An oral liquid formulation of anticoagulant drugs

Abstract

An oral liquid formulation of anticoagulant drugs comprising rivaroxaban, a salt or prodrug thereof; one or more viscosifying agents; at least one wetting agent; at least one vehicle, and one or more

Description

[0001] AN ORAL LIQUID FORMULATION OF ANTICOAGULANT DRUGS

[0002] RELATED APPLICATION

[0003] This application claims priority to IN Patent Application No. 202321052903 filed on August 7, 2023, the subject matter of which is incorporated by reference in its entirety.

[0004] FIELD OF THE INVENTION

[0005] The present invention is related to an oral liquid formulation of anticoagulant drugs. The present invention is specifically related to an oral liquid formulation of anticoagulant drugs comprising therapeutically effective amount of rivaroxaban, a salt or prodrug thereof; one or more viscosifying agents; one or more buffering agents; at least one wetting agent; at least one vehicle, and one or more pharmaceutically acceptable excipients. The present invention also related to process of preparation of an oral liquid formulation of anticoagulant drugs.

[0006] BACKGROUND OF THE INVENTION

[0007] Deep vein thrombosis (DVT) is a blood clot in a vein located deep inside the body of a person usually in a patient’s leg. DVT generally occurs when a thrombus (blood clot) develops in veins deep inside someone’s body because of the injured veins or the sluggish blood flowing through the veins. Symptoms can include pain, swelling, redness and enlarged veins in the affected area. The most common lifethreatening concern with DVT is the potential for a clot to embolize (detach from the veins), travel as an embolus through the right side of the heart, and become lodged in a pulmonary artery that supplies blood to the lungs. This is called a pulmonary embolism (PE). DVT and PE comprise the cardiovascular disease of venous thromboembolism (VTE).

[0008] Anticoagulants are a group of medications that decrease your blood’s ability to clot. They can break down existing clots or prevent clots from forming in the first place. These medications can help stop life-threatening conditions like strokes, heart attacks and pulmonary embolisms, all of which can happen because of blood clots. The anticoagulants include low molecular weight heparins (LMWHs), unfractionated heparin (UFH), factor Xa inhibitors: oral (eg: rivaroxaban, apixaban, edoxaban) and parenteral (fondaparinux), direct thrombin inhibitors: oral (dabigatran etexilate) and parenteral (argatroban, bivalirudin, desirudin), and warfarin.

[0009] Among the anticoagulant drugs, rivaroxaban is a tasteless, non -hygroscopic, white to yellowish powder, is a low-solubility, high-permeability drug used to prevent the formation of Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) in patients after hip and knee replacement. Can also be used for preventing cerebral apoplexy and non-central nervous system embolism of patients with non-valvular atrial fibrillation, and reducing the risk of coronary artery syndrome recurrence.

[0010] Rivaroxaban, sold under the brand name Xarelto among others, is an anticoagulant medication (blood thinner) used to treat and prevent blood clots. Specifically, it is used to treat deep vein thrombosis and pulmonary emboli and prevent blood clots in atrial fibrillation and following hip or knee surgery. It is generally administered orally.

[0011] Rivaroxaban competitively inhibits free and clot bound factor Xa. Factor Xa is needed to activate prothrombin (factor II) to thrombin (factor Ila). Thrombin is a serine protease that is required to activate fibrinogen to fibrin, which is the loose meshwork that completes the clotting process. Since one molecule of factor Xa can generate more than 1000 molecules of thrombin, selective inhibitors of factor Xa are profoundly useful in terminating the amplification of thrombin generation. The action of rivaroxaban is irreversible.

[0012] In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. Sometimes drug absorption is measured in terms of bioavailability. Bioavailability is the ability of a drug or other substance to be absorbed and used by the body. The rate of the drug absorbed determines the onset of action of the drug. The various formulations of the drugs take different time for getting absorbed and showing their effect on the site of action. Tablet and capsule formulation are the most used formulation, but the tablets and capsule takes time for absorption as first they need to be dissolve and disintegrate before absorption. To overcome the disadvantages of tablets and capsules, oral liquid formulations of different drugs have been developed. Liquid formulations of drugs have faster absorption rate and ultimately have a higher bioavailability. Also, liquid formulations are in better compliance with children and patients of various age groups as they are easy to administer.

[0013] Currently, the marketed formulation of rivaroxaban is in the form of tablets. Also, most of the suspensions available in the market are for the reconstitution of rivaroxaban into a suspension, but there are certain disadvantages of reconstitution. Inappropriately reconstituted medications, can lead to adverse effects, including both under doses and overdoses of drugs leading treatment failures. Moreover, reconstituting of drugs cannot be done by a common man thus leading to help from a technically advanced person. Thus, reconstituting of drugs sometimes require technical assistance. Hence, there is need to develop an oral liquid formulation of rivaroxaban which will overcome the above stated disadvantages of the above dosage forms and will also provide faster onset of action in life-threatening disease.

[0014] Therefore, the inventors in the present invention have arrived to an oral liquid formulation of anticoagulant drugs, preferably, rivaroxaban with aims to overcome problems cited above by preparing an oral liquid formulation of rivaroxaban as described herein.

[0015] OBJECTIVES OF THE INVENTION

[0016] The main objective of the present invention is to develop an oral liquid formulation of anticoagulant drugs. Another objective of this invention is to provide an oral liquid formulation of anticoagulant drugs which is stable.

[0017] Yet another objective of this invention is to provide an oral liquid formulation of anticoagulant drugs which provides better patient compliance.

[0018] Yet another objective of this invention is to provide an oral liquid formulation of anticoagulant drugs which is easy to manufacture at large scale.

[0019] Yet another objective of this invention is to provide an oral liquid formulation of anticoagulant drugs which gives faster absorption and quicker onset of action.

[0020] SUMMARY OF THE INVENTION

[0021] The present invention is all about to provide an oral liquid formulation of drugs from class of anticoagulant or factor Xa inhibitors like apixaban, rivaroxaban, edoxaban, betrixaban, fondaparinux, etc.

[0022] The main aspect of the present invention is to provide an oral liquid formulation of anticoagulant drugs.

[0023] The other main aspect of the present invention is to provide an oral liquid formulation of anticoagulant drugs comprising therapeutically effective amount of rivaroxaban, a salt or prodrug thereof; one or more viscosifying agents; one or more buffering agents; at least one wetting agent; at least one vehicle, and one or more pharmaceutically acceptable excipients.

[0024] The other main aspect of the present invention is to provide an oral liquid formulation of anticoagulant drugs consisting of therapeutically effective amount of rivaroxaban, a salt or prodrug thereof; one or more viscosifying agents; one or more buffering agents; at least one wetting agent; at least one vehicle, and one or more pharmaceutically acceptable excipients. The other main aspect of the present invention is to provide an oral liquid formulation comprising therapeutically effective amount of rivaroxaban, a salt or prodrug thereof; one or more viscosifying agents; one or more buffering agents; at least one wetting agent; at least one vehicle, and one or more pharmaceutically acceptable excipients.

[0025] The other main aspect of the present invention is to provide an oral liquid formulation consisting of therapeutically effective amount of rivaroxaban, a salt or prodrug thereof; one or more viscosifying agents; one or more buffering agents; at least one wetting agent; at least one vehicle, and one or more pharmaceutically acceptable excipients.

[0026] Another aspect of the present invention provides a process for the preparation of an oral liquid formulation of anticoagulant drugs comprising rivaroxaban, a salt or prodrug thereof.

[0027] One more aspect of the present invention is to provide an oral liquid formulation of anticoagulant drugs comprising therapeutically effective amount of rivaroxaban, a salt or prodrug thereof used for the treatment to inhibiting platelet aggregation induced by thrombin and preventing blood clots formation, reduction of risk of stroke and systemic embolism in nonvalvular atrial fibrillation, treatment of deep vein thrombosis, treatment of pulmonary embolism, reduction in the risk of recurrence of deep vein thrombosis and / or pulmonary embolism, prophylaxis of deep vein thrombosis following hip or knee replacement surgery, prophylaxis of venous thromboembolism in acutely ill medical patients at risk for thromboembolic complications not at high risk of bleeding, reduction of risk of major cardiovascular events in patients with coronary artery disease (CAD), reduction of risk of major thrombotic vascular events in patients with peripheral artery disease (PAD), including patients after lower extremity revascularization due to symptomatic PAD, treatment of venous thromboembolism and reduction in risk of recurrent venous thromboembolism in pediatric patients, thromboprophylaxis in pediatric patients with congenital heart disease after the fontan procedure.

[0028] One more aspect of the present invention is to provide an oral liquid formulation of anticoagulant drugs comprising therapeutically effective amount of rivaroxaban, a salt or prodrug thereof for use as a medicament for the treatment to inhibiting platelet aggregation induced by thrombin and preventing blood clots formation, reduction of risk of stroke and systemic embolism in nonvalvular atrial fibrillation, treatment of deep vein thrombosis, treatment of pulmonary embolism, reduction in the risk of recurrence of deep vein thrombosis and / or pulmonary embolism, prophylaxis of deep vein thrombosis following hip or knee replacement surgery, prophylaxis of venous thromboembolism in acutely ill medical patients at risk for thromboembolic complications not at high risk of bleeding, reduction of risk of major cardiovascular events in patients with coronary artery disease (CAD), reduction of risk of major thrombotic vascular events in patients with peripheral artery disease (PAD), including patients after lower extremity revascularization due to symptomatic PAD, treatment of venous thromboembolism and reduction in risk of recurrent venous thromboembolism in pediatric patients, thromboprophylaxis in pediatric patients with congenital heart disease after the fontan procedure.

[0029] One more aspect of the present invention is to provide an oral liquid formulation comprising therapeutically effective amount of rivaroxaban, a salt or prodrug thereof for use as a medicament for the treatment to inhibiting platelet aggregation induced by thrombin and preventing blood clots formation, reduction of risk of stroke and systemic embolism in nonvalvular atrial fibrillation, treatment of deep vein thrombosis, treatment of pulmonary embolism, reduction in the risk of recurrence of deep vein thrombosis and / or pulmonary embolism, prophylaxis of deep vein thrombosis following hip or knee replacement surgery, prophylaxis of venous thromboembolism in acutely ill medical patients at risk for thromboembolic complications not at high risk of bleeding, reduction of risk of major cardiovascular events in patients with coronary artery disease (CAD), reduction of risk of major thrombotic vascular events in patients with peripheral artery disease (PAD), including patients after lower extremity revascularization due to symptomatic PAD, treatment of venous thromboembolism and reduction in risk of recurrent venous thromboembolism in pediatric patients, thromboprophylaxis in pediatric patients with congenital heart disease after the fontan procedure.

[0030] One or more aspects of the present invention is rivaroxaban may be used alone or in combination with other anticoagulant agents.

[0031] DETAILED DESCRIPTION OF THE INVENTION

[0032] The main embodiment of the present invention is an oral liquid formulation of anticoagulant drugs.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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.

[0037] The following terms are used interchangeably herein: "active", "drug", and "active ingredient".

[0038] 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.

[0039] As used herein the word “liquid formulation” refers to liquid oral formulation like solution, suspension or emulsion, more preferably in the form of suspension.

[0040] 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.

[0041] By the term "pH", as used herein, is meant "apparent pH" wherein the pH measurement is carried out on the rivaroxaban containing composition in final form, for example, by measuring the pH of the formulation.

[0042] The main embodiment of the present invention is to provide an oral liquid formulation of anticoagulant drugs comprising therapeutically effective amount of rivaroxaban, a salt or prodrug thereof; one or more viscosifying agents; one or more buffering agents; at least one wetting agent; at least one vehicle, and one or more pharmaceutically acceptable excipients.

[0043] The other main embodiment of the present invention is to provide an oral liquid formulation of anticoagulant drugs consisting of therapeutically effective amount of rivaroxaban, a salt or prodrug thereof; one or more viscosifying agents; one or more buffering agents; at least one wetting agent; at least one vehicle, and one or more pharmaceutically acceptable excipients.

[0044] The other main embodiment of the present invention is to provide an oral liquid formulation comprising therapeutically effective amount of rivaroxaban, a salt or prodrug thereof; one or more viscosifying agents; one or more buffering agents; at least one wetting agent; at least one vehicle, and one or more pharmaceutically acceptable excipients.

[0045] The other main embodiment of the present invention is to provide an oral liquid formulation consisting of therapeutically effective amount of rivaroxaban, a salt or prodrug thereof; one or more viscosifying agents; one or more buffering agents; at least one wetting agent; at least one vehicle, and one or more pharmaceutically acceptable excipients.

[0046] As per one embodiment of the present invention, rivaroxaban 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 range in between thereof.

[0047] As per another embodiment one or more viscosifying agents in the present invention can be selected from Avicel-RC 591, a combination of microcrystalline cellulose, and carboxymethylcellulose sodium, microcrystalline cellulose, sodium carboxymethyl cellulose, hydroxypropylmethylcellulose (HPMC), xanthan gum, acacia, tragacanth, alginates, guar gum, and colloidal silicon dioxide or any combination thereof.

[0048] As per another embodiment of the present invention, Avicel-RC 591 or a combination of microcrystalline cellulose, and carboxymethylcellulose sodium are same or interchangeable.

[0049] As per one embodiment of the present invention, one or more viscosifying agents, preferably combination of two viscosifying agents. As per preferred embodiment of the present invention, combination of Avicel-RC 591, and xanthan gum is used as viscosifying agents.

[0050] As per one embodiment of the present invention, Avicel-RC 591 or one or more viscosifying agents can be used in the range of 0.5-30 mg / mL, preferably 0.5-20 mg / mL, more preferably 1-20 mg / mL, and most preferably 1-18 mg / mL or any other range in between thereof.

[0051] As per one embodiment of the present invention, xanthan gum or one or more viscosifying agents can be used in the range of 0.5-30 mg / mL, preferably 0.5-20 mg / mL, more preferably 1-20 mg / mL and most preferably 1-18 mg / mL or any other range in between thereof.

[0052] The buffers used in the present invention is generally recognized as safe (GRAS) by the U.S. Food and Drug Administration.

[0053] As per one embodiment of the present invention, one or more buffering agents can be selected from sodium citrate, sodium acetate trihydrate, phosphate, citric acid, tris, succinate, histidine, glycine, arginine, malic, tartaric, acetic, benzoic, gluconic, glyceric, lactic, adipic, ascorbic, carbonic, glutamic, ammonium chloride, triethanolamine and salts or acids thereof or any combination thereof.

[0054] As per one embodiment of the present invention, one or more buffering agents, preferably combination of two buffering agents. As per preferred embodiment of the present invention, combination of sodium citrate, and citric acid is used as buffering agents.

[0055] As per one embodiment of the present invention, sodium citrate or one or more buffering agents can be used in the range of 0.5-30 mg / mL, preferably 0.5-20 mg / mL, more preferably 1-20 mg / mL, and most preferably 1-15 mg / mL or any other range in between thereof.

[0056] As per one embodiment of the present invention, citric acid or one or more buffering agents can be used in the range of 0.5-30 mg / mL, preferably 1-30 mg / mL, more preferably 1-25 mg / mL, and most preferably 1-20 mg / mL or any other range in between thereof. As per one another embodiment of the present invention, at least one wetting agent can be selected from sodium lauryl sulphate, simethicone, sodium tetradecyl sulphate, dodecyl sulphate, poloxamers, tween 80, tween 20, tween 40, tween 60, sorbitan monolaurate, lauryl glucoside or any combination thereof.

[0057] As per preferred embodiment of the present invention, sodium lauryl sulphate is used as surfactant or a wetting agent.

[0058] As per one embodiment of the present invention, sodium lauryl sulphate or at least one wetting agent can be used in the range of 0.5-20 mg / mL, preferably 1-20 mg / mL, and most preferably 0.5-10 mg / mL or any other range in between thereof.

[0059] As per one embodiment of the present invention, the one or more pharmaceutically acceptable excipients can be selected from anti foaming agent, sweetening agent, preservative, and flavoring agent.

[0060] As per another embodiment of the present invention, the term inactive excipients or pharmaceutically acceptable excipients are same or interchangeable.

[0061] As per one embodiment of the present invention, at least one anti-foaming agent can be selected from simethicone, organic phosphates, stearates, alcohols, paraffin oils, and glycols or any combination thereof.

[0062] As per preferred embodiment of the present invention, simethicone is used as antifoaming agent.

[0063] As per one embodiment of the present invention, simethicone or at least one antifoaming agent can be used in the range of 0.5-20 mg / mL, preferably 1-20 mg / mL, and most preferably 1-10 mg / mL or any other range in between thereof. As per one embodiment of the present invention, at least one sweetening agent 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.

[0064] As per preferred embodiment of the present invention, sucralose is used as sweetening agent.

[0065] As per one embodiment of the present invention, at least one 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 other range in between thereof.

[0066] As per one embodiment of the present invention, at least one preservative 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.

[0067] As per preferred embodiment of the present invention, sodium benzoate can used as preservative.

[0068] As per one embodiment of the present invention, sodium benzoate or at least one 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 other range in between thereof. As per one embodiment of the present invention, at least one flavouring agent 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.

[0069] As per preferred embodiment of the present invention, frozen peppermint flavor is used as flavouring agent.

[0070] As per one embodiment of the present invention, at least one flavoring agent 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 other range in between thereof.

[0071] 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.

[0072] As per one embodiment of the present invention, at least one vehicle can be selected from purified water, glycerin, phosphate buffer, propylene glycol, polyethylene glycol (PEG), PEG 400, glycerin containing buffers or any combination thereof.

[0073] As per preferred embodiment of the present invention, glycerin or combination of glycerin, and purified water is used as vehicle.

[0074] As per one embodiment of the present invention, glycerin can be used in the range of 1-500 mg / mL, preferably 1-200 mg / mL, more preferably 1-100 mg / mL, and most preferably 1-50 mg / mL or any other range in between thereof. As per one embodiment of the present invention, purified water can be used to adjust the final volume of the formulation.

[0075] As per another main embodiment of the present invention, the process of preparation of an oral liquid formulation of anticoagulant drugs, comprising the steps of: mixing together a therapeutically effective amount of rivaroxaban, a salt or prodrug thereof; one or more viscosifying agents; one or more buffering agents; at least one wetting agent; at least one vehicle, and one or more pharmaceutically acceptable excipients.

[0076] Preferably the process includes solubilizing citric acid in purified water to act as one of the buffering agents.

[0077] Preferably the process includes adding the sodium citrate to the solution.

[0078] Preferably the process includes adding and mixing of sodium benzoate, sucralose, simethicone, Avicel-RC591 to the solution till gets completely solubilized.

[0079] Preferably the process includes adding and mixing of sodium lauryl sulphate, glycerin in solution till gets completely solubilized.

[0080] Preferably the process includes adding and mixing of rivaroxaban in solution till gets completely solubilized.

[0081] Preferably the process includes adding and mixing xanthan gum in remaining quantity of glycerin in separate vessel and mixing till get homogenously dispersed. Preferably the process includes adding and mixing flavoring agent in solution and mixing it till gets completely dispersed.

[0082] Preferably the process adjusting the volume using purified water, mixing and homogenizing the formulation using homogenizer till homogeneous formulation obtained.

[0083] Preferably the process includes storing the final formulation in a HDPE Bottle.

[0084] As per another main embodiment of the present invention, the process of preparation of oral liquid formulation of anticoagulant drugs comprising steps: a) Adding and mixing citric acid in purified water till gets completely solubilized; b) Adding and mixing sodium citrate in solution of step (a) till gets completely solubilized; c) Adding and mixing sodium benzoate in solution of step (b) till gets completely solubilized; d) Adding and mixing sucralose in solution of step (c) till gets completely solubilized; e) Adding and mixing simethicone in solution of step (d) till gets completely solubilized; f) Adding and mixing Avicel-RC591 in solution of step (e) till gets completely solubilized and till achieve desirable viscosity; g) Adding and mixing sodium lauryl sulphate in solution of step (f) till gets completely solubilized; h) Adding and mixing glycerin in solution of step (g) till gets completely solubilized; i) Adding and mixing rivaroxaban in solution of step (h) till gets completely solubilized; j) Adding xanthan gum in remaining quantity of glycerin in separate vessel and mixing till get homogenously dispersed; k) Adding solution of step (h) into slurry of step (j) and continuously stirring the solution till get homogenously dispersed; l) Adding flavoring agent in solution of step (k) and mixing it till gets completely dispersed; m) Adjusting the volume of step (1) using purified water, mixing and homogenizing the formulation using homogenizer till homogeneous formulation obtained. n) Storing the final formulation in a HDPE bottle.

[0085] As per one embodiment of the present invention, an oral liquid formulation of anticoagulant drugs comprising therapeutic effective amount of rivaroxaban, a salt or prodrug thereof; a combination of Avicel-RC 591, and xanthan gum as viscosifying agents; a combination of sodium citrate, and citric acid as buffering agents; a sodium lauryl sulphate as a wetting agent, and one or more pharmaceutically acceptable excipients.

[0086] As per one embodiment of the present invention, an oral liquid formulation of anticoagulant drugs consisting of therapeutic effective amount of rivaroxaban, a salt or prodrug thereof; a combination of Avicel-RC 591, and xanthan gum as viscosifying agents; a combination of sodium citrate, and citric acid as buffering agents; a sodium lauryl sulphate as a wetting agent, and one or more pharmaceutically acceptable excipients.

[0087] As per one embodiment of the present invention, an oral liquid formulation of anticoagulant drugs comprising 0.5-500 mg / mL rivaroxaban, a salt or prodrug thereof; a combination of 0.5-30 mg / mL Avicel-RC 591, and 0.5-20 mg / mL xanthan gum as viscosifying agents; a combination of 0.5-30 mg / mL sodium citrate, and 0.5-30 mg / mL citric acid as buffering agents; 0.5-20 mg / mL sodium lauryl sulphate as wetting agent, and one or more pharmaceutically acceptable excipients.

[0088] As per one embodiment of the present invention, an oral liquid formulation of anticoagulant drugs comprising rivaroxaban, a salt or prodrug thereof; a combination of Avicel-RC 591, and xanthan gum as viscosifying agents; a combination of sodium citrate, and a citric acid as buffering agents; a sodium lauryl sulphate as a wetting agent; a simethicone as antifoaming agent; a sucralose as a sweetening agent; a sodium benzoate as a preservative; a frozen peppermint as a flavouring agent, and a glycerin in water as a vehicle.

[0089] As per one embodiment of the present invention, an oral liquid formulation of anticoagulant drugs consisting of rivaroxaban, a salt or prodrug thereof; a combination of Avicel-RC 591, and xanthan gum as viscosifying agents; a combination of sodium citrate, and a citric acid as buffering agents; a sodium lauryl sulphate as a wetting agent; a simethicone as antifoaming agent; a sucralose as a sweetening agent; a sodium benzoate as a preservative; a frozen peppermint as a flavouring agent, and a glycerin in water as a vehicle.

[0090] As per one embodiment of the present invention, an oral liquid formulation of anticoagulant drugs comprising 1-10 mg / mL rivaroxaban, a salt or prodrug thereof; a combination of 1-15 mg / mL Avicel-RC 591, and 1-10 mg / mL xanthan gum as viscosifying agents; a combination of 1-15 mg / mL sodium citrate, and 1-20 mg / mL citric acid as buffering agents; 0.5-10 mg / mL sodium lauryl sulphate as wetting agent; 1-10 mg / mL simethicone as antifoaming agent; 0.5-5 mg / mL sucralose as sweetening agent; 0.05-3 mg / mL sodium benzoate as preservative; 0.05-0.5 mg / mL frozen peppermint as flavoring agent; 1-50 mg / mL of glycerin in water as vehicle.

[0091] As per one embodiment of the present invention, an oral liquid formulation of anticoagulant drugs comprising rivaroxaban having a pH range from about 3.5 to 4.5.

[0092] As per one embodiment of the present invention, the liquid formulation can be selected from solution, suspension or emulsion, preferably suspension.

[0093] As per one embodiment of the present invention, the liquid formulation is having at least 90 % purity and impurity is less than 5 % during the shelf life.

[0094] As per one embodiment of the present invention, an oral liquid formulation of anticoagulant drugs which is stable and provides better patient compliance.

[0095] As per one embodiment of the present invention, an oral liquid formulation of anticoagulant drugs comprising rivaroxaban, a salt or prodrug thereof can be useful in inhibiting platelet aggregation induced by thrombin and prevention of blood clots, reduction of risk of stroke and systemic embolism in nonvalvular atrial fibrillation, treatment of deep vein thrombosis, treatment of pulmonary embolism, reduction in the risk of recurrence of deep vein thrombosis and / or pulmonary embolism, prophylaxis of deep vein thrombosis following hip or knee replacement surgery, prophylaxis of venous thromboembolism in acutely ill medical patients at risk for thromboembolic complications not at high risk of bleeding, reduction of risk of major cardiovascular events in patients with coronary artery disease (CAD), reduction of risk of major thrombotic vascular events in patients with peripheral artery disease (PAD), including patients after lower extremity revascularization due to symptomatic PAD, treatment of venous thromboembolism and reduction in risk of recurrent venous thromboembolism in pediatric patients, thromboprophylaxis in pediatric patients with congenital heart disease after the fontan procedure.

[0096] As per one embodiment of the present invention, an oral liquid formulation of anticoagulant drugs comprising rivaroxaban, a salt or prodrug thereof for use as a medicament for the treatment to inhibiting platelet aggregation induced by thrombin and prevention of blood clots, reduction of risk of stroke and systemic embolism in nonvalvular atrial fibrillation, treatment of deep vein thrombosis, treatment of pulmonary embolism, reduction in the risk of recurrence of deep vein thrombosis and / or pulmonary embolism, prophylaxis of deep vein thrombosis following hip or knee replacement surgery, prophylaxis of venous thromboembolism in acutely ill medical patients at risk for thromboembolic complications not at high risk of bleeding, reduction of risk of major cardiovascular events in patients with coronary artery disease (CAD), reduction of risk of major thrombotic vascular events in patients with peripheral artery disease (PAD), including patients after lower extremity revascularization due to symptomatic PAD, treatment of venous thromboembolism and reduction in risk of recurrent venous thromboembolism in pediatric patients, thromboprophylaxis in pediatric patients with congenital heart disease after the fontan procedure. As per one embodiment of the present invention, an oral liquid formulation comprising rivaroxaban, a salt or prodrug thereof for use as a medicament for the treatment to inhibiting platelet aggregation induced by thrombin and prevention of blood clots, reduction of risk of stroke and systemic embolism in nonvalvular atrial fibrillation, treatment of deep vein thrombosis, treatment of pulmonary embolism, reduction in the risk of recurrence of deep vein thrombosis and / or pulmonary embolism, prophylaxis of deep vein thrombosis following hip or knee replacement surgery, prophylaxis of venous thromboembolism in acutely ill medical patients at risk for thromboembolic complications not at high risk of bleeding, reduction of risk of major cardiovascular events in patients with coronary artery disease (CAD), reduction of risk of major thrombotic vascular events in patients with peripheral artery disease (PAD), including patients after lower extremity revascularization due to symptomatic PAD, treatment of venous thromboembolism and reduction in risk of recurrent venous thromboembolism in pediatric patients, thromboprophylaxis in pediatric patients with congenital heart disease after the fontan procedure.

[0097] One or more aspects of the present invention is rivaroxaban may be used alone or in combination with other anticoagulant agents.

[0098] 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.

[0099] EXAMPLES

[0100] EXAMPLE 1: SCREENING FOR SELECTION OF VEHICLE

[0101] For the selection of vehicle drug was dissolved in different vehicles like glycerin alone or in combination with purified water and citrate and phosphate buffer. The stress study was conducted for those batches by 7 days exposure at 60°C. Compositions are summarized in below table:

[0102] Q.S.: Quantity Sufficient. Table 1: Trial batches for selection of vehicle

[0103] Result:

[0104]

[0105] Single max unknown: Any single unknown impurity; ND: Not Detected.

[0106] Table 2: Results of stress study of trial batches for selection of vehicle Based on above data it was concluded that, in presence of 100 mM phosphate buffer is not compatible with rivaroxaban (1003 A, B, C and D batches). PEG 400 is not compatible with rivaroxaban in presence of water (1001D batch). PG and glycerin are compatible with purified water and 100 mM citrate buffer. To avoid any pH fluctuation during stability and glycerin is being used widely in liquid oral products, further trials were optimized using citrate buffer in combination with glycerin.

[0107] EXAMPLE 2: EFFECT OF pH IN DEVELOPMENT OF ORAL LIQUID

[0108] FORMULATION OF RIVAROXABAN

[0109] Q.S.: Quantity Sufficient.

[0110] Table 3: Formulation batches to check the of effect of pH Result:

[0111] NMT: Not More Than; M: Months; RH: Relative Humidity; BQL: Below Quantitation Limit;

[0112] TRF No: Test Request Form No.

[0113] Table 4: Results of stability study to evaluate the effect of pH Based on above data it can be concluded that, batch no. RIRL / 080822 / 1030 (pH 6.25) showed increase level of impurities as compared to batches prepared with pH 3.8 and 5.5. As there is also presence of disodium phosphate in RIRL / 050822 / 1027 and possibility of increase in impurity at longer duration of time, it is concluded to move forward with citrate buffer-based composition (RIRL / 040822 / 1024) for further evaluation for stability studies.

[0114] EXAMPLE 3: OPTIMIZED FORMULATION OF ORAL LIQUID SUSPENSION OF RIVAROXABAN (RIRL / 070922 / 1032)

[0115] Q.S.: Quantity Sufficient

[0116] Table 5: Optimized formulation of oral liquid suspension of Rivaroxaban Procedure: a) The citric acid was added in purified water and mixed till gets completely solubilized; b) The sodium citrate was added in solution of step (a) and mixed till gets completely solubilized; c) The sodium benzoate was added in solution of step (b) and mixed till gets completely solubilized; d) The sucralose was added in solution of step (c) and mixed till gets completely solubilized; e) The simethicone was added in solution of step (d) till gets completely solubilized; f) The Avicel-RC591 was added in solution of step (e) and mixed till gets completely solubilized and till achieved desirable viscosity; g) The sodium lauryl sulphate was added in solution of step (f) and mixed till gets completely solubilized; h) The glycerin was added in solution of step (g) and mixed till gets completely solubilized; i) The rivaroxaban was added in solution of step (h) and mixed till gets completely solubilized; j) The xanthan gum was added in remaining quantity of glycerin in separate vessel and mixed till get homogenously dispersed; k) The solution of step (h) was added into slurry of step (j) and continuously stirred the solution till get homogenously dispersed; l) The flavoring agent was added in solution of step (k) and mixed it till gets completely dispersed; m) The volume of step (1) was adjusted using purified water, mixed and homogenized the formulation using homogenizer till homogeneous formulation obtained. n) The final formulation was stored in a HDPE bottle. EXAMPLE 4: THERMAL STABILITY DATA OF FINAL

[0117] FORMULATION

[0118] 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.

[0119] 5 NMT: Not More Than; NLT: Not Less Than; RH: Relative Humidity; M: Months; RSD: Relative

[0120] Standard Deviation; BQL: Below Quantitation Limit; Single max unknown: Any single unknown impurity. Table 6: Results of stability study

[0121] Based on above data, final formulation was found to be stable at accelerated condition up to 6 months and at real time temperature up to 9 months.

[0122] Particle Size: Particle size was measured by using Malvern Mastersizer 3000 instrument.

[0123] Sample Preparation: Accurately transfer about 4 gm sample into 50 ml beaker, added 20 ml water and mix well, sonicate it for 30 seconds.

[0124] Dispersant: Water

[0125] Note: Avoid bubbles during sample preparation.

[0126] Procedure:

[0127] 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 observe obscuration. If obscuration found stable and within the specified range then start sample measurement. Report average result of three measurements.

[0128] After completion of analysis wash dispersant tank with water once, followed by wash with methanol twice. In between the sample analysis wash dispersant tank once with methanol and following wash with dispersant.

[0129] Zeta Potential: Zeta potential was measured by using Malvern Zetasizer ZEN3600 instrument.

[0130] Sample preparation: Transfer 3 ml of sample suspension in to 10 ml volumetric flask and dilute up to mark with water (Milli-Q) and mix well. Precaution: Sample to be analyze immediately or else otherwise sedimentation of sample will be seen and due to that variation result will be occur.

[0131] Procedure:

[0132] Note: The cuvettes should be filled to a depth of between 6 mm to 8 mm.

[0133] 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.

[0134] Viscosity: Viscosity was measured by using Brookfield viscometer.

[0135] 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.

[0136] EXAMPLE 5: STRESS STUDIES

[0137] Stress studies (photostability 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.

[0138] 5.1: PHOTOSTABILITY STUDIES

[0139] 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.

[0140] Result:

[0141] BQL: Below Quantification Limit; NMT: Not More Than; Single max unknown: Any single unknown impurity.

[0142] Table 7: Results of photostability study

[0143] As per the results, when product was exposed to light filled in different bottles, there was no increase in impurities or decrease in assay of rivaroxaban and preservative observed, which suggest that product is not getting affected by exposure to light.

[0144] 5.2: FREEZE THAW STUDIES

[0145] 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 to three such cycles.

[0146] Result:

[0147] BQL: Below Quantification Limit; NMT: Not More Than; Single max unknown: Any single unknown impurity.

[0148] 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 withstand limited temperature excursions during the transportation process.

[0149] EXAMPLE 6: COMPARITIVE STUDY OF RIVAROXABAN MARKETED TABLET AND LIQUID FORMULATION-DISSOLUTION

[0150] Table 9: Result of dissolution study of Xarelto® tablet

[0151] Table 10: Result of dissolution study of final rivaroxaban oral suspension

[0152] The results of comparative dissolution study of rivaroxaban marketed tablet and liquid formulation proved that the rivaroxaban liquid formulation gives higher dissolution compare to marketed tablet formulation.

Claims

CLAIMS1. An oral liquid formulation of anticoagulant drugs comprising therapeutically effective amount of rivaroxaban, a salt or prodrug thereof; one or more viscosifying agents; one or more buffering agents; at least one wetting agent; at least one vehicle, and one or more pharmaceutically acceptable excipients.

2. The oral liquid formulation as claimed in claim 1, wherein said rivaroxaban used in the range of 0.5 to 500 mg / mL, more preferably in the range of 1 to 30 mg / mL, most preferably in the range of 1 to 10 mg / mL, or any other range in between thereof.

3. The oral liquid formulation as claimed in claim 1, wherein said one or more viscosifying agents can be selected from Avicel-RC 591, a combination of microcrystalline cellulose and carboxymethylcellulose sodium, microcrystalline cellulose, sodium carboxymethyl cellulose, hydroxypropylmethylcellulose (HPMC), xanthan gum, acacia, tragacanth, alginates, guar gum, and colloidal silicon dioxide or any combination thereof.

4. The oral liquid formulation as claimed in claim 1, wherein said one or more buffering agents can be selected from sodium citrate, sodium acetate trihydrate, phosphate, citric acid, tris, succinate, histidine, glycine, arginine, malic, tartaric, acetic, benzoic, gluconic, glyceric, lactic, adipic, ascorbic, carbonic, glutamic, ammonium chloride, triethanolamine, and salts or acids thereof or any combination thereof.

5. The oral liquid formulation as claimed in claim 1, wherein said wetting agent can be selected from sodium lauryl sulphate, simethicone, sodium tetradecyl sulphate, dodecyl sulphate, poloxamers, tween 80, tween 20,tween 40, tween 60, sorbitan monolaurate, lauryl glucoside or any combination thereof.

6. The oral liquid formulation as claimed in claim 1, wherein said one or more pharmaceutically acceptable excipients can be selected from anti foaming agent, sweetening agent, preservative, and flavoring agent or any combination thereof.

7. The oral liquid formulation as claimed in claim 1, comprising rivaroxaban, a salt or prodrug thereof; a combination of Avicel-RC 591, and xanthan gum as viscosifying agents; a combination of sodium citrate, and citric acid as buffering agents; sodium lauryl sulphate as wetting agent; glycerin in water as a vehicle, and one or more pharmaceutically acceptable excipients.

8. The oral liquid formulation as claimed in claim 1, comprising 0.5-500 mg / mL rivaroxaban, a salt or prodrug thereof; a combination of 0.5-30 mg / mL Avicel-RC 591, and 0.5-20 mg / mL xanthan gum as viscosifying agents; a combination of 0.5-30 mg / mL sodium citrate, and 0.5-30 mg / mL citric acid as buffering agents; 0.5-20 mg / mL sodium lauryl sulphate as wetting agent; 1-50 mg / mL of glycerin in water as a vehicle, and one or more pharmaceutically acceptable excipients.

9. The oral liquid formulation as claimed in claim 1, comprising rivaroxaban, a salt or prodrug thereof; a combination of Avicel-RC 591, and xanthan gum as viscosifying agents; a combination of sodium citrate, and citric acid as buffering agents; a sodium lauryl sulphate as wetting agent; a simethicone as antifoaming agent; a sucralose as sweetening agent; a sodium benzoate as preservative; a frozen peppermint as flavoring agent; a glycerin in water as vehicle.

10. The oral liquid formulation as claimed in claim 1, comprising 1-10 mg / mL rivaroxaban, a salt or prodrug thereof; a combination of 1-15 mg / mL Avicel-RC 591, and 1-10 mg / mL xanthan gum as viscosifying agents; a combination of 1-15 mg / mL sodium citrate, and 1-20 mg / mL citric acid as buffering agents; 0.5-10 mg / mL sodium lauryl sulphate as wetting agent; 1- 10 mg / mL simethicone as antifoaming agent; 0.5-5 mg / mL sucralose as sweetening agent; 0.05-3 mg / mL sodium benzoate as preservative; 0.05-0.5 mg / mL frozen peppermint as flavoring agent; 1-50 mg / mL of glycerin in water as vehicle.

11. The oral liquid formulation as claimed in claim 1, wherein said formulation having pH range from about 3.5 to about 4.5.

12. The oral liquid formulation as claimed in claim 1, wherein said liquid formulation can be selected from solution, suspension or emulsion, preferably suspension.

13. The oral liquid formulation as claimed in claim 1, wherein said liquid formulation is having at least 90 % purity.

14. The oral liquid formulation as claimed in claim 1, wherein said liquid formulation having impurity is less than 5 % during the shelf life.

15. A process of preparation of an oral liquid formulation of anticoagulant drugs, comprising the steps of: mixing together a therapeutically effective amount of rivaroxaban, a salt or prodrug thereof; one or more viscosifying agents; one or more buffering agents; one or more wetting agents; at least one vehicle, and one or more pharmaceutically acceptable excipients.

16. The process of preparation of an oral liquid formulation as claimed in claim15, comprising the steps of: the said process includes solubilizing citric acid in purified water to act as one of the buffering agents; the said process includes adding the sodium citrate to the solution; the said process includes adding and mixing of sodium benzoate, sucralose, simethicone, Avicel-RC591 to the solution till gets completely solubilized; the said process includes adding and mixing of sodium lauryl sulphate, glycerin in solution till gets completely solubilized; the said process includes adding and mixing of rivaroxaban in solution till gets completely solubilized; the said process includes adding and mixing xanthan gum in remaining quantity of glycerin in separate vessel and mixing till get homogenously dispersed; the said process includes adding and mixing flavoring agent in solution and mixing it till gets completely dispersed; the said process adjusting the volume using purified water, mixing and homogenizing the formulation using homogenizer till homogeneous formulation obtained; the said process includes storing the final formulation in a HDPE Bottle.

17. An oral liquid formulation comprising therapeutically effective amount of rivaroxaban, a salt or prodrug thereof; one or more viscosifying agents; one or more buffering agents; at least one wetting agent; at least one vehicle, and one or more pharmaceutically acceptable excipients.

18. The oral liquid formulation as claimed in claim 17, for use as a medicament for the treatment to inhibiting platelet aggregation induced by thrombin and prevention of blood clots, reduction of risk of stroke and systemic embolism in nonvalvular atrial fibrillation, treatment of deep vein thrombosis, treatment of pulmonary embolism, reduction in the risk of recurrence ofdeep vein thrombosis and / or pulmonary embolism, prophylaxis of deep vein thrombosis following hip or knee replacement surgery, prophylaxis of venous thromboembolism in acutely ill medical patients at risk for thromboembolic complications not at high risk of bleeding, reduction of risk of major cardiovascular events in patients with coronary artery disease(CAD), reduction of risk of major thrombotic vascular events in patients with peripheral artery disease (PAD), including patients after lower extremity revascularization due to symptomatic PAD, treatment of venous thromboembolism and reduction in risk of recurrent venous thromboembolism in pediatric patients, thromboprophylaxis in pediatric patients with congenital heart disease after the fontan procedure.