JP2016518313A - リゾホスファチジルコリン又はその誘導体を含む脂質ナノ物質、及びその製造方法 - Google Patents
リゾホスファチジルコリン又はその誘導体を含む脂質ナノ物質、及びその製造方法 Download PDFInfo
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- lysophosphatidylcholine
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Abstract
Description
[化学式1]
[化学式2]
(a)リゾホスファチジルコリン又はそのエーテル誘導体を水相溶媒、トリグリセリド、オイル及びレシチンと混合して脂質混合物溶液を得る工程;(b)工程(a)の脂質混合物溶液を均質化する工程;(c)工程(b)で均質化した脂質混合物溶液のpHを3〜7に調節する工程;そして、(d)工程(c)でpHが調節された脂質混合物溶液をエマルジョン化してナノサイズの脂質ナノ物質を形成する工程。
(i)本発明は、リゾホスファチジルコリン又はそのエーテル誘導体−含有脂質ナノ物質、その製造方法及びその用途に関するものである。
(ii)本発明の脂質ナノ物質は、溶解度、毒性、赤血球溶血及び凝集現象において、リゾホスファチジルコリン及び又はそのエーテル誘導体に比べて、著しく改善された特性を示す。
(iii)したがって、本発明は、リゾホスファチジルコリン又はそのエーテル誘導体を有効成分とする敗血症、細菌性感染疾患などの治療剤として有用に活用され得る。
リゾホスファチジルコリン(LPC 18:0、NOF)5.00g、エッグレシチン(Lipoid E−80)15.00g、大豆油5.00g、スクロース50.00g、EDTA2Na2H2O 27.5mg、及び中鎖トリグリセリド(Miglyol 812)5.00gに精製水を投入して総重量500gに作った。20〜25℃に保持しながら、ホモジナイザー(L5M−A,Silverson)で5,000rpmで3時間混合された溶液を均質化した。前記の過程を2回行って、均質化した溶液1,000gを0.1N水酸化ナトリウム溶液又は0.1N塩酸溶液を使ってpH5.5に調節した。pH調節後、30分間さらに均質化した後、もう一度pHを5.5に調節した。pH調節を行った溶液を10℃以下で冷蔵保管した。前記のような過程を8回繰り返してpH5.5に調節された溶液8,000gを製造した。
実施例1の脂質ナノ粒子サイズを粒子分析器(ELS−Z2,Otsuka)を用いて測定して、結果を表1及び図1に示した。
実施例1から製造された脂質ナノ粒子が含有された製剤内のリゾホスファチジルコリン化合物の濃度計算は、18:0LPC標準溶液を使ってELSD定量HPLC条件で分析したリゾホスファチジルコリン化合物の面積比を図1で示した標準曲線の面積比と対比して計算した。
実施例1から製造された脂質ナノ粒子を冷凍、冷蔵、室温及び加温しながら、保管する間に安定性を評価した。評価結果は、表2に示した。
5−1.実験の方法
実施例1から製造されたLPCを含む脂質ナノ粒子製剤(LPC−F;18:0 LPC濃度:10mg/mL)の局所刺激性を評価するために、除毛されたマウスの背中側の皮膚に20、10及び5mL/kg(18:0 LPC 200、100及び50mg/kg)の容量で単回皮下投与し、韓国食品医薬品安全庁告示第2009−116“医薬品などの毒性試験基準”[2009]に基づいて、14日間の死亡率、体重変化、臨床症状、及び投与部位周囲皮膚の肉眼及び組織病理学的の変化を同じ濃度のリゾホスファチジルコリン原料(LPC−API)10mg/mL生理食塩水懸濁液皮下投与群とそれぞれ比較検討した。本実験で、陰性対照物質として生理食塩水を使い、最高投与量200mg/kgは、げっ歯類最大許容投与容量である20mL/kg(Flecknell,1996;KFDA Guidelines,Notification 2009−116,2009;OECD Guidelines,#423,2001)を基準に設定して、中間及び低容量投与群では、それぞれ10及び5mL/kgに設定した。
<死亡率>
LPC−F投与と関連した死亡例は、14日間の観察期間の間に発生していない。
陰性媒体対照群及びあらゆる3容量のLPC−F投与群では、何らの異常症状が観察されていない。しかし、LPC−API 200、100及び50mg/kg投与群では、軽微[1+]であるか、中等度[2+]の投与部位周囲皮膚潰瘍所見が投与終了48時間後から表われ始めて、LPC−API 200、100及び50mg/kg投与群で多様な[1−3+]程度の投与部位周囲皮膚潰瘍所見が、投与後、3日からそれぞれ5例(5/5;100%)、3例(3/5;60%)、及び3例(3/5;60%)確認された(表4及び図3)。
陰性媒体対照群及びあらゆる3容量のLPC−F投与群では、投与部位周囲で意味のある肉眼剖検の所見が確認されていない一方、LPC−API 200、100及び50mg/kg投与群では、多様な[1−3+]程度の投与部位周囲皮膚潰瘍所見がそれぞれ5例(5/5;100%)、3例(3/5;60%)、及び3例(3/5;60%)確認された(表5及び図4)。
陰性媒体対照群及びあらゆる3容量のLPC−F投与群では、投与部位周囲皮膚で意味のある組織病理学的の変化が確認されていない。しかし、LPC−API 200、100及び50mg/kg投与群では、多様な[1−3+]程度の局所皮膚脱落、上皮増生、真皮結合組織のcoarse化、炎症細胞浸潤及び皮膚体幹筋の溶解所見などの典型的な皮膚潰瘍所見がそれぞれ5例(5/5;100%)、3例(3/5;60%)、及び3例(3/5;60%)確認された(表6及び図5)。
実験物質の皮下投与後、観察される投与部位周囲の肉眼及び組織病理学的の変化は、皮下投与物質の局所刺激性に対して迅速かつ信頼性のある証拠を提供し、それを通じて多様な物質の局所刺激性が評価された(Gunzel VP,et al.,Arzneimittelforschung.26:1476−9(1976);Limberger and Lenz,Dtsch Stomatol.41:407−10(1991);Reuling et al.,Dtsch Zahnarztl Z.46:694−81991(1991))。本実験の結果、LPC−APIの単回皮下投与は、著しい投与部位周囲の皮膚潰瘍を誘発したが、LPC−F投与群では、陰性媒体対照群と比較して何らの投与部位周囲皮膚の異常所見も確認されていない。
6−1.実験の方法
実施例1から製造されたLPCを含む脂質ナノ粒子(LPC−F;18:0 LPC濃度:10mg/mL)の溶血及び赤血球凝集誘発程度を評価するために、200μLの生理食塩水、滅菌蒸留水、6濃度(原液、2、4、8、16及び32倍希釈)のLPC−F、又は製剤化されていないリゾホスファチジルコリン(LPC−API)10mg/mL生理食塩水懸濁液を1mLのヘパリン処理ラット(SD rat)全血に添加した後、37℃の温度で振盪培養器(shaking incubator)で100rpmで3時間インキュベーションした。製造されたLPC−Fは、生理食塩水で倍数希釈して6濃度を準備し、LPC−APIを生理食塩水に懸濁して10mg/mLの濃度で準備した後、やはり生理食塩水で倍数希釈して原液を含んで6濃度で準備した。実験は、5回繰り返し実施し、可能であれば、同一動物から採血された血液を同一実験に使った。振盪培養器で100rpmでインキュベーションした後、形成された赤血球凝集素を半定量(semiquantitative)的に評価し、12,500rpmで10分間遠心分離した後、上澄み液で570nmの吸光度を測定して溶血性をそれぞれ評価した。赤血球の溶血は、下記の数式1によって計算し、溶血指数が5%以上である場合を溶血反応が陽性であると判断した。
溶血指数(%)=(ODサンプル−OD陰性)/(OD陽性−OD陰性)×100
陰性=食塩水、陽性=蒸留水
半定量赤血球凝集点数(最大=3)
0=非凝集;1=少し凝集;2=中間程度凝集;3=激しい凝集。
<溶血指数の変化>
LPC−F 4、8、16及び32倍希釈液、LPC−API生理食塩水懸濁液16及び32倍希釈液処理群では、陽性対照群である滅菌蒸留水処理群に比べて、有意性のある(p<0.01)吸光度の減少をそれぞれ示した。したがって、LPC−F原液、2、4、8、16及び32倍希釈処理群の溶血指数(%)は、それぞれ144.28±18.82、110.66±11.23、53.70±6.57、11.60±6.92、8.65±2.38、及び−1.54±3.16%に算出され、LPC−API生理食塩水懸濁液原液、2、4、8、16及び32倍希釈処理群では、157.68±10.44、148.65±15.01、129.70±7.23、117.67±5.97、78.74±3.30、及び26.86±6.40%にそれぞれ算出された(図6)。
非処理及び食塩水陰性対照群に比べて、有意性のある(p<0.01又はp<0.05)赤血球凝集点数の増加が、LPC−API生理食塩水懸濁液原液、2及び32倍希釈液処理群から確認されたが、最低処理濃度である32倍希釈液を含んだあらゆる濃度のLPC−API生理食塩水懸濁液処理群で赤血球凝集点数の著しい増加が観察された。しかし、本発明のLPC−F処理群では、滅菌蒸留水陽性対照群に比べて、著しく低い赤血球凝集があらゆる処理群から認められ、非処理及び陰性対照群に比べて、有意性のある赤血球凝集点数の増加が確認されていない(図7)。
Claims (12)
- (a)トリグリセリド、オイル及びレシチンを含む脂質構造物;及び
(b)薬剤学的活性成分としてリゾホスファチジルコリン又はそのエーテル誘導体を含むことを特徴とする脂質ナノ物質。 - 前記リゾホスファチジルコリンが、下記化学式1で表され、前記エーテル誘導体が、下記化学式2で表される請求項1に記載の脂質ナノ物質。
[化学式1]
[化学式2]
- 前記トリグリセリドが、中鎖トリグリセリドである請求項1に記載の脂質ナノ物質。
- 前記トリグリセリド:オイル:レシチンの重量比が、1:0.5〜3:2〜10である請求項1に記載の脂質ナノ物質。
- 前記リゾホスファチジルコリン又はそのエーテル誘導体と脂質構造物の重量比が、1:1〜50である請求項1に記載の脂質ナノ構造。
- 前記脂質ナノ物質が、1〜1,000nmのサイズを有するナノ粒子である請求項1に記載の脂質ナノ物質。
- 前記脂質ナノ物質が、リゾホスファチジルコリン又はそのエーテル誘導体に比べて、(i)溶解度の向上、(ii)毒性の減少、(iii)赤血球溶血現象の減少、又は(iv)赤血球凝集現象の減少を示す請求項1に記載の脂質ナノ物質。
- 次の工程を含むことを特徴とするリゾホスファチジルコリン又はそのエーテル誘導体−含有脂質ナノ物質の製造方法:
(a)リゾホスファチジルコリン又はそのエーテル誘導体を水相溶媒、トリグリセリド、オイル及びレシチンと混合して脂質混合物溶液を得る工程;
(b)工程(a)の脂質混合物溶液を均質化する工程;
(c)工程(b)で均質化した脂質混合物溶液のpHを3〜7に調節する工程;そして、
(d)工程(c)でpHが調節された脂質混合物溶液をエマルジョン化してナノサイズの脂質ナノ物質を形成する工程。 - 前記工程(a)では、脂質混合物溶液をホモジナイザー(homogenizer)に投入して2,000〜10,000rpmで均質化する請求項8に記載の製造方法。
- 次の工程を含むことを特徴とするリゾホスファチジルコリン又はそのエーテル誘導体の毒性を減少させる方法:
(a)リゾホスファチジルコリン又はそのエーテル誘導体を水相溶媒、トリグリセリド、オイル及びレシチンと混合して脂質混合物溶液を得る工程;
(b)工程(a)の脂質混合物溶液を均質化する工程;
(c)工程(b)で均質化した脂質混合物溶液のpHを3〜7に調節する工程;そして、
(d)工程(c)でpHが調節された脂質混合物溶液をエマルジョン化してナノサイズの脂質ナノ物質を形成する工程。 - 次の工程を含むことを特徴とするリゾホスファチジルコリン又はそのエーテル誘導体の赤血球溶血現象又は赤血球凝集現象を減少させる方法:
(a)リゾホスファチジルコリン又はそのエーテル誘導体を水相溶媒、トリグリセリド、オイル及びレシチンと混合して脂質混合物溶液を得る工程;
(b)工程(a)の脂質混合物溶液を均質化する工程;
(c)工程(b)で均質化した脂質混合物溶液のpHを3〜7に調節する工程;そして、
(d)工程(c)でpHが調節された脂質混合物溶液をエマルジョン化してナノサイズの脂質ナノ物質を形成する工程。 - (a)請求項1から7のいずれかに記載の脂質ナノ物質の薬剤学的有効量;及び
(b)薬剤学的に許容可能な担体を含むことを特徴とする経口又は非経口投与用の薬剤学的製剤。
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US11016085B2 (en) * | 2016-04-25 | 2021-05-25 | The Johns Hopkins University | ZNT8 assays for drug development and pharmaceutical compositions |
BR112019018989A2 (pt) | 2017-03-13 | 2020-04-14 | Sdg Inc | nanopartículas à base de lipídeo com estabilidade melhorada |
US11077173B2 (en) | 2017-03-13 | 2021-08-03 | Sdg, Inc. | Lipid-based nanoparticles and methods using same |
WO2019014044A1 (en) | 2017-07-12 | 2019-01-17 | The Johns Hopkins University | ZNT8 AUTO-ANTIGEN BASED ON PROTEOLIPOSOMES FOR THE DIAGNOSIS OF TYPE 1 DIABETES |
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WO2020254675A1 (en) | 2019-06-20 | 2020-12-24 | Aker Biomarine Antarctic As | Parenteral lysophosphatidylcholine formulations such as lpc-dha, lpc-epa and their use in therapy |
NL2023407B1 (en) | 2019-06-28 | 2021-02-01 | Aker Biomarine Antarctic As | Parenteral lysophosphatidylcholine formulations |
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS57145810A (en) * | 1982-02-01 | 1982-09-09 | Toyama Chem Co Ltd | Immunological activator containing lysophospholipid and preparation thereof |
US5543169A (en) * | 1993-06-11 | 1996-08-06 | Nestec S.A. | Protein-containing foods having stability to heat-treatment |
JP2005530488A (ja) * | 2002-03-11 | 2005-10-13 | ベーイーオー・メリュー | invitroで単球を成熟樹状細胞に分化させるためのL−α−リゾホスファチジルコリンの使用 |
JP2008514720A (ja) * | 2004-09-28 | 2008-05-08 | エスディー ファーマシューティカルズ インコーポレイティッド | タキソイドおよび他の不溶性薬物を送達するための低油乳剤組成物 |
JP2012255004A (ja) * | 2005-03-31 | 2012-12-27 | Takeda California Inc | ヒドロキシステロイドデヒドロゲナーゼ阻害剤 |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2046092B (en) * | 1979-03-05 | 1983-11-02 | Toyama Chemical Co Ltd | Pharmaceutical composition containing a lysophospholid and a phospholipid |
FR2836828A1 (fr) * | 2002-03-11 | 2003-09-12 | Bio Merieux | Utilisation de l-alpha-lysophosphatidylcholine pour obtenir la differenciation de monocytes en cellules dendritiques matures in vitro |
EP1490072B1 (en) * | 2002-03-25 | 2015-01-28 | Arimed Inc. | Novel therapeutical use of lpc, agonist ligands specific to g2a receptor |
KR100842159B1 (ko) | 2002-03-25 | 2008-06-27 | 주식회사 바이오시너젠 | 라이소포스파티딜콜린 또는 그 유사체를 포함하는 급성호흡곤란 증후군 및 다발성 장기부전의 예방 및 치료용조성물 |
KR100842160B1 (ko) | 2002-10-21 | 2008-06-27 | 주식회사 바이오시너젠 | 라이소포스파티딜콜린 또는 그 유사체를 포함하는 패혈증예방 및 치료용 조성물 |
KR100849448B1 (ko) | 2002-08-22 | 2008-07-30 | 주식회사 바이오시너젠 | 라이소포스파티딜콜린 또는 그 유사체를 포함하는 선천성면역 증강 조성물 |
KR20080110681A (ko) * | 2006-04-20 | 2008-12-18 | 암겐 인코포레이티드 | 안정적 에멀젼 조제물 |
US20080145411A1 (en) * | 2006-10-06 | 2008-06-19 | Kaneka Corporation | Composition of high absorbability for oral administration comprising oxidized coenzyme q10 |
ES2459876T3 (es) * | 2007-11-28 | 2014-05-12 | Commonwealth Scientific And Industrial Research Organisation | Nanoemulsiones |
US20090281065A1 (en) * | 2008-05-09 | 2009-11-12 | Kemin Industries, Inc. | Use of Lysophospholipids to Treat Inflammation |
WO2011153513A2 (en) * | 2010-06-03 | 2011-12-08 | Latitude Pharma | Nanoemulsion composition containing vitamin k |
KR101315483B1 (ko) * | 2011-06-23 | 2013-10-07 | 주식회사 아리바이오 | 항생제 및 라이소포스파티딜콜린을 포함하는 면역 증강 또는 세균성 감염 질환 치료용 조성물 |
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS57145810A (en) * | 1982-02-01 | 1982-09-09 | Toyama Chem Co Ltd | Immunological activator containing lysophospholipid and preparation thereof |
US5543169A (en) * | 1993-06-11 | 1996-08-06 | Nestec S.A. | Protein-containing foods having stability to heat-treatment |
JP2005530488A (ja) * | 2002-03-11 | 2005-10-13 | ベーイーオー・メリュー | invitroで単球を成熟樹状細胞に分化させるためのL−α−リゾホスファチジルコリンの使用 |
JP2008514720A (ja) * | 2004-09-28 | 2008-05-08 | エスディー ファーマシューティカルズ インコーポレイティッド | タキソイドおよび他の不溶性薬物を送達するための低油乳剤組成物 |
JP2012255004A (ja) * | 2005-03-31 | 2012-12-27 | Takeda California Inc | ヒドロキシステロイドデヒドロゲナーゼ阻害剤 |
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