WO2025022245A1 - A ready-to-use oral liquid formulation of warfarin sodium - Google Patents

Abstract

Disclosed herein is a ready-to-use oral liquid formulation comprising warfarin sodium, as well as methods of manufacture and use.

Description

A READY-TO-USE ORAL LIQUID FORMULATION OF WARFARIN SODIUM

RELATED APPLICATION

This application claims priority to IN Patent Application No. 202321049529 filed on July 22, 2023, the subject matter of which is incorporated by reference in its entirety.

FIELD OF INVENTION

The present disclosure relates generally to a ready -to-use oral liquid formulation of warfarin sodium, as well as methods of manufacture and use.

BACKGROUND OF INVENTION

Warfarin sodium is an anticoagulant drug normally used to prevent blood clot formation as well as migration. Coumadin® (warfarin sodium) tablets, for oral use, is indicated for: (i) prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism (PE); (ii) prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation (AF) and/or cardiac valve replacement; and (iii) reduction in the risk of death, recurrent myocardial infarction (MI), and thromboembolic events such as stroke or systemic embolization after myocardial infarction. Coumadin PI, Sect. 1.

Warfarin sodium has several properties that should be noted when used medicinally, including its ability to cross the placental barrier during pregnancy which can result in fatal bleeding, spontaneous abortion, preterm birth, stillbirth, and neonatal death. Additional adverse effects such as necrosis, purple toe syndrome, osteoporosis, valve and artery calcification, and drug interactions have also been documented with Warfarin sodium use. Warfarin sodium does not actually affect blood viscosity, rather, it inhibits vitamin K dependent synthesis of biologically active forms of various clotting factors in addition to several regulatory factors. Coumadin® (warfarin sodium) tablets contain warfarin sodium, an anticoagulant that acts by inhibiting vitamin K dependent coagulation factors. The chemical name of warfarin sodium is 3 (a-acetonylbenzyl)-4-hydroxy coumarin sodium salt, which is a racemic mixture of the /Cand A'-en anti omers. Crystalline warfarin sodium may be in the form of warfarin sodium clathrate. Warfarin sodium has the following chemical structure.

Crystalline warfarin sodium occurs as a white, odorless, crystalline powder that is discoloured by light. It is very soluble in water, freely soluble in alcohol, and very slightly soluble in chloroform and ether. Coumadin® (warfarin sodium) tablets for oral use include lactose, starch, magnesium stearate, and one or more colorants. Coumadin® PI, Sect. 11.

Numerous reports state that warfarin has a pKa of about 5. Connors, 804; Trissei, 615. Connors explains that warfarin is a lactone, an enol, and a ketone, and that ionization of the enol appears to stabilize the lactone with respect to hydrolysis. Connors, 804. In view of warfarin's pKa of about 5, an aqueous medium having a pH of about 5 or less includes a substantial amount of warfarin (enol). Connors reports that warfarin (enol) undergoes hydrolysis to give the corresponding cis- coumarinic acid. Connors, 805.

Link relates generally to a lyophilized composition including warfarin sodium and heparin sodium, to be used for intravenous or intramuscular injection. Link states that the lyophilized product be substantially free of moisture for overall stability during storage. Link, 4:44-52. Link's suggestion to minimize moisture (i.e., water) is consistent with Connors' report that warfarin undergoes hydrolytic degradation.

Coumadin®, a warfarin sodium drug marketed by Bristol-Myers Squibb Company, was available for intravenous injection as a vialed lyophilized powder. 2005 Coumadin PI, 2. The powder, when reconstituted, included warfarin sodium (2 mg/mL), sodium phosphate, dibasic, heptahydrate (4.98 mg/mL), sodium phosphate, monobasic, monohydrate (0.194 mg/mL), sodium chloride (0.1 mg/mL), mannitol (38.0 mg/mL), and sodium hydroxide, as needed for pH adjustment to 8.1 to 8.3. 2005 Coumadin PI, 2. The Coumadin® for intravenous injection must be used within 4 hours of reconstitution (2005 Coumadin® PI, 27) because the warfarin sodium formulation is chemically and physically stable only for 4 hours at room temperature.

Sharley reported the stability of mixtures formulated from warfarin tablets or powder. For instance, Sharley prepared a compounded formulation that included Coumadin® tablets (5 mg warfarin sodium per tablet, 60 tablets, 1 mg/mL), sodium phosphate (10 mg/mL), tragacanth mucilage (0.2 mL/mL), sorbitol compound syrup (0.25 mL/mL), compound hydroxybenzoate solution APF (0.01 mL/mL), and distilled water. Sharley, 96. The compounded formulation had a pH of about 7.6 to 8.2. Sharley, 97. Based on results presented therein, Sharley concluded that a compounded formulation including warfarin sodium (1 mg/mL), when stored at 22±2°C and protected from light, were chemically stable for 28 days. Sharley, 97.

Weldele relates generally to a stable warfarin sodium liquid formulation, where warfarin sodium is in solution. Weldele's stable liquid formulation includes warfarin sodium, glycerin, ethanol, and a buffer to maintain the pH above 7. Weldele, Abstract. Weldele evaluated exemplified formulations having warfarin sodium in solution in the presence and absence of glycerin. Weldele, 10:39-11 :40. Weldele explains that "providing a pH above 7, reversion of warfarin is avoided, thus preventing precipitation of warfarin sodium from the solution in the long term, which may be attributable to the reversion of the warfarin anion to its protonated form." Weldele, 5:27-31. Weldele also explains that glycerin and an alcohol help to inhibit precipitation of warfarin sodium. Weldele, 6:30-50. Based on results presented therein, Weldele showed that glycerin served as a stabilizer and that a phosphate buffer having a pH of about 8 also served as a stabilizer.

Rosemont discloses liquid formulation of warfarin sodium (1 mg/mL), which has been approved in the UK with inactive ingredients, including propylene glycol, benzoic acid, xanthan gum, polysorbate 80, citric acid, disodium phosphate, aluminium magnesium silicate, liquid maltitol, masking flavour, and purified water. Rosemont, Sect. 6.1. Rosemont does not disclose the amounts of the inactive ingredients, including the amount of buffer components (viz., citric acid and disodium phosphate), and further, there is no mention of the pH of the liquid formulation. Rosemont's liquid formulation contains a large list of inactive ingredients including hydroxy-containing excipients, such as propylene glycol and liquid maltitol having a known effect. Rosemont, Sect. 2. As stated above, Weldele states that an alcohol provides chemical stabilization. Weldele, 6:46-49.

The information cited herein discloses generally that warfarin sodium long-term stability may be achieved by use of a stabilizer (e.g., glycerin, ethanol, and propylene glycol), where the pH is about 7 (or higher).

Disclosed herein is a RTU oral liquid formulation of warfarin sodium that is free of stabilizer (e.g., glycerin, ethanol, and propylene glycol) having a pH below 7 having long-term stability.

OBJECTIVE OF INVENTION

An objective of this disclosure relates generally to the description of a ready -to-use oral liquid formulation comprising warfarin sodium, as well as methods of manufacture and use. Yet another objective of the present invention is to provide stable ready-to-use oral liquid formulation comprising warfarin sodium.

SUMMARY OF INVENTION

The present invention is all about a ready-to-use oral liquid formulation of warfarin sodium, as well as methods of manufacture and use.

The main aspect of the present invention is to provide a ready-to-use oral liquid formulation of warfarin sodium, comprising: warfarin sodium; one or more pharmaceutically acceptable polymers; a suitable buffer to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients; and water

DETAILED DESCRIPTION OF INVENTION

It is to be understood that RTU formulations disclosed herein are not limited to any particular exemplified formulation, example, or process parameter. It is also to be understood that the terminology used herein is for the purpose of describing embodiments and is not intended to be limiting.

As used herein, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood in this field. For instance, the expression "about" has its customary meaning, as defined in the USP, Section 8.20, which states that "about" indicates a quantity within 10%. One will appreciate that all physicochemical quantities/parameters reported herein may be associated with a certain variation even though a given numerical value of said quantity/parameter is not preceded by the qualifier "amount." As used herein the word “RTU” refers to ready to use and can interchangeably use for “ready to use” phrase.

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

A first embodiment relates to a RTU oral liquid formulation, comprising: warfarin sodium; one or more pharmaceutically acceptable polymers; a suitable buffer to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients; and water.

In one aspect, the formulation does not include a hydroxy-containing stabilizer including, for example, any one of glycerin, an alkyl alcohol (e.g., an alkyl alcohol (e.g., ethanol, isopropanol), a sugar alcohol (e.g., mannitol, maltitol, sorbitol), a sugar (e.g., glucose, lactose, and sucrose), and the like), propylene glycol, and benzyl alcohol.

One aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium; one or more pharmaceutically acceptable polymers; a suitable buffer to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients; and water; wherein the one or more pharmaceutically acceptable excipients does not include a substantial amount of one of a hydroxy-containing stabilizer, including, for example, glycerin, an alkyl alcohol, and propylene glycol.

One will appreciate that warfarin sodium clathrate includes two moles of warfarin sodium and one mole of isopropanol. Thus, manufacture of a RTU oral liquid formulation may include an insubstantial amount of isopropanol, including, for example, about 0.3 mg/mL isopropanol. Thus, an amount of hydroxy-containing stabilizer, if present, is less than about 10 mg/mL (or about 1% w/v). Another aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium; one or more pharmaceutically acceptable polymers; a suitable buffer to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients; and water; wherein the one or more pharmaceutically acceptable excipients does not include an amount of a hydroxy-containing stabilizer (e.g., glycerin, an alkyl alcohol, propylene glycol, etc) that exceeds about 10 mg/mL. In this regard, the amount of a hydroxy-containing stabilizer, if present, ranges from about 0 mg/mL to not more than about 10 mg/mL and all values in between, including, for example about 1 mg/mL, 2 mg/mL, 3 mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7 mg/mL, 8 mg/mL, and 9 mg/mL.

Alternatively, one aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium; one or more pharmaceutically acceptable polymers; a suitable buffer to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients; and water; wherein the one or more pharmaceutically acceptable excipients does not include any one of glycerin and propylene glycol.

In one aspect, the amount of warfarin sodium in the RTU oral liquid formulation may range from 0.01 mg/mL to 60 mg/mL and all values in between, such as for example, 0.02 mg/mL, 0.03 mg/mL, 0.04 mg/mL, 0.05 mg/mL, 0.06 mg/mL, 0.07 mg/mL, 0.08 mg/mL, 0.09 mg/mL, 0.1 mg/mL 0.2 mg/mL, 0.3 mg/mL, 0.4 mg/mL, 0.5 mg/mL, 0.6 mg/mL, 0.7 mg/mL, 0.8 mg/mL, 0.9 mg/mL, 1 mg/mL, 2 mg/mL, 3 mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7 mg/mL, 8 mg/mL, 9 mg/mL, 10 mg/mL, 20 mg/mL, 30 mg/mL, 40 mg/mL, and 50 mg/mL.

One aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium in an amount of about 1 mg/mL; one or more pharmaceutically acceptable polymers; a suitable buffer to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients; and water. The RTU oral liquid formulation disclosed herein may include particulate matter (e.g., particulate warfarin sodium) having a particle size distribution of: D(0.1, not more than 30 pm), D(0.50, not more than 75 pm), and a D(0.90, not more than 150 pm).

Accordingly, one aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium in an amount of about 1 mg/mL; one or more pharmaceutically acceptable polymers; a suitable buffer to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients; and water; wherein the RTU oral liquid formulation has particulate matter having D(0.90) of not more than about 150 pm.

The RTU oral liquid formulation disclosed herein includes one or more pharmaceutically acceptable polymers, each of which may increase viscosity of the RTU oral liquid formulation, suspend particulate matter in the RTU oral liquid formulation, facilitate resuspension of the particulate matter, or a combination thereof.

One or more pharmaceutically acceptable polymers may include an anionic polymer, a cationic polymer, a nonionic polymer or a combination thereof capable of increasing viscosity of the RTU oral liquid formulation, suspending particulate matter in the RTU oral liquid formulation, facilitating resuspension of the particulate matter, or a combination thereof.

Examples include, but are not limited to acrylate polymers such as sodium polyacrylate, polyethylacrylate, polyacrylamide, agar, algae colloids (algae extract), alginic acid-based polymers such as sodium alginate, alginic acid propylene glycol esters, alginin, an arabia gum, carboxymethyl cellulose or a pharmaceutically acceptable salt thereof, a carob gum, carrageen, carrageenan, cellulose powder, dextran, ethyl cellulose, fecula, galactan, a gellan gum, a guar gum, hydroxyethyl cellulose, hydroxypropyl guar gum, hydroxypropyl methyl cellulose, a karaya gum, a locust bean gum, methyl cellulose, microcrystalline cellulose, nitro cellulose, pectin, polyethyleneimine, polyvinyl alcohol, polyvinylpyrrolidone, pulleran, quince seed, sodium carboxymethyl cellulose, sodium cellulose sulfate, starch-based polymers such as carboxymethyl starch, methylhydroxypropyl starch, starches as arrowroot, cornstarch, katakuri starch, potato starch, sago, wheat flour, almond flour, tapioca and their starch derivatives, succinoglucan, a tragacanth gum, a xanthan gum.

The RTU oral liquid formulation disclosed herein includes an amount of one or more pharmaceutically acceptable polymers sufficient to increase viscosity of the RTU oral liquid formulation, suspend particulate matter in the RTU oral liquid formulation, facilitate resuspension of the particulate matter, or a combination thereof. Said amount may vary from 1 mg/mL to 100 mg/mL, and all values in between including, for example, 2 mg/mL, 3 mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7 mg/mL, 8 mg/mL, 9 mg/mL, 10 mg/mL, 11 mg/mL, 12 mg/mL, 13 mg/mL, 14 mg/mL, 15 mg/mL, 16 mg/mL, 17 mg/mL, 18 mg/mL, 19 mg/mL, 20 mg/mL, 21 mg/mL, 22 mg/mL, 23 mg/mL, 24 mg/mL, 25 mg/mL, 26 mg/mL, 27 mg/mL, 28 mg/mL, 29 mg/mL, 30 mg/mL, 40 mg/mL, 50 mg/mL, 60 mg/mL, 70 mg/mL, 80 mg/mL, and 90 mg/mL.

Accordingly, one aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium in an amount of 1 mg/mL; one or more pharmaceutically acceptable polymers in an amount of 1 mg/mL to 100 mg/mL; a suitable buffer to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients; and water.

Drug release and/or bioavailability may depend on viscosity, and thus, viscosity modulating aspects of one or more pharmaceutically acceptable polymers may be utilized to achieve a pharmaceutically acceptable drug release and/or achieve bioavailability. Accordingly, another aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium in an amount of 1 mg/mL; a suitable buffer to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients; water; and a means for providing a RTU oral liquid formulation viscosity of from about 5 cP to about 500 cP and all values in between, including, for example 10 cP, 20 cP, 30 cP, 40 cP, 50 cP, 60 cP, 70 cP, 80 cP, 90 cP, 100 cP, 110 cP, 120 cP, 130 cP, 140 cP, 150 cP, 160 cP, 170 cP, 180 cP, 190 cP, 200 cP, 210 cP, 220 cP, 230 cP, 240 cP, 250 cP, 260 cP, 270 cP, 280 cP, 290 cP, 300 cP, 310 cP, 320 cP, 330 cP, 340 cP, 350 cP, 360 cP, 370 cP, 380 cP, 390 cP, 400 cP, 410 cP, 420 cP, 430 cP, 440 cP, 450 cP, 460 cP, 470 cP, 480 cP, and 490 cP.

In one aspect, the one or more pharmaceutically acceptable polymers comprises microcrystalline cellulose ("MCC") and sodium carboxymethylcellulose ("CMC- Na"). Commercially available products that include MCC and CMC -Na include, for example, Avicel® RC-581, Avicel® RC-591, and Avicel® RC-611. These commercially available products provide for amounts of MCC that vary from 82% to 92% and for amounts of CMC -Na that vary from 8% to 18%, where the percentage is by weight of the composition. Thus, for example, Avicel® RC-591 includes a mixture of MCC and CMC-Na, where the amount of CMC-Na varies from 8.3 % by weight to 13.8 % percent by weight, with the remainder being MCC.

In yet another aspect, the one or more pharmaceutically acceptable polymers comprises a gum comprising one or more of an arabia gum, a carob gum, a gellan gum, a guar gum, a karaya gum, a locust bean gum, a tragacanth gum, a xanthan gum.

The amount of gum may range from 1 mg/mL to 30 mg/mL, including all values in between, such as 1.5 mg/mL, 2 mg/mL, 2.5 mg/mL, 3 mg/mL, 3.5 mg/mL, 4 mg/mL, 4.5 mg/mL, 5 mg/mL, 5.5 mg/mL, 6 mg/mL, 6.5 mg/mL, 7 mg/mL, 7.5 mg/mL, 8 mg/mL, 8.5 mg/mL, 9 mg/mL, 9.5 mg/mL, 10 mg/mL, 10.5 mg/mL, 11 mg/mL, 11.5 mg/mL, 12 mg/mL, 12.5 mg/mL, 13 mg/mL, 13.5 mg/mL, 14 mg/mL, 14.5 mg/mL, 15 mg/mL, 15.5 mg/mL, 16 mg/mL, 16.5 mg/mL, 17 mg/mL, 17.5 mg/mL, 18 mg/mL, 18.5 mg/mL, 19 mg/mL, 19.5 mg/mL, 20 mg/mL, 20.5 mg/mL, 21 mg/mL, 21.5 mg/mL, 22 mg/mL, 22.5 mg/mL, 23 mg/mL, 23.5 mg/mL, 24 mg/mL, 24.5 mg/mL, 25 mg/mL, 25.5 mg/mL, 26 mg/mL, 26.5 mg/mL, 27 mg/mL,

27.5 mg/mL, 28 mg/mL, 28.5 mg/mL, 29 mg/mL, and 29.5 mg/mL.

Another aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium (e.g., about 1 mg/mL); one or more pharmaceutically acceptable polymers comprising microcrystalline cellulose, sodium carboxymethylcellulose, and one or more of an arabia gum, a carob gum, a gellan gum, a guar gum, a karaya gum, a locust bean gum, a tragacanth gum, and a xanthan gum; a suitable buffer to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients; and water.

Yet another aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium (e.g., about 1 mg/mL); one or more pharmaceutically acceptable polymers comprising microcrystalline cellulose, sodium carboxymethylcellulose, and xanthan gum; a suitable buffer to provide a formulation pH of 3.5 to 5 ; one or more pharmaceutically acceptable excipients; and water.

A further aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium (e.g., about 1 mg/mL); one or more pharmaceutically acceptable polymers comprising microcrystalline cellulose, sodium carboxymethylcellulose, and xanthan gum; a suitable buffer to provide a formulation pH of 3.5 to 5 ; one or more pharmaceutically acceptable excipients; and water.

Yet another aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium (e.g., about 1 mg/mL); one or more pharmaceutically acceptable polymers comprising microcrystalline cellulose and sodium carboxymethylcellulose in an amount of 15 mg/mL to 25 mg/mL, and xanthan gum in an amount of 1.5 mg/mL to 5.5 mg/mL; a suitable buffer to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients; and water.

A further aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium (e.g., about 1 mg/mL); one or more pharmaceutically acceptable polymers comprising microcrystalline cellulose and sodium carboxymethylcellulose in an amount of about 20 mg/mL, and xanthan gum in an amount of about 3.5 mg/mL; a suitable buffer to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients; and water.

A further aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium (e.g., about 1 mg/mL); one or more pharmaceutically acceptable polymers comprising microcrystalline cellulose (MCC) and sodium carboxymethylcellulose (CMC-Na) in an amount of about 20 mg/mL, and xanthan gum in an amount of about 3.5 mg/mL; a suitable buffer to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients; and water; wherein the amounts of MCC range from 82% to 92% and the amounts of CMC-Na range from 8% to 18%, each of CMC-Na and MCC based on the total amount of MCC and CMC-Na.

An additional aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium (e.g., about 1 mg/mL); one or more pharmaceutically acceptable polymers comprising microcrystalline cellulose (MCC) and sodium carboxymethylcellulose (CMC-Na) in an amount of about 20 mg/mL, and xanthan gum in an amount of about 3.5 mg/mL; a suitable buffer to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients; and water; wherein the amount of CMC-Na varies from 8.3 % by weight to 13.8 % percent by weight, with the remainder being MCC, each of CMC-Na and MCC based on the total amount of MCC and CMC-Na.

The RTU oral liquid formulation disclosed herein includes an amount of a "buffer," which may function by maintaining the pH of the liquid medium. Examples of suitable buffers include, for example, one or more of citrate, acetate, aconitate, formate, glutarate, glutamate, malate, succinate, tartrate, phosphate, sulfamate, carbonate, tris, borate, glycinate, and the like. 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 a hydrated form, such as, a dihydrate or a pentahydrate. One will understand that the molar amounts of citric acid and sodium citrate, relative to each other, will depend on the pH of the composition. Therefore, one will appreciate that the amount of citrate (i.e., citric acid and sodium citrate) in the liquid composition refers to the amount added during manufacture. As stated herein, the buffer serves to maintain the pH less than about 5, and more specifically about 3.5 to about 5 and all values in between, including 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, and 4.9. Thus, the pH of the RTU oral liquid formulation may range from 3.5 to 4.5.

The amount of buffer may range from 1 mg/mL to 200 mg/mL, and all values in between, such as for example, 2 mg/mL, 3 mg/mL, 4 mg/mL, 5 mg/mL, 6, 7 mg/mL, 8 mg/mL, 9 mg/mL, 10 mg/mL, 11 mg/mL, 12 mg/mL, 13 mg/mL, 14 mg/mL, 15 mg/mL, 16 mg/mL, 17 mg/mL, 18 mg/mL, 19 mg/mL, 20 mg/mL, 21 mg/mL, 22 mg/mL, 23 mg/mL, 24 mg/mL, 25 mg/mL, 26 mg/mL, 27 mg/mL, 28 mg/mL, 29 mg/mL, 30 mg/mL, 40 mg/mL, 50 mg/mL, 60 mg/mL, 70 mg/mL, 80 mg/mL, 90 mg/mL, 100 mg/mL, 110 mg/mL, 120 mg/mL, 130 mg/mL, 140 mg/mL, 150 mg/mL, 160 mg/mL, 170 mg/mL, 180 mg/mL, and 190 mg/mL.

One may appreciate that an amount of buffer may be expressed in terms of millimolar ("mM" or mmol per liter), which relates to the mmol total of buffer components (in the medium) divided by the volume of the medium in liters. In that regard, the amount of buffer may range from about 0.1 mM to about 500 mM and all values in between, including, for example, about 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, 0.9 mM, 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 90 mM, 95 mM, 100 mM, 110 mM, 120 mM, 130 mM, 140 mM, 150 mM, 160 mM, 170 mM, 180 mM, 190 mM, 200 mM, 220 mM, 240 mM, 260 mM, 280 mM, 300 mM, 350 mM, 400 mM, and 450 mM.

Accordingly, another aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium (e.g., about 1 mg/mL); one or more pharmaceutically acceptable polymers comprising microcrystalline cellulose, sodium carboxymethylcellulose, and xanthan gum; a buffer in an amount of from 0.1 mM to 500 mM to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients; and water.

A further aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium (e.g., about 1 mg/mL); one or more pharmaceutically acceptable polymers comprising microcrystalline cellulose, sodium carboxymethylcellulose, and xanthan gum; a buffer in an amount of from 0.1 mM to 500 mM to provide a formulation pH of 3.5 to 4.5; one or more pharmaceutically acceptable excipients; and water.

Yet another aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium (e.g., about 1 mg/mL); one or more pharmaceutically acceptable polymers comprising microcrystalline cellulose and sodium carboxymethylcellulose in an amount of 15 mg/mL to 25 mg/mL, and xanthan gum in an amount of 1.5 mg/mL to 5.5 mg/mL; a buffer in an amount of from 0.1 mM to 500 mM to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients; and water.

Yet another aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium (e.g., about 1 mg/mL); one or more pharmaceutically acceptable polymers comprising microcrystalline cellulose and sodium carboxymethylcellulose in an amount of 15 mg/mL to 25 mg/mL, and xanthan gum in an amount of 1.5 mg/mL to 5.5 mg/mL; a buffer in an amount of from 0.1 mM to 500 mM to provide a formulation pH of 3.5 to 4.5; one or more pharmaceutically acceptable excipients; and water.

A further aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium (e.g., about 1 mg/mL); one or more pharmaceutically acceptable polymers comprising microcrystalline cellulose and sodium carboxymethylcellulose in an amount of about 20 mg/mL, and xanthan gum in an amount of about 3.5 mg/mL; a buffer in an amount of from 0.1 mM to 500 mM to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients; and water.

A further aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium (e.g., about 1 mg/mL); one or more pharmaceutically acceptable polymers comprising microcrystalline cellulose and sodium carboxymethylcellulose in an amount of about 20 mg/mL, and xanthan gum in an amount of about 3.5 mg/mL; a buffer in an amount of from 0.1 mM to 500 mM to provide a formulation pH of 3.5 to 4.5; one or more pharmaceutically acceptable excipients; and water.

A further aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium (e.g., about 1 mg/mL); one or more pharmaceutically acceptable polymers comprising microcrystalline cellulose (MCC) and sodium carboxymethylcellulose (CMC-Na) in an amount of about 20 mg/mL, and xanthan gum in an amount of about 3.5 mg/mL; a buffer in an amount of from 0.1 mM to 500 mM to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients; and water; wherein the amounts of MCC range from 82% to 92% and the amounts of CMC-Na range from 8% to 18%, each of CMC-Na and MCC based on the total amount of MCC and CMC-Na. A further aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium (e.g., about 1 mg/mL); one or more pharmaceutically acceptable polymers comprising microcrystalline cellulose (MCC) and sodium carboxymethylcellulose (CMC-Na) in an amount of about 20 mg/mL, and xanthan gum in an amount of about 3.5 mg/mL; a buffer in an amount of from 0.1 mM to 500 mM to provide a formulation pH of 3.5 to 4.5; one or more pharmaceutically acceptable excipients; and water; wherein the amounts of MCC range from 82% to 92% and the amounts of CMC-Na range from 8% to 18%, each of CMC-Na and MCC based on the total amount of MCC and CMC-Na.

An additional aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium (e.g., about 1 mg/mL); one or more pharmaceutically acceptable polymers comprising microcrystalline cellulose (MCC) and sodium carboxymethylcellulose (CMC-Na) in an amount of about 20 mg/mL, and xanthan gum in an amount of about 3.5 mg/mL; a buffer in an amount of from 0.1 mM to 500 mM to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients; and water; wherein the amount of CMC-Na varies from 8.3 % by weight to 13.8 % percent by weight, with the remainder being MCC, each of CMC-Na and MCC based on the total amount of MCC and CMC-Na.

An additional aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium (e.g., about 1 mg/mL); one or more pharmaceutically acceptable polymers comprising microcrystalline cellulose (MCC) and sodium carboxymethylcellulose (CMC-Na) in an amount of about 20 mg/mL, and xanthan gum in an amount of about 3.5 mg/mL; a buffer in an amount of from 0.1 mM to 500 mM to provide a formulation pH of 3.5 to 4.5; one or more pharmaceutically acceptable excipients; and water; wherein the amount of CMC-Na varies from 8.3 % by weight to 13.8 % percent by weight, with the remainder being MCC, each of CMC-Na and MCC based on the total amount of MCC and CMC-Na. The RTU oral suspension formulation disclosed herein includes an amount of one or more pharmaceutically acceptable excipients, including, for example, an antifoaming agent, a sweetener, a preservative, a flavour, or a combination thereof.

Accordingly, another aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium (e.g., about 1 mg/mL); one or more pharmaceutically acceptable polymers comprising microcrystalline cellulose, sodium carboxymethylcellulose, and xanthan gum; a suitable buffer to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients comprising an anti-foaming agent, a sweetener, a preservative, a flavour, or a combination thereof; and water.

Yet another aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium (e.g., about 1 mg/mL); one or more pharmaceutically acceptable polymers comprising microcrystalline cellulose and sodium carboxymethylcellulose in an amount of 15 mg/mL to 25 mg/mL, and xanthan gum in an amount of 1.5 mg/mL to 5.5 mg/mL; a suitable buffer to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients comprising an anti-foaming agent, a sweetener, a preservative, a flavour, or a combination thereof; and water.

A further aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium (e.g., about 1 mg/mL); one or more pharmaceutically acceptable polymers comprising microcrystalline cellulose and sodium carboxymethylcellulose in an amount of about 20 mg/mL, and xanthan gum in an amount of about 3.5 mg/mL; a suitable buffer to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients comprising an anti-foaming agent, a sweetener, a preservative, a flavour, or a combination thereof; and water.

A further aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium (e.g., about 1 mg/mL); one or more pharmaceutically acceptable polymers comprising microcrystalline cellulose (MCC) and sodium carboxymethylcellulose (CMC-Na) in an amount of about 20 mg/mL, and xanthan gum in an amount of about 3.5 mg/mL; a suitable buffer to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients comprising an anti-foaming agent, a sweetener, a preservative, a flavour, or a combination thereof; and water; wherein the amounts of MCC range from 82% to 92% and the amounts of CMC -Na range from 8% to 18%, each of CMC-Na and MCC based on the total amount of MCC and CMC-Na.

An additional aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium (e.g., about 1 mg/mL); one or more pharmaceutically acceptable polymers comprising microcrystalline cellulose (MCC) and sodium carboxymethylcellulose (CMC-Na) in an amount of about 20 mg/mL, and xanthan gum in an amount of about 3.5 mg/mL; a suitable buffer to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients comprising an anti-foaming agent, a sweetener, a preservative, a flavour, or a combination thereof; and water; wherein the amount of CMC-Na varies from 8.3 % by weight to 13.8 % percent by weight, with the remainder being MCC, each of CMC-Na and MCC based on the total amount of MCC and CMC-Na.

An "anti -foaming agent" aids in the removal of air, such as entrapped air, from the compositions described herein. Examples of anti-foaming agents include, but are not limited to insoluble oils, polydimethyl siloxanes and other silicones, stearates, glycols, 2-octanol, oleic acid, paraffinic waxes, amide waxes, sulfonated oils, organic phosphates, silicone oils, mineral oils, dimethylpolysiloxane (e.g., dimethicone), and simethicone (e.g., simethicone emulsion). Simethicone Emulsion is used as an anti-foaming agent in certain compositions described herein. Simethicone Emulsion is a water-dilutable, non-ionic emulsion containing about 30% simethicone, about 1-5 % silica gel, about 1-5% polyethylene glycol stearate, and water. Simethicone Emulsion is commercially available, used as purchased, and complies with USP-NF requirements. The amount of anti-foaming agent ranges from 0.1 mg/mL to 30 mg/mL, and all values in between, including, for example, 0.2 mg/mL, 0.3 mg/mL, 0.4 mg/mL, 0.5 mg/mL, 0.6 mg/mL, 0.7 mg/mL, 0.8 mg/mL, 0.9, 1 mg/mL, 1.2 mg/mL, 1.3 mg/mL, 1.4 mg/mL, 1.5 mg/mL, 1.6 mg/mL, 1.7 mg/mL, 1.8 mg/mL, 1.9 mg/mL, 2 mg/mL, 2.1 mg/mL, 2.2 mg/mL, 2.3 mg/mL, 2.4 mg/mL, 2.5 mg/mL, 2.6 mg/mL, 2.7 mg/mL, 2.8 mg/mL, 2.9 mg/mL, 3 mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7 mg/mL, 8 mg/mL, 9 mg/mL, 10 mg/mL, 15 mg/mL, 20 mg/mL, and 25 mg/mL.

Accordingly, another aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium (e.g., about 1 mg/mL); one or more pharmaceutically acceptable polymers comprising microcrystalline cellulose, sodium carboxymethylcellulose, and xanthan gum; a suitable buffer to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients comprising an anti-foaming agent in an amount of from 0.1 mg/mL to 30 mg/mL; and water.

Examples of sweeteners include, but are not limited to acesulfame or its potassium salt thereof; alitame; ammonium glycyrrhizinate; aspartame; cyclamate or its corresponding sodium or calcium salt; dulcin; neohesperidin dihydrochalcone; neotame; saccharin or its corresponding sodium, potassium or calcium salt; a steviol glycoside; thaumatin; sucralose; and any combinations thereof.

The amount a sweetener may range from 0.01 mg/mL to 10 mg/mL and all values in between, including, for example, 0.02 mg/mL, 0.03 mg/mL, 0.04 mg/mL, 0.05 mg/mL, 0.06 mg/mL, 0.07 mg/mL, 0.08 mg/mL, 0.09 mg/mL, 0.1 mg/mL, 0.12 mg/mL, 0.13 mg/mL, 0.14 mg/mL, 0.15 mg/mL, 0.16 mg/mL, 0.17 mg/mL, 0.18 mg/mL, 0.19 mg/mL, 0.2 mg/mL, 0.3 mg/mL, 0.4 mg/mL, 0.5 mg/mL, 0.6 mg/mL, 0.7 mg/mL, 0.8 mg/mL, 0.9 mg/mL, 1 mg/mL, 1.1 mg/mL, 1.2 mg/mL, 1.3 mg/mL, 1.4 mg/mL, 1.5 mg/mL, 1.6 mg/mL, 1.7 mg/mL, 1.8 mg/mL, 1.9 mg/mL, 2 mg/mL, 3 mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7 mg/mL, 8 mg/mL, and 9 mg/mL. Accordingly, another aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium (e.g., about 1 mg/mL); one or more pharmaceutically acceptable polymers comprising microcrystalline cellulose, sodium carboxymethylcellulose, and xanthan gum; a suitable buffer to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients comprising a sweetener in an amount of from 0.01 mg/mL to 10 mg/mL; and water.

Examples of preservatives include, but are not limited to phenoxyethanol, potassium benzoate, benzyl alcohol, benzoic acid, potassium sorbate, sorbic acid, benzalkonium chloride, benzethonium chloride, cetrimonium bromide, cetylpyridinium chloride, bronopol, chlorbutol, chlorocresol, cresol, butylparaben, methylparaben, propylparaben, ethylparaben, phenol, thymol, phenyl ethanol, sodium benzoate, and combinations thereof.

The amount of preservative may range from 0.01 mg/mL to 10 mg/mL and all values in between, including, for example, 0.02 mg/mL, 0.03 mg/mL, 0.04 mg/mL, 0.05 mg/mL, 0.06 mg/mL, 0.07 mg/mL, 0.08 mg/mL, 0.09 mg/mL, 0.1 mg/mL, 0.12 mg/mL, 0.13 mg/mL, 0.14 mg/mL, 0.15 mg/mL, 0.16 mg/mL, 0.17 mg/mL, 0.18 mg/mL, 0.19 mg/mL, 0.2 mg/mL, 0.3 mg/mL, 0.4 mg/mL, 0.5 mg/mL, 0.6 mg/mL, 0.7 mg/mL, 0.8 mg/mL, 0.9 mg/mL, 1 mg/mL, 1.1 mg/mL, 1.2 mg/mL, 1.3 mg/mL, 1.4 mg/mL, 1.5 mg/mL, 1.6 mg/mL, 1.7 mg/mL, 1.8 mg/mL, 1.9 mg/mL, 2 mg/mL, 3 mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7 mg/mL, 8 mg/mL, and 9 mg/mL.

Accordingly, another aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium (e.g., about 1 mg/mL); one or more pharmaceutically acceptable polymers comprising microcrystalline cellulose, sodium carboxymethylcellulose, and xanthan gum; a suitable buffer to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients comprising a preservative in an amount of from 0.01 mg/mL to 10 mg/mL; and water. Examples of flavours include, but are not limited to cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, oil of bitter almonds, and cassia oil and the like or any combinations thereof. Also useful as flavours are vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, banana, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, tutti-frutti, and so forth and the like or any combinations thereof. Solid forms, such as spray dried forms of flavours, may also be useful in the liquid compositions disclosed herein.

The amount of flavour may range from 0.01 mg/mL to 10 mg/mL and all values in between, including, for example, 0.02 mg/mL, 0.03 mg/mL, 0.04 mg/mL, 0.05 mg/mL, 0.06 mg/mL, 0.07 mg/mL, 0.08 mg/mL, 0.09 mg/mL, 0.1 mg/mL, 0.12 mg/mL, 0.13 mg/mL, 0.14 mg/mL, 0.15 mg/mL, 0.16 mg/mL, 0.17 mg/mL, 0.18 mg/mL, 0.19 mg/mL, 0.2 mg/mL, 0.3 mg/mL, 0.4 mg/mL, 0.5 mg/mL, 0.6 mg/mL, 0.7 mg/mL, 0.8 mg/mL, 0.9 mg/mL, 1 mg/mL, 1.1 mg/mL, 1.2 mg/mL, 1.3 mg/mL, 1.4 mg/mL, 1.5 mg/mL, 1.6 mg/mL, 1.7 mg/mL, 1.8 mg/mL, 1.9 mg/mL, 2 mg/mL, 3 mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7 mg/mL, 8 mg/mL, and 9 mg/mL.

Accordingly, another aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium (e.g., about 1 mg/mL); one or more pharmaceutically acceptable polymers comprising microcrystalline cellulose, sodium carboxymethylcellulose, and xanthan gum; a suitable buffer to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients comprising a flavour in an amount of from 0.01 mg/mL to 10 mg/mL; and water.

Accordingly, another aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium (e.g., about 1 mg/mL); one or more pharmaceutically acceptable polymers comprising microcrystalline cellulose, sodium carboxymethylcellulose, and xanthan gum; a suitable buffer to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients comprising an anti-foaming agent in an amount of from 0.1 mg/mL to 30 mg/mL, a sweetener in an amount of from 0.01 mg/mL to 10 mg/mL, a preservative in an amount of from 0.01 mg/mL to 10 mg/mL, and a flavour in an amount of from 0.01 mg/mL to 10 mg/mL; and water.

Yet another aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium (e.g., about 1 mg/mL); one or more pharmaceutically acceptable polymers comprising microcrystalline cellulose and sodium carboxymethylcellulose in an amount of 15 mg/mL to 25 mg/mL, and xanthan gum in an amount of 1.5 mg/mL to 5.5 mg/mL; a suitable buffer to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients comprising an anti-foaming agent in an amount of from 0.1 mg/mL to 30 mg/mL, a sweetener in an amount of from 0.01 mg/mL to 10 mg/mL, a preservative in an amount of from 0.01 mg/mL to 10 mg/mL, and a flavour in an amount of from 0.01 mg/mL to 10 mg/mL; and water.

A further aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium (e.g., about 1 mg/mL); one or more pharmaceutically acceptable polymers comprising microcrystalline cellulose and sodium carboxymethylcellulose in an amount of about 20 mg/mL, and xanthan gum in an amount of about 3.5 mg/mL; a suitable buffer to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients comprising an anti-foaming agent in an amount of from 0.1 mg/mL to 30 mg/mL, a sweetener in an amount of from 0.01 mg/mL to 10 mg/mL, a preservative in an amount of from 0.01 mg/mL to 10 mg/mL, and a flavour in an amount of from 0.01 mg/mL to 10 mg/mL; and water.

A further aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium (e.g., about 1 mg/mL); one or more pharmaceutically acceptable polymers comprising microcrystalline cellulose (MCC) and sodium carboxymethylcellulose (CMC-Na) in an amount of about 20 mg/mL, and xanthan gum in an amount of about 3.5 mg/mL; a suitable buffer to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients comprising an anti-foaming agent in an amount of from 0.1 mg/mL to 30 mg/mL, a sweetener in an amount of from 0.01 mg/mL to 10 mg/mL, a preservative in an amount of from 0.01 mg/mL to 10 mg/mL, and a flavour in an amount of from 0.01 mg/mL to 10 mg/mL; and water.

An additional aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium (e.g., about 1 mg/mL); one or more pharmaceutically acceptable polymers comprising microcrystalline cellulose (MCC) and sodium carboxymethylcellulose (CMC-Na) in an amount of about 20 mg/mL, and xanthan gum in an amount of about 3.5 mg/mL; a suitable buffer to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients comprising an anti-foaming agent in an amount of from 0.1 mg/mL to 30 mg/mL, a sweetener in an amount of from 0.01 mg/mL to 10 mg/mL, a preservative in an amount of from 0.01 mg/mL to 10 mg/mL, and a flavour in an amount of from 0.01 mg/mL to 10 mg/mL; and water.

The RTU oral liquid formulation disclosed herein includes a water vehicle, which may include any suitable water source, such as distilled water and/or purified water. In one aspect, the RTU oral liquid formulation disclosed herein includes a purified water.

Another aspect disclosed herein relates to a process for preparing a RTU oral liquid formulation, comprising one or more of the following manufacturing steps. In a suitable vessel, add a suitable amount of water (e.g., 60-90% (total amount) of purified water); subsequently adding one or more buffer components (e.g., citric acid and sodium citrate) mixing until complete solubilization to obtain a buffered solution (or first composition). In certain instances, it may be of interest to add a pH adjuster (e.g., hydrochloric acid and/or sodium hydroxide). To the buffered solution, add one or more of a preservative (e.g., sodium benzoate) and sweetener (e.g., sucralose, aspartame, etc.) with stirring until completely solubilized to obtain second composition. To the second composition add one or more pharmaceutically acceptable polymers (e.g., microcrystalline cellulose, carboxymethylcellulose sodium, and xanthan gum) and mix for a suitable time (e.g., about 10-15 minutes) while stirring at a suitable rate (e.g., 1000-1500 rpm) to obtain a dispersed composition (or third composition). To the dispersed composition add a suitable amount of warfarin sodium and mix for a suitable time while stirring at a suitable rate to obtain a fourth composition. To the fourth composition, add a suitable amount of flavoring agent and mix for a suitable time while stirring at a suitable rate to obtain a fifth composition. In certain instances, it may be of interest to add a pH adjuster (e.g., hydrochloric acid and/or sodium hydroxide) to achieve a composition pH that ranges of from 3.5 to 4.5. Add the remaining amount of purified water to achieve the desired warfarin sodium amount (e.g., about 1 mg/mL) and homogenize the formulation by mixing for a suitable time (e.g., 10-15 minutes) at a suitable rate (e.g., 7500-8000 rpm) to obtain a RTU oral liquid formulation disclosed herein. The RTU oral liquid formulation may be added to a pharmaceutically acceptable bottle that includes a pharmaceutically acceptable closure (e.g., cap).

One more aspect related to process for preparing a RTU oral liquid formulation includes that the RTU oral liquid formulation formulated at stirring speed of 1000- 1500 rpm.

One more aspect related to process for preparing a RTU oral liquid formulation includes that the RTU oral liquid formulation formulated at homogenization speed of 7500-8500 rpm.

The RTU oral liquid formulation disclosed herein can be selected from solution, suspension or emulsion, more preferably in the form of suspension.

One aspect relates to oral liquid formulation disclosed herein contained in a sealed bottle (e.g., 150 mL), where the bottle may comprise high density polyethylene (HDPE) which may include a suitable colorant (e.g., amber or brown colorant). The closure for said bottle may be comprised of a suitable polypropylene (PP), which may be child resistant (CR). Another aspect relates to a package comprising the RTU oral liquid formulation disclosed herein contained in a sealed bottle and packaging material comprising written instructions for use.

One aspect of a RTU oral liquid formulation disclosed herein relates to a pharmaceutically acceptable shelf-life, which includes not more than about 1% of total warfarin-related impurities after storage for about 2-years at 25±2°C and 60±5% relative humidity).

Accordingly, one aspect relates to a RTU oral liquid formulation, comprising: warfarin sodium in an amount of from about 0.01 mg/mL to about 60 mg/mL; one or more pharmaceutically acceptable polymers; a suitable buffer to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients; and water; wherein the formulation comprises not more than about 1% of total warfarin-related impurities after storage at 25±2°C and 60±5% relative humidity) for about 2-years.

Specifically identified warfarin-related impurities include, Impurity B (4- hydroxycoumarin, CAS No. 1076-38-6), Impurity C (4-phenyl-3-butene-2-one, CAS No. 122-57-6). Formulations disclosed herein include not more than 0.2% of each of Impurity B and Impurity C after storage at 25±2°C and 60±5% relative humidity) for about 2-years. Further, formulations disclosed herein include not more than 0.1% of each of Impurity B and Impurity C after storage at 25±2°C and 60±5% relative humidity) for about 2-years.

A RTU oral liquid formulation disclosed herein (e.g., Formulation 7B) may exhibit formal bioequivalence with a suitable reference listed drug (RLD), such as Coumadin® (5 mg) or its therapeutic equivalent. Administration to a subject of a 5 mg amount of a RTU oral liquid formulation provides for pharmacokinetic (PK) parameters (viz., AUC(O-t), AUC(inf), Cmax, Tmax) under either fasted or fed conditions provides a PK parameter that is about 90 % CI of a given PK parameter for Coumadin® (5 mg) or its therapeutic equivalent.

As stated above, Coumadin® is indicated for: (i) prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism (PE); (ii) prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation (AF) and/or cardiac valve replacement; and (iii) reduction in the risk of death, recurrent myocardial infarction (MI), and thromboembolic events such as stroke or systemic embolization after myocardial infarction.

Accordingly, an aspect of the RTU oral liquid formulation disclosed herein relates to a method for the (i) prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism (PE); (ii) prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation (AF) and/or cardiac valve replacement; and (iii) reduction in the risk of death, recurrent myocardial infarction (MI), and thromboembolic events such as stroke or systemic embolization after myocardial infarction, which comprises administering to a patient in need thereof a therapeutically effective amount of the RTU oral liquid formulation disclosed herein.

Alternatively, an aspect disclosed herein relates to the use of the RTU oral liquid formulation disclosed herein for (i) prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism (PE); (ii) prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation (AF) and/or cardiac valve replacement; and (iii) reduction in the risk of death, recurrent myocardial infarction (MI), and thromboembolic events such as stroke or systemic embolization after myocardial infarction.

As used herein, the term "therapeutically effective amount" can be understood to include an amount of warfarin sodium that is effective to prevent or treat a condition requiring anticoagulant therapy. Specific amounts of warfarin sodium may be ascertained by review of the Coumadin® PI. Therein, it is stated that the dosage and administration of warfarin sodium must be individualized for each patient according to the patient's International Normalized Ratio ("INR") response. Coumadin® PI, Sect. 2.1. The INR relates generally to the time required for a patient's blood to clot and numerous studies provide guidance on how to determine a patient's INR. See, e.g., Thomson, Shirazi, Olson, among others.

Accordingly, for a method for the prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism (PE), a therapeutically effective amount corresponds to a warfarin sodium dose to maintain a target INR of from 2 to 3 (e.g., INR of 2.5).

Further, for a method for prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation (AF), a therapeutically effective amount corresponds to a warfarin sodium dose to maintain a target INR of from 2 to 3 (e.g., INR of 2.5).

Moreover, for high-risk patients with MI (e.g., those with a large anterior MI, those with significant heart failure, those with intracardiac thrombus visible on transthoracic echocardiography, those with AF, and those with a history of a thromboembolic event), therapy with combined moderate-intensity (INR, 2.0-3.0) warfarin plus low-dose aspirin (<100 mg/day) for at least 3 months after the MI is recommended.

In view of the foregoing, it will be appreciated that a method for the reduction in the risk of death, recurrent myocardial infarction (MI), and thromboembolic events such as stroke or systemic embolization after myocardial infarction comprises administering to a patient in need thereof a therapeutically effective amount of the RTU oral liquid formulation disclosed herein, optionally, in combination with low- dose aspirin (<100 mg/day) for at least 3 months. The following examples serve to illustrate aspects of the RTU oral liquid formulation disclosed herein, it being understood that the particulars shown are by way of example only and should not be considered limiting.

In view of the information disclosed herein, one will appreciate that the expression comprising may be replaced with the expression consisting of.

EXAMPLES

Warfarin sodium may be obtained commercially or may be manufactured according to Evron (or a patent document cited therein, including, for example U.S. Patent Nos. 2,765,321; 3,077,481; 3,246,013). Any solid-state form, including polymorphic and amorphous forms, as well as warfarin sodium clathrate comprising two moles of warfarin sodium to one mole of 2-propanol.

Results reported herein may be determined by procedures disclosed in, for example, the USP (such as USP 28 (2005) USP 35 (2012), and/or USP 45 (2022)), including for example, USP <51> (preservative efficacy), USP <61> (microbial), USP <62> (E. coll), USP <621> (high-pressure liquid chromatography (HPLC)), USP <698> (deliverable volume), USP <711> (dissolution), USP <791> (pH), USP <905> (content uniformity), USP <912> (viscosity), and USP <1151> (suspension dosage forms).

Viscosity values reported herein bear units of centipoise (cP). A viscosity value of 1 cP is equivalent to 1 mPa»s.

Assay for warfarin sodium may be performed using HPLC according to known monographs, see, e.g., USP 38 at 2031-2033. Warfarin related substances, e.g., Impurity B (CAS No. 1076-38-6) and Impurity C (CAS No. 122-57-6), may be determined by HPLC. Particle size determinations may be performed using suitable instrumentation, e.g., Malvern Mastersizer. Formulations disclosed herein have release and shelf-life specifications of D(0.1) : NMT 30 pm, D(0.5): NMT 75 pm, and D(0.9): NMT 150 pm.

The HPLC results presented herein utilize the following abbreviations: ND (Not Detected), NMT (Not more than); and BQL (Below limit of quantification).

Example 1. Effect of glycerin on warfarin sodium stability

The goal of this study was to study the effect of glycerine on stability of Warfarin sodium. Compositional details are shown in Table 1 A, while Table IB includes the impurity profiles. Trials were taken for 0% and 13.3% glycerine and results are summarized in below table.

Table la. Compositional details for Formulations 1A and IB

Batch Manufacturing Procedure of Formulation 1 A: a) Take Citrate buffer of total batch size. b) Dispense and add Warfarin sodium with stirring until uniform dispersion is obtained. c) Batch Manufacturing Procedure of Formulation IB. d) Take Citrate buffer of total batch size. e) Dispense and add glycerin of total batch size and stir to obtain a clear solution. f) Dispense and add Warfarin sodium with stirring until uniform dispersion is obtained. Table lb reports the results of a comparative stress study of Formulations 1 and 2 analysing the effect of glycerin.

Table lb. Impurity profiles for Formulations 1 A and IB

Based on above data it can be concluded that warfarin sodium tends to degrade in the presence of glycerin and citrate buffer (pH 4). These results are contrary to Weldele's disclosure insofar that the presence of glycerin, according to Weldele, serves as a stabilizing agent.

Example 2. Effect of buffer on warfarin sodium stability

The goal of this study was to study the effect of buffer on stability of warfarin sodium. Trials were taken with and without buffer and results are summarized in below table.

Table 2a. Compositional details for Formulations 1 A and 2

Table 2b. Impurity profiles for Formulations 1 A and 2

Based on above data it can be concluded that, addition of buffer helps to prevent the degradation of warfarin sodium.

Example 3. Effect of different buffers

The goal of this study was to check the effect of different buffer system on stability of warfarin sodium. Trials were taken with citrate buffer and phosphate buffer and results are in Tables 3a-3b.

Table 3a. Compositional details for Formulations 1 A and 3

Table 3b. Impurity profile for Formulations 1 A and 3

Based on above data it can be concluded that warfarin sodium tends to degrade in the presence of phosphate buffer (pH 6.5) compared to citrate buffer (pH 4.).

Example 4: Effect of different buffer concentrations

The goal of this study was to check the effect of different concentration of buffer on stability of warfarin sodium. Trials were taken with different concentration of citrate buffer and results are summarized in Table 4.

Table 4. Comparative stress study of formulations with different concentration of buffer and impurity profiles for Formulations 1 A and 4

Based on above data it can be concluded that warfarin sodium degradation increases using 50 mM citrate buffer compared to 100 mM citrate buffer.

Example 5. Oral liquid formulations with differing amounts of Avicel® RC- 591 and xanthan gum

Amounts of Avicel® RC-591 and xanthan gum were evaluated to understand the effect, if any, on formulation viscosity and % drug release. Oral liquid formulations utilized an amount of Avicel® RC-591 ranging from 15 mg/mL to 25 mg/mL and an amount of xanthan gum ranging from 1.5 to 5.5 mg/mL. Specifically, liquid formulations were prepared, as described above, using the following amounts of RC-591 and xanthan gum: (i) Form. 5A (15 mg/mL (RC-591) and 1.5 mg /mL xanthan); (ii) Form. 5B (15 mg/mL (RC-591) and 3.5 mg /mL xanthan); (iii) Form. 5C (15 mg/mL (RC-591) and 5.5 mg /mL xanthan); (iv) Form. 5D (20 mg/mL (RC- 591) and 1.5 mg /mL xanthan); (v) Form. 5E (20 mg/mL (RC-591) and 3.5 mg /mL xanthan); (vi) Form. 5F (20 mg/mL (RC-591) and 5.5 mg /mL xanthan); (vii) Form. 5G (25 mg/mL (RC-591) and 1.5 mg /mL xanthan); (viii) Form. 5H (25 mg/mL (RC-591) and 3.5 mg /mL xanthan); and (ix) Form. 51 (25 mg/mL (RC-591) and 5.5 mg /mL xanthan). Results show that liquid formulation viscosity is directly proportional to the amount of xanthan gum. Results from these studies shows that viscosity values of from about 5 cP to about 500 cP may be achieved. Thus, varying the amount of one or more pharmaceutically acceptable polymers provides a means for obtaining formulation viscosities of from about 5 cP to about 500 cP and all values in between (as stated above), including for example, viscosity values from about 100 cP to about 200 cP.

Example 6. Formulations with differing amounts of Avicel® RC-591 and xanthan gum

Formulations with differing amounts of Avicel® RC-591 and xanthan gum may be prepared using the manufacturing methods reported herein, as shown in Table 6.

Table 6. Compositional makeup of formulations with varying amounts of RC-591 and xanthan gum

Example 7. Drug release study using varying amounts of xanthan gum

Drug release A dissolution study was conducted on formulations including 20 mg/mL of RC-591 and varying amounts of xanthan gum (viz., 1.5 mg/mL, 3.5 mg/mL, and 5.5 mg/mL) the compositional makeup of which is shown in Table 7.

Table 7. Compositional makeup for formulations with varying amounts of xanthan gum

Sodium).

^(b)Simethicone emulsion comprising about 30% simethicone.

The dissolution conditions were in accordance with USP 28 <711> (Type II (paddle), 50 rpm, pH 6.8 phosphate buffer (900 mL)). The mean cumulative (%) drug release was evaluated over 45-minutes. Results show that each batch showed similar drug release, which shows that variation in the concentration of xanthan gum does not have any significant impact on dissolution. Samples of Formulations 7A-7C were observed under rotational agitation (e.g., 1000 rpm for 5-min). Sedimentation was observed for 7 A, which may be reconstituted with gentle shaking. No sedimentation was observed for 7B and 7C. In view of the observed sedimentation behaviour, a xanthan gum amount of about 3.5 mg/mL (in combination with RC-591 in an amount of 20 mg/mL) was selected for further evaluation.

Example 8: Stable oral liquid formulations (Formulation Nos. 8A, 8B, 8C)

Batches of 2000 L or 2500 L were manufactured according to procedures disclosed herein, with different amounts of sodium benzoate. Table 8a. Compositional makeup of Formulations 8A-8C

Formulations were stored in a 150 mL HDPE bottle packed in secondary white box and analysed over a six-month period. Results for liquid Formulation 8C are representative and are presented in Table 8b.

Table 8b. Stability study results for Formulation 8C

Abbreviations and notes: TP (test parameter); NP (not performed); NMT (not more than); (a)W/OF (White to off-white liquid); (b) Assay (Assay of Warfarin Sodium); (c) Assay of Warfarin Sodium 95.0% to 105.0% of labelled amount; (d) COP (Content of preservative); (e)Sodium Benzoate : 90.0% to 105.0% of labelled amount; (f)Viscosity, in mPa»s, at 25°C and at step time 25 seconds, Shear Rate:0.10 (1/s)}; (g) Viscosity specification of 100-200 mPa»s; (h)ZP (Zeta potential); (i)Zeta potential specification of -10 mV - -35 mV; (j)SV (Sedimentation Volume); (k) Sedimentation volume specification: After standing a sample for 24 hours : Not more than 1.0 mL of clear liquid is found.); (l)PSD (Particle size distribution); (m)SMUI (Single maximum unknown impurity); (n)

A) Any unspecified Impurity: NMT 0.1%, B)Total impurities: NMT 0.5%; and (o)TI (total impurities).

Results show that Formulations 8 A, 8B, and 8C exhibit suitable stability for at least 6M when stored at 25°C±2°C/60±5%RH (e.g., inverted bottle). And these results also show that Formulations 8A, 8B, and 8C exhibit suitable room-temperature stability for at least 2-years, as evidenced by storage results presented for 40°C±2°C/NMT 75% RH.

Preservative efficacy tests, as per USP <51>, showed that Formulations 8A, 8B, and 8C exhibited satisfactory results. Shelf-life specifications of sodium benzoate at not less than 80% of labelled amount in the product is justified. Preservative levels within the shelf-life specifications would be capable of preventing growth of any inadvertent microbial contamination during the use of the product for the stated duration of 1 month after first opening of the container closure system.

Example 9. Preparation of liquid formulation using amorphous warfarin sodium

A batch (1000 mL) was prepared using amorphous warfarin, the compositional makeup of which is shown in Table 9.

Table 9. Liquid formulation using amorphous warfarin sodium

Batch Manufacturing Procedure: a) Take 80% purified water of total batch size and add citric acid anhydrous in it mix until completely solubilized. b) Dispense and add sodium citrate with stirring until completely solubilized. c) Dispense and add sodium benzoate with stirring until completely solubilized. d) Dispense and add sweetener (e.g., sucralose, aspartame, etc.) with stirring until completely solubilized. e) Dispense and add Avicel® RC-591 (Microcrystalline Cellulose and Carboxymethylcellulose Sodium), mix for 10 - 15 minutes at 1000 to 1500 RPM. f) Dispense and add xanthan gum with stirring until completely dispersed. g) Dispense and add Warfarin Sodium with stirring until completely dispersed. h) Dispense and add Tutti Frutti flavour with stirring until completely dispersed. i) Make up to volume using Purified water. j) Homogenize the liquid formulation at 7500 to 8000 RPM for 10 - 15 minutes. Example 9: Photo-stability studies

A 2000 L batch size (e.g., Form. 8B) was manufactured, according to procedures disclosed herein, filled into the 150 mL HDPE (or Clear) bottles subjected to a photostability study. The total light exposure would provide an overall illumination of 1.2 million lux hours and an integrated near ultraviolet energy of not less than 200- watt hours/square meter. Four alternative situations were evaluated: (i) HDPE bottle to evaluate the primary pack; (ii) Dark control (HDPE bottle wrapped with aluminum foil) as a control sample; (iii) HDPE bottle with secondary pack in cartons to simulate the actual market pack; and (iv) Product filled in Clear bottle.

Results show that when product was exposed to light in clear bottle Impurity B and Impurity C were not detected and Total impurities was BQL. Similar results were seen in case of product exposed in primary packaging (HDPE bottle). Accordingly, it may be concluded that the warfarin sodium may not be susceptible to degradation in presence of light.

Example 10. Freeze-thaw study

The freeze-thaw studies aim to understand the stability characteristics of the product (e.g., Form. 8B, supra) when subjected to extreme temperature conditions that may be encountered during the drug product distribution process. Freeze thaw studies were performed on Warfarin Sodium Oral Liquid Formulation 1 mg/ml. The product 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. A set of product bottles were withdrawn at the end of third cycle and analyzed.

When product bottles were exposed to the about -20°C for 2 days for three cycles, HDPE container remain as such and able to withstand the extreme freezing condition. Also, it was observed that when product temperature come to ambient temperature, product gains its original physical characteristics. Analytical results indicated that the product stability was not affected by the extreme temperature conditions encountered by the drug product. The product characteristics at the end of the third cycle were comparable to the initial product profile. Thus, results from the freeze-thaw data shows that the formulation can withstand limited temperature excursions during the transportation process.

Example 11. Water loss study

The objective of this study is to evaluate permeation of water from semi permeable container. The purpose of this study is to determine the water loss from packaging (150 mL HDPE bottles with PP CR Closure) used for the product Warfarin Sodium Oral Liquid Formulaion 1 mg/mL (e.g., Form. 8B). The outcome of this study defines a water loss percentage from the packaging for the Warfarin Sodium Oral Liquid Formulation 1 mg/mL at stability condition. Water loss study is conducted at 40°C ± 2°C / NMT 25% RH at (0, 3, and 6 months) and 25°C ± 2°C NMT 40% ± 5% RH (0, 3, 6, 9, and 12 months).

Results show that % water loss was found not more than 1.0% at accelerated stability condition (specifically water loss from 0.01% to 0.05% was observed) and real time stability condition which is well within the specification not more than 5.0%. It is concluded that there is no significant change in weight of container due to water loss up to 6 months accelerated stability condition and 6-month real time stability condition.

Practical Utility

A surprising feature of RTU oral liquid formulations disclosed herein, include minimal impurities after storage for up to 2-years after storage at 25±2°C and 60±5% relative humidity. This feature is surprising considered that the formulation pH is less than 5 (e.g., pH of about 3.5 to about 4.5) in view of the known hydrolytic degradation associated with warfarin. This feature is also surprising because the long-term storage stability observed herein occurs in the absence of a hydroxylcontaining stabilizer (e.g., glycerin, an alkyl alcohol, and/or propylene glycol). Additional surprising aspects reveal that RTU formulations disclosed herein exhibit pharmaceutically suitable content uniformity and exhibit antimicrobial activity for up to 2-years after storage at 25±2°C and 60±5% relative humidity.

Further, RTU formulations disclosed are pharmaceutically acceptable liquid formulations having viscosity values of from 5 cP to 500 cP (e.g., 100 cP to 200 cP). This is of particular interest for a geriatric patient that may suffer from arthritis and may be prohibited from vigorously shaking a bottled medicament.

Cited Information

All cited information is hereby incorporated by reference in its entirety. To the extent that the incorporated information conflicts with the meaning of information disclosed herein, the information disclosed herein shall control.

Coumadin® prescribing information as of September 2, 2005. ("2005 Coumadin® PI").

Coumadin® (warfarin sodium) tablets, for oral use, prescribing information as of August 14, 2017 ("Coumadin® PI").

G. L. Flynn, Buffers— pH Control within Pharmaceutical Systems, J. Parenteral Drug Assoc. (1980) 34(2): 139-162 ("Flynn").

Olson et al., Laboratory Reporting of the International Normalized Ratio, Arch. Pathol. Lab. Med. (2007) 131 : 1641-1647.

Parrish et al., Compounded Nonsterile Preparations and FDA-Approved Commercially Available Liquid Products for Children: A North American Update, Pharmaceutics (2022) 14, 1032: 1-19.

PCT Publication No. WO 2002/070503 Al, Process for purification of warfarin acid, warfarin alkali metal salts and corresponding clathrates, published on September 12, 2002 to Evron et al. of Taro Pharmaceutical Industries Ltd. ("Evron").

Sharley et al., Stability of mixtures formulated from warfarin tablets or powder, J. Pharm. Pract. Res. (2007) 37: 95-97 ("Sharley").

Shirazi, A. H., International Normalized Ratio (INR), Gomal Journal of Medical Sciences (2007) 5(1): 38-41

Thomson et al., The calibration of the second primary international reference preparation for thromboplastin (thromboplastin, human, plain, coded BCT/253), Thromb. Haemost (1984) 52(3): 336-342

U.S. Patent No. 2,999,049, Warfarin sodium and heparin sodium composition, issued on September 5, 1961 to Karl Paul Link of the Wisconsin Alumni Research Foundation ("Link").

U.S. Patent No. 7,259,185 B2, Stable warfarin sodium liquid formulation and method of making same, issued on August 21, 2007 to Weldele et al. of Morton Grove Pharmaceuticals, Inc. ("Weldele").

Warfarin monograph in Chemical Stability of Pharmaceuticals: A Handbook for Pharmacists, 2^nd Ed., Connors et al. (Eds.), 1986, pages 804-807 ("Connors").

Warfarin Sodium (1 mg/mL) Oral Suspension, Summary of UK Product Characteristics, marketed in the UK by Rosemont Pharmaceuticals Ltd. ("Rosemont").

Warfarin Sodium monograph in Trissel's Stability of Compounded Formulations, 6^th Ed., Trissei et al. (Eds.), 2018, pages 615-616 ("Trissei"). Additional Aspects

Aspects disclosed herein relate generally to variations of the embodiments and examples disclosed herein. The following additional aspects may be of interest for the present disclosure.

Aspect 1. A ready -to-use (RTU) oral liquid formulation, comprising: warfarin sodium; one or more pharmaceutically acceptable polymers; a suitable buffer to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients; and water.

Aspect 2. The RTU oral liquid formulation of Aspect 1, wherein the amount of warfarin sodium ranges from 0.1 mg/mL to 10 mg/mL.

Aspect 3. The RTU oral liquid formulation of any one of the preceding aspects, wherein the amount of warfarin sodium is present in an amount of about 1 mg/mL.

Aspect 4. The RTU oral liquid formulation of any one of the preceding aspects, wherein the warfarin sodium has a D(0.9) particle size of not more than about 150 pm.

Aspect 5. The RTU oral liquid formulation of any one of the preceding aspects, wherein the one or more pharmaceutically acceptable polymers is selected from an acrylate polymer, an agar, an algae colloid, an alginic acid-based polymer, an alginin, an arabia gum, a carboxymethyl cellulose or a pharmaceutically acceptable salt thereof, a carob gum, a carrageen, a carrageenan, a cellulose powder, a dextran, an ethyl cellulose, a fecula, a galactan, a gellan gum, a guar gum, a hydroxyethyl cellulose, a hydroxypropyl guar gum, a hydroxypropyl methyl cellulose, a karaya gum, a locust bean gum, a methyl cellulose, a microcrystalline cellulose, a nitro cellulose, a pectin, a polyethyleneimine, a polyvinyl alcohol, a polyvinylpyrrolidone, a pulleran, a quince seed, a sodium cellulose sulfate, a starch- based polymer, a starches a succinoglucan, a tragacanth gum, and a xanthan gum.

Aspect 6. The RTU oral liquid formulation of any one of the preceding aspects, wherein the one or more pharmaceutically acceptable polymers comprises microcrystalline cellulose, sodium carboxymethyl cellulose, an arabia gum, a carob gum, a gellan gum, a guar gum, a karaya gum, a locust bean gum, a tragacanth gum, and a xanthan gum.

Aspect 7. The RTU oral liquid formulation of any one of the preceding aspects, wherein the one or more pharmaceutically acceptable polymers is present in an amount of from 1 mg/mL to 100 mg/mL.

Aspect 8. The RTU oral liquid formulation of any one of the preceding aspects, wherein the one or more pharmaceutically acceptable polymers is present in an amount of from 1 mg/mL to 100 mg/mL and wherein the RTU oral liquid formulation has a viscosity of from 5 cP to about 500 cP.

Aspect 9. The RTU oral liquid formulation of any one of the preceding aspects, wherein the one or more pharmaceutically acceptable polymers is present in an amount of from 10 mg/mL to 35 mg/mL and wherein the RTU oral liquid formulation has a viscosity of from 100 cP to about 200 cP.

Aspect 10. The RTU oral liquid formulation of any one of the preceding aspects, wherein the one or more pharmaceutically acceptable polymers comprises microcrystalline cellulose and sodium carboxymethylcellulose in an amount of 15 mg/mL to 25 mg/mL, and a gum in an amount of 1.5 mg/mL to 5.5 mg/mL.

Aspect 11. The RTU oral liquid formulation of any one of the preceding aspects, wherein the one or more pharmaceutically acceptable polymers comprises microcrystalline cellulose and sodium carboxymethylcellulose in an amount of 15 mg/mL to 25 mg/mL, and a gum in an amount of 1.5 mg/mL to 5.5 mg/mL; and wherein the gum is selected from an arabia gum, a carob gum, a gellan gum, a guar gum, a karaya gum, a locust bean gum, a tragacanth gum, and a xanthan gum.

Aspect 12. The RTU oral liquid formulation of any one of the preceding aspects, wherein the one or more pharmaceutically acceptable excipients comprises a buffer in an amount of 0.1 mM to 500 mM.

Aspect 13. The RTU oral liquid formulation of any one of the preceding aspects, wherein the one or more pharmaceutically acceptable excipients comprises a buffer in an amount of 0.1 mM to 500 mM, and wherein the buffer comprises one or more of citrate, acetate, aconitate, formate, glutarate, glutamate, malate, succinate, tartrate, phosphate, carbonate, glycinate.

Aspect 14. The RTU oral liquid formulation of any one of the preceding aspects, wherein the formulation has a pH of 3.5 to 4.5; wherein the one or more pharmaceutically acceptable excipients comprises a buffer in an amount of 0.1 mM to 500 mM; and wherein the buffer comprises one or more of citrate, acetate, aconitate, formate, glutarate, glutamate, malate, succinate, tartrate, phosphate, carbonate, glycinate.

Aspect 15. The RTU oral liquid formulation of any one of the preceding aspects, wherein the one or more pharmaceutically acceptable excipients comprises an antifoaming agent, a sweetener, a preservative, a flavour, or a combination thereof.

Aspect 16. The RTU oral liquid formulation of any one of the preceding aspects substantially free of a hydroxy-containing stabilizer.

Aspect 17. The RTU oral liquid formulation of any one of the preceding aspects, wherein the formulation comprises: warfarin sodium is present in an amount of about 1 mg/mL; the one or more pharmaceutically acceptable polymers comprises microcrystalline cellulose and sodium carboxymethylcellulose in an amount of about 20 mg/mL, and xanthan gum in an amount of about 3.5 mg/mL; and the one or more pharmaceutically acceptable excipients comprises an anti-foaming agent in an amount of from 0.1 mg/mL to 30 mg/mL, a sweetener in an amount of from 0.01 mg/mL to 10 mg/mL, a preservative in an amount of from 0.01 mg/mL to 10 mg/mL, and a flavour in an amount of from 0.01 mg/mL to 10 mg/mL.

Aspect 18. The RTU oral liquid formulation of any one of the preceding aspects, wherein the formulation comprises: warfarin sodium is present in an amount of about 1 mg/mL; the one or more pharmaceutically acceptable polymers comprises microcrystalline cellulose and sodium carboxymethylcellulose in an amount of about 20 mg/mL, and xanthan gum in an amount of about 3.5 mg/mL; and the one or more pharmaceutically acceptable excipients comprises an anti-foaming agent in an amount of from 0.1 mg/mL to 30 mg/mL, a sweetener in an amount of from 0.01 mg/mL to 10 mg/mL, a preservative in an amount of from 0.01 mg/mL to 10 mg/mL, and a flavour in an amount of from 0.01 mg/mL to 10 mg/mL; and wherein the formulation is substantially free of a hydroxy-containing stabilizer.

Aspect 19. A package comprising the RTU oral liquid formulation any one of the preceding aspects contained in a sealed bottle and packaging material comprising written instructions for use.

Aspect 20. A method for the (i) prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism (PE); (ii) prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation (AF) and/or cardiac valve replacement; and (iii) reduction in the risk of death, recurrent myocardial infarction (MI), and thromboembolic events such as stroke or systemic embolization after myocardial infarction, which comprises administering to a patient in need thereof a therapeutically effective amount of the RTU oral liquid formulation of any one of the preceding aspects.

Claims

1. A ready -to-use oral liquid formulation of warfarin sodium, comprising: warfarin sodium; one or more pharmaceutically acceptable polymers; a suitable buffer to provide a formulation pH of 3.5 to 5; one or more pharmaceutically acceptable excipients; and water.

2. The ready-to-use oral liquid formulation of warfarin sodium as claimed in claim 1, wherein the amount of warfarin sodium ranges from 0.1 mg/mL to 10 mg/mL.

3. The ready-to-use oral liquid formulation of warfarin sodium as claimed in claim 1, wherein said oral liquid formulation can be selected from solution, suspension or emulsion, more preferably in the form of suspension.

4. The ready-to-use oral liquid formulation of warfarin sodium as claimed in claim 1, wherein the said warfarin sodium has a D(0.9) particle size of not more than about 150 pm and amount of warfarin sodium is present in an amount of about 1 mg/mL.

5. The ready-to-use oral liquid formulation of warfarin sodium as claimed in claim 1, wherein the one or more pharmaceutically acceptable polymers is selected from an acrylate polymer, an agar, an algae colloid, an alginic acidbased polymer, an alginin, an arabia gum, a carboxymethyl cellulose or a pharmaceutically acceptable salt thereof, a carob gum, a carrageen, a carrageenan, a cellulose powder, a dextran, an ethyl cellulose, a fecula, a galactan, a gellan gum, a guar gum, a hydroxyethyl cellulose, a hydroxypropyl guar gum, a hydroxypropyl methyl cellulose, a karaya gum, a locust bean gum, a methyl cellulose, a microcrystalline cellulose, a nitro cellulose, a pectin, a polyethyleneimine, a polyvinyl alcohol, a polyvinylpyrrolidone, a pulleran, a quince seed, a sodium cellulose sulfate, a starch-based polymer, a starches a succinoglucan, a tragacanth gum, and a xanthan gum.

6. The ready-to-use oral liquid formulation of warfarin sodium as claimed in claim 1, wherein the one or more pharmaceutically acceptable polymers comprises microcrystalline cellulose, sodium carboxymethyl cellulose, an arabia gum, a carob gum, a gellan gum, a guar gum, a karaya gum, a locust bean gum, a tragacanth gum, and a xanthan gum.

7. The ready-to-use oral liquid formulation of warfarin sodium as claimed in claim 1, wherein the one or more pharmaceutically acceptable polymers is present in an amount of from 1 mg/mL to 100 mg/mL and wherein the RTU oral liquid formulation has a viscosity of from 5 cP to about 500 cP.

8. The ready-to-use oral liquid formulation of warfarin sodium as claimed in claim 1, wherein the one or more pharmaceutically acceptable polymers is present in an amount of from 10 mg/mL to 35 mg/mL and wherein the RTU oral liquid formulation has a viscosity of from 100 cP to about 200 cP.

9. The ready-to-use oral liquid formulation of warfarin sodium as claimed in claim 1, wherein the one or more pharmaceutically acceptable polymers comprises microcrystalline cellulose and sodium carboxymethylcellulose in an amount of 15 mg/mL to 25 mg/mL, and a gum in an amount of 1.5 mg/mL to 5.5 mg/mL; and wherein the gum is selected from an arabia gum, a carob gum, a gellan gum, a guar gum, a karaya gum, a locust bean gum, a tragacanth gum, and a xanthan gum.

10. The ready-to-use oral liquid formulation of warfarin sodium as claimed in claim 1, wherein the formulation has a pH of 3.5 to 4.5; wherein the one or more pharmaceutically acceptable excipients comprises a buffer in an amount of 0.1 mM to 500 mM; and wherein the buffer comprises one or more of citrate, acetate, aconitate, formate, glutarate, glutamate, malate, succinate, tartrate, phosphate, carbonate, glycinate.

11. The ready-to-use oral liquid formulation of warfarin sodium as claimed in claim 1, wherein the one or more pharmaceutically acceptable excipients comprises an anti-foaming agent, a sweetener, a preservative, a flavour, or a combination thereof.

12. The ready-to-use oral liquid formulation of warfarin sodium as claimed in claim 1, wherein the formulation comprises: warfarin sodium is present in an amount of about 1 mg/mL; the one or more pharmaceutically acceptable polymers comprises microcrystalline cellulose and sodium carboxymethylcellulose in an amount of about 20 mg/mL, and xanthan gum in an amount of about 3.5 mg/mL; and the one or more pharmaceutically acceptable excipients comprises an anti foaming agent in an amount of from 0.1 mg/mL to 30 mg/mL, a sweetener in an amount of from 0.01 mg/mL to 10 mg/mL, a preservative in an amount of from 0.01 mg/mL to 10 mg/mL, and a flavour in an amount of from 0.01 mg/mL to 10 mg/mL; and wherein the formulation is substantially free of a hydroxy-containing stabilizer.

13. The ready -to-use oral liquid formulation of warfarin sodium as claimed in claim 1, wherein the said formulation is formulated at stirring speed of 1000-1500 rpm.

14. The ready-to-use oral liquid formulation of warfarin sodium as claimed in claim 1, wherein the said formulation is formulated at homogenization speed of 7500-8500 rpm.

15. A method for the (i) prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism (PE); (ii) prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation (AF) and/or cardiac valve replacement; and (iii) reduction in the risk of death, recurrent myocardial infarction (MI), and thromboembolic events such as stroke or systemic embolization after myocardial infarction, which comprises administering to a patient in need thereof a therapeutically effective amount of the RTU oral liquid formulation of claim 1.