An oral liquid formulation of apixaban

Abstract

The present invention is related to an oral liquid formulation of apixaban. The present invention is specifically related to an oral liquid formulation of apixaban which is comprising a therapeuticall

Description

RELATED APPLICATION This application claims priority to IN Patent Application No. 202321051585 filed on August 1, 2023, the subject matter of which is incorporated by reference in its entirety. FIELD OF THE INVENTION The present invention is related to an oral liquid formulation of apixaban. The present invention is specifically related to an oral liquid formulation of apixaban which is comprising a therapeutically effective amount of apixaban, a salt or prodrug thereof; one or more viscosifying agents; one or more buffering agents to provide a formulation pH of 3.5 to 4.5, and one or more pharmaceutically acceptable excipients. The present invention also related to process of preparation of an oral liquid formulation of apixaban. BACKGROUND OF THE INVENTION Atrial fibrillation (AFib or AF) is an abnormal heart rhythm (arrhythmia) characterized by rapid and irregular beating of the atrial chambers of the heart. An arrhythmia is when the heart beats too slowly, too fast, or in an irregular way. When a person has AFib, the normal beating in the upper chambers of the heart (the two atria) is irregular, and blood doesn’t flow as well as it should from the atria to the lower chambers of the heart (the two ventricles). AFib may happen in brief episodes, or it may be a permanent condition. Some of the symptoms are: Irregular heartbeat, Heart palpitations, Lightheadedness, Extreme fatigue, Shortness of breath and Chest pain. Apixaban, sold under the brand name Eliquis, is an anticoagulant medication used to treat and prevent blood clots and to prevent stroke in people with or without nonvalvular atrial fibrillation through directly inhibiting factor Xa. Also, it can be used to lower the risk of stroke and embolism in people with nonvalvular atrial fibrillation. Apixaban is a highly selective, orally bioavailable, and reversible direct inhibitor of free and clot-bound factor Xa. Factor Xa catalyzes the conversion of prothrombin to thrombin, the final enzyme in the coagulation cascade that is responsible for fibrin clot formation. Apixaban has no direct effect on platelet aggregation, but by inhibiting factor Xa, it indirectly decreases clot formation induced by thrombin. Drug absorption is a pharmacokinetic parameter that refers to the way a drug is absorbed from a pharmaceutical formulation into the bloodstream. Several factors can affect the absorption of a drug into the body. These include: • Physicochemical properties (e.g. solubility) • Drug formulation (e.g. tablets, capsules, solutions) • The route of administration (e.g. oral, buccal, sublingual, rectal, parenteral, topical, or inhaled) • The rate of gastric emptying. Currently, tablet and capsule formulation drugs are highly available in the market. But the absorption of these formulations take time when compared with the liquid formulations. The tablets and capsule takes time for absorption as they first need to be dissolve and disintegrate and then gets absorbed. Thus, there is always a need to develop formulations that can easily administered and can get easily absorbed. Liquid formulations generally overcome the drawbacks of solid and tablet formulations. Aiming at the problem of low bioavailability of apixaban, the present invention discloses an apixaban formulation which can improve the solubility and dissolution rate of a medicament, increase the permeability of the medicament, be conductive to improving the oral absorption characteristic of the apixaban and improve the bioavailability of the medicament. The Apixaban formulation has the advantages of simple prescription process, small using amount of the stabilizer and convenient production. Thus, the inventors in the present invention have arrived to an oral liquid formulation of apixaban with aims to overcome problems cited above by preparing an oral liquid formulation of apixaban as described herein. OBJECTIVES OF THE INVENTION The main objective of the present invention is to develop an oral liquid formulation of apixaban, a salt or prodrug thereof. Another objective of this invention is to provide an oral liquid formulation of apixaban, a salt or prodrug thereof which is stable. Yet another objective of this invention is to provide an oral liquid formulation of apixaban, a salt or prodrug thereof which provides better patient compliance. Yet another objective of this invention is to provide an oral liquid formulation of apixaban, a salt or prodrug thereof which is easy to manufacture at large scale. Yet another objective of this invention is to provide an oral liquid formulation of apixaban, a salt or prodrug thereof which gives faster absorption and quicker onset of action. SUMMARY OF THE INVENTION The present invention is all about to provide an oral liquid formulation of drug Apixaban from class of anticoagulant or Factor Xa inhibitors. The main aspect of the present invention is to provide an oral liquid formulation of apixaban, a salt or prodrug thereof. The main aspect of the present invention is to provide an oral liquid formulation of apixaban comprising a therapeutically effective amount of apixaban, a salt or prodrug thereof; one or more viscosifying agents; one or more buffering agents to provide a formulation pH of 3.5 to 4.5, and one or more pharmaceutically acceptable excipients. Another aspect of the present invention is to provide an oral liquid formulation of apixaban consisting of a therapeutically effective amount of apixaban, a salt or prodrug thereof; one or more viscosifying agents; one or more buffering agents to provide a formulation pH of 3.5 to 4.5, and one or more pharmaceutically acceptable excipients. Another aspect of the present invention provides a process for the preparation of an oral liquid formulation of apixaban. One more aspect of the present invention is to provide an oral liquid formulation of apixaban, a salt or prodrug thereof to reduce the risk of stroke and systemic embolism in patients with non valvular atrial fibrillation and deep vein thrombosis and pulmonary embolism. One more aspect of the present invention is to provide an oral liquid formulation of apixaban, a salt or prodrug thereof for use as a medicament for the treatment to reduce the risk of stroke and systemic embolism in patients with non valvular atrial fibrillation and deep vein thrombosis and pulmonary embolism. DETAILED DESCRIPTION OF THE INVENTION The main embodiment of the present invention is an oral liquid formulation of apixaban, a salt or prodrug thereof. The detailed description set forth below is intended as a description of exemplary embodiments and is not intended to represent the only forms in which the exemplary embodiments may be constructed and / or utilized. The description sets forth the functions and the sequence of steps for constructing and / or operating the exemplary embodiments. However, it is to be understood that the same or equivalent functions and sequences which may be accomplished by different exemplary methods are also intended to be encompassed within the spirit and scope of the invention. As defined herein, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. Although any process and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. As stated in the present invention herein, the singular forms “a,” “an” and “the” specifically also encompass the plural forms of the terms to which they refer, unless the content clearly dictates otherwise. The term “about” is used herein to means approximately, in the region of, roughly, or around. As stated herein, that it follows in a transitional phrase or in the body of a claim, the terms “comprise(s)” and “comprising” are to be interpreted as having an open ended meaning. That is, the terms are to be interpreted synonymously with the phrases “having at least” or “including at least”. When used in the context of a process, the term “comprising” means that the process includes at least the recited steps, but may include additional steps. When used in the context of a composition, the term “comprising” means that the composition includes at least the recited features or components, but may also include additional features or components. The following terms are used interchangeably herein: "active", "drug", and "active ingredient". A “therapeutically effective amount” or “effective amount” is that amount of a pharmaceutical agent to achieve a pharmacological effect. The term “therapeutically effective amount” includes, for example, a prophylactically effective amount. As used herein the word “liquid formulation” refers to liquid oral formulation like solution, suspension or emulsion, more preferably in the form of suspension. The term “about” is used synonymously with the term “approximately.” As one of ordinary skill in the art would understand, the exact boundary of “about” will depend on the component of the composition. Illustratively, the use of the term “about” indicates that values slightly outside the cited values, i.e., plus or minus 0.1% to 10%, which are also effective and safe. Thus compositions slightly outside the cited ranges are also encompassed by the scope of the present claims. By the term "pH", as used herein, is meant "apparent pH" wherein the pH measurement is carried out on the apixaban containing composition in final form, for example, by measuring the pH of the formulation. The main embodiment of the present invention is to provide an oral liquid formulation of apixaban comprising a therapeutically effective amount of apixaban, a salt or prodrug thereof; one or more viscosifying agents; one or more buffering agents to provide a formulation pH of 3.5 to 4.5, and one or more pharmaceutically acceptable excipients. Another aspect of the present invention is to provide an oral liquid formulation of apixaban consisting of a therapeutically effective amount of apixaban, a salt or prodrug thereof; one or more viscosifying agents; one or more buffering agents to provide a formulation pH of 3.5 to 4.5, and one or more pharmaceutically acceptable excipients. As per one embodiment of the present invention, apixaban, a salt or prodrug thereof can be present in the formulation of present invention in an amount from about 0.5 to 500 mg / mL, preferably in the range from about 1 to about 200 mg / mL, preferably in the range from about 1 to about 150 mg / mL, more preferably in the range from about 1 to 100 mg / mL, more preferably in the range from about 1 to 50 mg / mL, more preferably in the range from about 1 to 40 mg / mL, more preferably in the range from about 1 to 30 mg / mL, most preferably in the range from about 1 to 10 mg / mL, or any other value in between thereof. As per another embodiment one or more viscosifying agents in the present invention can be selected from methyl cellulose, hydroxyethyl cellulose, hypromellose, bentonite, hectorite, magnesium aluminium silicate, microcrystalline cellulose, sodium carboxymethyl cellulose, hydroxypropylmethylcellulose (HPMC), xanthan gum, acacia, tragacanth, alginates, guar gum, collodial silicon dioxide, sorbitol, liquid maltitol, sucrose, fructose, dextrose, maltodextrin and polydextrose, or any combination thereof. As per preferred embodiment, the viscosifying agent is liquid sorbitol. As per one embodiment of the present invention, one or more viscosifying agents can be used in the range of 10-500 mg / mL, preferably 50-500 mg / mL, more preferably 100-500 mg / mL and most preferably 100-300 mg / mL, or any value in between such as for example 20 mg / ml, 50 mg / ml, 100 mg / ml, 200 mg / ml, 300 mg / ml, 400 mg / ml, and 450 mg / ml. The buffers used in the present invention is generally recognized as safe (GRAS) by the U.S. Food and Drug Administration. As per one embodiment of the present invention, one or more buffering agents can be selected from citrate, acetate, aconitate, formate, glutarate, glutamate, malate, succinate, tartrate, phosphate, sulfamate, carbonate, tris, borate, glycinate, and salts or acids thereof, and any combination thereof. A specifically contemplated buffer is comprised of citric acid, monobasic citrate, dibasic citrate, and tribasic citrate, in which the mono-, di-, or tribasic citrate forms have associated counterions and thus, may collectively be referred to as citrate salts (viz., citrate buffer). The associated counterions include, for example, sodium, potassium, ammonium, calcium, etc. For instance, a particular citrate salt contemplated herein is sodium citrate, which may exist as an anhydrous form, hydrated form, such as, a dihydrate or a pentahydrate. As per preferred embodiment of the present invention, citrate (i.e., citric acid and sodium citrate) is used as or consists of the one or more buffering agents. As per one embodiment of the present invention, one or more buffering agents used in the range of 0.5-50 mg / mL, preferably 0.5-30 mg / mL, more preferably 1-30 mg / mL and most preferably 1-20 mg / mL, or any value in between such as for example 1 mg / ml, 5 mg / ml, 10 mg / ml, 10.50 mg / ml, 12.25 mg / ml, 15 mg / ml, 20 mg / ml, 22.75 mg / ml, 30 mg / ml, 40 mg / ml, and 45 mg / ml. As per another embodiment of the present invention, one or more pharmaceutically acceptable excipients comprises an antifoaming agents, thickening agents, a humectants, a sweetening agents, a preservatives, a flavouring agents, or a combination thereof. As per one embodiment of the present invention, one or more antifoaming agents can be selected from sodium lauryl sulfate, simethicone, sodium tetradecyl sulfate, dodecyl sulfate, poloxamers, Tween 80, Tween 20, Tween 40, Tween 60, sorbitan monolaurate, and lauryl glucoside, or any combination thereof. As per preferred embodiment of the present invention, simethicone is used as antifoaming agent. As per on embodiment of the present invention, one or more antifoaming agents used in the range of 0.5-20 mg / mL, preferably 0.5-15 mg / mL, more preferably 1-15 mg / mL and most preferably 1-10 mg / mL, or any value in between such as for example 1 mg / ml, 2 mg / ml, 3 mg / ml, 4 mg / ml, 5 mg / ml, 10 mg / ml, 15 mg / ml, and 19 mg / ml. As per one embodiment of the present invention, one or more thickening agents can be selected from methyl cellulose, hydroxyethyl cellulose, hypromellose, bentonite, hectorite, magnesium aluminium silicate, microcrystalline cellulose, sodium carboxymethyl cellulose, hydroxypropylmethylcellulose (HPMC), xanthan gum, acacia, tragacanth, alginates, guar gum and collodial silicon dioxide, or any combination thereof. As per preferred embodiment of the present invention, xanthan gum is used as thickening agent. As per on embodiment of the present invention, one or more thickening agents used in the range of 0.5-20 mg / mL, preferably 0.5-15 mg / mL, more preferably 1-15 mg / mL and most preferably 1-10 mg / mL, or any value in between such as for example 1 mg / ml, 2 mg / ml, 3 mg / ml, 4 mg / ml, 4.5 mg / ml, 5 mg / ml, 10 mg / ml, 15 mg / ml, and 19 mg / ml. As per one embodiment of the present invention, one or more humectants can be selected from glycerin, hyaluronic acid, salicylic acid, alpha hydroxy acids (AHAs), such as glycolic acid and lactic acid, propylene glycol, honey, and sorbitol, or any combination thereof. As per preferred embodiment of the present invention, glycerin is used as humectant, thickening agent, and a vehicle. As per one embodiment of the present invention, glycerin or the humectant is used in the range of 1-500 mg / mL, preferably 1-400 mg / mL, more preferably 1-300 mg / mL and most preferably 1-250 mg / mL, or any value in between such as for example 2 mg / ml, 5 mg / ml, 10 mg / ml, 20 mg / ml, 50 mg / ml, 100 mg / ml, 200 mg / ml, 300 mg / ml, 400 mg / ml, and 450 mg / ml. As per one embodiment of the present invention, one or more sweetening agents can be selected from but not limited to glucose, sucralose, trehalose, fructose, xylose, dextrose, galactose, tagatose, maltose, sucrose, glycerol, dulcitol, mannitol, lactitol, sorbitol, xylitol, saccharine or the corresponding sodium, potassium or calcium salt, cyclamate or the corresponding sodium or calcium salt, aspartame, or acesulfame or the potassium salt thereof, ammonium glycyrrhizinate, alitame, inulin, isomalt, neohesperidin dihydrochalcone, thaumatin and the like or any combination thereof. As per preferred embodiment of the present invention, sucralose is used as sweetening agent. As per one embodiment of the present invention, sucralose or the sweetening agent can be used in the range of 0.1-20 mg / mL, preferably 0.1-10 mg / mL, more preferably 0.5-10 mg / mL and most preferably 0.5-5 mg / mL, or any value in between such as for example 0.2 mg / ml, 0.5 mg / ml, 1 mg / ml, 2 mg / ml, 3 mg / ml, 4 mg / ml, 5 mg / ml, 10 mg / ml, 15 mg / ml, and 19 mg / ml. As per one embodiment of the present invention, one or more preservatives can be selected from but not limited to benzoic acid, potassium sorbate, sodium benzoate, chlorobutanol, ethanol, butyl paraben, propyl paraben, methyl paraben benzalkonium chloride, benzethonium chloride, benzyl alcohol, chlorobutanol, m- cresol, myristyl gamma picolinium chloride, phenol, 2-phenoxyethanol, phenyl mercuric nitrate, phenyl ethyl alcohol, EDTA or any combination thereof. As per preferred embodiment of the present invention, sodium benzoate is used as preservative. As per one embodiment of the present invention, sodium benzoate or the preservative can be used in the range of 0.01-10 mg / mL, preferably 0.01-8 mg / mL, more preferably 0.05-5 mg / mL, and most preferably 0.05-3 mg / mL, or any value in between such as for example 0.02 mg / ml, 0.05 mg / ml, 0.1 mg / ml, 0.5 mg / ml, 1 mg / ml, 2 mg / ml, 4 mg / ml, 6 mg / ml, 8 mg / ml, and 9 mg / ml. As per one embodiment of the present invention, one or more flavouring agents can be selected from but not limited to vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, banana, pear, peach, strawberry, raspberry, cherry, plums pineapple, apricot, peppermint, tutti frutti flavor and so forth and the like or any combination thereof. As per preferred embodiment of the present invention, frozen peppermint flavor is used as flavouring agent. As per one embodiment of the present invention, one or more flavouring agents can be used in the range of 0.01-1 mg / mL, preferably 0.05-1 mg / mL, more preferably 0.05-0.8 mg / mL, and most preferably 0.05-0.5 mg / mL, or any value in between such as for example 0.02 mg / ml, 0.05 mg / ml, 0.1 mg / ml, 0.5 mg / ml, and 0.9 mg / ml. Vehicle can be considered as any inert substance, or mixture of substances, added to increase the volume of the liquid composition of present invention in order to make the liquid formulation of the present invention suitable form. As per one embodiment of the present invention, the vehicle can be selected from purified water, glycerin, phosphate buffer, propylene glycol, glycerin containing buffers, polyethylene glycol, and polyethylene glycol 400, or any combination thereof. As per preferred embodiment of the present invention, combination of glycerin and purified water is used as vehicle. As per one embodiment of the present invention, glycerin or the vehicle can be used in the range of 1-500 mg / mL, preferably 1-400 mg / mL, more preferably 1-300 mg / mL, and most preferably 1-250 mg / mL, or any value in between such as for example 2 mg / ml, 5 mg / ml, 10 mg / ml, 20 mg / ml, 50 mg / ml, 100 mg / ml, 200 mg / ml, 300 mg / ml, 400 mg / ml, and 450 mg / ml. As per one embodiment of the present invention, purified water can be used to adjust the final volume of the formulation. As per one embodiment of the present invention, the process of preparation of an oral liquid formulation of apixaban comprising the steps of: Mixing together a therapeutically effective amount of apixaban, a salt or prodrug thereof; one or more viscosifying agents; one or more buffering agents to provide a pH of 3.5 to 4.5, and one or more pharmaceutically acceptable excipients. Preferably the method includes dissolving the one or more buffering agents in purified water before adding the same to the formulation; Preferably the method further includes adding a preservative, a sweetening agent, a humectant and an antifoaming agent; Preferably the method includes adding of thickening agents; Preferably the method includes adding one or more flavouring agents; Preferably the method includes mixing the formulation using a magnetic stirrer, and further preferably mixing at 500-1000 rpm, 4000-6000 rpm, or 500-6000 rpm; Preferably the method includes storing the final formulation in a HDPE Bottle. As per another main embodiment of the present invention, the process of preparation of an oral liquid formulation of apixaban comprises steps: a) Dissolving buffering agent in purified water; b) Adding preservative, sweetening agent, humectant, antifoaming agent in solution of step (a) and mixing with magnetic stirrer at 500 to 1000 rpm; c) Adding Apixaban in step (b) and mixing with magnetic stirrer at 4000 -6000 rpm; d) Adding thickening agent in vessel containing vehicle and mixing with magnetic stirrer at 500 to 1000 rpm; e) Adding solution of step (d) into solution of step (c) and mixing with magnetic stirrer at 1000 - 1200 rpm; f) Adding viscosifying agent and flavouring agent in solution of step (e) and mixing with magnetic stirrer at 1000 - 1200 rpm; g) Adjusting the volume with purified water and mixing with magnetic stirrer at 5500 - 6500 rpm till getting uniform formulation; h) Storing the final formulation of step (g) High Density Polyethylene (HDPE) Bottle. As per one embodiment of the present invention, the liquid formulation can be selected from solution or suspension, more preferably suspension. As per one embodiment of the present invention, an oral liquid formulation of apixaban, a salt or prodrug thereof is stable and provides better patient compliance. As per one embodiment of the present invention, the oral liquid formulation of apixaban, a salt or prodrug thereof used to reduce the risk of stroke and systemic embolism in patients with non valvular atrial fibrillation and deep vein thrombosis and pulmonary embolism. As per one embodiment of the present invention, preferably the patient is a human patient. 5 The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. 0 EXAMPLES EXAMPLE 1: SCREENING FOR SELECTION OF VEHICLE For the selection of vehicle drug was dissolved in different vehicles like purified water alone or in combination with glycerin, propylene glycol, and PEG 400. Ingredients APXL / 170621 / 1001A APXL / 170621 / 1001B APXL / 170621 / 1001C APXL / 170621 / 1001D Quantity (mg / ml) Apixaban 1.00 1.00 1.00 1.00 Purified Water 999.00 504.00 583.00 547.00 Glycerin - 495.00 - - Propylene glycol - - 416.00 - PEG 400 - - - 452.00 Table 1: Batches for selection of Vehicle Result: Batch No. Time Point Single Maximum Unknown Total Impurities H-AXBRC02 H-AXBRC01 APXL / 170621 / 10 01A 60°C, 7 days BQL 0.25% BQL(0.01%) BQL(0.02%) APXL / 170621 / 10 01B 60°C, 7 days BQL 0.42% BQL(0.01%) BQL(0.02%) APXL / 170621 / 10 01C 60°C, 7 days BQL 0.26% BQL(0.01%) ND APXL / 170621 / 10 01D 60°C, 7 days 0.13% (RRT-0.77) 0.78% BQL(0.09%) BQL(0.02%) BQL: Below Quantitation Limit; RRT: Relative Retention Time. Table 2: Result of batches for selection of Vehicle Based on above data it can be concluded that only water or combination of water with glycerin and PG indicates less impurities as compared to batch with combination of water with polyethylene glycol 400. Glycerin is well accepted vehicle in liquid oral. Therefore, water and its combination with glycerin is 5 finalized to be used as a vehicle for initial product development. EXAMPLE 2: SCREENING FOR SELECTION OF BUFFERING AGENT For the selection of buffering agent trial drug was dissolved in citrate buffer and phosphate buffer alone and in presence of glycerin, propylene glycol, and PEG 400. Ingredients APXL / 170621 / 1002A APXL / 170621 / 1002B APXL / 1 70621 / 1002C APXL / 170621 / 1002D APXL / 170621 / 1003A APXL / 170621 / 1003B APXL / 17062 1 / 1003 C APXL / 1 70621 / 1 003D Quantity (mg / ml) Apixaban 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 lOOmM Citrate buffer pH 4 999.00 495.00 583.00 547.00 - - - - lOOmM Phosphate buffer pH 7 - - - - 999.00 495.00 583.00 547.00 Glycerin - 504.00 - - - 504.00 - - Propylene glycol - - 416.00 - - - 416.00 - PEG 400 - - - 452.00 - - - 452.00 10 Table 3: Batches for evaluating effect of buffer Result: Batch No. Time Point Single Maximum Unknown Total Impurities H-AXBRC02 H-AXBRC01 APXL / 170621 / 1002A 60°C, 7 days BQL 0.37% BQL(0.02%) BQL(0.02%) APXL / 170621 / 1002B 60°C, 7 days BQL 0.33% BQL(0.01%) BQL(0.02%) APXL / 170621 / 1002C 60°C, 7 days 0.12% (RRT- 0.55) 0.45% BQL(0.02%) BQL(0.02%) APXL / 170621 / 1002D 60°C, 7 days 0.13% (RRT- 0.34) 0.54% BQL(0.02%) BQL(0.02%) APXL / 170621 / 1003A 60°C, 7 days BQL 0.23% BQL(0.05%) BQL(0.01%) APXL / 170621 / 1003B 60°C, 7 days 0.28% (RRT- 0.90) 0.93% 0.32% BQL(0.01%) APXL / 170621 / 1003C 60°C, 7 days 0.12% (RRT- 0.55) 0.72% 0.32% BQL(0.00%) APXL / 170621 / 1003D 60°C, 7 days 0.28% (RRT- 1.05) 1.42% 0.22% BQL(0.01%) BQL: Below Quantitation Limit; RRT: Relative Retention Time Table 4: Results for evaluating effect of buffer Based on above data it can be concluded that, in presence of glycerin and lOOmM 5 citrate buffer in combination showed less impurities as compared to batches in combination with propylene glycol and polyethylene glycol 400. In presence of glycerin, propylene glycol or polyethylene glycol 400 in combination with lOOmM phosphate buffer showed relatively higher but acceptable higher impurities. Therefore, glycerin with lOOmM citrate buffer was finalized to be used as a vehicle 10 for initial product development. EXAMPLE 3: OPTIMIZED FORMULATION OF ORAL LIQUID SUSPENSION OF APIXABAN (APXL / 100522 / 1021) Sr. No. Ingredients Quantity (mg) / mL 1 Apixaban 1.00 2 Sucralose 2.00 3 Xanthan gum 4.50 4 Sodium benzoate 1.00 5 Citric acid anhydrous 12.25 6 Sodium citrate 10.50 7 Simethicone 3.00 8 Liquid sorbitol 200 9 Frozen peppermint 0.10 10 Glycerine 200 11 Purified water QS to 1 mL Table 5: Optimized formulation of oral liquid suspension of Apixaban Procedure: a) The Citric acid anhydrous and Sodium citrate was dissolved in purified water; b) The Sodium benzoate, Sucralose, glycerin, simethicone were added in solution of step (a) and mixed with magnetic stirrer at 500 to 1000 rpm; c) Apixaban was added in step (b) and mixed with magnetic stirrer at 4000 -6000 rpm; d) The xanthan gum was added in vessel containing glycerin and mixed with magnetic stirrer at 500 to 1000 rpm; e) The solution of step (d) was added into solution of step (c) and mixed with magnetic stirrer at 1000 - 1200 rpm; f) The Liquid sorbitol and frozen peppermint was added in solution of step (e) and mixed with magnetic stirrer at 1000 - 1200 rpm; g) The volume was adjusted with purified water and mixed with magnetic stirrer at 5500 - 6500 rpm till getting uniform formulation; h) Storing the final formulation of step (g) High Density Polyethylene (HDPE) Bottle. EXAMPLE 4: THERMAL STABILITY DATA OF FINAL FORMULATION The thermal stability study was conducted for final formulation at accelerated stability condition 40°C±2°C / NMT 75% RH and 25°C±2°C / 60±5%RH. Batch no. APXL / 100522 / 1021 Pack Details 185 CC HDPE bottle packed in secondary white box Test paramete rs Storage condition Initial 40°C±2°C / NMT 75% RH 25°C±2°C / 60±5%RH IM 3M 6M IM 3M 6M 9M 12M Specificatio n Inver t Inver t Invert Invert Invert Invert Invert Invert Descripti on Off white-to-white suspension Compli es Comp lies Comp lies Compli es Compl ies Compli es Compli es Compli es Compli es Assay of Apixaba n 90.0% to 110.0% of labelled amount 97.3 97.1 98.9 95.9 98.1 98 98.2 101.9 99.6 Assay of Sodium Benzoate 80% to 110.0% of labelled amount 96.3 95.4 95.2 94.6 96.4 95.3 97.1 100 99.3 PH Should be between 3.5 to 4.5 3.9 4.01 4.03 4.01 3.99 4.02 4.02 4.00 4.02 Zeta potential Between -10 mV to -50 mV -16.9 mV NA -17.7 mV -18.1 mV NA -17.6 mV -20.6 mV -21.3 mV -24.9 mV Viscosity Should be between 150 cP to 250 cP 203 cP NA 189 cP 189 cP NA 197 cP 205 cP 189.3 cP 190.8c P Particle size D(10): NMT 35.0 pm 21.3 pm NA 22.4 pm 20.6 pm NA 20.1 pm 20.1 pm 20.1 pm 19.6 pm D (50): NMT 90.0 pm 64.8 pm 63.2 pm 63.4 pm 63.3 pm 61.7 pm 62.7 pm 62.2 pm D(10): NMT 170.0 pm 129 pm 127 pm 128 pm 128 pm 125 pm 127 pm 126 pm Related substances (By HPLC) Impurity H-AXBRC 01 NMT 0.5% BQL BQL BQL BQL BQL BQL BQL BQL BQL Impurity H-AXBRC 02 NMT 0.5% BQL BQL BQL BQL BQL BQL BQL BQL BQL Single Max unknow n NMT 0.2% BQL BQL 0.06 % 0.06% 0.06% 0.06% 0.06% BQL BQL Total Impuriti es NMT 1.5% NA NA 0.06 % 0.06% 0.06% 0.06% 0.06% 0.00% 0.00% NMT: Not More Than; RH: Relative Humidity; M: Months Table 6: Results of stability study Particle Size: Particle size was measured by using Malvern Mastersizer 3000 instrument. Sample Preparation: Take 20 ml water into 50 ml beaker and transfer accurately 10 ml sample into it and vortex for one minute. Avoid bubbles during sample preparation. Dispersant: Water Procedure: Note: After adding the sample into dispersion tank wait for two minutes before measurement. Wash dispersant tank first with water and with methanol followed by twice wash with water and finally fill dispersant tank with dispersant. Set method parameters as mentioned above. Initialize instrument and measure background. Once initialization and background finished, add sample preparation with continuous stirring to dispersant tank and wait for two minutes. If obscuration found stable and within the specified range then start sample measurement. Report average result of three measurements. After completion of analysis wash dispersant tank with chloroform twice, once with isopropyl alcohol and followed by wash with methanol twice. In between the sample analysis wash dispersant tank once with chloroform and following wash with dispersant. Zeta Potential: Zeta potential was measured by using Malvern Zetasizer ZEN3600 instrument. Sample preparation: Transfer 1 ml of sample suspension in to 10 ml volumetric flask and dilute up to mark with water (Milli-Q) and mix well. Procedure: Note: The cuvette should be filled to a depth of between 6 mm to 8 mm. Fill the sample in to cuvettes, then insert dip cell with cuvette in to sample holder and start to measure sample. Avoid bubbles in sample preparation while filling dip cell. Thoroughly rinse dip cell with pure dispersant before next sample analysis. Viscosity: Viscosity was measured by using Brookfield viscometer. Procedure: Set the instrument as per the requirement, add sample in the Beaker / Suitable container and maintain the temperature 25 ± 2°C. Select the spindle and run the instrument at 50 rpm. Record results. Based on above data, final formulation was found to be stable at accelerated condition up to 6 months and at real time temperature (i.e. 25°C±2°C) up to 12M. EXAMPLE 5: STRESS STUDIES Stress studies (photo stability and freeze-thaw) were performed to evaluate and verify the final product processing and handing during the storage and transportation to establish controlled storage and handling. 5.1: PHOTO STABILITY STUDIES The final formulation was filled into the 185 mL HDPE bottle subjected to a photo stability study. The total light exposure of an overall illumination of 1.2 million lux hours and an integrated near ultraviolet energy of not less than 200- watt hours / square meter was provided. Result: Condition | Specification | Photostability Study Time Point Primary pack Secondary pack Clear PET Bottle Aluminium Wrapped bottle 1 Description White to off white suspension White Suspension White Suspension White Suspension White Suspension 2 Assay of Apixaban 90.0% to 110.0% of labelled amount 98.8 98.3 98.6 98.7 3 Assay of Sodium Benzoate 80% to 110.0% of labelled amount 99.7 98.9 100.1 99.3 4 pH 3.5-4.5 3.95 3.95 3.97 3.96 5 Related substances (By HPLC) H-AXBRC02 NMT 0.5% ND ND ND ND H-AXBRC01 NMT 0.5% BQL BQL BQL BQL Single Max unknown NMT 0.2% BQL BQL BQL BQL Total Impurities NMT 1.5% 0.00% 0.00% 0.00% 0.00% ND: Not Detected Table 7: Results of photostability study As per the results, when product was exposed to light in clear bottle single maximum impurity was detected BQL and total impurities was 0.0%, which 5 suggested that product was not getting affected by exposure to light. 5.2: FREEZE THAW STUDIES The final formulation bottles were subjected to a temperature cycle of -20°C ± 5°C for 2 days followed by 40°C ± 2°C for 2 days. The product bottles were subjected 10 to three such cycles. Result: Condition Specification Freeze Thaw 3rd cycle 1 Description To be decided White Suspension 2 Assay of Apixaban 90.0% to 110.0% 98.5% of labelled amount 3 Assay of Sodium Benzoate 80% to 110.0% of labelled amount 99.4 4 pH 3.5-4.5 3.96 5 Related substances (By HPLC) H-AXBRC02 NMT 0.5% ND H-AXBRC01 NMT 0.5% BQL (0.02%) Single Max unknown NMT 0.2% BQL Total Impurities NMT 1.5% 0.00% Single Max unknown: Any single unknown impurity Table 8: Results of freeze thaw study The results indicated that the product stability was not affected by the extreme temperature conditions encountered by the drug product and the product can 5 withstand limited temperature excursions during the transportation process. EXAMPLE 6: COMPARITIVE STUDY OF APIXABAN MARKETED 5 MG TABLET (ELIQUIS) AND LIQUID FORMULATION-DISSOLUTION IN 0.01 N HC1 + 0.05% SLS Time (minutes) Marketed Formulation Apixaban Suspension 0 0 0 5 29 82 10 64 90 15 79 95 10 Table 9: Apixaban dissolution study result in 0.01N HC1 and 0.05%SLS EXAMPLE 7: COMPARITIVE STUDY OF APIXABAN MARKETED 5 MG TABLET (ELIQUIS) AND LIQUID FORMULATION-DISSOLUTION-pH 4.5 Acetate Buffer + 0.05% SLS Time (minutes) Marketed Formulation Apixaban Suspension 0 0 0 5 42 82 10 83 93 15 90 96 Table 10: Apixaban dissolution study result in phosphate buffer (pH 4.5) 5 and 0.05%SLS EXAMPLE 8: COMPARITIVE STUDY OF APIXABAN MARKETED 5 MG TABLET (ELIQUIS) AND LIQUID FORMULATION-APIXABAN DISSOLUTION- pH 6.8 Phosphate Buffer + 0.05% SLS Time (minutes) Marketed Formulation Apixaban Suspension 0 0 0 5 35 76 10 71 92 15 87 96 10 Table 11: Apixaban dissolution study result in phosphate buffer (pH 6.8) and 0.05%SLS The results of comparative dissolution study of apixaban marketed tablet and liquid formulation proved that the Apixaban liquid formulation gives higher dissolution 15 compare to marketed tablet formulation.

Claims

17 12251. An oral liquid formulation, consisting of: apixaban in an amount of 1 mg / mL;5 a thickening agent comprising xanthan gum in an amount of 4.5 mg / mL;a buffering agent comprising citric acid in an amount of 12.25 mg / mL, and sodium citrate in an amount of 10.5 mg / mL;an antifoaming agent comprising simethicone in an amount of 3 mg / mL;a viscosifying agent comprising sorbitol in an amount of 200 mg / mL;10 one or more pharmaceutically acceptable excipients comprising a sweetening agent, a preservative, a flavoring agent, or a combination thereof; anda vehicle comprising glycerin in an amount of 200 mg / mL, and water, wherein the oral liquid formulation is in the form of suspension and has a15 pH of from 3.5 to 4.5.

2. The oral liquid formulation of claim 1, wherein the sweetening agent comprises sucralose in an amount of 2 mg / mL.20 3. The oral liquid formulation of claim 1, wherein the preservative comprisessodium benzoate in an amount of 1 mg / mL.

4. The oral liquid formulation of claim 1, wherein the flavoring agent comprises frozen peppermint in an amount of 0.1 mg / mL.

255. The oral liquid formulation of claim 1, wherein the formulation is stable after storage at 40°C±2°C up to 6 months.

6. The oral liquid formulation of claim 1, wherein the formulation has a total30 apixaban impurity content of 0.06% after storage at 40°C±2°C / NMT 75% RH up to 6 months.

7. The oral liquid formulation of claim 1, wherein the formulation is stableafter storage at 25°C±2°C up to 12 months.17 12258. The process for preparation of an oral liquid formulation of apixaban as5 claimed in claim 1, comprises steps: a) Dissolving buffering agents in purified water; b) Adding preservative, sweetening agent, vehicle purified water and glycerin, antifoaming agent in solution of step (a) and mixing with magnetic stirrer at 500 to 1000 rpm; 10 c) Adding apixaban in step (b) and mixing with magnetic stirrer at 4000 - 6000 rpm; d) Adding thickening agent in vessel containing vehicle and mixing with magnetic stirrer at 500 to 1000 rpm; e) Adding solution of step (d) into solution of step (c) and mixing with 15 magnetic stirrer at 1000 - 1200 rpm; f) Adding viscosifying agent and flavouring agent in solution of step (e) and mixing with magnetic stirrer at 1000 - 1200 rpm; g) Adjusting the volume with purified water and mixing with magnetic stirrer at 5500 - 6500 rpm till getting uniform formulation; 20 h) Storing the final formulation of step (g) in high density polyethylene(HDPE) bottle.