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EP4522123A1 - Liquid oral formulation of apixaban or pharmaceutically acceptable salt thereof - Google Patents
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EP4522123A1 - Liquid oral formulation of apixaban or pharmaceutically acceptable salt thereof - Google Patents

Liquid oral formulation of apixaban or pharmaceutically acceptable salt thereof

Info

Publication number
EP4522123A1
EP4522123A1 EP23803183.5A EP23803183A EP4522123A1 EP 4522123 A1 EP4522123 A1 EP 4522123A1 EP 23803183 A EP23803183 A EP 23803183A EP 4522123 A1 EP4522123 A1 EP 4522123A1
Authority
EP
European Patent Office
Prior art keywords
apixaban
liquid formulation
stable
stable liquid
formulation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP23803183.5A
Other languages
German (de)
French (fr)
Inventor
Girish Shantilal Achliya
Sanjaykumar D POPTANI
Shreyaskumar Vikasbhai BHAVSAR
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Syri Research Private Ltd
Original Assignee
Syri Research Private Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Syri Research Private Ltd filed Critical Syri Research Private Ltd
Publication of EP4522123A1 publication Critical patent/EP4522123A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone

Definitions

  • Liquid oral formulation of apixaban or pharmaceutically acceptable salt thereof Liquid oral formulation of apixaban or pharmaceutically acceptable salt thereof
  • the present invention relates to a liquid oral formulation of apixaban or pharmaceutically acceptable salt thereof.
  • the present invention particularly relates to oral suspension formulation of apixaban or pharmaceutically acceptable salt thereof.
  • Apixaban is prominently used as direct and reversible inhibitor of FXa, and it inhibits free FXa.
  • Apixaban is an anticoagulant used for the prophylaxis of stroke and systemic embolism in nonvalvular atrial fibrillation, and deep vein thrombosis (DVT). It is a pyrazole derivative and chemically described as l-(4-methoxyphenyl) -7- oxo -6- [4-(2-oxopiperidin-l-yl) phenyl]-4,5,6,7-tetrahydro-l/Z-pyrazolo[3,4c] pyridine-3-carboxamide.
  • Apixaban was disclosed first time in patent EP1427415B1.
  • the PCT publication no. W02007022165A2 describes an injectable Factor Xa inhibitor formulation of razaxaban or apixaban, a solubilizing agent which is a substituted P-cyclodextrin, preferably, sulfobutyl ether P-cyclodextrin (SBE-CD) or hydroxypropyl- P-cyclodextrin (HPB-CD), and water.
  • SBE-CD sulfobutyl ether P-cyclodextrin
  • HPB-CD hydroxypropyl- P-cyclodextrin
  • Eliquis® (apixaban) tablet label for patients who are unable to swallow whole tablets, 5 mg and 2.5 mg Eliquis® tablets may be crushed and suspended in water, 5% dextrose in water (D5W), or apple juice, or mixed with applesauce and promptly administered orally. Alternatively, Eliquis® tablets may be crushed and suspended in 60 mL of water or D5W and promptly delivered through a nasogastric tube. This label further state that the crushed Eliquis® tablets are stable in water, D5W, apple juice, and applesauce only for up to 4 hours. Apixaban has poor water solubility and oral bio availability. Low aqueous solubility of apixaban (0.04 mg/mL) is a major hurdle to the development of a liquid formulation of apixaban. The formulator thus faces significant challenges in assuring acceptable oral bioavailability.
  • a prior art patent US 9,452,134 describes a liquid formulation comprising apixaban and a vehicle wherein the vehicle can comprise water and at least two solubilizers selected from the group consisting of a non-ionic surfactant, an ionic surfactant, a hydrophilic polymer, ethanol, a polyhydric alcohol, a polyethylene glycol, and a carbohydrate and the solubility of apixaban in this vehicle can be at least 0.50 mg/mL.
  • the US patent no. US 9,452,134 determined that a concentration of 0.4 mg/mL of apixaban in an oral liquid formulation adequately supports a desired dosage range of 0.04 mg to 5.0 mg with acceptable volumes ranging, for example, between 0.10 mL and 12.5 mL, which can be accurately measured and conveniently administered in the target patient population. Accordingly, for 5 mg dose, 12.5 mL of solution need to be administered. The administrations of such larger volumes are cumbersome and raise the problems of patient non-compliance.
  • the present invention provides solution for problems arising from prior arts.
  • the present invention also provides solution for problems arising due to controlled release solid dosage form such as dose dumping and difficulty in adjustment of dose.
  • the present invention discloses a stable liquid formulation of apixaban comprising apixaban or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable ingredient, wherein the formulation is stable for at least one month under storage condition of 25°C/60% RH and/or 30°C/65% RH and/or 40°C/75% and/or 2-8°C.
  • the present invention further discloses a stable liquid formulation of apixaban, wherein the liquid formulation is in the form of suspension, solution or the like and any combination thereof.
  • apixaban is present at a concentration of 0.5 mg/ml to 5 mg/ml in liquid formulation of apixaban.
  • the liquid formulation of apixaban has a pH of about 3 to about 7.
  • apixaban has a particle size distribution D(90) less than about 20pm.
  • the liquid formulation of apixaban is suitable for oral administration and/or administration through a nasogastric tube and/or gastronomy tube using a dosing syringe.
  • Another embodiment of the present invention is a method for treating a thromboembolic disorder, comprising administering to a patient in need thereof a therapeutically effective amount of the liquid formulation of apixaban.
  • the present inventors have surprisingly found that the liquid formulations of apixaban can be administered effectively in the paediatric population and adults who are unable to swallow a solid dosage form. It is an object of the present invention to provide a stable liquid formulation of apixaban. Further object of the present invention is to provide a stable aqueous suspension formulation of apixaban.
  • Apixaban as used herein is defined to mean apixaban as its base or pharmaceutically acceptable salts or solvates or non-solvates or prodrugs or ester or metabolite or analogue or isomer or polymorph or pre-mix thereof.
  • the term “pharmaceutically acceptable” refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refer to derivatives of the apixaban wherein the apixaban is modified by making acid or base salts thereof.
  • the term “therapeutically effective amount” refers to the amount of apixaban or a pharmaceutically acceptable salt or prodrug thereof contained in the composition administered is of sufficient quantity to achieve the intended use, in this case, to treat the patient with thromboembolic disorders.
  • the storage conditions used in the present invention are 25°C/60% RH and/or 30°C/65% RH and/or 40°C/75% and/or 2-8°C.
  • the ‘storage condition of 25°C/60% RH’ means storage at a temperature of 25°C and 60% relative humidity.
  • the ‘storage condition of 30°C/65% RH’ means storage at a temperature of 30°C and 65% relative humidity
  • the ‘storage condition of 40°C/75% RH’ means storage at a temperature of 40°C and 75% relative humidity.
  • the ‘storage condition of 2-8°C’ means storage at a temperature of 2 to 8°C.
  • the present invention discloses a stable liquid formulation of apixaban comprising apixaban or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable ingredient.
  • the present invention further discloses a stable liquid formulation of apixaban, wherein the liquid formulation is in the form of suspension, solution or the like and any combination thereof.
  • the stable liquid formulation of apixaban is in the form of a suspension.
  • the stable liquid formulation of apixaban is in the form of a solution.
  • the present invention discloses a stable liquid formulation of apixaban comprising apixaban or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable ingredient, wherein the formulation is stable for at least one month under storage condition of 25°C/60% RH and/or 30°C/65% RH and/or 40°C/75% and/or 2-8°C.
  • the liquid formulation is stable for at least two months, preferably for at least three months, preferably for at least four months, more preferably for at least five months under storage condition of 25°C/60% RH. In another embodiment of the present invention, the liquid formulation is stable for at least six months under storage condition of 25°C/60% RH.
  • the liquid formulation is stable for at least two months, preferably for at least three months, preferably for at least four months, more preferably for at least five months under storage condition of 30°C/65% RH. In another embodiment of the present invention, the liquid formulation is stable for at least six months under storage condition of 30°C/65% RH.
  • the liquid formulation is stable for at least two months, preferably for at least three months, preferably for at least four months, more preferably for at least five months under storage condition of 40°C/75% RH. In another embodiment of the present invention, the liquid formulation is stable for at least six months under storage condition of 40°C/75% RH.
  • the liquid formulation is stable for at least two months, preferably for at least three months, preferably for at least four months, more preferably for at least five months under storage condition of 2-8°C. In another embodiment of the present invention, the liquid formulation is stable for at least six months under storage condition of 2- 8 °C.
  • the liquid formulation of apixaban comprises 0.5 mg to 5 mg of apixaban per mL of the formulation.
  • the concentration of apixaban in the liquid formulation may be, for example, 5 mg/mL, 4.5 mg/mL, 4 mg/mL, 3.5 mg/mL, 3 mg/mL, 2.5 mg/mL, 2 mg/mL, 1.5 mg/mL, 1 mg/mL or at least 0.5 mg/mL.
  • the concentration of apixaban is at least 0.5 mg/mL.
  • the concentration of apixaban is at least 1 mg/mL.
  • the concentration of apixaban is 1 mg/mL.
  • the liquid formulation of apixaban has pH of about 3 to about 7.
  • the pH of the liquid formulation may be, for example, about 3, about 3.5, about 4, about 5, about 5.5, about , about 6, about 6.5 or about 7.
  • the liquid formulation of apixaban has pH of about 4 to about 6, preferably about 4.5 to 5.5, more preferably about 5.
  • apixaban has a particle size distribution D(90) less than about 20pm, preferably less than about 15pm, more preferably less than about 10pm.
  • the liquid formulation of apixaban is oral aqueous suspension or powder for oral suspension which meant to be administered after reconstitution in a suitable solvent.
  • the one or more pharmaceutically acceptable ingredients are selected from group consisting of suspending agents, buffers (pH adjusting agents), preservatives, antioxidants, solubilizers, complexing agents, antifoaming agents, sweeteners, flavouring agents and suitable vehicle.
  • Suspending agents which may be used according to the present invention, include, but are not limited to, xanthan gum, guar gum, microcrystalline cellulose, sodium carbo xymethylcellulose, a mixture of carbo xymethylcellulose and microcrystalline cellulose, propylene glycol alginate and combinations thereof.
  • the suspending agent is xanthan gum and/or sodium carboxymethylcellulose.
  • the suspending agent can be present in an amount from about 0.10 to about 10% w/v of the liquid formulation, preferably about 0.10 to about 1% w/v of the liquid formulation.
  • Buffers which may be used, according to the present invention, include suitable buffers that are not chemically reactive with the other ingredients, and which may be present in an amount sufficient to provide the desired degree of pH buffering.
  • a buffer system comprising of an aqueous mixture of an acid, wherein the acid is citric, succinic, tartaric, lactic, or phosphoric acid, and a base, wherein the base is sodium citrate dihydrate, sodium hydroxide, or disodium hydrogen phosphate, is for maintaining the pH in the range from 3 to 7.
  • Preservatives which may be used according to the present invention, include, but are not limited to, benzoic acid, sodium benzoate, potassium sorbate, cresol, cetrimide, citric acid and sodium citrate, and alkyl hydroxybenzoates (parabens).
  • the preservative is selected from an alkyl hydroxybenzoate, such as methyl hydroxybenzoate (MHB), ethyl hydroxybenzoate (EHB), propyl hydroxybenzoate (PHB) (as base or sodium salt) or a combination thereof.
  • the preservative is combination of MHB and PHB. More preferably, the preservative is combination of Na MHB and Na PHB.
  • Preservative can be present in an amount from about 0.001 to about 1% w/v of the liquid formulation, preferably about 0.01 to about 0.5% w/v of the liquid formulation, more preferably about 0.05 to about 0.1% w/v of the liquid formulation.
  • Non-limiting examples of non-ionic surfactants that can be used in the liquid formulation are polyoxyethylene sorbitan fatty acid esters (polysorbates), poloxamers, polyoxyethylene castor oil derivatives, polyoxyglycerides, vitamin E polyethylene glycol succinate, and macrogol 15 hydroxystearate.
  • Non- limiting examples of hydrophilic polymers that can be used in the liquid formulation are povidone (for example PVPK 12, Povidone K30), copovidone, hydroxypropyl cellulose, and hydroxypropyl methylcellulose.
  • Non-limiting examples of polyhydric alcohols that can be used in the liquid formulation are glycerin, propylene glycol, sorbitol, and mannitol.
  • Non-limiting examples of polyethylene glycols that can be used in the liquid formulation are polyethylene glycol 200, polyethylene glycol 300, and polyethylene glycol 400.
  • Non-limiting examples of carbohydrates that can be used in the liquid formulation are fructose, sucrose, and lactose.
  • Anti-foaming agent can be a silicone based antifoam.
  • Antifoaming agent is preferably simethicone emulsion.
  • the antifoaming agent can be present in an amount from about 0.01 to about 1% w/v of the liquid formulation, preferably about 0.01 to about 0.5% w/v of the liquid formulation.
  • Antioxidants which may be used according to the present invention, include, but are not limited to, sodium metabisulfate, ascorbic acid, sodium formaldehyde, sulfoxylate, or mixtures thereof.
  • Complexing agents which may be used according to the present invention, include, but are not limited to, a-cyclodextrin, P-cyclodextrin, y-cyclodextrin and their derivatives such as, for example, hydroxypropyl- P-cyclodextrin.
  • Sweeteners which may be used according to the present invention, may be any natural or artificial sweetener.
  • natural sweeteners these include, but are not limited to, glucose, fructose, invert sugar, sorbitol, sucrose, maltose, xylose, ribose, mannose, corn syrup solids, xylitol, mannitol, maltodextrins, and mixtures thereof.
  • artificial sweeteners these include, but are not limited to, sucralose, aspartame and saccharin.
  • the artificial sweetener is sucralose.
  • Sweetener can be present in an amount from about 0.01% to about 2% w/v of the liquid formulation, preferably about 0.01% to about 1% w/v of the liquid formulation.
  • Flavouring agents incorporated in the liquid formulation may be chosen from synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plant leaves, flowers, fruits, and so forth and combinations thereof. Also useful as flavors are vanilla, citrus oils, including lemon, orange, lime and grapefruit, and fruit essence, including apple, grape, banana, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, and so forth. Flavouring agent can be present in an amount from about 0.01% to about 1% w/v of the liquid formulation.
  • the vehicle used in the formulation of the invention is selected from glycerin, propylene glycol, water or combination thereof.
  • the vehicle used in the formulation of the invention is preferably water, although other suitable water-containing (aqueous) vehicles known to the skilled person may also be used. Water can be present in an amount from about 70% to about 99% w/v of the liquid formulation.
  • the liquid formulation of apixaban is suitable for oral administration.
  • the liquid formulation of apixaban is suitable for administration through a nasogastric tube (NGT) and/or through a gastronomy tube (G-tube) using a dosing syringe.
  • NGT nasogastric tube
  • G-tube gastronomy tube
  • enteral meal may be administered.
  • the liquid formulation of apixaban provides similar bioavailability and pharmacokinetic properties to apixaban oral tablet available as Eliquis®.
  • the liquid formulation of apixaban has a C max , AUCi n f, and/or AUC(O-T) from 80% to 125% of the C max , AUCinf, and/or AU O-T), respectively, of Eliquis® (apixaban) tablet.
  • Another embodiment of the present invention is a method for treating a thromboembolic disorder comprising administering to a patient in need thereof a therapeutically effective amount of a liquid formulation of apixaban described above.
  • a stable liquid formulation of apixaban comprising apixaban or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable ingredients.
  • apixaban is present at a concentration of 5 mg/mL, 4.5 mg/mL, 4 mg/mL, 3.5 mg/mL, 3 mg/mL, 2.5 mg/mL, 2 mg/mL, 1.5 mg/mL, 1 mg/mL or at least 0.5 mg/mL.
  • apixaban according to embodiment 1, wherein the one or more pharmaceutically acceptable ingredients are selected from group consisting of suspending agents, buffers (pH adjusting agents), preservatives, antioxidants, solubilizers, complexing agents, antifoaming agents, sweeteners, flavouring agents and suitable vehicle.
  • the one or more pharmaceutically acceptable ingredients are selected from group consisting of suspending agents, buffers (pH adjusting agents), preservatives, antioxidants, solubilizers, complexing agents, antifoaming agents, sweeteners, flavouring agents and suitable vehicle.
  • apixaban The stable liquid formulation of apixaban according to embodiment 23, wherein the sweetener is selected from glucose, fructose, invert sugar, sorbitol, sucrose, maltose, xylose, ribose, mannose, corn syrup solids, xylitol, mannitol, maltodextrins or mixtures thereof.
  • the sweetener is selected from glucose, fructose, invert sugar, sorbitol, sucrose, maltose, xylose, ribose, mannose, corn syrup solids, xylitol, mannitol, maltodextrins or mixtures thereof.
  • a method for treating a thromboembolic disorder comprising administering to a patient in need thereof a therapeutically effective amount of the liquid formulation of apixaban according to embodiments 1-36.
  • apixaban 39.
  • one or more pharmaceutically acceptable ingredients comprises: a) 0.05-0.5% w/v of apixaban or pharmaceutically acceptable salt thereof; b) 0.001-1% w/v of preservative; c) 0.10%- 10% w/v of suspending agent; d) 0.5-20% w/v of solubilizer; e) 0.01-1% w/v of anti-foaming agent; f) 0.01-2% w/v of sweetener; g) 0.01-2% w/v of buffer; h) 0.01-1% w/v of flavouring agent; and i) Q. S. to vehicle.
  • Example 1 Suspension formulation of apixaban
  • step-1 Mixture of step-1 was added into mixture of step-2. 4. Separately, Apixaban was added and dispersed into glycerol.
  • step-4 was added into mixture of step-3.
  • Xanthan gum was added and dispersed in purified water.
  • step-1 was added into mixture of step-2.
  • PVPK12 was added and dissolved into purified water.
  • step-4 was added into mixture of step-3.
  • step-6 Mixture of step-6 was added into mixture of step-5. 8. Sodium citrate dihydrate, Citric acid anhydrous and Orange Flavour were added into above suspension.
  • Example 6-9 Suspension formulations of apixaban
  • the formulation was prepared according to the example 3.
  • Example 9 Stability study
  • the suspension formulation of example 2 found to be stable for 6 months at storage conditions 25°C/60% RH, 30°C/65% RH, 40°C/75% RH and 2-8°C.
  • Stability data of suspension formulation of example 3, packed in glass bottle is shown below.
  • the suspension formulation of example 3 found to be stable for 6 months at storage condition 25°C/60% RH, stable for at least 3 months at storage condition 30°C/65% RH, stable for at least 2 months at storage condition 40°C/75% RH and stable for 6 months at storage condition 2- 8 °C.
  • the suspension formulation of example 4 found to be stable for 6 months at storage condition 25°C/60% RH, stable for at least 3 months at storage condition 30°C/65% RH, stable for at least 2 months at storage condition 40°C/75% RH and stable for 6 months at storage condition 2- 8 °C.
  • Example 12 Stability study Stability data of suspension formulation of example 6, packed in glass bottle is shown below.
  • the suspension formulation of example 6 found to be stable for at least 1 month at storage conditions 25°C/60% RH, 30°C/65% RH and stable for at least 2 months at storage condition 40°C/75% RH.
  • the suspension formulation of example 7 found to be stable for at least 1 month at storage conditions 25°C/60% RH, 30°C/65% RH and 40°C/75% RH.
  • Dissolution profile data for suspension formulation of example 6 is shown below.

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Abstract

The present invention relates to a liquid oral formulation of apixaban or pharmaceutically acceptable salt thereof. The present invention particularly discloses a stable suspension formulation of apixaban comprising apixaban or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable ingredient, wherein the formulation is stable for at least one month under storage condition of 25°C/60% RH and/or 30°C/65% RH and/or 40°C/75% and/or 2-8°C. The stable suspension formulation of apixaban of the present invention is suitable for oral administration and/or administration through a nasogastric tube and/or gastronomy tube using a dosing syringe and for patients who have swallowing difficulties as in case of paediatric as well as geriatric patients.

Description

Liquid oral formulation of apixaban or pharmaceutically acceptable salt thereof
FIELD OF THE INVENTION
The present invention relates to a liquid oral formulation of apixaban or pharmaceutically acceptable salt thereof. The present invention particularly relates to oral suspension formulation of apixaban or pharmaceutically acceptable salt thereof.
BACKGROUND OF THE INVENTION
Apixaban is prominently used as direct and reversible inhibitor of FXa, and it inhibits free FXa. Apixaban is an anticoagulant used for the prophylaxis of stroke and systemic embolism in nonvalvular atrial fibrillation, and deep vein thrombosis (DVT). It is a pyrazole derivative and chemically described as l-(4-methoxyphenyl) -7- oxo -6- [4-(2-oxopiperidin-l-yl) phenyl]-4,5,6,7-tetrahydro-l/Z-pyrazolo[3,4c] pyridine-3-carboxamide.
Apixaban was disclosed first time in patent EP1427415B1. The PCT publication no. W02007022165A2 describes an injectable Factor Xa inhibitor formulation of razaxaban or apixaban, a solubilizing agent which is a substituted P-cyclodextrin, preferably, sulfobutyl ether P-cyclodextrin (SBE-CD) or hydroxypropyl- P-cyclodextrin (HPB-CD), and water.
The practice of compounding the oral liquid dosage form from marketed solid dosage form is very conventional and well known for patients who have swallowing difficulties as in case of paediatric as well as geriatric patients, where administration of accurate dose is compromised. For these patients, one or more Apixaban tablets are crushed to powder and mixed with suitable solvent like water to form an easily administered extemporaneous suspension. But, this varies the rate of release of an active ingredient.
According to the Eliquis® (apixaban) tablet label, for patients who are unable to swallow whole tablets, 5 mg and 2.5 mg Eliquis® tablets may be crushed and suspended in water, 5% dextrose in water (D5W), or apple juice, or mixed with applesauce and promptly administered orally. Alternatively, Eliquis® tablets may be crushed and suspended in 60 mL of water or D5W and promptly delivered through a nasogastric tube. This label further state that the crushed Eliquis® tablets are stable in water, D5W, apple juice, and applesauce only for up to 4 hours. Apixaban has poor water solubility and oral bio availability. Low aqueous solubility of apixaban (0.04 mg/mL) is a major hurdle to the development of a liquid formulation of apixaban. The formulator thus faces significant challenges in assuring acceptable oral bioavailability.
It is desirable to have a liquid formulation for administration of apixaban in the paediatric population and adults who are unable to swallow a solid dosage form. A prior art patent US 9,452,134 describes a liquid formulation comprising apixaban and a vehicle wherein the vehicle can comprise water and at least two solubilizers selected from the group consisting of a non-ionic surfactant, an ionic surfactant, a hydrophilic polymer, ethanol, a polyhydric alcohol, a polyethylene glycol, and a carbohydrate and the solubility of apixaban in this vehicle can be at least 0.50 mg/mL.
The US patent no. US 9,452,134 determined that a concentration of 0.4 mg/mL of apixaban in an oral liquid formulation adequately supports a desired dosage range of 0.04 mg to 5.0 mg with acceptable volumes ranging, for example, between 0.10 mL and 12.5 mL, which can be accurately measured and conveniently administered in the target patient population. Accordingly, for 5 mg dose, 12.5 mL of solution need to be administered. The administrations of such larger volumes are cumbersome and raise the problems of patient non-compliance.
Low aqueous solubility is the major challenging factor for development of suitable dosage form for Apixaban. The present invention provides solution for problems arising from prior arts. The present invention also provides solution for problems arising due to controlled release solid dosage form such as dose dumping and difficulty in adjustment of dose.
SUMMARY OF THE INVENTION
The present invention discloses a stable liquid formulation of apixaban comprising apixaban or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable ingredient, wherein the formulation is stable for at least one month under storage condition of 25°C/60% RH and/or 30°C/65% RH and/or 40°C/75% and/or 2-8°C. The present invention further discloses a stable liquid formulation of apixaban, wherein the liquid formulation is in the form of suspension, solution or the like and any combination thereof.
In one embodiment of the present invention, apixaban is present at a concentration of 0.5 mg/ml to 5 mg/ml in liquid formulation of apixaban.
In another embodiment of the present invention, the liquid formulation of apixaban has a pH of about 3 to about 7.
According to another embodiment of the present invention, apixaban has a particle size distribution D(90) less than about 20pm.
In an embodiment of the present invention, the liquid formulation of apixaban is suitable for oral administration and/or administration through a nasogastric tube and/or gastronomy tube using a dosing syringe.
Another embodiment of the present invention is a method for treating a thromboembolic disorder, comprising administering to a patient in need thereof a therapeutically effective amount of the liquid formulation of apixaban.
DETAILED DESCRIPTION OF THE INVENTION
The present inventors have surprisingly found that the liquid formulations of apixaban can be administered effectively in the paediatric population and adults who are unable to swallow a solid dosage form. It is an object of the present invention to provide a stable liquid formulation of apixaban. Further object of the present invention is to provide a stable aqueous suspension formulation of apixaban.
The term “Apixaban” as used herein is defined to mean apixaban as its base or pharmaceutically acceptable salts or solvates or non-solvates or prodrugs or ester or metabolite or analogue or isomer or polymorph or pre-mix thereof.
As used herein, the term "pharmaceutically acceptable" refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. As used herein, the term "pharmaceutically acceptable salts" refer to derivatives of the apixaban wherein the apixaban is modified by making acid or base salts thereof.
As used herein, the term “therapeutically effective amount” refers to the amount of apixaban or a pharmaceutically acceptable salt or prodrug thereof contained in the composition administered is of sufficient quantity to achieve the intended use, in this case, to treat the patient with thromboembolic disorders.
The storage conditions used in the present invention are 25°C/60% RH and/or 30°C/65% RH and/or 40°C/75% and/or 2-8°C. The ‘storage condition of 25°C/60% RH’ means storage at a temperature of 25°C and 60% relative humidity. Likewise the ‘storage condition of 30°C/65% RH’ means storage at a temperature of 30°C and 65% relative humidity, the ‘storage condition of 40°C/75% RH’ means storage at a temperature of 40°C and 75% relative humidity. The ‘storage condition of 2-8°C’ means storage at a temperature of 2 to 8°C.
The present invention discloses a stable liquid formulation of apixaban comprising apixaban or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable ingredient. The present invention further discloses a stable liquid formulation of apixaban, wherein the liquid formulation is in the form of suspension, solution or the like and any combination thereof.
In one embodiment of the present invention, the stable liquid formulation of apixaban is in the form of a suspension.
In one embodiment of the present invention, the stable liquid formulation of apixaban is in the form of a solution.
The present invention discloses a stable liquid formulation of apixaban comprising apixaban or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable ingredient, wherein the formulation is stable for at least one month under storage condition of 25°C/60% RH and/or 30°C/65% RH and/or 40°C/75% and/or 2-8°C.
In an embodiment of the present invention, the liquid formulation is stable for at least two months, preferably for at least three months, preferably for at least four months, more preferably for at least five months under storage condition of 25°C/60% RH. In another embodiment of the present invention, the liquid formulation is stable for at least six months under storage condition of 25°C/60% RH.
In yet another embodiment of the present invention, the liquid formulation is stable for at least two months, preferably for at least three months, preferably for at least four months, more preferably for at least five months under storage condition of 30°C/65% RH. In another embodiment of the present invention, the liquid formulation is stable for at least six months under storage condition of 30°C/65% RH.
In further embodiment of the present invention, the liquid formulation is stable for at least two months, preferably for at least three months, preferably for at least four months, more preferably for at least five months under storage condition of 40°C/75% RH. In another embodiment of the present invention, the liquid formulation is stable for at least six months under storage condition of 40°C/75% RH.
In another embodiment of the present invention, the liquid formulation is stable for at least two months, preferably for at least three months, preferably for at least four months, more preferably for at least five months under storage condition of 2-8°C. In another embodiment of the present invention, the liquid formulation is stable for at least six months under storage condition of 2- 8 °C.
In one embodiment of the present invention, the liquid formulation of apixaban comprises 0.5 mg to 5 mg of apixaban per mL of the formulation. The concentration of apixaban in the liquid formulation may be, for example, 5 mg/mL, 4.5 mg/mL, 4 mg/mL, 3.5 mg/mL, 3 mg/mL, 2.5 mg/mL, 2 mg/mL, 1.5 mg/mL, 1 mg/mL or at least 0.5 mg/mL. In another embodiment of the invention, the concentration of apixaban is at least 0.5 mg/mL. In yet another embodiment of the invention, the concentration of apixaban is at least 1 mg/mL. In further embodiment of the invention, the concentration of apixaban is 1 mg/mL. In another embodiment of the present invention, the liquid formulation of apixaban has pH of about 3 to about 7. The pH of the liquid formulation may be, for example, about 3, about 3.5, about 4, about 5, about 5.5, about , about 6, about 6.5 or about 7. In yet another embodiment of the present invention, the liquid formulation of apixaban has pH of about 4 to about 6, preferably about 4.5 to 5.5, more preferably about 5.
According to another embodiment of the present invention, apixaban has a particle size distribution D(90) less than about 20pm, preferably less than about 15pm, more preferably less than about 10pm.
In another embodiment of the present invention, the liquid formulation of apixaban is oral aqueous suspension or powder for oral suspension which meant to be administered after reconstitution in a suitable solvent.
The one or more pharmaceutically acceptable ingredients are selected from group consisting of suspending agents, buffers (pH adjusting agents), preservatives, antioxidants, solubilizers, complexing agents, antifoaming agents, sweeteners, flavouring agents and suitable vehicle.
Suspending agents, which may be used according to the present invention, include, but are not limited to, xanthan gum, guar gum, microcrystalline cellulose, sodium carbo xymethylcellulose, a mixture of carbo xymethylcellulose and microcrystalline cellulose, propylene glycol alginate and combinations thereof. Preferably, the suspending agent is xanthan gum and/or sodium carboxymethylcellulose. The suspending agent can be present in an amount from about 0.10 to about 10% w/v of the liquid formulation, preferably about 0.10 to about 1% w/v of the liquid formulation.
Buffers (pH adjusting agents) which may be used, according to the present invention, include suitable buffers that are not chemically reactive with the other ingredients, and which may be present in an amount sufficient to provide the desired degree of pH buffering. In this regard, a buffer system comprising of an aqueous mixture of an acid, wherein the acid is citric, succinic, tartaric, lactic, or phosphoric acid, and a base, wherein the base is sodium citrate dihydrate, sodium hydroxide, or disodium hydrogen phosphate, is for maintaining the pH in the range from 3 to 7. Preservatives, which may be used according to the present invention, include, but are not limited to, benzoic acid, sodium benzoate, potassium sorbate, cresol, cetrimide, citric acid and sodium citrate, and alkyl hydroxybenzoates (parabens). Preferably, the preservative is selected from an alkyl hydroxybenzoate, such as methyl hydroxybenzoate (MHB), ethyl hydroxybenzoate (EHB), propyl hydroxybenzoate (PHB) (as base or sodium salt) or a combination thereof. Preferably, the preservative is combination of MHB and PHB. More preferably, the preservative is combination of Na MHB and Na PHB. Preservative can be present in an amount from about 0.001 to about 1% w/v of the liquid formulation, preferably about 0.01 to about 0.5% w/v of the liquid formulation, more preferably about 0.05 to about 0.1% w/v of the liquid formulation.
Solubilizers, which may be used according to the present invention, include, but are not limited to, polyhydric alcohol, ethanol, polyethylene glycol, non-ionic surfactant, an ionic surfactant, a hydrophilic polymer and a carbohydrate. Solubilizer can be present in an amount from about 0.5 to about 20% w/v of the liquid formulation.
Non-limiting examples of non-ionic surfactants that can be used in the liquid formulation are polyoxyethylene sorbitan fatty acid esters (polysorbates), poloxamers, polyoxyethylene castor oil derivatives, polyoxyglycerides, vitamin E polyethylene glycol succinate, and macrogol 15 hydroxystearate.
Non-limiting examples of ionic surfactants that can be used in the liquid formulation are sodium lauryl sulfate and docusate sodium.
Non- limiting examples of hydrophilic polymers that can be used in the liquid formulation are povidone (for example PVPK 12, Povidone K30), copovidone, hydroxypropyl cellulose, and hydroxypropyl methylcellulose.
Non-limiting examples of polyhydric alcohols that can be used in the liquid formulation are glycerin, propylene glycol, sorbitol, and mannitol.
Non-limiting examples of polyethylene glycols that can be used in the liquid formulation are polyethylene glycol 200, polyethylene glycol 300, and polyethylene glycol 400. Non-limiting examples of carbohydrates that can be used in the liquid formulation are fructose, sucrose, and lactose.
Anti-foaming agent can be a silicone based antifoam. Antifoaming agent is preferably simethicone emulsion. The antifoaming agent can be present in an amount from about 0.01 to about 1% w/v of the liquid formulation, preferably about 0.01 to about 0.5% w/v of the liquid formulation.
Antioxidants, which may be used according to the present invention, include, but are not limited to, sodium metabisulfate, ascorbic acid, sodium formaldehyde, sulfoxylate, or mixtures thereof.
Complexing agents, which may be used according to the present invention, include, but are not limited to,a-cyclodextrin, P-cyclodextrin, y-cyclodextrin and their derivatives such as, for example, hydroxypropyl- P-cyclodextrin.
Sweeteners, which may be used according to the present invention, may be any natural or artificial sweetener. In terms of natural sweeteners, these include, but are not limited to, glucose, fructose, invert sugar, sorbitol, sucrose, maltose, xylose, ribose, mannose, corn syrup solids, xylitol, mannitol, maltodextrins, and mixtures thereof. In terms of artificial sweeteners, these include, but are not limited to, sucralose, aspartame and saccharin. In one embodiment, the artificial sweetener is sucralose. Sweetener can be present in an amount from about 0.01% to about 2% w/v of the liquid formulation, preferably about 0.01% to about 1% w/v of the liquid formulation.
Flavouring agents incorporated in the liquid formulation may be chosen from synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plant leaves, flowers, fruits, and so forth and combinations thereof. Also useful as flavors are vanilla, citrus oils, including lemon, orange, lime and grapefruit, and fruit essence, including apple, grape, banana, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, and so forth. Flavouring agent can be present in an amount from about 0.01% to about 1% w/v of the liquid formulation.
The vehicle used in the formulation of the invention is selected from glycerin, propylene glycol, water or combination thereof. The vehicle used in the formulation of the invention is preferably water, although other suitable water-containing (aqueous) vehicles known to the skilled person may also be used. Water can be present in an amount from about 70% to about 99% w/v of the liquid formulation.
In an embodiment of the present invention, the liquid formulation of apixaban is suitable for oral administration. Alternatively, or in addition, the liquid formulation of apixaban is suitable for administration through a nasogastric tube (NGT) and/or through a gastronomy tube (G-tube) using a dosing syringe. In clinical situations, Dextrose 5% (D5W) may be used to flush NGT in infants who do not have fluid restriction, while infant formula may be used in infants who have fluid restriction. For adults who cannot swallow a solid dosage form, enteral meal may be administered.
Preferably, the liquid formulation of apixaban provides similar bioavailability and pharmacokinetic properties to apixaban oral tablet available as Eliquis®. For example, the liquid formulation of apixaban has a Cmax, AUCinf, and/or AUC(O-T) from 80% to 125% of the Cmax, AUCinf, and/or AU O-T), respectively, of Eliquis® (apixaban) tablet.
Another embodiment of the present invention is a method for treating a thromboembolic disorder comprising administering to a patient in need thereof a therapeutically effective amount of a liquid formulation of apixaban described above.
In another embodiment of the present invention, the liquid formulation of apixaban is administered once daily or twice daily. In yet another embodiment of the invention, the dose of liquid formulation of apixaban is not more than 5 mL.
Various aspects of the present invention can be described as follows:
1. A stable liquid formulation of apixaban comprising apixaban or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable ingredients.
2. The stable liquid formulation of apixaban according to embodiment 1, wherein the liquid formulation is in the form of suspension, solution or the like and any combination thereof.
3. The stable liquid formulation of apixaban according to embodiment 1, wherein the liquid formulation is in the form of a suspension.
4. The stable liquid formulation of apixaban according to embodiment 1, wherein the liquid formulation is in the form of a solution. 5. The stable liquid formulation of apixaban according to embodiment 1, wherein the liquid formulation is suitable for oral administration.
6. The stable liquid formulation of apixaban according to embodiment 1, wherein the formulation is stable for at least one month under storage condition of 25°C/60% RH and/or 30°C/65% RH and/or 40°C/75% and/or 2-8°C.
7. The stable liquid formulation of apixaban according to embodiment 1, wherein apixaban is present at a concentration of 0.5 mg/ml to 5 mg/ml in liquid formulation of apixaban.
8. The stable liquid formulation of apixaban according to embodiments 1, wherein the liquid formulation has a pH of about 3 to about 7.
9. The stable liquid formulation of apixaban according to embodiment 1, wherein apixaban has a particle size distribution D(90) less than about 20pm.
10. The stable liquid formulation of apixaban according to embodiment 6, wherein the formulation is stable for at least two months under storage condition of 25°C/60% RH and/or 30°C/65% RH and/or 40°C/75% and/or 2-8°C.
11. The stable liquid formulation of apixaban according to embodiment 6, wherein the formulation is stable for at least three months under storage condition of 25°C/60% RH and/or 30°C/65% RH and/or 40°C/75% and/or 2-8°C.
12. The stable liquid formulation of apixaban according to embodiment 6, wherein the formulation is stable for at least four months under storage condition of 25°C/60% RH and/or 30°C/65% RH and/or 40°C/75% and/or 2-8°C.
13. The stable liquid formulation of apixaban according to embodiment 6, wherein the liquid is stable for at least five months under storage condition of 25°C/60% RH and/or 30°C/65% RH and/or 40°C/75% and/or 2-8°C.
14. The stable liquid formulation of apixaban according to embodiment 6, wherein the formulation is stable for at least six months under storage condition of 25°C/60% RH and/or 30°C/65% RH and/or 40°C/75% and/or 2-8°C.
15. The stable liquid formulation of apixaban according to embodiment 7, wherein apixaban is present at a concentration of 5 mg/mL, 4.5 mg/mL, 4 mg/mL, 3.5 mg/mL, 3 mg/mL, 2.5 mg/mL, 2 mg/mL, 1.5 mg/mL, 1 mg/mL or at least 0.5 mg/mL.
16. The stable liquid formulation of apixaban according to embodiment 7, wherein apixaban is present at a concentration of 1 mg/mL.
17. The stable liquid formulation of apixaban according to embodiment 8, wherein the formulation has a pH of about 4 to about 6. 18. The stable liquid formulation of apixaban according to embodiment 8, wherein the formulation has a pH of about 4.5 to about 5.5.
19. The stable liquid formulation of apixaban according to embodiment 8, wherein the formulation has a pH of about 3, about 3.5, about 4, about 5, about 5.5, about , about 6, about 6.5 or about 7.
20. The stable liquid formulation of apixaban according to embodiment 8, wherein the formulation has a pH of about 5.
21. The stable liquid formulation of apixaban according to embodiment 9, wherein apixaban has a particle size distribution D(90) less than about 15 pm.
22. The stable liquid formulation of apixaban according to embodiment 9, wherein apixaban has a particle size distribution D(90) less than about 10pm.
23. The stable liquid formulation of apixaban according to embodiment 1, wherein the one or more pharmaceutically acceptable ingredients are selected from group consisting of suspending agents, buffers (pH adjusting agents), preservatives, antioxidants, solubilizers, complexing agents, antifoaming agents, sweeteners, flavouring agents and suitable vehicle.
24. The stable liquid formulation of apixaban according to embodiment 23, wherein the suspending agent is xanthan gum, guar gum, microcrystalline cellulose, sodium carbo xymethylcellulose, a mixture of carbo xymethylcellulose and microcrystalline cellulose, propylene glycol alginate or combinations thereof.
25. The stable liquid formulation of apixaban according to embodiment 23, wherein the buffer is citric acid and sodium citrate dihydrate.
26. The stable liquid formulation of apixaban according to embodiment 23, wherein the preservative is combination of MHB and PHB.
27. The stable liquid formulation of apixaban according to embodiment 23, wherein the preservative is combination of Na MHB and Na PHB.
28. The stable liquid formulation of apixaban according to embodiment 23, wherein the solubilizer is selected from povidone, copovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, glycerin, propylene glycol, sorbitol, mannitol, polyethylene glycol, sodium lauryl sulfate, docusate sodium or combination thereof.
29. The stable liquid formulation of apixaban according to embodiment 28, wherein the solubilizer is combination of glycerin and sodium lauryl sulfate.
30. The stable liquid formulation of apixaban according to embodiment 28, wherein the solubilizer is combination of propylene glycol and sodium lauryl sulfate. 31. The stable liquid formulation of apixaban according to embodiment 28, wherein the solubilizer is combination of polyethylene glycol and docusate sodium.
32. The stable liquid formulation of apixaban according to embodiment 23, wherein the antifoaming agent is simethicone emulsion.
33. The stable liquid formulation of apixaban according to embodiment 23, wherein the sweetener is selected from glucose, fructose, invert sugar, sorbitol, sucrose, maltose, xylose, ribose, mannose, corn syrup solids, xylitol, mannitol, maltodextrins or mixtures thereof.
34. The stable liquid formulation of apixaban according to embodiment 33, wherein the sweetener is sucralose.
35. The stable liquid formulation of apixaban according to embodiment 23, wherein the vehicle is selected from glycerin, propylene glycol, water or combination thereof.
36. The stable liquid formulation of apixaban according to embodiment 35, wherein the water is present in an amount from about 70% to about 99% w/v of the liquid formulation.
37. The stable liquid formulation of apixaban according to embodiments 1-36, wherein the said liquid formulation is suitable for oral administration and/or administration through a nasogastric tube and/or gastronomy tube using a dosing syringe.
38. A method for treating a thromboembolic disorder, comprising administering to a patient in need thereof a therapeutically effective amount of the liquid formulation of apixaban according to embodiments 1-36.
39. The stable liquid formulation of apixaban according to embodiment 1, wherein one or more pharmaceutically acceptable ingredients comprises: a) 0.05-0.5% w/v of apixaban or pharmaceutically acceptable salt thereof; b) 0.001-1% w/v of preservative; c) 0.10%- 10% w/v of suspending agent; d) 0.5-20% w/v of solubilizer; e) 0.01-1% w/v of anti-foaming agent; f) 0.01-2% w/v of sweetener; g) 0.01-2% w/v of buffer; h) 0.01-1% w/v of flavouring agent; and i) Q. S. to vehicle.
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. The invention is further illustrated by the following non-limiting examples which are provided for illustrative purposes only in order to facilitate a more complete understanding of representative embodiments. These examples should not be construed to limit any of the embodiments described in the present specification.
EXAMPLES
Example 1 - Suspension formulation of apixaban
Procedure:
1. Methyl parahydroxybenzoate and Propyl parahydroxybenzoate were added and dissolved into water with the aid of heating to get a clear, colourless solution.
2. Simethicone 30% (USP) was added into above mixture.
3. Povidone K30 was added.
4. Separately, Apixaban was added in glycerol, mix it manually and was added.
5. Sodium Lauryl sulphate was added into above suspension.
6. Sucralose, Sodium citrate dihydrate, Citric acid anhydrous and Orange flavour were added into above suspension.
7. The volume was adjusted with purified water. Examples 2 to 5 - Suspension formulations of apixaban
Table 1- Examples 2 to 5 Suspension formulations of apixaban Procedure for examples 2, 4 and 5:
1. Xanthan gum/ Sodium CMC was added and dispersed in purified water.
2. Separately, sodium methyl parahydroxybenzoate, sodium propyl parahydroxybenzoate and sucralose were added and dissolved into purified water.
3. Mixture of step-1 was added into mixture of step-2. 4. Separately, Apixaban was added and dispersed into glycerol.
5. Mixture of step-4 was added into mixture of step-3.
6. Simethicone, sodium lauryl sulfate, Sodium citrate dihydrate, Citric acid anhydrous and Orange Flavour were added into above suspension.
7. The volume was adjusted with purified water. Procedure for example 3:
1. Xanthan gum was added and dispersed in purified water.
2. Separately, sodium methyl parahydroxybenzoate, sodium propyl parahydroxybenzoate and sucralose were added and dissolved into purified water. 3. Mixture of step-1 was added into mixture of step-2.
4. Separately, PVPK12 was added and dissolved into purified water.
5. Mixture of step-4 was added into mixture of step-3.
6. Separately, Apixaban was added and dispersed into glycerol.
7. Mixture of step-6 was added into mixture of step-5. 8. Sodium citrate dihydrate, Citric acid anhydrous and Orange Flavour were added into above suspension.
11. The volume was adjusted with purified water.
Example 6-9 - Suspension formulations of apixaban
Table 2- Examples 6 to 9 Suspension formulations of apixaban Procedure for examples 6, 8 and 9:
The formulations were prepared according to the example 2. Procedure for example 7 :
The formulation was prepared according to the example 3.
Example 8 - Stability study
Stability data of suspension formulation of example 1, packed in glass bottle is shown below.
The suspension formulation of example 1 found to be stable for 6 months at storage conditions 25°C/60% RH, 30°C/65% RH, 40°C/75% RH and 2-8°C. Example 9 - Stability study
Stability data of suspension formulation of example 2, packed in glass bottle is shown below.
The suspension formulation of example 2 found to be stable for 6 months at storage conditions 25°C/60% RH, 30°C/65% RH, 40°C/75% RH and 2-8°C.
Example 10 - Stability study
Stability data of suspension formulation of example 3, packed in glass bottle is shown below. The suspension formulation of example 3 found to be stable for 6 months at storage condition 25°C/60% RH, stable for at least 3 months at storage condition 30°C/65% RH, stable for at least 2 months at storage condition 40°C/75% RH and stable for 6 months at storage condition 2- 8 °C.
Example 11 - Stability study
Stability data of suspension formulation of example 4, packed in glass bottle is shown below.
The suspension formulation of example 4 found to be stable for 6 months at storage condition 25°C/60% RH, stable for at least 3 months at storage condition 30°C/65% RH, stable for at least 2 months at storage condition 40°C/75% RH and stable for 6 months at storage condition 2- 8 °C.
Example 12 - Stability study Stability data of suspension formulation of example 6, packed in glass bottle is shown below.
The suspension formulation of example 6 found to be stable for at least 1 month at storage conditions 25°C/60% RH, 30°C/65% RH and stable for at least 2 months at storage condition 40°C/75% RH.
Example 13 - Stability study
Stability data of suspension formulation of example 7, packed in glass bottle is shown below.
The suspension formulation of example 7 found to be stable for at least 1 month at storage conditions 25°C/60% RH, 30°C/65% RH and 40°C/75% RH.
Example 14 - Dissolution profile
Dissolution profile data for suspension formulation of example 6 is shown below.
Conditions: 0.1 N HCl/Paddle/500 ML/50 RPM

Claims

Claims:
1. A stable oral liquid formulation of apixaban comprising apixaban or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable ingredients.
2. The stable liquid formulation of apixaban according to claim 1, wherein the liquid formulation is in the form of suspension, solution or the like and any combination thereof.
3. The stable liquid formulation of apixaban according to claim 1, wherein the liquid formulation is in the form of a suspension.
4. The stable liquid formulation of apixaban according to claim 1, wherein the formulation is stable for at least one month under storage condition of 25°C/60% RH and/or 30°C/65% RH and/or 40°C/75% and/or 2-8°C.
5. The stable liquid formulation of apixaban according to claim 1, wherein apixaban is present at a concentration of 0.5 mg/ml to 5 mg/ml in liquid formulation of apixaban.
6. The stable liquid formulation of apixaban according to claim 1, wherein the liquid formulation has a pH of about 3 to about 7.
7. The stable liquid formulation of apixaban according to claim 1, wherein apixaban has a particle size distribution D(90) less than about 20pm.
8. The stable liquid formulation of apixaban according to claim 5, wherein apixaban is present at a concentration of 1 mg/mL.
9. The stable liquid formulation of apixaban according to claim 1, wherein the one or more pharmaceutically acceptable ingredients are selected from group consisting of suspending agents, buffers (pH adjusting agents), preservatives, antioxidants, solubilizers, complexing agents, antifoaming agents, sweeteners, flavouring agents and suitable vehicle.
10. The stable liquid formulation of apixaban according to claim 9, wherein the suspending agent is xanthan gum, guar gum, microcrystalline cellulose, sodium carbo xymethylcellulose, a mixture of carbo xymethylcellulose and microcrystalline cellulose, propylene glycol alginate or combinations thereof.
11. The stable liquid formulation of apixaban according to claim 9, wherein the buffer is citric acid and sodium citrate dihydrate.
12. The stable liquid formulation of apixaban according to claim 9, wherein the preservative is selected from combination of MHB and PHB or combination of Na MHB and Na PHB.
13. The stable liquid formulation of apixaban according to claim 9, wherein the solubilizer is selected from povidone, copovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, glycerin, propylene glycol, sorbitol, mannitol, polyethylene glycol, sodium lauryl sulfate, docusate sodium or combination thereof.
14. The stable liquid formulation of apixaban according to embodiment 9, wherein the antifoaming agent is simethicone emulsion.
15. The stable liquid formulation of apixaban according to claim 9, wherein the sweetener is selected from glucose, fructose, invert sugar, sorbitol, sucrose, maltose, xylose, ribose, mannose, corn syrup solids, xylitol, mannitol, maltodextrins or mixtures thereof.
16. The stable liquid formulation of apixaban according to claim 9, wherein the vehicle is selected from glycerin, propylene glycol, water or combination thereof.
17. The stable liquid formulation of apixaban according to claim 16, wherein the water is present in an amount from about 70% to about 99% w/v of the liquid formulation.
18. The stable liquid formulation of apixaban according to claim 1-17, wherein the said liquid formulation is suitable for oral administration and/or administration through a nasogastric tube and/or gastronomy tube using a dosing syringe.
19. A method for treating a thromboembolic disorder comprising administering to a patient in need thereof a therapeutically effective amount of the liquid formulation of apixaban according to claims 1-17. 0. The stable liquid formulation of apixaban according to claim 1, wherein one or more pharmaceutically acceptable ingredients comprises: a) 0.05-0.5% w/v of apixaban or pharmaceutically acceptable salt thereof; b) 0.001-1% w/v of preservative; c) 0.10%- 10% w/v of suspending agent; d) 0.5-20% w/v of solubilizer; e) 0.01-1% w/v of anti-foaming agent; f) 0.01-2% w/v of sweetener; g) 0.01-2% w/v of buffer; h) 0.01-1% w/v of flavouring agent; and i) Q. S. to vehicle.
EP23803183.5A 2022-05-09 2023-05-07 Liquid oral formulation of apixaban or pharmaceutically acceptable salt thereof Withdrawn EP4522123A1 (en)

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