates, hemihydrates, solvate-hydrate, all pharmaceutically acceptable salts, esters, amides, isomers and stereo isomers and polymorphic form including amorphous form. For example “Canagliflozin” means Canagliflozin hemihydrate.

The term “therapeutically effective amount” is defined to mean the amount or quantity of the active drug (e.g. Canagliflozin 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 suspension, solution or 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.

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 Canagliflozin may be present in the form of a pharmaceutically acceptable salt include, without being restricted thereto lithium, sodium, potassium, calcium, magnesium, zinc, aluminium, ammonium, choline, diethanolamine, lysine, ethylenediamine, t-butylamine, t- octylamine, tris(hydroxymethyl)aminomethane, N-methyl glucosamine, triethanolamine, dehydroabietylamine, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, aspartic acid, glutamic acid, etc.

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

The present invention relates to a liquid formulation comprising Canagliflozin 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 Canagliflozin or its pharmaceutically acceptable salt thereof, wherein Canagliflozin or its pharmaceutically acceptable salt thereof is present at a concentration of 0.4 to 30% w/v in the liquid formulation. Preferably, Canagliflozin or its pharmaceutically acceptable salt thereof is present at a concentration of 0.5 to 10% w/v in the liquid formulation. Additionally, Canagliflozin or its pharmaceutically acceptable salt thereof is present at a concentration of 100 mg per ml to 100 mg per 5 ml.

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

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

The present invention relates to a liquid formulation comprising Canagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein the liquid formulation has a pH ranging from about 4 to about 8. For example, the pH of the liquid formulation can be adjusted to a pH of about 4, about 4.5, about 5, about 5.5, about 6, about 6.5 or about 7 or about 7.5 or about 8.

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

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

The one or more pharmaceutically acceptable excipient which are selected from the group consisting of suspending agents (or thickening agents), surface active agents (or surfactants or wetting agents), preservatives, viscosity modifiers (or viscosity enhancer), solubilizers or solubilizing agents, buffering agents (or buffers or pH modifiers), sweetening agents (or sweeteners), antifoaming agents, flavoring agents (or flavours), vehicles (or solvents), cosolvents, taste masking agents, stabilizing agents (or stabilizers), antioxidants, chelating agents and colouring agents (or colorants).

The examples of suspending agents (or thickening agents) according to the present invention include but not limited to group comprising acacia, agar, alginic acid, bentonite, calcium stearate, carbomers, carrageenan, powdered cellulose, cellulose, microcrystalline cellulose, carbo xymethylcellulose sodium, colloidal silicon dioxide, hydroxymethyl cellulose, hydroxy ethyl cellulose, hydroxy ethylmethyl cellulose, hydroxypropyl cellulose, hypromellose, microcrystalline cellulose and carbo xymethylcellulose sodium (Avicel RC 591), maltitol solution, medium-chain triglycerides, methylcellulose, phospholipids, polycarbophil, polyethylene glycol, polyoxyethylene sorbitan fatty acid esters, potassium alginate, povidone, propylene glycol alginate, sodium starch glycolate, sorbitan esters, tragacanth, vitamin E polyethylene glycol succinate, and xanthan gum. The preferred suspending agent is microcrystalline cellulose and carboxymethylcellulose sodium (Avicel RC 591). The suspending agent can be present in an amount from about 0.1 to about 10% w/v of the liquid formulation.

The examples of surface active agents (or surfactants or wetting agents) according to the present invention include but not limited to group comprising polyoxyethylene sorbitan fatty acid esters (polysorbates), poloxamers, polyoxyethylene castor oil derivatives, polyoxyglycerides, vitamin E polyethylene glycol succinate, and macrogol 15 hydroxystearate, polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80, poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, and poloxamer 407, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyethylene glycol-8 caprylic/capric glycerides, sodium lauryl sulfate and docusate sodium. The preferred surface active agents are polysorbates (polysorbate 20). The surface active agents are present in an amount of about 0.1% w/v to about 10% w/v of the liquid formulation.

The examples of preservatives according to the present invention include but not limited to group comprising parabens (p-hydroxybenzoate), methyl p-hydroxybenzoate (methylparaben), ethyl p-hydroxybenzoate (ethylparaben), propyl p-hydroxybenzoate (propylparaben), butyl p-hydroxybenzoate (butylparaben), sorbic acid, sodium sorbate, potassium sorbate, calcium sorbate, benzoic acid, sodium benzoate, potassium benzoate, calcium benzoate, sodium citrate, halogenated diphenyl ether, herbal extracts and essential oils, bisguanide antiseptics, quaternary ammonium compounds. The preferred preservatives are methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sodium benzoate and sorbic acid. The preservatives are present in an amount of about 0.001% w/v to about 4% w/v of the liquid formulation. Particularly, the preservative is present in an amount of about 0.015 % w/v to about 3% w/v of the liquid formulation.

The examples of viscosity modifiers or viscosity enhancers according to the present invention include but not limited to group comprising cellulose derivatives, hydroxyethyl cellulose, hydroxy ethylmethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methylcellulose, carboxymethyl cellulose, carbo xymethylcellulose and its salts/derivatives, sodium carboxymethyl cellulose (sodium carmellose), microcrystalline cellulose, microcrystalline cellulose and carbo xymethylcellulose sodium, acacia, agar, alginic acid, bentonite, carrageenan, colloidal silicon dioxide, glycerin, guar gum, maltodextrin, myristyl alcohol, polydextrose, polyethylene glycol, polyvinyl alcohol. The preferred viscosity modifiers or viscosity enhancers are sodium carbo xymethylcellulose (sodium carmellose). The viscosity modifiers or viscosity enhancers are present in an amount of about 0.01 to about 15% w/v of the liquid formulation. Particularly, the viscosity modifiers or viscosity enhancers are present in an amount of about 0.015% to about 12% w/v of the liquid formulation. More particularly, the viscosity modifiers or viscosity enhancers are present in an amount of about 0.1% to about 10% w/v of the liquid formulation.

The examples of solubilizers or solubilizing agents 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, 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. The preferred solubilizers are hydroxypropyl-P-cyclodextrin (HP-P-CD). The solubilizers are present in an amount of about 0.01% to about 40% w/v of the liquid formulation. Particularly, the solubilizers are present in an amount of about 0.1% to about 20% w/v of the liquid formulation. More particularly, the solubilizers are present in an amount of about 0.5% to about 15% w/v of the liquid formulation.

The examples of buffering agents or buffers according to the present invention include but not limited to group comprising disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, citric acid, sodium citrate, sodium tartarate, sodium acetate, sodium carbonate, polyphosphates, pyrophosphates, trisodium phosphate, tripotassium phosphate, sodium acetate, calcium chloride, calcium hydroxide, calcium carbonate, calcium bicarbonate, and other calcium salts and/or combinations thereof. The preferred buffering agent is disodium hydrogen phosphate or sodium dihydrogen phosphate.

The examples of sweeteners or sweetening agents according to the present invention include but not limited to group comprising sucralose, glucose, maltose, sucrose, aspartame, mannitol, sorbitol, xylitol, dextrose, saccharin, saccharin sodium, mannose, glycerol or glycerin and/or combinations thereof. The preferred sweetener is sucralose. Preferably, sweetener is present in an amount of from about 0.01 to about 20% w/v, more preferably from about 0.1 to 3% w/v of the liquid formulation.

The examples of vehicles or solvents according to the present invention include but not limited to group comprising water, propylene glycol, dipropylene glycol, polypropylene glycol, ethylene glycol, polyethylene glycol, glycerin, butylene glycol, hexylene glycol, polyoxyethylene, and/or combinations thereof.

The examples of antifoaming agents to the present invention include but not limited to group comprising insoluble oils, polydimethylsiloxanes (e.g., simethicone) and other silicones, stearates and glycols. The preferred antifoaming agents are simethicone. Preferably, antifoaming agents are present in an amount of from about 0.01 to about 3% w/v of the liquid formulation.

The examples of antioxidants according to the present invention include but not limited to group comprising butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, ascorbic acid and/or combinations thereof.

The examples of flavouring agents or flavours according to the present invention include but not limited to group comprising mix fruit flavour, grapefruit, orange, lime, lemon, mandarin, pineapple, strawberry, raspberry, mango, passion fruit, kiwi, apple, pear, peach, apricot, cherry, grapes, banana, spearmint, peppermint, eucalyptus, and/or combinations thereof. The preferred flavour is raspberry or mix fruit flavour. The examples of colorants include but are not limited to caramel colorant, red colorant enocianin, indigo yellow, quinoline yellow, quinizarine green, FD&C blue #1 aluminum lake, 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 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: a) 0.5-10% w/v of Canagliflozin or its pharmaceutically acceptable salt thereof; b) 0.015-3% w/v of a preservative; c) 0.1-10% w/v of a viscosity modifier; and d) one or more pharmaceutically acceptable excipient.

The present invention relates to a liquid formulation comprising: a) 0.5-10% w/v of Canagliflozin or its pharmaceutically acceptable salt thereof; b) 0.015-3% w/v of a preservative; c) 0.1-10% w/v of a suspending agent; d) 0.1-10% w/v of a surface active agent; and e) one or more pharmaceutically acceptable excipient.

The present invention relates to an oral suspension formulation comprising: a) 0.5-10% w/v of Canagliflozin or its pharmaceutically acceptable salt thereof; b) 0.015-3% w/v of a preservative; c) 0.1-10% w/v of a viscosity modifier; and e) one or more pharmaceutically acceptable excipient, wherein the formulation has a pH ranging from about 4 to about 8.

The present invention relates to an oral suspension formulation comprising: a) 0.5-10% w/v of Canagliflozin or its pharmaceutically acceptable salt thereof; b) 0.015-3% w/v of a preservative; c) 0.1-10% w/v of a suspending agent; d) 0.1-10% w/v of a surface active agent; and e) one or more pharmaceutically acceptable excipient, wherein the formulation has a pH ranging from about 4 to about 8.

The present invention relates to a process for the preparation of a liquid formulation, comprising: a) Separately soaking a viscosity modifier in a vehicle; b) separately dissolving a preservative in the vehicle at a desired temperature, getting a clear solution and subsequently cooling down the preservative-containing solution; c) adding and dispersing Canagliflozin or its pharmaceutically acceptable salt thereof into the step b) of above solution and mixing using a suitable mixer at the desired speed and time to obtain a homogeneous suspension; d) adding and mixing a sweetener and an antifoaming agent into the above suspension using a suitable mixer at the desired speed and time to obtain a suspension; e) adding and mixing the dispersion from step a) into the above suspension using a suitable mixer at the desired speed and time to get a suspension; f) adding a flavour into the above dispersion using a suitable mixer at the desired speed and time to get a homogeneous dispersion; g) adding a buffering agent into the above dispersion and mixing for a desired time, followed by checking the pH of the dispersion; and h) making up the volume with a vehicle and mixing for a desired time using a suitable mixer at the desired speed to get a homogeneous dispersion.

The present invention relates to a process for the preparation of a liquid formulation, comprising: a) Separately dispersing a suspending agent in a vehicle using a suitable mixer; b) separately dissolving a preservative in the vehicle with heating to a desired temperature. After getting a clear solution, cooling down the preservative-containing solution; c) mixing the dispersion from step a) and the solution from step b) to get a homogeneous suspension; d) adding and dispersing Canagliflozin or its pharmaceutically acceptable salt thereof in a surfactant to get a homogeneous suspension; e) adding the dispersion from step d) into the suspension from step c) using a suitable mixer at the desired speed and time to get a suspension; f) adding and mixing a sweetener and an antifoaming agent into the above suspension using a suitable mixer at the desired speed and time to get a suspension; g) adding a flavour into the above dispersion using a suitable mixer at the desired speed and time to get a homogeneous dispersion; h) adding a buffering agent into the above dispersion and mixing for a desired time followed by checking the pH of the dispersion; i) making up the volume with a vehicle and mixing for a desired time using a suitable mixer at the desired speed to get a homogeneous dispersion; and j) passing the suspension through a colloidal mill for a desired time.

The present invention relates to a liquid formulation comprising Canagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient is used for the treatment of type 2 diabetes mellitus and associated cardiovascular and renal complications.

The present invention relates to a liquid formulation comprising Canagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient provides flexibility in dosage options while ensuring a consistent and controlled concentration of the Canagliflozin or its pharmaceutically acceptable salt thereof for effective therapeutic use.

The present invention relates to a liquid formulation comprising Canagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient provides simple manufacturing process, enhance patient compliance, improving the solubility and enhancing the stability. The liquid formulation can be conveniently packaged in various pharmaceutically acceptable containers, such as bottles, depending on the required dosage form.

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

Canagliflozin 100mg/5ml Oral Suspension:

Manufacturing Process: a) Carmellose sodium was separately soaked in 20% of the total volume of water; b) methyl p-hydroxybenzoate and propyl p-hydroxybenzoate were separately dissolved in 30% of the total volume of water, heated up to 90°C. After getting a clear solution, the preservative-containing solution was cooled down; c) Canagliflozin was added and dispersed in the above step b) solution and mixed using a suitable mixer at a speed of 2000-3000 RPM for 15 minutes to get a homogeneous suspension; d) sucralose and simethicone were added and mixed into the above suspension using a suitable mixer at a speed of 2000-3000 RPM for 15 minutes to get a suspension; e) the step a) dispersion was added and mixed into the above suspension using a suitable mixer at a speed of 2000-3000 RPM for 45 minutes to get a suspension; f) raspberry flavor was added in the above dispersion using a suitable mixer at a speed of 2000-3000 RPM for 5 minutes to get a homogeneous dispersion; g) disodium hydrogen phosphate was added into the above dispersion and mixed for 5 minutes. The pH of the dispersion was checked; and h) the volume was made up with water and mixed for 10 minutes using a suitable mixer at a speed of 3000-4000 RPM to get a homogeneous dispersion.

Example 2

Canagliflozin 100mg/5ml Oral Suspension:

Manufacturing Process: a) Microcrystalline cellulose and carbo xymethylcellulose sodium (Avicel RC 591) was separately dispersed in 20% of the total volume of water using a suitable mixer; b) methyl p-hydroxybenzoate and propyl p-hydroxybenzoate were separately dissolved in 30% of the total volume of water, heated up to 90°C. After getting a clear solution, the preservative-containing solution was cooled down; c) step a) and Step b) were mixed to get a homogeneous suspension; d) Canagliflozin was added and dispersed in polysorbate 20 to get a homogeneous suspension; e) step d) was added to Step c) using a suitable mixer at a speed of 2000-3000 RPM for 15 minutes to get a suspension; f) sucralose and simethicone were added and mixed into the above suspension using a suitable mixer at a speed of 2000-3000 RPM for 15 minutes to get a suspension; g) a raspberry flavor was added into the above dispersion using a suitable mixer at a speed of 2000-3000 RPM for 5 minutes to get a homogeneous dispersion; h) disodium hydrogen phosphate was added into the above dispersion and mixed for 5 minutes. The pH of the dispersion was checked; i) the volume was made up with water, and the mixture is mixed for 10 minutes using a suitable mixer at a speed of 3000-4000 RPM to get a homogeneous dispersion; and j) the suspension is passed through a colloidal mill for 10 minutes.

Example 3

Canagliflozin 100mg/5ml Oral Solution:

Manufacturing Process: a) Separately taken part quantity of water in a beaker, heated to a temperature range of 80- 90°C, methyl p-hydroxybenzoate, sodium benzoate and sorbic acid were added and dissolved to get a clear solution and allowed to cool up to 40°C; b) hydroxypropyl beta-cyclodextrin was slowly added and dissolved in another portion of water using a stirrer at a speed of 1500 - 2500 RPM for 30 minutes to get a clear solution; c) Canagliflozin was slowly added and dissolved to the above solution and mixed using stirrer at the speed of 1500 - 2500 RPM for 30 minutes to get clear solution; d) carmellose sodium was added and dissolved in the above solution, and the mixture is stirred using a stirrer at a speed of 1500 - 2500 RPM for 30 minutes to get clear solution; e) step-d) solution was added to the step-a) solution using a stirrer operating at a speed of 1500 - 2500 RPM for 15 minutes to get a clear solution, The Step-d) solution was rinsed with 100 g of water; f) sucralose was added to the above solution and mixed using a stirrer at a speed of 1500 - 2500 RPM for 10 minutes to get a clear solution. g) mix fruit flavor was added into the above solution and mixed using a stirrer at a speed of 1500 - 2500 RPM for 5 minutes to get a clear solution; and h) The volume is made up with water and the mixture is stirred for 10 minutes using a stirrer at a speed of 1500 - 2500 RPM to obtain a clear solution.

Claims

Claims:

1. An oral liquid formulation comprising Canagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein Canagliflozin or its pharmaceutically acceptable salt thereof is present at a concentration of 0.5 to 10% 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,

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

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

5. The liquid formulation according to claim 1, wherein the liquid formulation has a pH ranging from about 4 to about 8.

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

7. The liquid formulation according to claim 1, wherein the one or more pharmaceutically acceptable excipient which are selected from the group consisting of suspending agents (or thickening agents), surface active agents (or surfactants), preservatives, viscosity modifiers (or viscosity enhancer), solubilizers (or solubilizing agents), buffering agents (or buffers), sweetening agents (or sweeteners), antifoaming agents, flavoring agents (or flavours), vehicles (or solvents), co-solvents, taste masking agents, stabilizing agents (or stabilizers), antioxidants, chelating agents and colouring agents.

8. A liquid formulation comprising: a) 0.5-10% w/v of Canagliflozin or its pharmaceutically acceptable salt thereof; b) 0.015-3% w/v of a preservative; c) 0.1-10% w/v of a viscosity modifier; and e) one or more pharmaceutically acceptable excipient.

9. A liquid formulation comprising: a) 0.5-10% w/v of Canagliflozin or its pharmaceutically acceptable salt thereof; b) 0.015-3% w/v of a preservative; c) 0.1-10% w/v of a suspending agent; d) 0.1-10% w/v of a surface active agent; and e) one or more pharmaceutically acceptable excipient.

10. An oral suspension formulation comprising: a) 0.5-10% w/v of Canagliflozin or its pharmaceutically acceptable salt thereof; b) 0.015-3% w/v of a preservative; c) 0.1-10% w/v of a viscosity modifier; and d) one or more pharmaceutically acceptable excipient, wherein the formulation has a pH ranging from about 4 to about 8.

11. An oral suspension formulation comprising: a) 0.5-10% w/v of Canagliflozin or its pharmaceutically acceptable salt thereof; b) 0.015-3% w/v of a preservative; c) 0.1-10% w/v of a suspending agent; d) 0.1-10% w/v of a surface active agent; and e) one or more pharmaceutically acceptable excipient, wherein the formulation has a pH ranging from about 4 to about 8.

12. A process for the preparation of an oral suspension formulation, comprising: a) separately soaking a viscosity modifier in a vehicle; b) separately dissolving a preservative in the vehicle at a desired temperature, getting a clear solution and subsequently cooling down the preservative-containing solution; c) adding and dispersing Canagliflozin or its pharmaceutically acceptable salt thereof into the step b) of above solution and mixing using a suitable mixer at the desired speed and time to obtain a homogeneous suspension; d) adding and mixing a sweetener and an antifoaming agent into the above suspension using a suitable mixer at the desired speed and time to obtain a suspension; e) adding and mixing the dispersion from step a) into the above suspension using a suitable mixer at the desired speed and time to get a suspension; f) adding a flavour into the above dispersion using a suitable mixer at the desired speed and time to get a homogeneous dispersion; g) adding a buffering agent into the above dispersion and mixing for a desired time, followed by checking the pH of the dispersion; and h) making up the volume with a vehicle and mixing for a desired time using a suitable mixer at the desired speed to get a homogeneous dispersion.

13. A process for the preparation of an oral suspension formulation, comprising: a) separately dispersing a suspending agent in a vehicle using a suitable mixer; b) separately dissolving a preservative in the vehicle with heating to a desired temperature. After getting a clear solution, cooling down the preservative-containing solution; c) mixing the dispersion from step a) and the solution from step b) to get a homogeneous suspension; d) adding and dispersing Canagliflozin or its pharmaceutically acceptable salt thereof in a surfactant to get a homogeneous suspension; e) adding the dispersion from step d) into the suspension from step c) using a suitable mixer at the desired speed and time to get a suspension; f) adding and mixing a sweetener and an antifoaming agent into the above suspension using a suitable mixer at the desired speed and time to get a suspension; g) adding a flavour into the above dispersion using a suitable mixer at the desired speed and time to get a homogeneous dispersion; h) adding a buffering agent into the above dispersion and mixing for a desired time followed by checking the pH of the dispersion; i) making up the volume with a vehicle and mixing for a desired time using a suitable mixer at the desired speed to get a homogeneous dispersion; and j) passing the suspension through a colloidal mill for a desired time.

14. The method of using the liquid formulation according to claim 1, wherein said liquid formulation comprising Canagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient is used for the treatment of type 2 diabetes mellitus and associated cardiovascular and renal complications.