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WO2024261701A1 - Formulation d'edoxaban. - Google Patents

Formulation d'edoxaban. Download PDF

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Publication number
WO2024261701A1
WO2024261701A1 PCT/IB2024/056059 IB2024056059W WO2024261701A1 WO 2024261701 A1 WO2024261701 A1 WO 2024261701A1 IB 2024056059 W IB2024056059 W IB 2024056059W WO 2024261701 A1 WO2024261701 A1 WO 2024261701A1
Authority
WO
WIPO (PCT)
Prior art keywords
edoxaban
composition
pharmaceutical composition
pharmaceutical
pharmaceutically acceptable
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.)
Pending
Application number
PCT/IB2024/056059
Other languages
English (en)
Inventor
Piyush Babubhai PATEL
Manishkumar Jayantibhai CHAUHAN
Ashish Sehgal
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.)
Intas Pharmaceuticals Ltd
Original Assignee
Intas Pharmaceuticals 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 Intas Pharmaceuticals Ltd filed Critical Intas Pharmaceuticals Ltd
Publication of WO2024261701A1 publication Critical patent/WO2024261701A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone

Definitions

  • the present invention is related to a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said formulation is devoid of sugar alcohol.
  • Edoxaban is a factor Xa inhibitor and is chemically described as N'-(5- chloropyridin-2-yl)-N-[(lS,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7- dihydro-4H-[l,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide.
  • Edoxaban is approved in the form of immediate release tablets and marketed by Daiichi Sankyo under the brand name LIXIANA® (Innovator product).
  • the immediate release tablets are approved in the strengths of 15 mg, 30 mg and 60 mg and are indicated in prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation (NVAF) with one or more risk factors, such as congestive heart failure, hypertension, age > 75 years, diabetes mellitus, prior stroke or transient ischaemic attack (TIA).
  • NVAF nonvalvular atrial fibrillation
  • TIA transient ischaemic attack
  • Lixiana® is also indicated in treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and for the prevention of recurrent DVT and PE in adults.
  • EP1405852 patent discloses an edoxaban as compound.
  • the compounds of the patent are useful for treating and/or preventing thrombosis or embolism.
  • EP2140867 patent discloses a film coated tablet composition
  • a film coated tablet composition comprising edoxaban or a pharmacologically acceptable salt thereof or its hydrate, a sugar alcohol and a water-swelling additive; with improved dissolution property.
  • EP2548556 patent discloses a method for preparation of granules comprising edoxaban or a pharmaceutically acceptable salt thereof, or a solvate thereof, one or more excipients selected from the group consisting of a sugar alcohol and a water-swelling additive, a disintegrant and a binder, wherein the process is wet granulation and the maximum water content of the granules during granulation is 10% or less.
  • EP2742941 patent discloses a solid formulation containing edoxaban or a pharmacologically acceptable salt thereof or a solvate thereof and one or more components selected from the group consisting of carmellose and fumaric acid, wherein a dosage form of the solid formulation is a tablet or a capsule which have an improved dissolution property.
  • EP2444087 patent discloses a tablet composition containing edoxaban or a pharmacologically acceptable salt thereof or a solvate thereof, wherein the content of edoxaban is 0.5% by weight or more and less than 10% by weight with respect to the total weight of the pharmaceutical composition.
  • EP3549585 patent application discloses an orally disintegrating tablet comprising edoxaban or a pharmacologically acceptable salt thereof or a solvate thereof, an organic acid, a water soluble polymer and a disintegrant.
  • EP3177290 patent discloses the pharmaceutical composition
  • edoxaban or a pharmaceutically acceptable salt thereof a water soluble vinylpyrrolidone polymer selected from the group consisting of povidone and copovidone, and a cellulose ether and not is devoid of sugar alcohol.
  • EP3744320 patent application discloses a tablet composition
  • a tablet composition comprising edoxaban or a salt thereof or a hydrate, lactose as a water-soluble filler and crospovidone and sodium starch glycolate as disintegrants.
  • EP4076406 patent application discloses a tablet comprising edoxaban or a pharmaceutically acceptable salt thereof, a lactose as a first diluent and a starch as a second diluent.
  • compositions comprising edoxaban disclose compositions comprising edoxaban.
  • the present invention provides a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said formulation is devoid of sugar alcohol and has comparable dissolution properties and is bioequivalent to innovator product (Lixiana®).
  • the primary object of the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said formulation is devoid of sugar alcohol.
  • Another object of the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said formulation is devoid of sugar alcohol, and wherein D90 particle size of edoxaban is not more than 10 micron.
  • Another object of the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said formulation is devoid of sugar alcohol, and wherein the said water swelling additive is selected from the group consisting of microcrystalline cellulose, pregelatinized starch and combinations thereof.
  • Another object of the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said formulation is devoid of sugar alcohol, wherein D90 particle size of edoxaban is not more than 10 micron, and wherein the said water swelling additive is selected from the group consisting of microcrystalline cellulose, pregelatinized starch and combinations thereof.
  • Another object of the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said formulation is devoid of sugar alcohol, wherein D90 particle size of edoxaban is not more than 10 micron, wherein the said water swelling additive is selected from the group consisting of microcrystalline cellulose, pregelatinized starch and combinations thereof, and wherein the said one or more pharmaceutical acceptable excipient is selected from one or more diluents, one or more binders, one or more disintegrants, one or more solvents, one or more lubricants or the mixtures thereof.
  • Another object of the present invention is to provide a process for preparation of pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutically acceptable excipients, wherein the said formulation is devoid of sugar alcohol.
  • Another object of the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said formulation is devoid of sugar alcohol, and wherein the release of edoxaban is in line with the innovator product (Lixiana®) when the said composition is subjected to the dissolution test using USP Type 2 apparatus method at a rotation of 50 rpm in 0.1 M Hydrochloric acid in 900 mL of volume.
  • Another object of the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said formulation is devoid of sugar alcohol, and wherein edoxaban is released more than 95% at 60 minutes when the said composition is subjected to the dissolution test using USP Type 2 apparatus method at a rotation of 50 rpm in 0.1 M Hydrochloric acid in 900 mL of volume.
  • Another object of the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein release of edoxaban is in line with the innovator product (Lixiana®) when the said composition is subjected to the dissolution test using USP Type 2 apparatus method at a rotation of 50 rpm in Acetate buffer pH 4.5 in 900 mL of volume.
  • Another object of the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein edoxaban is released more than 95% at 60 minutes when the said composition is subjected to the dissolution test using USP Type 2 apparatus method at a rotation of 50 rpm in Acetate buffer pH 4.5 in 900 mL of volume.
  • Another object of the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the release of edoxaban is in line with the innovator product (Lixiana®) when the said composition is subjected to the dissolution test using USP Type 2 apparatus method at a rotation of 50 rpm in Phosphate buffer pH 6.8 in 900 mL of volume.
  • Another object of the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein edoxaban is released more than 75% at 60 minutes when the said composition is subjected to the dissolution test using USP Type 2 apparatus method at a rotation of 50 rpm in Phosphate buffer pH 6.8 in 900 mL of volume.
  • Another object of the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said composition does not have more than 2.0% (w/w) of total impurity of edoxaban, after being stored at specific storage conditions.
  • Another object of the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said composition is bioequivalent to innovator product (Lixiana®).
  • the present invention related to a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said formulation is devoid of sugar alcohol.
  • the present invention is related to a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said formulation is devoid of sugar alcohol.
  • the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said formulation is devoid of sugar alcohol, wherein D90 particle size of edoxaban is not more than 10 micron.
  • Edoxaban used throughout the specification refers to not only their base per se, but also their other pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof.
  • pharmaceutically acceptable means salt, carriers, excipients, and other formulation ingredients that are compatible with all other pharmaceutical ingredients of a composition and are not deleterious to an individual treated with the said composition.
  • stable refers to a pharmaceutical composition in which the active pharmaceutical ingredient edoxaban is present in an amount of at least 90% of the original label specified amount for each such ingredient during specific storage conditions.
  • specific storage conditions refers to the pharmaceutical composition of present invention stored for at least 1 month at 40°C/75% RH.
  • the pharmaceutical composition of present invention can be stored for at least 6 month at 40°C/75% RH and 25° C/60% RH.
  • the term “about” shall mean a variation up to 10% (plus or minus 10%) of the particular term.
  • the term “D90” shall mean a pharmaceutical composition in which 90% of the edoxaban particles have a particle size of less than about 10 microns.
  • an assay value of edoxaban in pharmaceutical composition of edoxaban is within the limits of 95% to 105% after stability study according to ICH guidelines which is comparable when compared with reference product Lixiana®.
  • stable refers to a pharmaceutical composition in which the active pharmaceutical ingredient edoxaban is present in an amount of at least 90% of the original label specified amount for each such ingredient during specific storage conditions.
  • bioequivalence refers to an extent and rate to which the active drug ingredient or active moiety from the drug product is absorbed and becomes available at the site of drug action.
  • Cmax refers to the highest (peak) concentration of a drug in the bloodstream or other part of the body after drug administration. Cmax is a key pharmacokinetic measure and informs dosing schedules.
  • AUC refers an area under the curve that means the area under the plasma drug concentration-time curve reflects the actual body exposure to drug after administration of a dose of the drug. The information is useful for determining dosing and for identifying potential drug interactions.
  • AUCo-inf refers an area under the curve extrapolated to infinity.
  • the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said formulation is devoid of sugar alcohol, and wherein the said water swelling additive is selected from the group consisting of microcrystalline cellulose, pregelatinized starch and combinations thereof.
  • the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said formulation is devoid of sugar alcohol, wherein D90 particle size of edoxaban is not more than 10 micron, and wherein the said water swelling additive is selected from the group consisting of microcrystalline cellulose, pregelatinized starch and combinations thereof.
  • the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said formulation is devoid of sugar alcohol, wherein D90 particle size of edoxaban is not more than 10 micron, wherein the said water swelling additive is selected from the group consisting of microcrystalline cellulose, pregelatinized starch and combinations thereof, and wherein the said one or more pharmaceutical acceptable excipient is selected from one or more diluents, one or more binders, one or more disintegrants, one or more solvents, one or more lubricants or the mixtures thereof.
  • the water-swelling additive employed in the present invention refers to an additive for pharmaceuticals which swells with water added thereto.
  • Examples of the water-swelling additive in the present invention include diluents and bases which are water-swellable.
  • the water swelling additive can be selected from the group comprising of but not limited to microcrystalline cellulose, pregelatinized starch, a-starch, sodium starch glycolate, carmellose, carmellose calcium, croscarmellose sodium, soybean lecithin, low-substituted hydroxypropyl cellulose, powdered tragacanth, bentonite and combinations thereof.
  • the water swelling additive can be present in a concentration of from about 40% to about 80% by weight of the total weight of the composition.
  • the sugar alcohol can refer to mannitol, xylitol, erythritol.
  • the diluents can be selected from the group comprising of but not limited to dibasic calcium phosphate anhydrous, com starch, sucrose or other sugar or sugar derivatives, low substituted HPC or mixture thereof.
  • the disintegrant can be selected from the group comprising of but not limited to croscarmellose sodium, crospovidone, sodium starch glycolate, starch, com starch or mixture thereof, more preferably crospovidone.
  • the disintegrant can be present in a concentration of from about 2% to about 8% by weight of the total weight of the composition.
  • the binder can be selected from the group comprising of but not limited to polyvinylpyrrolidone, povidone, copovidone, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, maize starch or mixture thereof, more preferably hydroxypropyl cellulose.
  • the binder can be present in a concentration of from about 2% to about 6% by weight of the total weight of the composition.
  • the lubricant can be selected form the group comprising of agar, calcium stearate, ethyl oleate, ethyl laureate, glycerin, glyceryl palmitostearate, hydrogenated vegetable oil, magnesium oxide, magnesium stearate, sodium stearyl, sorbitol, stearic acid, talc, and zinc stearate or mixture thereof, more preferably magnesium stearate.
  • the lubricant can be present in a concentration of from about 1% to about 4% by weight of the total weight of the composition.
  • the solvent can be selected from the group of pharmaceutically acceptable solvents comprising of purified water, dichloromethane, isopropyl alcohol or mixtures thereof.
  • the present invention is to provide a process for preparation of pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutically acceptable excipients, wherein the said formulation is devoid of sugar alcohol. Further, one of the process for preparation of pharmaceutical composition of edoxaban according to the present invention comprising following steps:
  • step 3 Sifted material of step 1 was transferred to rapid mixer granulator and dry mixed.
  • step 3 Dry mix material of step 3 was granulated using binder solution of step 2 in the rapid mixer granulator.
  • step 4 Granules of step 4 were dried in rapid dryer.
  • step 5 Dried granules of step 5 were milled through co-mill.
  • Lubricant was sifted and mixed with the blend of step 7 in the blender.
  • step 8 The common blend of step 8 was bifurcated for compression of tablets.
  • Lubricated blend was compressed at theoretical weight of tablet by using appropriate tooling in compression machine.
  • the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said formulation is devoid of sugar alcohol, and wherein the release of edoxaban is in line with the innovator product (Lixiana®) when the said composition is subjected to the dissolution test using USP Type 2 apparatus method at a rotation of 50 rpm in 0.1 M Hydrochloric acid in 900 mL of volume.
  • innovator product Lixiana®
  • the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said formulation is devoid of sugar alcohol, and wherein edoxaban is released more than 95% at 60 minutes when the said composition is subjected to the dissolution test using USP Type 2 apparatus method at a rotation of 50 rpm in 0.1 M Hydrochloric acid in 900 mL of volume.
  • the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein release of edoxaban is in line with the innovator product (Lixiana®) when the said composition is subjected to the dissolution test using USP Type 2 apparatus method at a rotation of 50 rpm in Acetate buffer pH 4.5 in 900 mL of volume.
  • innovator product Lixiana®
  • the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein edoxaban is released more than 95% at 60 minutes when the said composition is subjected to the dissolution test using USP Type 2 apparatus method at a rotation of 50 rpm in Acetate buffer pH 4.5 in 900 mL of volume.
  • the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the release of edoxaban is in line with the innovator product (Lixiana®) when the said composition is subjected to the dissolution test using USP Type 2 apparatus method at a rotation of 50 rpm in Phosphate buffer pH 6.8 in 900 mL of volume.
  • innovator product Lixiana®
  • the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein edoxaban is released more than 75% at 60 minutes when the said composition is subjected to the dissolution test using USP Type 2 apparatus method at a rotation of 50 rpm in Phosphate buffer pH 6.8 in 900 mL of volume.
  • the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said composition does not have more than 2.0% (w/w) of total impurity of edoxaban, after being stored at specific storage conditions.
  • the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said composition is having a ratio of test vs reference value of more than 90 % with the innovator product (Lixiana®).
  • the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said composition having coefficient of variation less than 30 % with the innovator product (Lixiana®).
  • the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said composition having confidence interval value more than 80 % with the innovator product (Lixiana®).
  • the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said composition is bioequivalent to innovator product (Lixiana®).
  • step 3 Sifted material of step 1 was transferred to rapid mixer granulator and dry mixed.
  • step 4 Dry mix material of step 3 was granulated using binder solution of step 2 in the rapid mixer granulator. 5. Granules of step 4 were dried in rapid dryer.
  • step 5 Dried granules of step 5 were milled through co-mill.
  • step 8 Lubricant was sifted and mixed with blend of step 7 in the blender. 9. Common blend of step 8 was bifurcated for compression of tablets.
  • Lubricated blend was compressed at theoretical weight of tablet by using appropriate tooling in compression machine.
  • step 3 Sifted material of step 1 was transferred to rapid mixer granulator and dry mixed.
  • step 3 Dry mix material of step 3 was granulated using binder solution of step 2 in the rapid mixer granulator.
  • step 4 Granules of step 4 were dried in rapid dryer.
  • step 5 Dried granules of step 5 were milled through co-mill.
  • Lubricant was sifted and mixed with blend of step 7 in the blender.
  • step 8 Common blend of step 8 was bifurcated for compression of tablets.
  • Lubricated blend was compressed at theoretical weight of tablet by using appropriate tooling in compression machine.
  • the tablets were coated with coating agent using auto coater.
  • step 3 Sifted material of step 1 was transferred to rapid mixer granulator and dry mixed.
  • step 3 Dry mix material of step 3 was granulated using binder solution of step 2 in the rapid mixer granulator.
  • step 4 Granules of step 4 were dried in rapid dryer.
  • step 5 Dried granules of step 5 were milled through co-mill.
  • Magnesium stearate was sifted and mixed with blend of step 7 in the blender.
  • step 8 Common blend of step 8 was bifurcated for compression of tablets.
  • Lubricated blend was compressed at theoretical weight of tablet by using appropriate tooling in compression machine.
  • the tablets were coated with coating agent using auto coater.
  • Example 4 was tested for dissolution study as per USP Apparatus 2 (Paddle type) at 50 rpm using 0.1 M Hydrochloric acid in 900 mL of volume and gave the following results as Table 1.
  • Table 1 The above dissolution study shows the release of edoxaban tablet is comparable to the innovator product (Lixiana®).
  • Example 4 was tested for dissolution study as per USP Apparatus 2 (Paddle type) at 50 rpm using Acetate buffer pH 4.5 in 900 mL of volume and gave the following results as Table 2.
  • Example 4 was tested for dissolution study as per USP Apparatus 2 (Paddle type) at 50 rpm using Phosphate buffer pH 6.8 in 900 mL of volume and gave the following results as Table 3.
  • Table 3 :
  • Table 4 Stability data of edoxaban tablet 15mg, 30mg & 60mg under 1 month time interval at condition of 40°C / 75 % RH in Alu- Alu Blister.
  • Table 5 Stability data of edoxaban tablet 15mg, 30mg & 60mg under 1 month time interval at condition of 40°C / 75 % RH in HDPE bottle. The above data shows a total impurity not more than 2% in the formulation and assay value within the range of ICH guideline, indicative of stability of edoxaban in the drug product.
  • Table 6 Stability data of edoxaban tablet 15mg, 30mg & 60mg under 3 month
  • Table 7 Stability data of edoxaban tablet 15mg, 30mg & 60mg under 3 month & 6 month time interval at condition of 25° C / 60% RH in Alu- Alu Blister.
  • Table 8 Stability data of edoxaban tablet 15mg, 30mg & 60mg under 3 month & 6 month time interval at condition of 40°C / 75 % RH in HDPE bottle.
  • Table 9 Stability data of edoxaban tablet 15mg, 30mg & 60mg under 3 month & 6 month time interval at condition of 25° C / 60% RH in HDPE bottle.
  • Tablet 10 Bioequivalence data of edoxaban tablets 60mg in fasting condition of healthy adult human.
  • the above data shows a value of Cmax, AUCo-t & AUCo-inf within the range of FDA guideline, indicative of bioequivalent of edoxaban tablet with Lixiana® edoxaban tablets 60 mg.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne une composition pharmaceutique d'edoxaban comprenant de l'edoxaban ou son sel pharmaceutiquement acceptable, un additif gonflant à l'eau et un ou plusieurs excipients pharmaceutiquement acceptables, ladite formulation étant exempte d'alcool de sucre.
PCT/IB2024/056059 2023-06-23 2024-06-21 Formulation d'edoxaban. Pending WO2024261701A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN202321041818 2023-06-23
IN202321041818 2023-06-23

Publications (1)

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WO2024261701A1 true WO2024261701A1 (fr) 2024-12-26

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022129535A1 (fr) * 2020-12-18 2022-06-23 Krka, D.D., Novo Mesto Formulation d'edoxaban ne contenant pas d'alcools de sucre
IN202141043435A (fr) * 2021-09-24 2023-03-31

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022129535A1 (fr) * 2020-12-18 2022-06-23 Krka, D.D., Novo Mesto Formulation d'edoxaban ne contenant pas d'alcools de sucre
IN202141043435A (fr) * 2021-09-24 2023-03-31

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