WO2020175897A1 - Formulation à libération contrôlée contenant du mirabegron ou un sel pharmaceutiquement acceptable de ce dernier - Google Patents

Formulation à libération contrôlée contenant du mirabegron ou un sel pharmaceutiquement acceptable de ce dernier Download PDF

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Publication number
WO2020175897A1
WO2020175897A1 PCT/KR2020/002708 KR2020002708W WO2020175897A1 WO 2020175897 A1 WO2020175897 A1 WO 2020175897A1 KR 2020002708 W KR2020002708 W KR 2020002708W WO 2020175897 A1 WO2020175897 A1 WO 2020175897A1
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WO
WIPO (PCT)
Prior art keywords
release
mirabegron
formulation
agent
sustained
Prior art date
Application number
PCT/KR2020/002708
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English (en)
Korean (ko)
Inventor
권석영
박윤상
한종권
구대환
Original Assignee
신일제약주식회사
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.)
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Application filed by 신일제약주식회사 filed Critical 신일제약주식회사
Publication of WO2020175897A1 publication Critical patent/WO2020175897A1/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
    • A61K9/2004—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
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating

Definitions

  • the present invention relates to a pharmaceutical preparation containing mirabegron or a pharmaceutically acceptable salt thereof.
  • a release controlling preparation containing mirabegron, isomalt, and a sustained release agent a drug.
  • a drug As the generation of harmful substances due to decomposition of the drug is suppressed, a certain therapeutic effect can be expected even for long-term storage. More specifically, it shows the drug release pattern and bioavailability equivalent to those of the currently marketed products not only in vitro but also in vivo. It is characterized by being able to secure sufficient drug efficacy only for recovery.
  • Mirabegron the active ingredient of the present invention, is a compound represented by the following chemical formula, whose chemical name is
  • PEG Polyethylene glycol
  • Korean Patent Application Publication No. 10-2018-0106924 and Korean Patent Publication No. 10-2018. -0106185 discloses a release-controlled pharmaceutical composition consisting only of a sustained fire retardant without using polyethylene glycol
  • Korean Patent Publication No. 10-2018-0104259 discloses a release-controlled pharmaceutical composition through a hydrophobic non-hydrogel matrix.
  • Korean Patent Laid-Open No. 10-2017-0088783 discloses a formulation containing a homogeneous granule using a silicate compound.
  • betamy ® Since it does not contain polyethylene glycol, betamy ® is not desirable because it is unlikely to be bioequivalent to sustained-release tablets in real life.
  • This release regulator proposed development that can secure a beta Micah ® sustained-release tablet and bioequivalence is required at the same time to solve the problem.
  • Patent Document 1 Korean Patent Registration No. 057400
  • Patent Document 2 Korean Patent Registration No. 1524164
  • Patent Document 3 Korean Patent Publication No. 10-2018-0106924
  • Patent Document 4 Korean Patent Publication No. 10-2018-0106185
  • Patent Document 5 Korean Patent Publication No. 10-2018-0106924
  • Patent Document 6 Korean Patent Publication No. 10-2018-0104259
  • Patent Document 7 Korean Patent Publication No. 10-2017-0088783
  • the present inventor is mutually compatible with the drug Mirabegron when using isomalt, which was not mentioned at all in the release control formulations containing the known Mirabegron. Since no action occurs, harmful substances due to decomposition of Mirabegron are not generated, and not only in vitro, but also
  • the present invention was completed by confirming that it was possible to manufacture a release-controlling formulation capable of securing a stable drug release pattern and excellent bioavailability in vivo.
  • the present invention is for the prevention or treatment of overactive bladder, urinary urgency, urinary incontinence, and frequency
  • the solution is to provide an anti-inflammatory agent, and it contains Mirabegron as an active ingredient, and it does not generate harmful substances due to the decomposition of the drug Mirabegron using isomalt, so that a certain therapeutic effect can be expected even for long-term storage.
  • Providing controlled-release formulations is a specific challenge.
  • a special challenge is to provide a release-controlled formulation that can show a pattern and secure excellent bioavailability in vivo.
  • a release-controlled preparation comprising mirabegrone or a pharmaceutically acceptable salt thereof, isomalt, and a sustained-release agent is disclosed.
  • the sustained-release agent is polyethylene oxide, hydroxypropylmethylcellulose,
  • Hydroxypropyl cellulose sodium carboxymethyl cellulose
  • It may be one or two or more selected from the group consisting of ethyl cellulose.
  • the sustained-release agent may be polyethylene oxide.
  • the isomalt is 20 to 90% by weight based on the total weight of the release control agent
  • the sustained-release agent may be included in an amount of 5 to 50% by weight based on the total weight of the release control agent.
  • the release-controlling formulation may further contain one or more selected from excipients, binders, disintegrants, antioxidants, surfactants, lubricants and coating bases.
  • the release controlling agent of the present invention is Mirabegron or its
  • the release control formulation according to the present invention exhibits the effect of preventing or treating overactive bladder, urinary urgency, urinary incontinence, and frequent urination. More particularly, by using isomalt as a water-soluble additive, the drug Mirabegron is decomposed. Due to the fact that no harmful substances are generated, constant therapeutic effects can be maintained even for long-term storage.
  • the release-controlled formulation of the present invention releases drugs similar to those of commercially available sustained-release tablets not only in vitro but also in vivo. The 2020/175897 PCT/KR2020/002708 pattern can be secured, indicating excellent bioavailability.
  • 1 is a graph showing the dissolution patterns of Mirabegron from the release-controlling formulation of the present invention, a comparative example, and a commercial formulation.
  • Figure 2 shows the dissolution pattern of Mirabegron from the release control formulation of the present invention
  • FIG. 3 is a graph showing a comparison of the concentration of Mirabegron in blood of the release control formulation of the present invention and a commercial product.
  • the drug mirabegron when using polyethylene glycol, which is a representative water-soluble base, the drug mirabegron is decomposed and the therapeutic effect is reduced during long-term storage due to the harmful substance, whereas the release control including the known mirabegron
  • the release control including the known mirabegron This is based on the fact that the use of Isomalt, which has not been mentioned in the formulation at all, prevents the decomposition of the drug Mirabegron, so that the therapeutic effect can be maintained during long-term storage. In particular, it is tested without causing a reaction with the drug. Not only in the hall
  • release-controlled formulations for the prevention or treatment of overactive bladder, urinary urgency, urinary incontinence, and frequency of urine include Mirabegron or its pharmaceutically acceptable salts, isomalt and sustained-release agents.
  • Usable mirabegron of the present invention is a free base of mirabegron or a pharmaceutically acceptable acid addition salt thereof (hereinafter, in the specification, unless otherwise indicated, mirabegron or a pharmaceutically acceptable salt thereof To'Miravegron'
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, benzoic acid, methanesulfonic acid, hydroxyethanesulfonic acid, toluenesulfonic acid, ethanesulfonic acid, etc.
  • Organic carboxylic acids such as folic acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, and glutamic acid.
  • Isomalt a water-soluble agent used in the release control formulation of the present invention, is non-toxic
  • the representative water-soluble base polyethylene glycol is very hygroscopic, while isomalt is non-topically moisturized up to 85% relative humidity (Handbook of Pharmaceutical Excipients. Sixth edition. 2009), and its melting point is also 141 ⁇ 171°Cof pharmaceutical Excipients. Sixth edition. 2009)
  • sustained-release agent used in the release controlling agent of the present invention can be used as long as it is a pharmaceutically acceptable sustained-release agent, preferably polyethylene oxide, hydroxypropylmethylcellulose, hydroxypropylcellulose,
  • It may be one or two or more selected from the group consisting of sodium carboxymethylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, methylcellulose and ethylcellulose. More preferably, polyethylene oxide £0) can be used, molecular weight Is 100,000 7,000, 000.
  • the controlled release formulation of the present invention may contain 1 to 50% by weight of Mirabegron, 20 to 90% by weight of isomalt, and 5 to 50% by weight of a sustained release agent based on the total weight of the composition.
  • isomalt Preferably, 30 to 80% by weight of isomalt, 10 to 40% by weight of a sustained-release agent, more
  • the release control formulation of the present invention is the release rate of Mirabegron from the formulation by controlling the content of isomalt and the sustained-release agent. Can be adjusted.
  • the release controlling agent of the present invention may additionally contain additives such as excipients, binders, disintegrants, antioxidants, surfactants, lubricants, and coating bases.
  • the excipients include starch, lactose, anhydrous lactose, microcrystalline cellulose, silicified microcrystalline cellulose, hypromellose, anhydrous silicic acid, calcium phosphate, anhydrous calcium phosphate, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, calcium silicate, Dextrin, dextrose, dextrate, mannitol, maltose, sorbitol, sucrose, polyethylene glycol, sodium chloride, etc. can be mentioned, and these can be used in one or a combination of two or more.
  • binder examples include povidone, copovidone, methylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxypropylcellulose,
  • Hydroxyethyl cellulose, gelatin, guar gum, xan gum, etc. are mentioned, and these can be used in one type or in a combination of two or more.
  • the disintegrants include crospovidone, croscarmellose sodium, sodium glycolate starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, grain starch, etc., which are one or two or more combinations Can be used as
  • the antioxidants include dibutylhydroxytoluene, butylhydroxytoluene,
  • Butylhydroxyanisole, tertiary butyl hydroquinone, propyl molar acid, vitamin 0, etc. can be used, and these can be used in one type or a combination of two or more.
  • the surfactant is sodium lauryl sulfate, sodium stearate,
  • magnesium stearate, stearic acid, talc, silicon dioxide, sodium stearyl fumarate, sodium lauryl sulfate, poloxamer, etc. may be mentioned, and these may be used in one or a combination of two or more. .
  • Polyvinyl acetate phthalate, shellac, cellulose acetate phthalide, sugar, methacrylic acid amino ester copolymers, etc. can be mentioned, and these can be used in one or two or more combinations, and can be used together with an appropriate plasticizer and colorant.
  • the dissolution rate of Mirabegron from the release controlling agent of the present invention was less than 30% in 2 hours, 30-80% in 5 hours, and 12 hours.
  • the manufacturing method of the controlled release formulation of the present invention is
  • Step of preparing a blend by mixing the ingredients in the granules according to the composition of Tables 1 and 2 below; Compressing the blend; Sizing the pressurized material; Mixing the sizing material and the non-granular components ; Compressing the mixture into tablets to obtain uncoated tablets; And through the step of film-coating the uncoated tablets to prepare the release control formulations of Examples 1 to.
  • Comparative Example 1 Preparing a blend by mixing the ingredients in the granules according to the composition of Table 5 below; Compressing the blend; Sizing the crushed product; Mixing the sizing product and the extragranular components; Compressing the mixture with a tablet to obtain uncoated tablets; And through the step of film coating the uncoated tablets.
  • the release control formulation of Comparative Example 1 was prepared that did not contain malt. Comparative Example 1 was the same water solubility as the commercial product. 2020/175897 1» (:1 ⁇ 1 ⁇ 2020/002708) It was prepared using a base (polyethylene glycol) and a sustained release agent (polyethylene oxide).
  • Beta Miga ® Western-release tablets 5013 ⁇ 4 (hereinafter referred to as the control treaty).
  • the release control formulation of the present invention is a commercial product
  • Test Example 2 Hygroscopicity evaluation
  • Comparative Example 1 prepared using the base and the commercial product Betamiga ® Sustained-release tablet (50113 ⁇ 4) (hereinafter referred to as reference drug) was packaged in a bottle and administered to a stability test chamber under high temperature and humidity conditions (50 ⁇ (:, 75% relative humidity) ) To measure the hygroscopicity by observing the ratio of the increase in the tablet weight, and the results are shown in Table 7.
  • the commercially available product was found to be at 70% level, whereas the release control formulation of the present invention was found to be at 57-58% level. Through this, the release control formulation of the present invention may occur during distribution and sale of pharmaceuticals. It was confirmed that it is a more stable formulation than a commercial product in a high temperature and high humidity environment.
  • the production amount of related substances is comparative example, polyethylene glycol is used as a water-soluble base), whereas the commercially available product is more than 90%, whereas the release control formulation of the present invention is 70%, the amount of related substances is significantly low
  • the amount of related substances is significantly low
  • the packaging unit cost is high and packaging time is required
  • the packaging is a packaging type that is easy to manufacture. Controlled release formulations have better stability than commercial products in this packaging form.
  • Test Example 4 In vivo test
  • Beta Miga ® Sustained-release tablet (50113 ⁇ 4) (hereinafter referred to as a control treaty) and the release-controlled formulation prepared in Examples 2, 4 and 6 were divided into 4 groups of 12 beagle dogs, and after cross-administration on an empty stomach over 4 periods, blood Mirabe The concentration of Gron was measured to calculate the pharmacokinetic parameters, Show 11 (:, (: 11), and the results are shown in Table 9 and Fig. 3 below.
  • the release control agent according to the present invention is used for overactive bladder, urinary urgency, urinary incontinence, and

Abstract

La présente invention concerne une formulation à libération contrôlée, comprenant : du Mirabegron ou un sel pharmaceutiquement acceptable de ce dernier ; de l'isomalt ; et un agent à libération prolongée. L'invention concerne une formulation dans laquelle le Mirabegron, un médicament, ne se décompose pas, ce qui permet à son effet thérapeutique d'être maintenu constant pendant un stockage à long terme. De plus, le Mirabegron peut être libéré de manière stable et durable in vivo, ce qui permet la manifestation d'un effet médicinal suffisant même lorsque la formulation est administrée une fois par jour.
PCT/KR2020/002708 2019-02-26 2020-02-25 Formulation à libération contrôlée contenant du mirabegron ou un sel pharmaceutiquement acceptable de ce dernier WO2020175897A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2019-0022741 2019-02-26
KR1020190022741A KR102062791B1 (ko) 2019-02-26 2019-02-26 미라베그론 또는 그의 약제학적으로 허용되는 염을 함유한 방출조절 제제

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WO2020175897A1 true WO2020175897A1 (fr) 2020-09-03

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Publication number Priority date Publication date Assignee Title
KR102062791B1 (ko) * 2019-02-26 2020-01-06 신일제약 주식회사 미라베그론 또는 그의 약제학적으로 허용되는 염을 함유한 방출조절 제제
KR102546923B1 (ko) 2020-03-03 2023-06-26 동광제약 주식회사 미라베그론을 포함하는 제어 방출 제제
CN114617881A (zh) * 2022-02-19 2022-06-14 苏州海景医药科技有限公司 一种米拉贝隆组合物

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JP2014503470A (ja) * 2010-10-14 2014-02-13 アボット ゲーエムベーハー ウント カンパニー カーゲー クルクミノイド固体分散製剤
KR20150045500A (ko) * 2012-08-31 2015-04-28 아스텔라스세이야쿠 가부시키가이샤 경구 투여용 의약 조성물
KR101524164B1 (ko) * 2008-09-30 2015-06-01 아스텔라스세이야쿠 가부시키가이샤 방출 제어 의약 조성물
KR101731078B1 (ko) * 2016-01-07 2017-04-27 한림제약(주) 베포타스틴 또는 이의 염을 포함하는 이중층 정제
KR102062791B1 (ko) * 2019-02-26 2020-01-06 신일제약 주식회사 미라베그론 또는 그의 약제학적으로 허용되는 염을 함유한 방출조절 제제

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KR101524164B1 (ko) * 2008-09-30 2015-06-01 아스텔라스세이야쿠 가부시키가이샤 방출 제어 의약 조성물
JP2014503470A (ja) * 2010-10-14 2014-02-13 アボット ゲーエムベーハー ウント カンパニー カーゲー クルクミノイド固体分散製剤
KR20150045500A (ko) * 2012-08-31 2015-04-28 아스텔라스세이야쿠 가부시키가이샤 경구 투여용 의약 조성물
KR101731078B1 (ko) * 2016-01-07 2017-04-27 한림제약(주) 베포타스틴 또는 이의 염을 포함하는 이중층 정제
KR102062791B1 (ko) * 2019-02-26 2020-01-06 신일제약 주식회사 미라베그론 또는 그의 약제학적으로 허용되는 염을 함유한 방출조절 제제

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Title
KALLAI, N. ET AL.: "Evaluation of Drug Release From Coated Pellets Based on Isomalt, Sugar, and Microcrystalline Cellulose Inert Cores", AAPS PHARMSCITECH, vol. 11, no. 1, March 2010 (2010-03-01), pages 383 - 391, XP055024443, DOI: 10.1208/s12249-010-9396-x *

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