EP4251155A1 - Procédés améliorés de granulation par voie humide pour formulations comprenant de l'apixaban - Google Patents

Procédés améliorés de granulation par voie humide pour formulations comprenant de l'apixaban

Info

Publication number
EP4251155A1
EP4251155A1 EP20963794.1A EP20963794A EP4251155A1 EP 4251155 A1 EP4251155 A1 EP 4251155A1 EP 20963794 A EP20963794 A EP 20963794A EP 4251155 A1 EP4251155 A1 EP 4251155A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
composition according
solid oral
oral pharmaceutical
apixaban
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
EP20963794.1A
Other languages
German (de)
English (en)
Other versions
EP4251155A4 (fr
Inventor
Erol KIRESEPI
Ersin Yildirim
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.)
Santa Farma Ilac Sanayi AS
Original Assignee
Santa Farma Ilac Sanayi 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 Santa Farma Ilac Sanayi AS filed Critical Santa Farma Ilac Sanayi AS
Publication of EP4251155A1 publication Critical patent/EP4251155A1/fr
Publication of EP4251155A4 publication Critical patent/EP4251155A4/fr
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • A61K9/2027—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
    • 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
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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

Definitions

  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising Apixaban or one of its pharmaceutically acceptable salt thereof has a D90 less than 20 microns and at least one pharmaceutically acceptable excipient manufactured by using wet granulation method wherein Apixaban is in non-hydrolyzed form.
  • Apixaban is novel, orally active, selective inhibitor of the coagulation factor Xa (FXa) which directly and reversibly binds to the active site of FXa, and decreases the conversion of prothrombin to thrombin due to exerting antithrombotic and anticoagulant effects.
  • FXa coagulation factor Xa
  • Apixaban drug substance is a white to pale yellow, non-hygroscopic crystalline powder and a non-ionizable compound which means that, any changes in pH does not affect to the aqueous solubility of Apixaban.
  • the molecule has no chiral central, therefore, no stereoisomers exist. It shows polymorphism and a number of hydrates and solvates were identified. However, only one form is consistently produced by the proposed synthetic process.
  • Apixaban was firstly commercially authorized by the European Medicines Agency in May 2011. The medicinal product of it been launched in the film-coated tablet form under the name of the ELIQUIS® which is used for the treatment for preventing venous thromboembolism in adults following elective knee or hip replacement surgery and for reducing the risk of stroke or systemic embolism in adults with non-valvular atrial fibrillation.
  • ELIQUIS ® film coated tablets are available for oral administration in strengths of 2.5 mg and 5 mg of Apixaban with the following inactive ingredients: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate.
  • the film coating contains lactose monohydrate, hypromellose, titanium dioxide, triacetine, and yellow iron oxide for 2.5 mg tablets or red iron oxide for 5 mg tablets.
  • Absorption of apixaban is approximately 50%. Peak plasma concentrations are observed around 3 to 4 hours post dose after oral following administration. 87% of Apixaban is bound to the plasma proteins. By being prolonged absorption, the pharmacokinetics of Apixaban are complicated. Its short clearance half-life is about 6 hours, but the apparent half-life during following dose is about 12 hours. Thus, it continues the anticoagulation effective for at least a day, even when the drug is stopped for surgery. Its absorption takes place throughout the gastrointestinal tract. Food does not significantly affect bioavailability of Apixaban, thus; it can be taken without to food.
  • BMS Bristol-Myers Squibb
  • Pfizer as an anticoagulant and antithrombotic agent.
  • Apixaban base and its pharmaceutically acceptable salts first have been declared in EP1427415.
  • Example 18 at the EP1427415 discloses the preparation of Apixaban base.
  • EP2538925 relates to a pharmaceutical composition
  • a pharmaceutical composition comprising crystalline Apixaban particles having a D90 equal to or less than 89 pm and a pharmaceutically acceptable diluent or carrier excipients wherein the prepared composition is manufactured by using a dry granulation process.
  • EP2538925 patent document has many divisional applications.
  • One of the divisional application EP3017811 discloses to the dry granulation process steps of the prepared pharmaceutical formulations comprising Apixaban and a pharmaceutically acceptable diluent or carrier excipients.
  • Another divisional application EP3251660 discloses to a pharmaceutical composition comprising crystalline Apixaban particles having a D90 less than 50 pm and a pharmaceutically acceptable diluent or carrier excipients.
  • Another divisional application EP3246021 discloses to a pharmaceutical composition exhibits dissolution properties such that an amount of the drug equivalent to at least 77% dissolves within 30 minutes, wherein the dissolution test is performed in an aqueous media buffered to a pH range 1 to 7.4 and controlled at 37°C.
  • Another divisional application EP3257500 discloses to a pharmaceutical composition
  • a pharmaceutical composition comprising crystalline Apixaban particles and a pharmaceutically acceptable diluent or carrier and a surfactant, wherein the surfactant is present in a concentration of 0.25% to 2% by weight, also wherein the composition is manufactured by using an air-jet milling process to reduce Apixaban particle size to the desired size and dry granulation.
  • Another divisional application EP3643301 discloses to a pharmaceutical composition exhibits dissolution properties such that an amount of the drug equivalent to at least 77% dissolves within 30 minutes, wherein the dissolution test is performed in 900 mL of dissolution medium containing 0.05 M sodium phosphate at pH 6.8 with 0.05% SDS at 37°C using USP Apparatus 2 (paddles) at a rotation speed of 50-75 rpm.
  • EP3662899 is rather close with the EP3643301 patent document wherein EP3662899 patent document discloses to the dose/solubility ratio of the Apixaban in the tablet which is less than 250 mL.
  • the given dissolution properties are same with the EP3643301 patent document.
  • EP3405195 relates to a pharmaceutical composition
  • a pharmaceutical composition comprising Apixaban or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable polymer wherein the polymer is graft copolymer of polyvinyl caprolactam, polyvinyl acetate and polyethylene glycol obtained by using of hot-melt method.
  • WO2019177318 relates to a pharmaceutical composition
  • a pharmaceutical composition comprising Apixaban was prepared according to a preparation method comprising the steps of; mixing Apixaban and a water- soluble polymer to prepare a mixture; and wet kneading and vacuum drying of the mixture.
  • WO2017221209 relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the crystalline Apixaban particles having a D90 value more than 89 microns and a pharmaceutically acceptable carrier wherein the crystalline Apixaban is Form M.
  • EP3243505 relates to a pharmaceutical composition comprising amorphous Apixaban or a salt thereof together with one or more pharmaceutically acceptable excipients or carriers, wherein the composition exhibits an in vitro dissolution profile measured in phosphate buffer at pH 6.8 containing 0.05 % weight/volume of sodium lauryl sulfate according to which: at least 30% of Apixaban is dissolved after 5 minutes and at least 60% of Apixaban is dissolved after 10 minutes.
  • EP2907507 relates to a pharmaceutical composition
  • a pharmaceutical composition comprising Apixaban and a particularly selected polymer having low viscosity as binder.
  • W02017163170 relates to a pharmaceutical composition
  • a pharmaceutical composition comprising Apixaban prepared by a non-aqueous wet granulation process wherein the composition releases at least 80% of Apixaban in 30 minutes.
  • EP3107530 relates to a pharmaceutical composition
  • a pharmaceutical composition comprising Apixaban and a polymer having low viscosity as binder wherein the polymer is selected from the group consisting of povidone, hypromellose, hydroxypropyl cellulose, polyvinyl alcohol, copovidone, polyvinyl alcohol-polyethylene glycol graft copolymer, respectively having low viscosity, and a mixture thereof and wherein the composition prepared by wet granulation process.
  • W02017121340 relates to a pharmaceutical composition
  • a pharmaceutical composition comprising non-micronized Apixaban and pharmaceutically acceptable excipients wherein the povidone is selected as binder as is dissolved in DMSO.
  • EP2554159 relates to a pharmaceutical composition comprising micronized Apixaban and a content uniformity enhancer manufactured by using direct compression.
  • WO2017182908 relates to a pharmaceutical composition comprising micronized Apixaban and pharmaceutically acceptable excipients manufactured by using direct compression wherein the amount of the micronized Apixaban is present up to 20% of the total weight.
  • EP3582777 relates to a pharmaceutical composition
  • a pharmaceutical composition comprising Apixaban having a D90 particle size of more than 100 microns, a diluent, a surfactant, a disintegrant and a lubricant manufactured by using wet granulation method wherein Apixaban is dispersed in the binder solution.
  • TR2017/17703 relates to a pharmaceutical composition
  • a pharmaceutical composition comprising Apixaban or a pharmaceutically acceptable salt thereof manufactured by using wet granulation method wherein Apixaban is dispersed into the solvent or solvent mixture to prepare the granulating solution.
  • composition comprising Apixaban particles having a D90 value less than 20 microns and at least one pharmaceutically acceptable excipient is developed in the immediate release oral solid dosage form with improved solubility by using wet granulation method wherein Apixaban is in non-hydrolyzed form.
  • Also present invention particularly relates to a process for the preparation of a pharmaceutical composition manufactured by using wet granulation method, including the steps of: a. Apixaban, Lactose monohydrate, Croscarmellose sodium, Microcrystalline cellulose and specified amount of Povidone are screened through a proper sieve, transferred into the high shear mixer through screening with a proper sieve and stirred, b. Poloxamer is dissolved in a sufficient amount of the deionized water till to dissolve completely, c. The rest amount of the Povidone is added into the granulation solution prepared in Step b and stirred till to obtain homogenous mixture, d. The solution in Step c is added into the powder blend prepared in Step a to perform granulation process, e.
  • the pharmaceutical composition comprising at least one filler which can be selected from dibasic calcium phosphate dehydrate, polysaccharides, primarily microcrystalline cellulose, lactose anhydrous, lactose monohydrate, mannitol, sugars, sorbitol, sucrose, inorganic salts, primarily calcium salts and the like and mixtures thereof.
  • filler is the combination of lactose anhydrous and microcrystalline cellulose.
  • the pharmaceutical composition comprises at least a binder which can be selected from hypromeliose, sodium carboxymethyl cellulose, cellulose or cellulose derivatives, povidone, starch, sucrose, polyethylene glycol, or mixtures thereof.
  • the binder is povidone.
  • the pharmaceutical composition comprising at least one lubricant which can be selected from sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid and mixtures thereof.
  • the lubricant is magnesium stearate.
  • Typical granulation solutions usually selected as water, ethanol, isopropanol and methylene chloride either alone or in combination. Also, it can be used alone or, more usually, as a solvent containing a dissolved binder/suspension/gelatinized binder to ensure particle adhesion once the granule is dry.
  • preferred solvent in the granulation solution is selected as water.
  • preferred solvent in the granulation solution contains binder and surfactant.
  • Surfactant is used in tablet formulation to increase the dissolution rate or active ingredient release amount by increasing hydrophilicity within the tablet matrix.
  • the pharmaceutical composition comprising at least one suitable surfactant which is selected from polyoxyethylene fatty alcohol ethers, sorbitan fatty acid esters, stearyl alcohol, poloxamers, potassium laureate, sodium lauryl sulfate, benzalkonium chloride and mixtures thereof.
  • the surfactant is poloxamer.
  • the pharmaceutical composition of the present invention is manufactured by using wet granulation method, wherein the process comprised the steps of: a. Co-sifting Apixaban, filler, disintegrant and specified amount of the binder through a proper sieve and stir to prepare the powder blend, b. Dissolving the surfactant in the granulation solution, c. Preparing the binder solution by adding it into the prepared granulation solution in Step b, d. Adding the binder solution into the prepared pow'der blend in Step a to preform granulation process, e. Drying the granules in fludizied bed dryer and sifting the dried granules through a proper sieve, f. Sifting the lubricant through a proper sieve and adding to the prepared granule in Step e, g, Compressing the final blend in Step f.
  • the embodiment in accordance with the present invention was designed with adjusted quantitative composition composed of pharmaceutically acceptable ingredients mentioned above by using wet granulation method.
  • Example 1 was given in the Table- 1 below.
  • the proposed embodiment based on the invention provides an immediate release oral solid pharmaceutical composition wherein the amounts in w/w% by w'eight of the total composition are as stated below: Table 1: Unit Formula of Example 1
  • the process for the preparation of a pharmaceutical composition manufactured by using wet granulation method including the steps of: a. Apixaban, Lactose monohydrate, Croscarmellose sodium, Microcrystalline cellulose and specified amount of Povidone are screened through a proper sieve, transferred into the high shear mixer and stirred, b. Poloxamer is dissolved in a sufficient amount of the deionized water till to dissolve completely, c. The rest amount of the Povidone is added into the granulation solution prepared in Step b and stirred till to obtain homogenous mixture, d. The solution in Step c is added into the powder blend prepared in Step a to perform granulation process, e.
  • the granule prepared in Step d is dried in fludizied bed dryer and shifted through a proper sieve, f.
  • Magnesium stearate is screened through a proper sieve and added to the powder granulation prepared in Step e and are stirred to obtain a uniform final blend, g. Tablet compression is performed with the final blend in Step f.
  • Example 1 Based on the results presented in Table 1 above, the in-vitro dissolution results of Example 1 were similar with the Reference drug product.
  • the proper dissolution profile was obtained which was developed in the immediate release dosage form comprising Apixaban having a D90 value less than 20 microns and at least one pharmaceutical excipient manufactured by using wet granulation method, wherein Apixaban was only present in the powder blend and binder solution was made of dissolved povidone and poloxamer which enable the aqueous povidone-based binder solution to decrease the interfacial tension between the poorly soluble Apixaban particles.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition pharmaceutique comprenant de l'apixaban ou l'un de ses sels pharmaceutiquement acceptables ayant un D90 inférieur à 20 microns et au moins un excipient pharmaceutiquement acceptable fabriqué en utilisant un procédé de granulation par voie humide dans lequel l'apixaban est sous une forme non hydrolysée.
EP20963794.1A 2020-11-27 2020-11-27 Procédés améliorés de granulation par voie humide pour formulations comprenant de l'apixaban Pending EP4251155A4 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/TR2020/051185 WO2022115052A1 (fr) 2020-11-27 2020-11-27 Procédés améliorés de granulation par voie humide pour formulations comprenant de l'apixaban

Publications (2)

Publication Number Publication Date
EP4251155A1 true EP4251155A1 (fr) 2023-10-04
EP4251155A4 EP4251155A4 (fr) 2024-07-31

Family

ID=81754730

Family Applications (1)

Application Number Title Priority Date Filing Date
EP20963794.1A Pending EP4251155A4 (fr) 2020-11-27 2020-11-27 Procédés améliorés de granulation par voie humide pour formulations comprenant de l'apixaban

Country Status (2)

Country Link
EP (1) EP4251155A4 (fr)
WO (1) WO2022115052A1 (fr)

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2329881T3 (es) 2001-09-21 2009-12-02 Bristol-Myers Squibb Company Compuestos que contienen lactama y derivados de los mismos como inhibidores del factor xa.
BR112012021337A8 (pt) 2010-02-25 2016-11-29 Bristol Myers Squibb Co formulações de apixaban.
EP2554159A1 (fr) 2011-08-04 2013-02-06 ratiopharm GmbH Formes pharmaceutiques comportant de l'apixaban et améliorant d'uniformité de contenu
CN104644593A (zh) * 2013-11-23 2015-05-27 天津市汉康医药生物技术有限公司 阿哌沙班组合物及其制备方法
EP2907507A1 (fr) 2014-02-17 2015-08-19 Sandoz Ag Composition pharmaceutique comprenant de l'apixaban
CN108472261B (zh) * 2016-01-12 2021-12-03 广东东阳光药业有限公司 阿哌沙班固体组合物及其制备方法
EP3195860A1 (fr) 2016-01-22 2017-07-26 STADA Arzneimittel AG Procede de fabrication d'un granule d'apixaban
WO2017163170A1 (fr) 2016-03-21 2017-09-28 Sun Pharmaceutical Industries Limited Composition pharmaceutique comprenant de l'apixaban
WO2017182908A1 (fr) 2016-04-18 2017-10-26 Emcure Pharmaceuticals Limited Compositions pharmaceutiques d'apixaban
EP3243505A1 (fr) 2016-05-13 2017-11-15 Zaklady Farmaceutyczne Polpharma SA Composition pharmaceutique comprenant de l'apixaban amorphe
WO2017221209A1 (fr) 2016-06-23 2017-12-28 Lupin Limited Formulations pharmaceutiques d'apixaban
US11510909B2 (en) 2017-02-17 2022-11-29 Unichem Laboratories Ltd. Pharmaceutical composition of apixaban
TR201717703A2 (tr) 2017-11-10 2019-05-21 Ali Raif Ilac Sanayi Ve Ticaret Anonim Sirketi Api̇ksaban formülasyonlari
KR102128321B1 (ko) 2018-03-13 2020-06-30 주식회사 종근당 아픽사반을 포함하는 가용화를 위한 약제학적 제제 및 이의 제조 방법

Also Published As

Publication number Publication date
EP4251155A4 (fr) 2024-07-31
WO2022115052A1 (fr) 2022-06-02

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