JP4987704B2 - 糖脂質を用いた、脂質系アジュバント製剤を安定化する組成物及び方法 - Google Patents
糖脂質を用いた、脂質系アジュバント製剤を安定化する組成物及び方法 Download PDFInfo
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- JP4987704B2 JP4987704B2 JP2007519615A JP2007519615A JP4987704B2 JP 4987704 B2 JP4987704 B2 JP 4987704B2 JP 2007519615 A JP2007519615 A JP 2007519615A JP 2007519615 A JP2007519615 A JP 2007519615A JP 4987704 B2 JP4987704 B2 JP 4987704B2
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Description
実施例1
濃度を増加させたTDBを含有するDDA小胞の調製
TDBを含有するDDA小胞を、薄脂質フィルム法を用いて作った。ジメチルジオクタデシルアンモニウムブロミド(DDA−B、重量平均分子量(Mw)=630.97)及びD−(+)−トレハロース6,6’−ジベヘネート(TDB、Mw=987.5(Avanti Polar Lipids,Alabaster,Al)をクロロホルムメタノール(9:1)に別々に、10mg/mlの濃度になるように溶解した。指定容積の各化合物をガラス製試験管の中で混合した。緩やかなN2気流を用いて溶媒を蒸発させ、脂質フィルムを一晩、低圧下で乾燥させ微量の溶媒を取り除いた。乾燥した脂質フィルムをTris緩衝液(10mM、pH=7.4)で、表1に指定した濃度に水和し、70℃の水槽に20分間入れ、サンプルを5分ごとに激しく振盪した。
TDBはDDA製剤の長期安定性を高める
濃度を増加したTDBを含むDDA−B小胞の製剤を4℃に保存し、1日後及び2ヶ月後にもう一度、各製剤の外観を評価した(表2及び図2)。評価は、TDBがDDA小胞を安定化することを明瞭に証明した。1日後、TDBを含まない水性緩衝液のDDA懸濁液は沈殿を形成したが、一方10モル%を超えるTDBを含有するDDA懸濁液には沈殿は形成されなかった。TDB濃度がせいぜい6%と低い懸濁液では、極少量の沈殿だけが形成され、これは軽く振盪することによって簡単に再懸濁された。
TDBをDDA小胞の脂質二重層内に組み込む
合成ジアルキルジメチルアンモニウムから形成された脂質二重層は、特徴的な相転移温度Tmにおいて、ゲルから液晶への主相転移を起こす。相転移は、小胞二重層中のジアルキル鎖の溶解を含み、鎖の構成が高い立体規則性を特徴とする状態から、不規則性がより高い状態へと変化する。鎖の溶解プロセスには、大きな転移エンタルピーを伴う。このエンタルピーの変化は、転移温度の最大値Tmを示す熱容量曲線のピークとして検出される。転移温度並びに熱容量曲線の形は、極性頭部基の性質、対イオン、ジアルキル鎖の長さによって決まる。一般にTm値は、鎖長が短くなるに従って、またアルキル鎖の非対称性が増加するほど上がる。サーモトロピック相の挙動に対する第2ジアルキル界面活性剤の影響は、2つの構成成分間の相互作用に関する有益な情報を提供できる。
TDB含有DDAリポソームの粒子サイズ
実施例4A
TDBの組み込みによってDDA−Bの安定性を高める
増加濃度のTDBを含有する、フィルム法で調製したDDA−Bの粒子安定性を、Malvern ZetaSizer 4(Malvern Instruments Ltd.UK)を用いた動的光散乱測定により測定した。0モル%、6モル%、11モル%及び20モル%のTDBを組み込んだDDA−B粒子製剤を、0日目にpH7.4の10mM Tris緩衝液中に分散した。調製後0日目、14日目、28日目、42日目、56日目及び105日目に測定を実施した(図5)。経時的に粒子サイズ安定性を比較すると、TDBの組み込みがDDA−B粒子を安定化し、それらが凝集を形成するのを防ぐことがわかる。逆に、DDA単独の製剤は、4℃で数日保存後に凝集し、42日後には凝集のために、それ以上のサイズ測定は不可能であった。これらのデータは、図2に示した、DDA及びDDA/TDB製剤の視覚的印象を裏付けるものである。
水熱法による2成分混合法、又はトレハロースである糖部分を加える代わりに、TDBを組み込むことでDDA−B粒子の安定性を効率的に高める
DDA−B粒子を安定化させるためのDDA−B粒子内へのTDBを組み込みの必要性を、Malvern ZetaSizer 4(Malvern Instruments Ltd.UK)を用いた動的光散乱測定により調べた。フィルム法で調製した11モル%のTDBを含有するDDA−B粒子の粒子サイズを、11モル%のTDBと混合したDDA−B粒子(Holten−Andersenにより前に記載されている水熱法)と比較した。両製剤をpH7.4の10mM Tris緩衝液中に分散した。調製後0日後、14日後及び28日後に測定を実施した(図6)。経時的に粒子サイズ安定性を比較すると、TDBの組み込みが、2成分を混合した場合に比べDDA−B粒子を安定化し、それらが凝集するのを防ぐことがわかる。
抗原をTDB含有DDA小胞に吸着する
最終の、すぐに使用できるワクチンの、遠心分離したAg85B−ESAT−6の上清及び再懸濁した沈殿物のSDS−PAGE分析を行い、カチオン性リポソームに吸着した抗原を視覚化した。アジュバントは、15モル%の糖脂質TDBを組み込んで安定化したDDAから構成されるカチオン性リポソームを含んでいた。最終ワクチンのAg85B−ESAT−6(Mw45KDa)は、40マイクログラム/ml、80マイクログラム/ml、160マイクログラム/ml及び200マイクログラム/mlであり、DDA及びTDBの濃度はそれぞれ10mM及び0.6mMであった。ワクチンを超遠心分離(100,000g)に30分間かけ、上清及び元の容積のTris緩衝液に再懸濁した沈殿物についてSDS−PAGE分析を実施した(図8)。Ag85B−ESAT−6を50マイクログラム/ml含有する参照サンプルをレーン1にロードし、分子量マーカーをレーン2にロードした。タンパク質のバンドはクマシー(coomassie)染色で視覚化した。上清をロードしたレーンには肉眼で見えるバンドは無かったが、再懸濁した沈殿物をロードしたレーンには分子量約45KDaに明瞭なバンドが観察され、全ての、又はほとんど全ての抗原がカチオン性リポソームに吸着していることを示した。
TDBと結びついたDDAは、Ag85B−ESAT−6に対する効率的な免疫反応を促進する
アジュバントはある種の免疫反応の誘導に選択性を有することは、一般的に認められている。INF−γ産生に基づくTh1サイトカイン放出の重要性が、TBに対する耐性に必須であることが示されている(Flynn et al.,1993;Cooper et al.,1993)。20モル%のTDBを含有するDDA−Bリポソームを、本発明の実施例1に記載の通りに調製し、Ag85B−ESAT−6のTris緩衝液と混合して最終ワクチンにした。最終ワクチンでの濃度は、DDAは250μg、TDBは100μg、及びAg85B−ESAT−6は2μgであった。比較のために、同一量のDDA及びDDBからなるが、既に述べたようにDMSO(Holten−Andersen et al,2004)で、即ちフィルム法によるリポソーム内へのTDBの組み込みをしないで調製した。マウスを3回免疫感作させ、3回目のワクチン接種後1週目に血液細胞の特異的免疫反応を調べた(図9)。フィルム法で調製したDDA/TDBを用いて免疫感作したものについては、既に述べた方法に比べはるかに高い反応が観察され、フィルム法で調製したDDA/TDB製剤がDDA/TDBの単純な混合物に比べ、アジュバント効果を高めることが証明された。
DDA/TDBの組み合わせへ第3成分を組み込むことにより免疫反応を強化
最近、Toll様受容体(TLR)のリガンドが、新規アジュバント製剤に加えるべき魅力的な標的と考えられている。他の免疫刺激性成分、即ちTLRリガンドをDDA/TDB製剤に組み入れる効果を調べるために、マウスを、250μgのDDA/50μgのTDBに2μgのAg85B−ESAT−6を加えたものと、選択した免疫調整剤を用いて免疫感作させた。これらに、前もって形成されたDDA−TDBリポソームに、TLR3のリガンドとして知られるPoly IC(ポリイノシン酸−ポリシチジル酸、Sigma Aldrich)100μgを加えたもの、並びに25μgのTLR2/TLR4を活性化するムラミールジペプチド(MDP)を含有させた。MDPは、水和前のDDA−TDB脂質フィルムに含有させた。
TDB以外の糖脂質の組み込みによって、DDA−B粒子の安定性を効率的に高める
DDA−B粒子が、TDB以外の糖脂質、11モル%のβ−D−ラクトシルセラミド(β−LacCer)、11モル%のβ−ガラクトシルセラミド(β−GalCer)及び44w/w%G(M1)ガングリオシドそれぞれの組み込みによって安定化できることを例示する。製剤はフィルム法で調製し、0日目にpH7.4の10mM Tris緩衝液に分散させた。粒子サイズは、Malvern Zeta−Sizer 4(Malvern Instruments Ltd.UK)を用いた動的光散乱測定により測定した。測定は調整後0日目、14日目及び28日目に実施した(図12)。経時的に粒子サイズ安定性を比較すると、糖脂質の組み込みがDDAを安定化することがわかる。
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Claims (23)
- リポソーム内に糖脂質を組み込むことによって、水性製剤中のカチオン性脂質のリポソームを安定化する方法、ここで
前記カチオン性脂質は両親媒性第四アンモニウム化合物である、および
前記糖脂質は、その疎水性部分が二重膜の疎水性領域内に埋め込まれ、その極性頭部基部分が膜の親水性表面に向かって配置される形で、脂質二重層内に安定的に組み込まれている。 - 請求項1に記載のリポソームを安定化する方法において、前記両親媒性第四アンモニウム化合物が、各々、1本又は2本の脂肪鎖を有することを特徴とする方法。
- 請求項2に記載のリポソームを安定化する方法において、前記各脂肪鎖が、12〜20個の炭素原子を含むことを特徴とする方法。
- 請求項3に記載のリポソームを安定化する方法において、前記両親媒性第四アンモニウム化合物が、ジメチルジオクタデシルアンモニウムブロミド(DDA−B)、ジメチルジオクタデシルアンモニウムクロリド(DDA−C)、ジメチルジオクタデシルアンモニウムスルフェート、ホスフェート、またはアセテート(DDA−X)、ジメチルジオクタデセニルアンモニウムブロミド(DODA−B)、ジメチルジオクタデセニルアンモニウムクロリド(DODA−C)、ジメチルジオクタデセニルアンモニウムスルフェート、ホスフェート、またはアセテート(DODA−X)、1,2−ジオレオイル−3−トリメチルアンモニウムプロパン(DOTAP)、ジオレオイル−3−ジメチルアンモニウムプロパン(DODAP)およびN−[1−(2,3−ジオレイルオキシ)プロピル]−N,N,N−トリメチルアンモニウム(DOTMA)からなる群から選択されることを特徴とする方法。
- 請求項1から4のいずれか1項に記載のリポソームを安定化する方法において、前記糖脂質が、各々、糖部分の1つ又は2つの単糖残基に結合した1本又は3本までの脂肪族炭化水素鎖から形成されるアシル化グリコシドであることを特徴とする方法。
- 請求項5に記載のリポソームを安定化する方法において、前記糖脂質が、各々、2本のアシル鎖を有する二糖を含むことを特徴とする方法。
- 請求項5又は6に記載のリポソームを安定化する方法において、前記アシル鎖が、15〜90個の炭素原子を含むことを特徴とする方法。
- 請求項7に記載のリポソームを安定化する方法において、糖脂質が、アルファ,アルファ’−トレハロース6,6’−ジベヘネート(TDB)又はアルファ,アルファ’−トレハロース6,6’−ジミコレート(TDM)であることを特徴とする方法。
- 請求項1から8のいずれか1項に記載のリポソームを安定化する方法において、糖脂質のモル百分率が、0.5〜95モル%であることを特徴とする方法。
- 請求項1から9のいずれか1項に記載のリポソームを安定化する方法において、糖脂質のモル百分率が、2.5〜20モル%であることを特徴とする方法。
- 請求項1から10のいずれか1項に記載のリポソームを安定化する方法において、糖脂質のモル百分率が5〜18モル%であることを特徴とする方法。
- 請求項1から11のいずれか1項に記載の方法により安定化されたリポソーム生成物。
- 請求項12に記載のリポソーム生成物において、抗原性化合物がリポソームにカプセル化されていることを特徴とするリポソーム生成物。
- 請求項12に記載のリポソーム生成物において、抗原がリポソームに吸着または共有結合していることを特徴とするリポソーム生成物。
- リポソームが、アルファ,アルファ’−トレハロース6,6’−ジベヘネート(TDB)又はアルファ,アルファ’−トレハロース6,6’−ジミコレート(TDM)により安定化されていることを特徴とする、請求項12から14のいずれか1項に記載のリポソーム生成物。
- 薬物送達に使用するための、請求項12から15のいずれか1項に記載のリポソーム生成物。
- アジュバントとして使用するための、請求項12から15のいずれか1項に記載のリポソーム生成物。
- 請求項12から15のいずれか1項に記載のリポソーム生成物を含むことを特徴とするワクチンアジュバント。
- 免疫賦活剤をさらに含む請求項18に記載のアジュバント。
- 免疫賦活剤が、モノホスホリル脂質A(MPL)、ポリイノシンポリシチジル酸(ポリIC)、ムラミールジペプチド(MDP)、ザイモサン、二本鎖RNA(dsRNA)、DC−Chol、CpGオリゴデオキシヌクレオチド、及びタモキシフェンからなる群から選択される、請求項19に記載のアジュバント。
- ムラミールジペプチド(MDP)及び/又はポリイノシンポリシチジル酸(ポリIC)をさらに含む請求項18から20のいずれか1項に記載のアジュバント。
- クラミジア、マラリア又は結核に対するワクチンで使用するための、請求項18から21のいずれか1項に記載のアジュバント。
- 請求項18から21のいずれか1項に記載のアジュバントを含むことを特徴とするクラミジア、マラリア又は結核に対するワクチン。
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CN114657147B (zh) * | 2022-01-27 | 2023-12-01 | 安徽智飞龙科马生物制药有限公司 | 一种生物材料的保护剂及其应用 |
CN115068602B (zh) * | 2022-08-22 | 2022-11-01 | 北京华诺泰生物医药科技有限公司 | 一种表面改性氧化铝的复合疫苗佐剂、制备方法及应用 |
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US5108934A (en) * | 1983-11-30 | 1992-04-28 | Kabushiki Kaisha Toshiba | Quantitative immunoassay utilizing liposomes |
JP2714972B2 (ja) * | 1988-02-02 | 1998-02-16 | 千葉製粉株式会社 | リン脂質集合体用修飾剤、リン脂質小胞体用凝集防止剤、リン脂質小胞体用融合防止剤およびリン脂質膜用表面固定化剤 |
JPH03249561A (ja) * | 1990-02-28 | 1991-11-07 | Toshiba Corp | 免疫分析試薬 |
JPH0482824A (ja) * | 1990-07-23 | 1992-03-16 | Nippon Oil & Fats Co Ltd | リポソーム及び水中油型エマルション |
JPH0616688A (ja) * | 1992-06-30 | 1994-01-25 | Nippon Oil & Fats Co Ltd | 脂肪酸糖エステル |
JP3329554B2 (ja) * | 1993-03-10 | 2002-09-30 | 千葉製粉株式会社 | 乾燥小胞体 |
JP3884488B2 (ja) * | 1993-03-10 | 2007-02-21 | 千葉製粉株式会社 | オリゴ糖脂質 |
US5885613A (en) * | 1994-09-30 | 1999-03-23 | The University Of British Columbia | Bilayer stabilizing components and their use in forming programmable fusogenic liposomes |
JPH0925287A (ja) * | 1995-07-13 | 1997-01-28 | Eisai Co Ltd | 合成脂質 |
JPH09110722A (ja) * | 1995-10-20 | 1997-04-28 | Toray Ind Inc | 抗腫瘍活性物質の腫瘍細胞内導入用イムノリポソーム及びその調製法 |
US6183774B1 (en) * | 1996-01-31 | 2001-02-06 | Collaborative Laboratories, Inc. | Stabilizing vitamin A derivatives by encapsulation in lipid vesicles formed with alkylammonium fatty acid salts |
US6210707B1 (en) * | 1996-11-12 | 2001-04-03 | The Regents Of The University Of California | Methods of forming protein-linked lipidic microparticles, and compositions thereof |
GB9808268D0 (en) * | 1998-04-17 | 1998-06-17 | Imp College Innovations Ltd | Compound |
GB0007150D0 (en) * | 2000-03-24 | 2000-05-17 | Lamellar Therapeutics Limited | Immunotherapeutic methods and compositions |
WO2003000227A2 (en) * | 2001-06-25 | 2003-01-03 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | A method for preparation of vesicles loaded with biological material and different uses thereof |
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AU2005259685B2 (en) | 2010-04-08 |
BRPI0512757B8 (pt) | 2021-05-25 |
ATE406874T1 (de) | 2008-09-15 |
BRPI0512757A (pt) | 2008-04-08 |
ZA200701043B (en) | 2007-12-27 |
EP1765289A2 (en) | 2007-03-28 |
EP1765289B1 (en) | 2008-09-03 |
PL1765289T3 (pl) | 2009-02-27 |
SI1765289T1 (sl) | 2009-02-28 |
JP2008505131A (ja) | 2008-02-21 |
CA2572985A1 (en) | 2006-01-12 |
WO2006002642A3 (en) | 2006-05-18 |
DE602005009535D1 (de) | 2008-10-16 |
CA2572985C (en) | 2014-04-22 |
WO2006002642A2 (en) | 2006-01-12 |
DK1765289T3 (da) | 2008-12-15 |
CN1980638B (zh) | 2011-10-12 |
KR20070051847A (ko) | 2007-05-18 |
PT1765289E (pt) | 2008-12-05 |
AU2005259685A1 (en) | 2006-01-12 |
BRPI0512757B1 (pt) | 2021-04-06 |
KR101275837B1 (ko) | 2013-06-18 |
ES2315880T3 (es) | 2009-04-01 |
CN1980638A (zh) | 2007-06-13 |
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