EP4178577A1 - Comprimé comprenant de l'apixaban - Google Patents

Comprimé comprenant de l'apixaban

Info

Publication number
EP4178577A1
EP4178577A1 EP21838041.8A EP21838041A EP4178577A1 EP 4178577 A1 EP4178577 A1 EP 4178577A1 EP 21838041 A EP21838041 A EP 21838041A EP 4178577 A1 EP4178577 A1 EP 4178577A1
Authority
EP
European Patent Office
Prior art keywords
sodium
tablet according
weight
apixaban
mixtures
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
EP21838041.8A
Other languages
German (de)
English (en)
Other versions
EP4178577A4 (fr
Inventor
Abdullah TASKIN
Yavuz Dedeoglu
Muge ULUSOY BOZYEL
Fatih Sunel
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.)
Sanovel Ilac Sanayi ve Ticaret AS
Original Assignee
Sanovel Ilac Sanayi ve Ticaret AS
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 Sanovel Ilac Sanayi ve Ticaret AS filed Critical Sanovel Ilac Sanayi ve Ticaret AS
Publication of EP4178577A1 publication Critical patent/EP4178577A1/fr
Publication of EP4178577A4 publication Critical patent/EP4178577A4/fr
Pending 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • 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
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin

Definitions

  • the present invention relates to a tablet comprising apixaban and at least one binder wherein apixaban and at least one binder are dissolved in a solvent.
  • the present invention also relates to a simple, rapid, cost effective, time-saving and industrially convenient process.
  • Apixaban is a highly selective, orally bioavailable, and reversible direct inhibitor of free and clot-bound factor Xa.
  • Factor Xa catalyzes the conversion of prothrombin to thrombin, the final enzyme in the coagulation cascade that is responsible for fibrin clot formation.
  • Apixaban has no direct effect on platelet aggregation, but by inhibiting factor Xa, it indirectly decreases clot formation induced by thrombin.
  • apixaban is 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1- yl)phenyl]-4,5,6,7-tetrahydro-1 FI-pyrazolo[3,4-c]pyridine-3-carboxamide and its chemical structure is shown in the Formula 1.
  • Apixaban sold under the tradename Eliquis, is an anticoagulant for the treatment of venous thromboembolic events. It is taken orally. It is a direct factor Xa inhibitor and apixaban has poor solubility in water (0.028 mg/mL at 24 °C) and a relatively low oral bioavailability (about 50% for a single 10 mg dose). Apixaban has poor solubility in water (0.028 mg/ml_ at 24 °C) and a relatively low oral bioavailability (about 50% for a single 10 mg dose).
  • compositions comprising the poorly soluble active ingredient apixaban are known in the art.
  • several publications teach preparing pharmaceutical compositions comprising apixaban having a particular particle size, for example, WO 2017/182908 A1 describes compositions prepared by using apixaban of particles d(0.9) about 20 pm.
  • US 2013/0045245 application discloses a composition with improved dissolution rate by using crystalline apixaban having D90 equal to or less than 89 pm and a method for improving the dissolution rate of apixaban as a water insoluble drug by controlling the particle size distribution.
  • apixaban and at least one binder are dissolved in a solvent. So, this formulation overcomes the above problems. In this way, an even higher quality of the formulations can be guaranteed with independent of the physical and chemical parameters of apixaban.
  • the main object of the present invention is to eliminate problems and bringing additional advantages to the relevant prior art.
  • the more clearly main object of the present invention is to provides a tablet comprising apixaban having desired dissolution profile and desired stability with independent of the physical and chemical parameters of apixaban.
  • Another object of the present invention is to provide a tablet having improved content uniformity.
  • Another object of the present invention is to provides a process for a tablet comprising apixaban.
  • the process is a simple, rapid, cost effective, time-saving and industrially convenient method.
  • apixaban refers to apixaban in the form of free base or in the form of pharmaceutically acceptable salts, crystalline polymorph, solvates, hydrates, esters or in an amorphous form or mixtures thereof.
  • aqueous solubility is the major problem encountered with formulation development.
  • Apixaban has poor solubility in water (0.028 mg/mL at 24 °C) and a relatively low oral bioavailability (about 50% for a single 10 mg dose). It is desirable to provide an oral dosage form for active agents of low water solubility in a pharmaceutically acceptable dose.
  • a tablet comprises apixaban, wherein apixaban and at least one binder are dissolved in solvent.
  • the low solubility problem of apixaban was overcome by dissolving apixaban in a solvent except for water.
  • good solubility was achieved independent of the particle size of the apixaban.
  • at least one binder is dissolved in the same solvent.
  • at least one binder and apixaban matrix are obtained. This matrix has an amorphous structure. Thanks to this process, the desired dissolution profile and stability are provided independent of the initial form of the apixaban.
  • the weight ratio of at least one binder to apixaban is between 1 :1 and 5:1 , preferably between 1 :1 and 3:1. It has been observed that, this ratio is an important factor for achieving desired dissolution profile. When apixaban and at least one binder are used in these ratios, it is also easier to provide a formulation has improved content uniformity with wet granulation.
  • the amount of apixaban is between 0.5% and 10.0% by weight in the total formulation. Preferably, it is between 1.0% and 8.0% or between 1 .0% and 5.0% or between 1.0% and 3.0% by weight in the total formulation.
  • Suitable binders are selected from the group comprising polyvinylpyrrolidone, sodium carboxymethyl cellulose, crospovidone, polyethylene glycol, polyvinyl alcohol, pregelatinized starch, glucose, natural gums, sucrose, sodium alginate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxy methyl cellulose, methyl cellulose, gelatin, carrageenan, guar gum, carbomer, polymethacrylates, methacrylate polymers, gelatin, alginate, alginic acid, xanthan gum, hyaluronic acid, pectin, polysaccharides, carbomer, poloxamer, polyacrylamide, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof.
  • the amount of binders is between 0.5% and 10.0% by weight in the total formulation. Preferably, it is between 1.0% and 8.0% or between 1 .0% and 5.0% by weight in the total formulation.
  • the binder is polyvinylpyrrolidone.
  • Suitable solvent is selected from the group comprising dichloromethane, isopropyl alcohol, ethanol, methanol, acetonitrile, dimethyl sulfoxide, dimethylformamide, ethyl acetate, acetone or mixtures.
  • solvent is dichloromethane.
  • a tablet further comprises at least one pharmaceutically acceptable excipient which is selected from the group comprising fillers, disintegrants, surfactants, lubricants/glidants, coating agents or mixtures.
  • Suitable fillers are selected from the group comprising microcrystalline cellulose, lactose, mannitol, spray-dried mannitol, lactose monohydrate, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof.
  • the amount of fillers is between 50.0% and 95.0% by weight in the total formulation. Preferably, it is between 65.0% and 90.0% or between 72.0% and 88.0% by weight in the total formulation.
  • the filler is microcrystalline cellulose or lactose or mixtures thereof.
  • Suitable disintegrants are selected from the group comprising croscarmellose sodium, starch, crospovidone, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, low substituted hydroxypropyl cellulose, polyacryline potassium, sodium alginate, corn starch, sodium starch glycolate, alginic acid, alginates, ion-exchange resins, magnesium aluminium silica, sodium dodesyl sulphate, poloxamer, sodium glycine carbonate or mixtures thereof.
  • the amount of disintegrants is between 2.0% and 25.0% by weight in the total formulation. Preferably, it is between 3.0% and 5.0%, between 5.0% and 20.0% or between 10.0% and 20.0% by weight in the total formulation.
  • the disintegrant is croscarmellose sodium or starch or mixtures thereof.
  • Suitable surfactants are selected from the group comprising sodium lauryl sulphate, sodium docusate, glyceryl monooleate, polyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, sorbic acid, sorbitan fatty acid ester, polyoxyethylene stearates, polyethylene glycol, sodium benzoate, docusate sodium, alpha tocopherol, ascorbyl palmitate, citric acid, polyethoxylated fatty acid esters, polyoxyethylene hydrogenated castor oil or mixtures thereof.
  • the amount of surfactants is between 0.5% and 8.0% by weight in the total formulation. Preferably, it is between 1.0% and 6.0% or between 1.0% and 4.0% by weight in the total formulation.
  • the surfactant is sodium lauryl sulphate.
  • Suitable lubricants/glidants are selected from the group comprising from magnesium stearate, talc, colloidal silicon dioxide, corn, calcium stearate, zinc stearate, waxes, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, stearic acid, fatty acid, fumaric acid, glyceryl palmito sulphate, sodium stearyl fumarate or mixtures thereof.
  • the amount of lubricants/glidants is between 0.05% and 4.0% by weight in the total formulation. Preferably, it is between 0.1% and 3.0% by weight in the total formulation.
  • the lubricant/glidant is magnesium stearate.
  • particle size distribution means the cumulative volume size distribution as tested by any conventionally accepted method such as the laser diffraction method (i.e. malvern analysis) .
  • d(0.9) means, the size at which 90% by volume of the particles are finer.
  • the tablet comprises apixaban having a particle size of d(0.9) greater than 90 pm.
  • the tablet comprises apixaban having a particle size of d(0.9) 90 pm to 99 pm.
  • the tablet comprises;
  • microcrystalline cellulose • 30.0 - 45.0% by weight of microcrystalline cellulose
  • the tablet of the present invention may be prepared, using standard techniques and manufacturing processes well known in the art, such as direct compression, wet or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion/spheronization, slugging, spray drying and solvent evaporation.
  • the tablet is obtained by using a wet granulation method therefore, a simple and low-cost production method was employed.
  • Example 2 The tablet formulation comprising apixaban
  • Process for example 1 or 2 a) Dissolving apixaban in a solvent, b) Adding polyvinylpyrrolidone in the solvent and dissolving polyvinylpyrrolidone and then obtained granulation solution, c) Mixing starch, lactose and microcrystalline cellulose and charging the mixture to fluid bed granulator-dryer, d) Then, coating the mixture with the granulation solution comprising apixaban using spray granulation, e) Adding sodium lauryl sulfate and croscarmellose sodium and then mixing, f) Adding magnesium stearate and then mixing, g) Compressing to form of tablets, h) Coating tablets with coating agents.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention concerne un comprimé comprenant de l'apixaban et au moins un liant, l'apixaban et au moins un liant étant dissous dans un solvant. La présente invention concerne également un procédé simple, rapide, économique, économe en temps et industriellement pratique.
EP21838041.8A 2020-07-07 2021-05-07 Comprimé comprenant de l'apixaban Pending EP4178577A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2020/10729A TR202010729A1 (tr) 2020-07-07 2020-07-07 Api̇ksaban i̇çeren bi̇r tablet
PCT/TR2021/050445 WO2022010437A1 (fr) 2020-07-07 2021-05-07 Comprimé comprenant de l'apixaban

Publications (2)

Publication Number Publication Date
EP4178577A1 true EP4178577A1 (fr) 2023-05-17
EP4178577A4 EP4178577A4 (fr) 2024-04-24

Family

ID=79552638

Family Applications (1)

Application Number Title Priority Date Filing Date
EP21838041.8A Pending EP4178577A4 (fr) 2020-07-07 2021-05-07 Comprimé comprenant de l'apixaban

Country Status (3)

Country Link
EP (1) EP4178577A4 (fr)
TR (1) TR202010729A1 (fr)
WO (1) WO2022010437A1 (fr)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105982870B (zh) * 2015-02-03 2020-05-01 山东新时代药业有限公司 一种阿哌沙班片剂
WO2017121340A1 (fr) * 2016-01-12 2017-07-20 广东东阳光药业有限公司 Composition solide d'araxaban et procédé de préparation de cette composition
TR201717703A2 (tr) * 2017-11-10 2019-05-21 Ali Raif Ilac Sanayi Ve Ticaret Anonim Sirketi Api̇ksaban formülasyonlari
CN108553441B (zh) * 2018-06-08 2019-11-08 北京阳光诺和药物研究有限公司 一种阿哌沙班片及其制备方法

Also Published As

Publication number Publication date
EP4178577A4 (fr) 2024-04-24
TR202010729A1 (tr) 2022-01-21
WO2022010437A1 (fr) 2022-01-13

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