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WO2018169325A1 - Composition pharmaceutique pour le contrôle de la libération, comprenant du mirabegron ou un sel de celui-ci - Google Patents

Composition pharmaceutique pour le contrôle de la libération, comprenant du mirabegron ou un sel de celui-ci Download PDF

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Publication number
WO2018169325A1
WO2018169325A1 PCT/KR2018/003043 KR2018003043W WO2018169325A1 WO 2018169325 A1 WO2018169325 A1 WO 2018169325A1 KR 2018003043 W KR2018003043 W KR 2018003043W WO 2018169325 A1 WO2018169325 A1 WO 2018169325A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
peo
mirabegron
present
polyethylene oxide
Prior art date
Application number
PCT/KR2018/003043
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English (en)
Korean (ko)
Inventor
김수연
김민수
서혜진
박신정
Original Assignee
주식회사 종근당
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 주식회사 종근당 filed Critical 주식회사 종근당
Priority to CN201880018616.8A priority Critical patent/CN110446490B/zh
Priority to JP2019548680A priority patent/JP2020510679A/ja
Publication of WO2018169325A1 publication Critical patent/WO2018169325A1/fr

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    • 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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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

Definitions

  • the present invention relates to a pharmaceutical composition for controlled release comprising a mirabegron or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a pharmaceutical composition for controlling release, including polyethylene oxide for controlling the release of Mirabegron as an active ingredient, which is harmless to the human body and is easy to prepare pharmaceutically.
  • Mirabegron is a compound having the structure of Formula 1 below, and its chemical name is (R) -2- (2-aminothiazol-4-yl) -4 '- ⁇ 2-[(2-hydroxy-2- Phenylethyl) amino] ethyl ⁇ acetanilide.
  • Mirabegron or a pharmaceutically acceptable salt thereof has ⁇ 3 adrenergic receptor agonist action.
  • Mira GRONLUND bay is used for the treatment of symptoms of urgency, frequency or urge incontinence, which can occur in patients with overactive bladder, it is commercially available in the name of Micah Beta ® sustained-release tablet in Korea.
  • Miravegron relaxes the bladder in the storage phase, where urine fills the bladder, and this bladder relaxation effect improves the storage capacity of the bladder (Naunyn Schmiedebergs Arch Pharmacol 2013; 386: 71-8).
  • studies using a mouse model of ischemia in the bladder have shown that mirabegron reduces bladder overactivity by protecting bladder function and morphology (Eur Urol 2013; 64: 664-71).
  • Korean Patent No. 1524164 discloses a pharmaceutical composition for controlling release including Mirabegron, by including (a) a hydrophilic additive for infiltrating water into the formulation and (b) a polymer material forming a hydrogel.
  • a formulation for controlled release is disclosed wherein the drug dissolution rate is 75% or less from the formulation at 1.5 hours and 75% or more and 100% or less at 7 hours.
  • Korean Patent No. 507400 discloses a pharmaceutical composition with no change in drug dissolution upon storage under light irradiation, comprising: (a) a hydrophilic base, (b) polyethylene oxide having an average molecular weight of 2 million or more, and Disclosed is an oral pharmaceutical composition comprising.
  • the above patents all include a hydrophilic base and use polyethylene glycol (PEG) as a representative material of the hydrophilic base.
  • PEG polyethylene glycol
  • polyethylene glycol as a hydrophilic base has been found to cause delayed and immediate hypersensitivity of polyethylene glycol (Sapna Shah MD, et al., Hypersensitivity to Polyethylene Glycols, The Journal of Clinical Pharmacology).
  • polyethylene glycol is likely to cause changes in pharmacokinetic behavior due to ABC Phenomenon (accelerated blood clearance) (U.S. Schuber et al., Polyethylene glycol in Drug delivery, Angewandte chemie).
  • the inventors of the present invention have attempted to develop a pharmaceutical composition that is harmless to the human body and is stable in the preparation of a release-controlling formulation containing Mirabegron.
  • Polyethyleneglycols are generally considered to be biologically inert and safe. However, it has the disadvantage of causing hypersensitivity to a small number of people and altering pharmacokinetic behavior.
  • the present inventors have completed the present invention as a result of the development of a pharmaceutical composition and formulation which is safe and pharmaceutically easy to prepare without including a hydrophilic base such as polyethylene glycol.
  • the present invention relates to a pharmaceutical composition for controlled release comprising a mirabegron or a pharmaceutically acceptable salt thereof as an active ingredient and a polyethylene oxide (PEO) as a sustained release agent.
  • a pharmaceutical composition for controlled release comprising a mirabegron or a pharmaceutically acceptable salt thereof as an active ingredient and a polyethylene oxide (PEO) as a sustained release agent.
  • PEO polyethylene oxide
  • the polyethylene oxide (PEO) of the present invention is very excellent in pharmacokinetics and dissolution rate to exhibit a continuous effect of the drug when it includes both PEO 300,000 and PEO 100 million.
  • PEO polyethylene oxide
  • the polyethylene oxide has an average molecular weight of about 300,000 or more.
  • the average molecular weight of polyethylene oxide is preferably 1 million or less, but is not limited thereto.
  • Suitable polyethylene oxides for use in the present invention are commercially available.
  • Polyox WSR N-12K, Polyox N-60K, Polyox N-750, Polyox WSR 301 NF or Polyox WSR 303NF can be used in the dosage forms of the present invention. But it is not limited thereto.
  • the present invention may be a pharmaceutical composition characterized by comprising less than 5% hydrophilic base.
  • Hydrophilic bases include water-soluble polymers such as polyvinylpyrrolidone (PVP); Sugar alcohols such as D-mannitol, sorbitol and xylitol; Sugars such as lactose, white sugar, maltose anhydrous, D-fructose, dextran and glucose; Surfactant, such as polyoxyethylene hardened castor oil and polyoxyethylene sorbitan higher fatty acid ester; Salts such as sodium chloride and magnesium chloride; Organic acids such as citric acid and tartaric acid; Amino acids such as glycine, alanine, and lysine hydrochloride; Amino acid saccharides such as meglumine and the like.
  • PVP polyvinylpyrrolidone
  • Sugar alcohols such as D-mannitol, sorbitol and xylitol
  • Sugars such as lactose, white sugar, maltose anhydrous, D-fructose, dextran and glucose
  • the present invention may further comprise a colorant.
  • the colorant may be carmine, caramel, ⁇ -carotene, titanium oxide, talc, riboflavin sodium phosphate, yellow aluminum lake, and the like, and preferably aluminum lake.
  • the pharmaceutical composition of the present invention contains Mirabegron or a pharmaceutically acceptable salt thereof as an active ingredient, and is a conventional agent in the pharmaceutical field, such as tablets, capsules, beads, beadlets, granules, pills, tro It may be formulated as an oral preparation such as a key preparation, a liquid preparation, a suspension, or a parenteral preparation, and in particular, may be a tablet for oral administration.
  • the pharmaceutical formulation of the present invention may further include a pH adjusting agent, suspending agent, preservative, flavoring agent, colorant, sweetener, adsorbent and the like as necessary.
  • a pH adjusting agent suspending agent, preservative, flavoring agent, colorant, sweetener, adsorbent and the like.
  • the content of such additives is not particularly limited in the present invention and may be appropriately adjusted as necessary.
  • the formulation of the present invention may be packaged in a container, preferably packaged in an airtight package, and the container includes both an airtight container and a sealed container.
  • the tablet for oral administration of the present invention is preferably packaged in aluminum silver foil (alu-alu) packaging container, but is not limited thereto.
  • compositions comprising a mirabegron or a pharmaceutically acceptable salt thereof according to the present invention have the advantage of long-lasting pharmacological effects through control of release, harmless to the human body, and easy to manufacture pharmaceuticals.
  • Figure 1 shows the dissolution test results by the paddle method (50rpm, 37 °C) in pH 6.8 eluate of Examples 1 to 5 and Comparative Examples.
  • the present invention relates to a pharmaceutical composition for controlling release, comprising Mirabegron or a pharmaceutically acceptable salt thereof as an active ingredient and polyethylene oxide (PEO) as a sustained release agent.
  • the polyethylene oxide (PEO) of the present invention may include only one million PEO and only 30 PEO. It is preferable to include only 300,000 PEO and 100 million PEO in a weight ratio of 1: 0.1 to 1: 5.
  • the average molecular weight of polyethylene oxide (PEO) is preferably 1 million or less.
  • the present invention includes pharmaceutical compositions that do not contain at least 5% hydrophilic base.
  • the present invention is characterized in that it does not contain polyethylene glycol (PEG) as a hydrophilic base.
  • PEG polyethylene glycol
  • the present invention includes an agent for controlling the release of the pharmaceutical composition is formulated, which may be an oral tablet, but is not limited thereto.
  • the formulation may be packaged in a plastic container, with the plastic container being preferably aluminum silver foil (Alu-Alu).
  • the sieved material was put into a mixer, the colloidal silicon dioxide and magnesium stearate were passed through a sieve, and then mixed to prepare a final mixture.
  • the final mixture was compressed into tablets using an automatic tablet press (XP1, Korsh, Germany) to give a tablet of 250 mg in total weight.
  • XP1 Korsh, Germany
  • Example 2 Example 3
  • Example 4 Example 5 1T (mg) % 1T (mg) % 1T (mg) % 1T (mg) % 1T (mg) % 1T (mg) % mix Mirabegron 50.0 19.8 50.0 20.0 50.0 20.0 50.0 20.0 50.0 20.0 50.0 20.0 PEO 2,000,000 70.0 27.7 - - - - - - - - - - PEO 1,000,000 - - 187.1 74.8 153.5 61.4 117.5 47.0 92.5 37.0 67.1 26.8 PEO 300,000 - - - - 33.6 13.4 69.6 27.8 94.6 37.8 120.0 48.0 PEG 8,000 119.6 47.4 - - - - - - - - - - Binder ethanol 50.0 - 50.0 - 50.0 - 50.0 - 50.0 - BHT 0.4 0.2 0.4 0.2 0.4 0.4 0.4 0.4 0.4
  • Dissolution test was performed at pH 6.8 (900 mL, 50 rpm) of the tablets prepared in Examples 1 to 5 and Comparative Examples, and the liquid chromatograph measuring method thereof is as follows.
  • Mobile phase A To 900 mL of water add 8.7 mL of perchloric acid (70%) and 3.0 g of sodium hydroxide, adjust the pH to 2.0 mL with 0.1 N aqueous sodium hydroxide solution and adjust to 1000 mL.

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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)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medical Preparation Storing Or Oral Administration Devices (AREA)

Abstract

La présente invention concerne une composition pharmaceutique pour le contrôle de la libération, comprenant du mirabegron ou un sel pharmaceutiquement acceptable de celui-ci. En particulier, la présente invention concerne une composition pharmaceutique pour le contrôle de la libération, qui comprend de l'oxyde de polyéthylène pour contrôler la libération de mirabegron en tant que principe actif et est inoffensive pour le corps humain et facile à préparer pharmaceutiquement.
PCT/KR2018/003043 2017-03-17 2018-03-15 Composition pharmaceutique pour le contrôle de la libération, comprenant du mirabegron ou un sel de celui-ci WO2018169325A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201880018616.8A CN110446490B (zh) 2017-03-17 2018-03-15 包含米拉贝隆或其盐的用于调节释放的药剂学组合物
JP2019548680A JP2020510679A (ja) 2017-03-17 2018-03-15 ミラベグロンまたはその塩を含む放出調節用薬剤学的組成物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020170033944A KR102051132B1 (ko) 2017-03-17 2017-03-17 미라베그론 또는 이의 염을 포함하는 방출조절용 약제학적 조성물
KR10-2017-0033944 2017-03-17

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WO2018169325A1 true WO2018169325A1 (fr) 2018-09-20

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JP (2) JP2020510679A (fr)
KR (1) KR102051132B1 (fr)
CN (1) CN110446490B (fr)
WO (1) WO2018169325A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4338729A1 (fr) 2022-09-19 2024-03-20 Sanovel Ilac Sanayi Ve Ticaret A.S. Comprimé comprenant du mirabegron
WO2024144207A1 (fr) * 2022-12-26 2024-07-04 Rexpharmtech Co., Ltd Comprimé à libération prolongée comprenant de l'apixaban
EP4410279A1 (fr) 2023-01-25 2024-08-07 Sanovel Ilac Sanayi Ve Ticaret A.S. Comprimé de film comprenant du mirabegron

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021069944A1 (fr) * 2019-10-09 2021-04-15 Alvogen Korea Co., Ltd. Composition pharmaceutique comprenant du mirabégron et son procédé de fabrication
KR102546923B1 (ko) 2020-03-03 2023-06-26 동광제약 주식회사 미라베그론을 포함하는 제어 방출 제제
WO2023022520A1 (fr) * 2021-08-18 2023-02-23 주식회사 삼양홀딩스 Composition de comprimé oral de ruxolitinib et son procédé de préparation

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KR20050072809A (ko) * 2002-11-07 2005-07-12 아스텔라스세이야쿠 가부시키가이샤 아세트산 아닐리드 유도체를 유효성분으로 하는 과활동방광 치료제
US20100144807A1 (en) * 2008-09-30 2010-06-10 Astellas Pharma Inc Pharmaceutical composition for modified release
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AU2004308973A1 (en) * 2003-12-23 2005-07-14 Alza Corporation Methods and dosage forms for increasing solubility of drug compositions for controlled delivery
SA07280459B1 (ar) * 2006-08-25 2011-07-20 بيورديو فارما إل. بي. أشكال جرعة صيدلانية للتناول عن طريق الفم مقاومة للعبث تشتمل على مسكن شبه أفيوني
MX2015002633A (es) * 2012-08-31 2015-06-24 Astellas Pharma Inc Composicion medica oralmente administrada.
EP3292864A1 (fr) * 2017-10-12 2018-03-14 Synthon B.V. Composition de comprimé à libération modifiée comprenant mirabegron

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Publication number Priority date Publication date Assignee Title
KR20050072809A (ko) * 2002-11-07 2005-07-12 아스텔라스세이야쿠 가부시키가이샤 아세트산 아닐리드 유도체를 유효성분으로 하는 과활동방광 치료제
US20100144807A1 (en) * 2008-09-30 2010-06-10 Astellas Pharma Inc Pharmaceutical composition for modified release
US20110236436A1 (en) * 2010-03-29 2011-09-29 Astellas Pharma Inc. Pharmaceutical composition for modified release
US20150031734A1 (en) * 2012-03-30 2015-01-29 Astellas Pharma Inc. Pharmaceutical composition containing mirabegron
CN104288116A (zh) * 2014-09-05 2015-01-21 南京华威医药科技开发有限公司 一种米拉贝隆缓释片组合物
KR20170088783A (ko) * 2017-07-07 2017-08-02 지엘팜텍주식회사 미라베그론의 습식과립 조성물

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4338729A1 (fr) 2022-09-19 2024-03-20 Sanovel Ilac Sanayi Ve Ticaret A.S. Comprimé comprenant du mirabegron
WO2024144207A1 (fr) * 2022-12-26 2024-07-04 Rexpharmtech Co., Ltd Comprimé à libération prolongée comprenant de l'apixaban
EP4410279A1 (fr) 2023-01-25 2024-08-07 Sanovel Ilac Sanayi Ve Ticaret A.S. Comprimé de film comprenant du mirabegron

Also Published As

Publication number Publication date
CN110446490A (zh) 2019-11-12
KR102051132B1 (ko) 2019-12-02
JP2020510679A (ja) 2020-04-09
JP2021185139A (ja) 2021-12-09
KR20180106185A (ko) 2018-10-01
CN110446490B (zh) 2023-04-04

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