JP2016520566A - レバミピド又はこの前駆体を含む眼球乾燥症候群の予防又は治療のための経口用薬剤学的組成物 - Google Patents
レバミピド又はこの前駆体を含む眼球乾燥症候群の予防又は治療のための経口用薬剤学的組成物 Download PDFInfo
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- JP2016520566A JP2016520566A JP2016508869A JP2016508869A JP2016520566A JP 2016520566 A JP2016520566 A JP 2016520566A JP 2016508869 A JP2016508869 A JP 2016508869A JP 2016508869 A JP2016508869 A JP 2016508869A JP 2016520566 A JP2016520566 A JP 2016520566A
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- rebamipide
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- dry eye
- eye syndrome
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Abstract
Description
本発明は、レバミピド又はこの前駆体、又はこれらの薬剤学的に許容可能な塩を有効成分として含む眼球乾燥症候群の予防又は治療のための経口用薬剤学的組成物を提供する。
本発明の組成物に有効成分として使用可能なレバミピド前駆体の薬剤学的に許容可能な塩とは、酸を用いて形成する酸付加塩のことをいい、前記酸の例としては、塩酸、硫酸、硝酸、リン酸、臭素化水素酸、ヨウ素化水素酸、酒石酸、ギ酸、クエン酸、酢酸、トリクロロ酢酸、トリフルオロ酢酸、グルコン酸、安息香酸、乳酸、シュウ酸、フマル酸、マロン酸、マレイン酸、メタンスルホン酸、ベンゼンスルホン酸、p−トルエンスルホン酸又はナフタレンスルホン酸が挙げられる。中でも、好適な例としては、硫酸、マロン酸又はシュウ酸により形成される酸付加塩が挙げられる。
精製水100mLに分散剤としてのポリソルベート80(フルカ社製)3.0gを溶解させて薬物を懸濁化させるためのビークルを調製した。ここにレバミピド(一般式1)(ハンソケム社製)1、2、4及び6gをそれぞれ添加し、10分間攪拌して懸濁液(実施例1〜4)を製造した。眼球乾燥症候群が誘発された8週齢の雄性C57BL/6マウスに前記懸濁液(5mL/kg)を表1の容量にて一日につき二回投薬した。
精製水100mLに安定化剤としてのクエン酸(シグマアルドリッチ社製)0.1g及び懸濁化剤としてのヒプロメロース2910(Pharmacoat 615、信越社製)2gを溶解させて薬物を懸濁化させるためのビークルを調製した。ここにレバミピド前駆体I〜VI(一般式2〜7、サンジン製薬社製)1gをそれぞれ添加し、10分間攪拌して懸濁液を製造した(実施例5〜10)。前記懸濁液(5mL/kg)を眼球乾燥症候群が誘発された8週齢の雄性C57BL/6マウスに表1の容量にて一日につき二回投薬した。
実施例5〜10において、レバミピド前駆体I〜VIの代わりにこのマロン酸塩(サンジン製薬社製)を各前駆体ベースを基準として1g相当量使用した以外は、実施例5〜10の過程を繰り返し行って懸濁液(実施例11〜16)を製造した。前記懸濁液(5mL/kg)を眼球乾燥症候群が誘発された8週齢の雄性C57BL/6マウスに表1の容量にて一日につき二回投薬した。
実施例5〜10において、レバミピド前駆体I〜VIの代わりにこのシュウ酸塩(サンジン製薬社製)を各前駆体ベースを基準として1g相当量使用した以外は、実施例5〜10の過程を繰り返し行って懸濁液(実施例11〜16)を製造した。前記懸濁液(5mL/kg)を眼球乾燥症候群が誘発された8週齢の雄性C57BL/6マウスに表1の容量にて一日につき二回投薬した。
実施例5〜10において、レバミピド前駆体I〜VIの代わりにこの硫酸塩(サンジン製薬社製)を各前駆体ベースを基準として1g相当量使用した以外は、実施例5〜10のの過程を繰り返し行って懸濁液(実施例11〜16)を製造した。前記懸濁液(5mL/kg)を眼球乾燥症候群が誘発された8週齢の雄性C57BL/6マウスに表1の容量にて一日につき二回投薬した。
<1−1> 眼球乾燥症候群動物モデルの製造
8週齢の雄性C57BL/6マウス(チャールスリバー研究所、米国)を一週間検疫・順化させた後、各マウスの平均体重及び標準偏差を計算して各グループ当たりに8匹ずつ均等に分配した。
前記薬物を投与してから10日目に正常眼、対照群及び実験群の涙量を測定した。涙量は、フェノールレッド綿糸の先端をマウスの両眼の外眼角下眼瞼に当て、所定の時間だけ放置して涙が濡らされて下降する面積(mm2)をイメージインサイドプログラム (Image Inside、Ver 2.32)を用いて分析して評価した。前記測定結果を図1から図5に示す。
角膜の表面状態を分析するために、10日目に各グループのマウスを安楽死させた。次いで、角膜の表面をデジタルズーム実体顕微鏡(ニコン社製)を用いて観察した後、角膜不規則性スコア(4点法、0.5点:正常、1点:最小、1.5点:軽症、3点:中間及び4点:重症)に基づいて数値化させた。前記数値は、熟練された専門家2名の結果を平均して算出した。前記実験結果を図6から図10に示す。
角膜表面の上皮細胞の損傷度を評価するために、蛍光染料であるフルオレセインナトリウム塩(シグマアルドリッチ社製)1%を平衡塩類溶液に溶解させて製造した溶液5μLをマウスの結膜嚢に点眼し、絆創膏を用いて1時間以上目をつぶらせておいた。次いで、未透過の余分の蛍光染料を精製水で洗い落とした後、眼球を摘出して角膜に浸透された緑色の蛍光発光度を観察して写真撮影を行った。撮影した写真をImageJ 1.38x(http://rsb.info.nih.gov,NIH、ボルチモア、米国)プログラムを用いて分析して角膜の緑色強さを数値化させた。角膜上皮の損傷度を3点:正常、6点:最小、9点:軽症、12点:中間及び15点:重症に点数化させた。
Claims (12)
- レバミピド又はこの前駆体、又はこれらの薬剤学的に許容可能な塩を有効成分として含む眼球乾燥症候群の予防又は治療のための経口投与用薬剤学的組成物。
- 前記レバミピドの前駆体の塩が、塩酸、硫酸、硝酸、リン酸、臭素化水素酸、ヨウ素化水素酸、酒石酸、ギ酸、クエン酸、酢酸、トリクロロ酢酸、トリフルオロ酢酸、グルコン酸、安息香酸、乳酸、シュウ酸、フマル酸、マロン酸、マレイン酸、メタンスルホン酸、ベンゼンスルホン酸、p−トルエンスルホン酸及びナフタレンスルホン酸から選ばれる酸により形成されることを特徴とする、請求項1に記載の薬剤学的組成物。
- 前記レバミピドの前駆体の塩が、硫酸、マロン酸又はシュウ酸により形成されることを特徴とする、請求項1に記載の薬剤学的組成物。
- 前記レバミピド又はこの前駆体、又はこれらの薬剤学的に許容可能な塩が、組成物の総量を基準として1〜50重量%用いられることを特徴とする、請求項1から5のうちのいずれか一項に記載の薬剤学的組成物。
- 薬剤学的に許容可能な担体又は添加剤をさらに含むことを特徴とする、請求項1に記載の薬剤学的組成物。
- 前記薬剤学的に許容可能な添加剤が、賦形剤、崩解剤、結合剤、滑沢剤、湿潤剤、分散剤及び安定化剤よりなる群から選ばれるいずれか一種以上であることを特徴とする、請求項7に記載の薬剤学的組成物。
- 請求項1に記載の組成物により製造される薬剤学的剤形。
- 前記薬剤学的剤形が、粉末、顆粒、錠剤、懸濁剤、エマルジョン、シロップ、エアロゾール、若しくは、軟質又は硬質ゼラチンカプセルであることを特徴とする、請求項9に記載の薬剤学的剤形。
- レバミピド又はこの前駆体、又はこれらの薬剤学的に許容可能な塩をこれを必要とする対象に投与することを含む、対象における眼球乾燥症候群の予防又は治療方法。
- 眼球乾燥症候群の予防又は治療用薬剤の製造のためのレバミピド又はこの前駆体、又はこれらの薬剤学的に許容可能な塩の用途。
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JP2022505588A (ja) * | 2018-10-23 | 2022-01-14 | サムジン ファーマシューティカル カンパニー,リミテッド | シェーグレン症候群の予防または治療用組成物 |
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KR101840256B1 (ko) * | 2017-09-21 | 2018-03-21 | 대우제약 주식회사 | 레바미피드를 함유하는 새로운 안구건조증 치료용 점안 조성물 및 이의 가용화 및 안정화 방법 |
KR101923519B1 (ko) | 2018-06-26 | 2019-02-27 | 대우제약 주식회사 | 레바미피드를 함유하는 안구 건조증 치료용 수용성 다회용 점안제 조성물 및 이의 가용화 및 안정화 방법 |
KR20200019451A (ko) | 2018-08-14 | 2020-02-24 | 대우제약 주식회사 | 레바미피드를 함유하는 안구 건조증 치료용 수용성 다회용 점안제 조성물 및 이의 가용화 및 안정화 방법 |
CN114404379B (zh) * | 2022-01-29 | 2024-01-26 | 杭州沐源生物医药科技有限公司 | 一种瑞巴派特缓释片及其制备方法 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH09301866A (ja) * | 1995-10-12 | 1997-11-25 | Otsuka Pharmaceut Co Ltd | 眼疾患治療剤 |
WO2008074853A1 (en) * | 2006-12-21 | 2008-06-26 | Novartis Ag | Ophthalmic rebamipide solution |
JP2011524854A (ja) * | 2008-06-19 | 2011-09-08 | 大塚製薬株式会社 | レバミピドの医薬組成物 |
JP2015522585A (ja) * | 2012-06-26 | 2015-08-06 | サムジン ファーマシューティカル カンパニー,リミテッド | 新規なレバミピド前駆体及びその製造方法と用途 |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AR004214A1 (es) | 1995-10-12 | 1998-11-04 | Otsuka Pharma Co Ltd | Una preparación de gotas oftálmicas para la cura de enfermedades oftálmicas |
TWI363626B (en) | 2004-11-15 | 2012-05-11 | Otsuka Pharma Co Ltd | Aqueous ophthalmic suspension of crystalline rebamipide |
ATE513827T1 (de) * | 2005-02-22 | 2011-07-15 | Pfizer | Oxyindol-derivate als 5ht4-rezeptor-agonisten |
ES2389566T3 (es) * | 2005-05-17 | 2012-10-29 | Santen Pharmaceutical Co., Ltd. | Agente preventivo o terapéutico para tratar un transtorno de la córnea y la conjuntiva |
US20090131303A1 (en) * | 2007-11-16 | 2009-05-21 | Bor-Shyue Hong | Methods and compositions for treating dry eye |
EP2276508A4 (en) * | 2008-04-15 | 2011-12-28 | Sarcode Bioscience Inc | RELEASE OF LFA-1 ANTAGONISTS AGAINST THE GAS-DARM SYSTEM |
WO2009139817A2 (en) * | 2008-04-15 | 2009-11-19 | Sarcode Corporation | Crystalline pharmaceutical and methods of preparation and use thereof |
JP2009301866A (ja) | 2008-06-13 | 2009-12-24 | Panasonic Corp | プラズマディスプレイパネルの製造方法 |
KR101692578B1 (ko) * | 2013-04-18 | 2017-01-03 | 삼진제약주식회사 | 레바미피드 또는 이의 전구체를 포함하는 안구건조증의 예방 또는 치료를 위한 경구용 약제학적 조성물 |
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH09301866A (ja) * | 1995-10-12 | 1997-11-25 | Otsuka Pharmaceut Co Ltd | 眼疾患治療剤 |
WO2008074853A1 (en) * | 2006-12-21 | 2008-06-26 | Novartis Ag | Ophthalmic rebamipide solution |
JP2011524854A (ja) * | 2008-06-19 | 2011-09-08 | 大塚製薬株式会社 | レバミピドの医薬組成物 |
JP2015522585A (ja) * | 2012-06-26 | 2015-08-06 | サムジン ファーマシューティカル カンパニー,リミテッド | 新規なレバミピド前駆体及びその製造方法と用途 |
JP6032451B2 (ja) * | 2012-06-26 | 2016-11-30 | サムジン ファーマシューティカル カンパニー,リミテッド | 新規なレバミピド前駆体及びその製造方法と用途 |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2020531473A (ja) * | 2017-08-18 | 2020-11-05 | ザ スケペンス アイ リサーチ インスティテュート,インコーポレイテッド | ドライアイの処置のための組成物およびその使用の方法 |
JP2022505588A (ja) * | 2018-10-23 | 2022-01-14 | サムジン ファーマシューティカル カンパニー,リミテッド | シェーグレン症候群の予防または治療用組成物 |
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CA2909806C (en) | 2020-04-21 |
EP2987491B1 (en) | 2020-06-03 |
PH12015502406A1 (en) | 2016-02-22 |
US20160081922A1 (en) | 2016-03-24 |
AU2014254621A1 (en) | 2015-11-19 |
AR096045A1 (es) | 2015-12-02 |
RU2015146417A (ru) | 2017-05-24 |
JP6249194B2 (ja) | 2017-12-20 |
AU2014254621B2 (en) | 2017-06-08 |
EP2987491A1 (en) | 2016-02-24 |
EP2987491A4 (en) | 2016-12-28 |
KR20140125230A (ko) | 2014-10-28 |
ES2813649T3 (es) | 2021-03-24 |
RU2632107C2 (ru) | 2017-10-02 |
CN105142637B (zh) | 2021-08-17 |
MX2015014672A (es) | 2016-02-19 |
SA114350449B1 (ar) | 2016-05-08 |
WO2014171748A1 (ko) | 2014-10-23 |
US11712414B2 (en) | 2023-08-01 |
BR112015026332B1 (pt) | 2022-05-03 |
TWI535441B (zh) | 2016-06-01 |
IL242143B (en) | 2021-03-25 |
BR112015026332A2 (pt) | 2017-07-25 |
CN105142637A (zh) | 2015-12-09 |
CA2909806A1 (en) | 2014-10-23 |
KR101692578B1 (ko) | 2017-01-03 |
TW201442710A (zh) | 2014-11-16 |
MY183526A (en) | 2021-02-24 |
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