WO2020022824A1 - Formulation pharmaceutique comprenant de l'edoxaban et son procédé de préparation - Google Patents

Formulation pharmaceutique comprenant de l'edoxaban et son procédé de préparation Download PDF

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Publication number
WO2020022824A1
WO2020022824A1 PCT/KR2019/009309 KR2019009309W WO2020022824A1 WO 2020022824 A1 WO2020022824 A1 WO 2020022824A1 KR 2019009309 W KR2019009309 W KR 2019009309W WO 2020022824 A1 WO2020022824 A1 WO 2020022824A1
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WIPO (PCT)
Prior art keywords
formulation
preparation
formula
compound represented
pharmaceutically acceptable
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PCT/KR2019/009309
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English (en)
Korean (ko)
Inventor
김영목
김용한
Original Assignee
보령제약 주식회사
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Application filed by 보령제약 주식회사 filed Critical 보령제약 주식회사
Priority to JP2021528317A priority Critical patent/JP2022507838A/ja
Publication of WO2020022824A1 publication Critical patent/WO2020022824A1/fr

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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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/282—Organic compounds, e.g. 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/282—Organic compounds, e.g. fats
    • A61K9/2826—Sugars or sugar alcohols, e.g. sucrose; Derivatives thereof

Definitions

  • the present invention relates to a preparation comprising the edoxaban as an active ingredient and a preparation method thereof.
  • Edoxaban is a compound that inhibits activated blood coagulation factor X (also referred to as activation factor X or FXa) and is useful as a prophylactic and / or therapeutic drug for thrombotic diseases, wherein N 1- (5-chloropyridine- 2-yl) -N 2 -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5 , 4-c] pyridin-2-yl) carbonyl] aminocyclohexyl) ethanediamide.
  • activated blood coagulation factor X also referred to as activation factor X or FXa
  • FXa activation factor X
  • Edoxaban is commercialized in the form of p-toluenesulfonic acid salt, hydrate, represented by the following formula (2), and sold as lyciana.
  • the present inventors have completed the present invention by developing a novel formulation containing Edoxaban as an active ingredient and a preparation method thereof.
  • Patent Document 1 Republic of Korea Patent Publication No. 10-2018-0022125
  • the present invention is a compound represented by the following formula (1), or a pharmaceutically acceptable salt or hydrate thereof; And pea starch as a coating agent.
  • the present invention provides a method for preparing a preparation comprising coating the compound represented by Formula 1, or a pharmaceutically acceptable salt or hydrate thereof with pea starch.
  • the present invention is a compound represented by the following formula (1), or a pharmaceutically acceptable salt or hydrate thereof; And pea starch as a coating agent.
  • the compound represented by Formula 1 is N 1- (5-chloropyridin-2-yl) -N 2 -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-[(5 -Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] aminocyclohexyl) ethanediamide and is called edoxaban.
  • compositions in the present invention when physiologically acceptable and administered to a human, are usually self-pharmaceutical formulations having ordinary skill in the art without causing gastrointestinal disorders, allergic reactions such as dizziness or the like. It may mean that the conventional use in the manufacture.
  • Such pharmaceutically acceptable salts may refer to salts formed with inorganic or organic acids or bases.
  • it may be any one selected from the group consisting of tartarate, hydrochloride, citrate, malate, phosphate, sulfate, malonate, oxalate, bromate and tosylate.
  • the 'hydrate' is that the doxaban or a pharmaceutically acceptable salt thereof and the like water is coupled to the non-covalent intermolecular force may include a stoichiometric amount of water.
  • the hydrate may include about 0.25 mol to about 10 mol of water based on 1 mol of the active ingredient, more specifically about 0.5 mol, about 1 mol, about 1.5 mol, about 2 mol, about 2.5 moles, about 3 moles, about 5 moles, and the like.
  • the hydrate may be a monohydrate of edoxaban citric acid salt.
  • pea starch means starch derived from pea. This is starch having an amylose content of at least about 50% by weight of starch.
  • Pea starch is a modified (eg, substituted with C2-C8 hydroxy alkyl group, eg, hydroxy propyl or hydroxy ethyl group, as well as unmodified pea starch, as well as functional groups (eg, hydroxyl groups) of the starch). ) Contains both pea starch.
  • a preferred example of such modified pea starch is pregelatinized hydroxypropyl pea starch.
  • Pregelatinized hydroxypropyl pea starch contains, for example, 2-7% of hydroxypropyl groups.
  • Examples of such modified pea starch include Lycoat ® and the like. Specifically, Lycoat ® RS780, Lycoat ® RS720 and the like.
  • the formulation uses pea starch as a coating agent.
  • a preparation of the present invention shows an excellent dissolution pattern by using pea starch as a coating agent is excellent in bioavailability.
  • it has the advantage of showing a similar dissolution pattern compared to commercially available drugs, and the low viscosity significantly reduces the time and cost in the preparation of the formulation.
  • the formulation of the present invention is preferably a tablet.
  • Tablets according to the invention can be prepared by wet granulation, direct tableting or dry granulation methods, preferably by wet granulation or direct tableting.
  • the formulation includes 7 to 30% by weight, preferably 10 to 25% by weight of the compound represented by Formula 1 based on the total weight of the preparation.
  • the formulation comprises 1 to 7% by weight, preferably 1.5 to 5% by weight, of a coating comprising pea starch, relative to the total weight of the formulation.
  • the formulations of the present invention may comprise any one or more excipients selected from the group consisting of mannitol, erythritol, xylitol, pregelatinized starch and crystalline cellulose as excipients.
  • the excipients are mannitol and pregelatinized starch.
  • Mannitol and pregelatinized starch can be used as an excipient to improve the solubility of the compound of formula 1 to aid in dissolution.
  • the formulation comprises 40 to 80% by weight, preferably 50 to 70% by weight, based on the total weight of the formulation.
  • the formulations of the present invention may comprise any one or more disintegrants selected from the group consisting of crospovidone, carmellose and carboxy methyl starch sodium as disintegrants.
  • the disintegrant is crospovidone.
  • the formulation comprises 1 to 10% by weight, preferably 2 to 8% by weight, of disintegrant, based on the total weight of the formulation.
  • the formulation of the present invention may include any one or more binders selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone and vinylpyrrolidone as binders.
  • the binder is hydroxypropylcellulose.
  • the formulation comprises from 3 to 15% by weight, preferably from 4 to 10% by weight, of the binder relative to the total weight of the formulation.
  • the formulation of the present invention may include any one or more lubricants selected from the group consisting of talc, colloidal silicon oxide, magnesium stearate, and sodium stearyl fumarate as lubricants.
  • lubricants selected from the group consisting of talc, colloidal silicon oxide, magnesium stearate, and sodium stearyl fumarate as lubricants.
  • the lubricant is talc and colloidal silicon oxide.
  • the formulation comprises 3 to 15% by weight, preferably 4 to 10% by weight, based on the total weight of the formulation.
  • the formulation of the present invention may further comprise sorbitol and propylene glycol in addition to pea starch as a coating.
  • Pea starch as a coating agent is preferably included in 50 to 70% by weight of the total coating content.
  • the present invention may further include a colorant, and may further include a commonly used colorant such as titanium oxide, yellow iron oxide, and the like.
  • the preparations of the present invention preferably comprise a compound represented by formula (1), or a pharmaceutically acceptable salt or hydrate thereof;
  • excipients selected from the group consisting of mannitol, erythritol, xylitol, pregelatinized starch and crystalline cellulose;
  • At least one binder selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone and vinylpyrrolidone;
  • the formulation of the present invention is a compound represented by formula (1), or a pharmaceutically acceptable salt or hydrate thereof;
  • a formulation comprising a coating that is pea starch.
  • the preparations according to the invention are preparations for use in the prevention or treatment of thrombotic diseases.
  • the thrombotic disease may be at least one selected from the group consisting of cerebral infarction, cerebral embolism, pulmonary infarction, pulmonary embolism, myocardial infarction, angina pectoris, thrombosis and embolism.
  • the present invention provides a method for preparing a preparation comprising coating the compound represented by Formula 1, or a pharmaceutically acceptable salt or hydrate thereof with pea starch.
  • the preparations according to the invention are preferably tablets and can be prepared by wet granulation, dry granulation or direct tableting. More preferably by wet granulation or direct tableting methods.
  • the preparation method of the formulation is preferably
  • Excipients, binders, disintegrants and glidants in the preparation method are as described above in the formulation.
  • Steps (a) and (b) may be performed by appropriate modification at a level that is normally applicable by wet granulation or direct tableting.
  • step (a) it preferably comprises more than 10% moisture.
  • the granules are largely prepared in the mixing process, thereby improving the flowability of the mixture.
  • the coating of step (c) may further comprise sorbitol and propylene glycol as a coating component in addition to pea starch.
  • pea starch By using the pea starch can provide a low viscosity of the coating agent to perform the coating quickly in a short time.
  • the process for the preparation of the preparations according to the invention exhibits an excellent effect in terms of preparations and methods for their preparation by providing preparations with good dissolution rates, while significantly reducing time and cost in the preparation of the preparations.
  • the present invention is a compound represented by Formula 1, or a pharmaceutically acceptable salt or hydrate thereof; And it provides a pharmaceutical composition comprising a formulation comprising pea starch as a coating.
  • the pharmaceutical composition is useful as a prophylactic and / or therapeutic agent for blood coagulation preparations, blood clots or embolisms in that it exhibits a high activating blood coagulation factor X (FXa) inhibitory effect.
  • the pharmaceutical composition of the present invention is a pharmaceutical, activated blood coagulant X factor inhibitor, a blood coagulation inhibitor, a thrombus and / or embolism prevention and / or treatment for mammals, including humans, and a prophylaxis and / or treatment of thrombotic disease, May include cerebral infarction, cerebral embolism, pulmonary infarction, pulmonary embolism, myocardial infarction, angina pectoris and / or embolism associated with non-membranous atrial cell (NVAF), deep vein thrombosis, deep vein thrombosis after surgical operation, artificial stool / joint replacement Thrombosis, thromboembolism after total hip arthroplasty (THR), thromboembolism after
  • the present invention is a compound represented by Formula 1, or a pharmaceutically acceptable salt or hydrate thereof; And a pharmaceutical composition comprising a preparation comprising pea starch as a coating agent in a therapeutically effective amount.
  • the present invention provides the use of an agent according to the invention for the manufacture of a medicament for the prophylaxis or treatment of thrombotic disease.
  • the formulation comprising the edoxaban of the present invention as an active ingredient shows an excellent dissolution pattern and excellent bioavailability and significantly reduces the time and cost in the preparation of the formulation through the low viscosity of the coating agent, the characteristics of the formulation itself and its manufacturing method Excellent effect in terms of appearance.
  • HSM 100 mL of purified water. High speed mixer). HSM (SM-5C, Sejong Pharmatech) was used for wet granulation. The granules were dried in a fluid bed dryer. Fluid bed dryer was used (GPCG-1, Glatt GmbH). The dried granules were sized with a sizing machine. The sizing machine used Comil (197, Quadro).
  • 16.00 g of crospovidone are mixed with 352.80 g of the formulation and mixed with 28.00 g of talc and 3.20 g of colloidal silicon oxide.
  • the final mixture was compressed using a single tablet press (EK-0, Korsch) and a rotary tablet press (GRC-7S, Sejong Pharmatech).
  • Tablets were prepared for the Edoxaban of Table 2 below, or a pharmaceutically acceptable salt or hydrate thereof.
  • HSM High Speed Mixer
  • purified water was used in excess of 10% of the total weight.
  • HSM (SM-5C, Sejong Pharmatech) was used for wet granulation.
  • the granules were dried in a fluid bed dryer. Fluid bed dryer was used (GPCG-1, Glatt GmbH).
  • the dried granules were sized with a sizing machine.
  • the sizing machine used Comil (197, Quadro).
  • D-mannitol, pregelatinized starch, crospovidone, hydroxypropyl cellulose and edoxaban, or a pharmaceutically acceptable salt or hydrate thereof are mixed, and then talc and colloidal silicon oxide are added thereto. Mixed.
  • the final mixture was compressed using a single tablet press (EK-0, Korsch) and a rotary tablet press (GRC-7S, Sejong Pharmatech).
  • Prepurified hydroxypropyl pea starch, D-sorbitol, propylene glycol 6000, titanium oxide and yellow iron oxide were added to purified water, and a suspension was prepared by using a homogenizer (Ultra-turrax T 50, IKA) and stirred. Tablets were placed in a coating machine (LCM, O'HARA) and film-coated so that the coating amount was 12 mg / tablet as a coating suspension.
  • Tablets were prepared in the compositions of Tables 4 and 5 below based on the formulation examples described in the Examples of Korean Patent No. 10-1424843.
  • Example 1 using pregelatinized hydroxypropyl pea starch (LYCOAT ® ) it took about 32 minutes to complete the coating at 3% by weight of the total weight of the tablet in the uncoated state.
  • LYCOAT ® pregelatinized hydroxypropyl pea starch
  • the present invention not only significantly shortens the coating time by changing the coating agent, but also does not require an additional drying or device cleaning step required after preparing the coated tablet. It has excellent advantages in the manufacturing process. This has been shown to significantly increase the cost and time efficiency in the preparation of the formulation.
  • the KP 11 dissolution test method 2 (paddle) using pH 1.2 solution (the first solution of KP 11 disintegration test method), pH 4.0 solution, the pH 6.8 solution (the second solution of KP 11 disintegration test method), and water Elution test at 50 rpm.
  • Example 1 For dissolution rate testing, 60 mg of Lyxiana tablets were used as the formulation of Example 1 and commercially available Edoxaban tablets.
  • Example 1 As confirmed in the above table, it was confirmed that the formulation of Example 1 exhibited a similar dissolution phenomenon as compared to a commercially available product.
  • the present invention provides an excellent formulation by exhibiting a dissolution rate equivalent to that of a commercially available formulation while greatly shortening the production time and greatly reducing the cost required for the production process.

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une formulation comprenant de l'edoxaban comme principe actif et son procédé de préparation. La formulation comprenant de l'edoxaban comme principe actif, selon la présente invention, présente un excellent diagramme de dissolution, ainsi qu'une excellente biodisponibilité, et, en raison de la faible viscosité d'un agent de revêtement, permet une réduction significative du temps et des coûts nécessaires à la préparation de la formulation, présentant ainsi d'excellents effets dans la formulation elle-même et son procédé de préparation.
PCT/KR2019/009309 2018-07-27 2019-07-26 Formulation pharmaceutique comprenant de l'edoxaban et son procédé de préparation WO2020022824A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2021528317A JP2022507838A (ja) 2018-07-27 2019-07-26 エドキサバンを含む薬学的製剤およびその製造方法

Applications Claiming Priority (2)

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KR1020180088173A KR102222774B1 (ko) 2018-07-27 2018-07-27 에독사반을 포함하는 약학적 제제 및 이의 제조방법
KR10-2018-0088173 2018-07-27

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WO2020022824A1 true WO2020022824A1 (fr) 2020-01-30

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Cited By (1)

* 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

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220098654A1 (en) 2019-02-14 2022-03-31 Md Healthcare Inc. Nanovesicles derived from bacteria of genus rothia, and use thereof

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KR20100121483A (ko) * 2008-02-11 2010-11-17 다이닛본 스미토모 세이야꾸 가부시끼가이샤 용출성이 개선된 정제
KR20100129740A (ko) * 2008-02-19 2010-12-09 맥네일-피피씨, 인코포레이티드 아밀로스 함량이 높은 전분을 포함하는 침지 코팅 조성물
WO2013026553A1 (fr) * 2011-08-22 2013-02-28 Ratiopharm Gmbh Composition comprenant de l'edoxaban
KR20140102675A (ko) * 2011-12-14 2014-08-22 다이이찌 산쿄 가부시키가이샤 고도 신장 기능 장애를 갖는 혈전 색전증 환자의 혈전 색전증의 예방 치료제
KR20160098508A (ko) * 2013-12-23 2016-08-18 라보라토리오스 델 드라. 에스테브.에스.에이. 경구용 약학 조성물

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FI2140867T4 (fi) * 2007-03-29 2023-09-14 Farmaseuttinen koostumus
HUE031059T2 (en) * 2010-03-19 2017-06-28 Daiichi Sankyo Co Ltd Procedure for improving anticoagulant administration
KR20180022125A (ko) 2016-08-23 2018-03-06 동화약품주식회사 디아민 유도체의 산부가염 및 이의 제조 방법

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20100121483A (ko) * 2008-02-11 2010-11-17 다이닛본 스미토모 세이야꾸 가부시끼가이샤 용출성이 개선된 정제
KR20100129740A (ko) * 2008-02-19 2010-12-09 맥네일-피피씨, 인코포레이티드 아밀로스 함량이 높은 전분을 포함하는 침지 코팅 조성물
WO2013026553A1 (fr) * 2011-08-22 2013-02-28 Ratiopharm Gmbh Composition comprenant de l'edoxaban
KR20140102675A (ko) * 2011-12-14 2014-08-22 다이이찌 산쿄 가부시키가이샤 고도 신장 기능 장애를 갖는 혈전 색전증 환자의 혈전 색전증의 예방 치료제
KR20160098508A (ko) * 2013-12-23 2016-08-18 라보라토리오스 델 드라. 에스테브.에스.에이. 경구용 약학 조성물

Cited By (1)

* 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

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JP2022507838A (ja) 2022-01-18
KR102222774B1 (ko) 2021-03-04

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