JP2022534299A - リセドロン酸亜鉛マイクロ/ナノアジュバントの作製及びワクチンアジュバントとしてのその使用 - Google Patents
リセドロン酸亜鉛マイクロ/ナノアジュバントの作製及びワクチンアジュバントとしてのその使用 Download PDFInfo
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- JP2022534299A JP2022534299A JP2021570808A JP2021570808A JP2022534299A JP 2022534299 A JP2022534299 A JP 2022534299A JP 2021570808 A JP2021570808 A JP 2021570808A JP 2021570808 A JP2021570808 A JP 2021570808A JP 2022534299 A JP2022534299 A JP 2022534299A
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- Prior art keywords
- zinc
- adjuvant
- risedronate
- micro
- vaccine
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Abstract
Description
a)亜鉛イオンを含有する可溶性塩溶液を準備する工程と、
b)様々な方法で工程a)の可溶性塩溶液とリセドロン酸及び水酸化ナトリウムのアルカリ溶液又はリセドロン酸及びリン酸ナトリウムのアルカリ溶液とを混合することによって亜鉛イオンとホスホン酸基、リン酸塩ラジカル及び水酸化物ラジカルとを共沈させ、それによりリセドロン酸亜鉛アジュバントを得る工程と、
を含む。
以下、本発明の実施形態を実施例と併せて詳細に説明する。実施例において具体的な条件が示されていない場合には、従来の条件又は製造業者によって推奨される条件に従って行うものとする。製造業者の指定なしに使用される試薬又は機器は全て、商業的に購入することができる従来の製品である。
リセドロン酸ナトリウム(C7H10NNaO7P2):Hunan Huateng Pharmaceutical Co., Ltd.から購入
無水塩化亜鉛(ZnCl2):Xilong Chemicalから購入
リン酸水素二ナトリウム十二水和物(Na2HPO4・12H2O):Xilong Chemicalから購入
水酸化ナトリウム(NaOH):Xilong Chemicalから購入
1:0.25のZn/リセドロン酸のモル濃度比に従い、50mLの31.11mM塩化亜鉛溶液を調製し、溶液Aとし、50mLの溶液(7.78mMリセドロン酸+36mM水酸化ナトリウム+15.55mMリン酸水素二ナトリウム)を調製し、溶液Bとした。溶液A及び溶液Bを後の使用のために0.22μmのフィルター膜で濾過した。
図1Aに示すスキームに従い、溶液A及び溶液Bを使用してリセドロン酸亜鉛アジュバント懸濁液を形成した。すなわち、調製した溶液Bを1:1の体積比で全てが添加されるまで溶液Aに滴加し、懸濁液を形成した。
試薬の供給元は調製例1に見ることができる。
1:1のZn/リセドロン酸のモル濃度比に従い、50mLの31.11mM塩化亜鉛溶液を調製し、溶液Aとし、50mLの溶液(31.11mMリセドロン酸+60mM水酸化ナトリウム)を調製し、溶液Bとした。溶液A及び溶液Bを後の使用のために0.22μmのフィルター膜で濾過した。
詳細については調製例1を参照されたい。
試薬の供給元は調製例1に見ることができる。
1:0.125のZn/リセドロン酸のモル濃度比に従い、1Lの124.44mM塩化亜鉛溶液を調製し、溶液Aとし、1Lの溶液(15.56mMリセドロン酸+60mM水酸化ナトリウム+184mMリン酸水素二ナトリウム)を調製し、溶液Bとした。溶液A及び溶液Bを後の使用のために0.22μmのフィルター膜で濾過した。
詳細については調製例1を参照されたい。
溶液の調製:試薬の供給元は調製例1に見ることができる。
溶液A及び溶液Bを1:1の体積比で調製した。調製は図1Aのスキームに従って行い、調製した溶液Bを1:1の体積比で全てが添加されるまで溶液Aに滴加し、懸濁液を形成した。混合後に得られた懸濁液を121℃で60分間滅菌した。
溶液の調製:試薬の供給元は調製例1に見ることができる。
混合後に得られたリセドロン酸亜鉛懸濁液を121℃で60分間、1回滅菌し、減菌後のpH値、粒径及び粒子形態、金属イオン沈殿率等の物理的及び化学的特性、並びに他の物理的及び化学的特性を測定した。
リセドロン酸亜鉛アジュバントを脱イオン水で50倍希釈した後、日本電子株式会社のJEM-2100透過型電子顕微鏡(TEM)を用いて観察を行った。具体的な工程は以下の通りであった:アジュバントサンプルを、炭素膜でコーティングした銅メッシュ上に滴下し、10分間吸着させ、残液を濾紙で拭き取り、サンプルを透過型電子顕微鏡のサンプルチャンバーに送ってサンプルの形態を観察し、更なる分析のために撮影する。
試験対象のサンプルを取り、室温で少なくとも30分間平衡化し、SartoriusのpHガラス電極を用いて測定した。
BeckmanのLS 13320レーザー粒径分析装置の電源を入れ、15分間予熱した。
測定用の機器:Nanobrook Omni(Brookhaven)
BSA標準の標準曲線のプロット:希釈バッファーとして150mM NaClを使用し、BSA標準(2mg/mL)を階段希釈し、280nmでの吸光度をUV2100 proで検出した。OD280は、0.2~0.8(0.2~1.5に拡大)で高い精度を示した。
方法:フレーム原子吸光分析でアジュバントの上清中の亜鉛元素の含有量を測定することにより、その金属イオン沈殿率を算出した。
電源を入れる:コンピューター、AA-6300Cの電源スイッチ、エアコンプレッサーのスイッチ(圧力を0.35MPaに設定した)、及び換気システムのスイッチを入れた。
方法:UV分光光度法、機器:UV800(Beckman coulter)。
調製したZn-リセドロン酸アジュバントを、Zn/リセドロン酸のモル濃度比がそれぞれ1:1及び1:0.25のアジュバントとして使用した。これらをアジュバントとして別個に使用し、VZV gE抗原と1:1の体積比で混合してワクチンを形成した後、ワクチンを筋肉内注射によってマウスに投与し、産生された特異抗体価を決定した。具体的な方法は以下の通りであった:
実験動物:Balb/Cマウス、6週~8週、5匹のマウス/群、雌性。
実験群:(1)アルミニウムアジュバント群(Al-002);(2)Zn-リセドロン酸(1/0.25)群;(3)Zn-リセドロン酸(1/1)群。
1.抗原コーティング溶液:1×PB 7.4緩衝溶液(4.343gのNa2HPO4・7H2O;0.456gのNaH2PO4)。
2.洗浄溶液:PBST、INNOVAX Co.のELISAキット
3.ブロッキング溶液:2×ED(Enzyme Dilution):シーリング及びサンプル希釈のために超純水又は蒸留水で1倍に希釈した1×PBS+0.5%カゼイン+2%ゼラチン+0.1%防腐剤(proclin-300)。
4.発色溶液A:INNOVAX Co.のELISAキット。
5.発色溶液B:INNOVAX Co.のELISAキット。
6.停止溶液:INNOVAX Co.のELISAキット。
(1)プレートのコーティング:VZV gE抗原をPB7.4コーティング緩衝溶液で一定濃度に希釈した。これを96ウェルポリスチレンプレートに100μL/ウェルで添加し、プレートを4℃で一晩コーティングした。
(2)ブロッキング:ウェル内のコーティング溶液を捨て、プレートをPBST洗浄溶液で1回洗浄し、遠心乾燥し、ブロッキング溶液を200μL/ウェルで添加し、ブロッキングを室温で4時間行った。
(3)一定希釈度の血清の添加:ウェル内のブロッキング溶液を捨て、プレートをPBSTで1回洗浄し、遠心乾燥し、最初のウェルに試験対象の血清を150μL/ウェルで添加し、その後のウェルのそれぞれにED希釈剤を100μL/ウェルで添加し、3倍の勾配で希釈し、25℃で1時間インキュベートして反応させた。
(4)酵素標識抗体(GAM-HRP)の添加:ウェル内の血清希釈剤を捨て、プレートをPBSTで5回洗浄し、遠心乾燥し、酵素標識抗体(GAM-HRP、V:V=1:5000)を100μL/ウェルで添加し、25℃で1時間インキュベートして反応させた。
(5)発色:ウェル内の二次抗体を捨て、プレートをPBSTで5回洗浄し、遠心乾燥し、A及びBを同量で混合した100μL/ウェルの発色溶液を添加し、25℃で10分間反応させた。
(6)停止:2M硫酸停止溶液を50μL/ウェルで添加し、反応を停止させた。
(7)プレートの読取り:450nm及び630nmの二波長をマイクロプレートリーダーでの測定波長として設定し、各反応ウェルのOD値を測定した。
調製したZn-リセドロン酸アジュバントを、Zn/リセドロン酸のモル濃度比が1:0.25のアジュバントとして使用した。これをアジュバントとしてVZV gE抗原と組み合わせてマウスに筋肉内注射し、産生された特異抗体価を測定した。具体的な方法は以下の通りであった:
実験動物:Balb/Cマウス、6週~8週、5匹のマウス/群、雌性。
実験群:(1)アルミニウムアジュバント群(Al-002);(2)Zn-リセドロン酸(1/0.25)群。
1.抗原コーティング溶液:1×PB 7.4緩衝溶液(4.343gのNa2HPO4・7H2O;0.456gのNaH2PO4)。
2.洗浄溶液:PBST、Beijing Wantai社のELISAキット。
3.ブロッキング溶液:2×ED(Enzyme Dilution):シーリング及びサンプル希釈のために超純水又は蒸留水で1倍に希釈した1×PBS+0.5%カゼイン+2%ゼラチン+0.1%防腐剤(proclin-300)。
4.発色溶液A:Beijing Wantai社のELISAキット。
5.発色溶液B:Beijing Wantai社のELISAキット。
6.停止溶液:Beijing Wantai社のELISAキット。
(1)プレートのコーティング:VZV gE抗原をPB7.4コーティング緩衝溶液で一定濃度に希釈し、96ウェルポリスチレンプレートに100μL/ウェルで添加し、プレートを4℃で一晩コーティングした。
(2)ブロッキング:ウェル内のコーティング溶液を捨て、プレートをPBSTで1回洗浄し、遠心乾燥し、ブロッキング溶液を200μL/ウェルで添加し、ブロッキングを室温で4時間行った。
(3)試験対象の血清の添加:ウェル内のブロッキング溶液を捨て、プレートをPBSTで1回洗浄し、遠心乾燥し、一定希釈度の試験対象の血清を100μL/ウェルで添加し、25℃で1時間インキュベートして反応させた。
(4)酵素標識抗体の添加:ウェル内の血清希釈剤を捨て、プレートをPBSTで5回洗浄し、遠心乾燥し、各抗体アイソタイプ(IgG1、V:V=1:30000;IgG2a、V:V=1:1000;IgG2b、V:V=1:1000)を特異的に認識する酵素標識抗体を100μL/ウェルで添加し、25℃で1時間インキュベートして反応させた。
(5)発色:ウェル内の酵素標識抗体を捨て、プレートをPBSTで5回洗浄し、遠心乾燥し、発色溶液、すなわちA及びBを同量で混合し、3倍希釈した発色溶液を100μL/ウェルで添加し、25℃で10分間反応させた。
(6)停止:50μL/ウェルの2M硫酸停止溶液を添加して、反応を停止させた。
(7)プレートの読取り:450nm及び630nmの二波長をマイクロプレートリーダーでの測定波長として設定し、各反応ウェルのOD値を測定した。
実施例4に記載の実験手順を用いて、B型肝炎治療用タンパク質と組み合わせたリセドロン酸亜鉛アジュバントでマウスを筋肉内注射によって免疫し、血清抗体価を検出した。具体的な方法は以下の通りであった:
実験動物:Balb/Cマウス、6週~8週、5匹のマウス/群、雌性。
実験群:(1)生理食塩水;(2)アルミニウムアジュバント群(Al-001-840);(3)リセドロン酸ナトリウム群;(4)Zn-リセドロン酸(1/0.125)群;このうち、群(3)のリセドロン酸ナトリウムの含有量は、群(4)のリセドロン酸亜鉛と同じであった。詳細については調製例3を参照されたい。
実施例4に記載の実験手順を用いて、B型肝炎治療用タンパク質と組み合わせたリセドロン酸亜鉛アジュバントでマウスを筋肉内注射によって免疫し、血清抗体価を検出した。具体的な方法は以下の通りであった:
実験動物:Balb/Cマウス、6週~8週、5匹のマウス/群、雌性。
実験群分け1:(1)アルミニウムアジュバント群(Al-001-840);(2)2×Zn-リセドロン酸(1/0.125)群;(3)0.75×Zn-リセドロン酸(1/0.125)群;(4)0.35×Zn-リセドロン酸(1/0.125)群。
実験群分け2:(1)アルミニウムアジュバント群(Al-001-840);(2)2×Zn-リセドロン酸(1/0.125)群;(3)1×Zn-リセドロン酸(1/0.125)群。
Claims (8)
- 亜鉛とリセドロン酸とを1:1、4:1又は8:1から選択される亜鉛:リセドロン酸のモル濃度比で含み、任意に、リン酸塩を1.5:1及び4:1から選択される亜鉛:リン酸塩のモル濃度比で更に含み、任意に、アルミニウムを0.375:1、0.5:1及び0.8:1から選択される亜鉛:アルミニウムのモル濃度比で更に含む、リセドロン酸亜鉛マイクロ/ナノ粒子アジュバント。
- 前記リセドロン酸亜鉛マイクロ/ナノ粒子アジュバントが、
a)亜鉛イオンを含有する可溶性塩溶液、好ましくは前記溶液が塩酸の溶液を含む、亜鉛イオンを含有する可溶性塩溶液を準備する工程と、
b)連続沈殿、分離沈殿後の混合、又は共沈の様式で、工程a)の前記可溶性塩溶液とリセドロン酸及び水酸化ナトリウムとを均一に混合するか、又は工程a)の前記可溶性塩溶液とリセドロン酸及び水酸化ナトリウム、リン酸ナトリウム溶液とを均一に混合し、リセドロン酸亜鉛アジュバントを得る工程と、
を含み、好ましくは工程b)の混合物を滅菌に供して、後の使用のために2℃~8℃で保管することを更に含み、好ましくは該滅菌が高温及び高圧滅菌法を用いる滅菌、例えば121℃で30分~60分間、好ましくは60分間行われる滅菌を含む方法によって作製される、請求項1に記載のリセドロン酸亜鉛マイクロ/ナノ粒子アジュバント。 - (1)前記リセドロン酸亜鉛マイクロ/ナノ粒子アジュバントが8.0~9.0の滅菌前のpHを有すること、
(2)前記リセドロン酸亜鉛マイクロ/ナノ粒子アジュバントが6.0~8.0の滅菌後のpHを有すること、
(3)前記リセドロン酸亜鉛マイクロ/ナノ粒子アジュバントが1μm~10μmの粒径を有すること、
(4)前記リセドロン酸亜鉛マイクロ/ナノ粒子アジュバントが4.0~11.4の粒子ゼロ電荷点を有すること、
(5)前記リセドロン酸亜鉛マイクロ/ナノ粒子アジュバントが60%超のタンパク質吸着率を有し、好ましくは、タンパク質がウシ血清アルブミンを含むこと、
の1つ以上を特徴とする、請求項1又は2に記載のリセドロン酸亜鉛マイクロ/ナノ粒子アジュバント。 - リセドロン酸亜鉛マイクロ/ナノ粒子アジュバントを作製する方法であって、
a)亜鉛イオンを含有する可溶性塩溶液、好ましくは前記溶液が塩酸の溶液を含む、亜鉛イオンを含有する可溶性塩溶液を準備する工程と、
b)連続沈殿、分離沈殿後の混合、又は共沈の様式で、工程a)の前記可溶性塩溶液とリセドロン酸及び水酸化ナトリウムとを均一に混合するか、又は工程a)の前記可溶性塩溶液とリセドロン酸、水酸化ナトリウム及びリン酸ナトリウム溶液とを均一に混合し、リセドロン酸亜鉛アジュバントを得る工程と、
を含み、好ましくは工程b)の混合物を滅菌に供して、後の使用のために2℃~8℃で保管することを更に含み、好ましくは該滅菌が高温及び高圧滅菌法を用いる滅菌、例えば121℃で30分~60分間、好ましくは60分間行われる滅菌を含み、
得られるリセドロン酸亜鉛アジュバントが1:1、4:1及び8:1から選択される亜鉛:リセドロン酸のモル濃度比を有する、方法。 - (1)得られるリセドロン酸亜鉛アジュバントが8.0~9.0の滅菌前のpHを有すること、
(2)得られるリセドロン酸亜鉛アジュバントが6.0~8.0の滅菌後のpHを有すること、
(3)得られるリセドロン酸亜鉛アジュバントが1μm~10μmの粒径を有すること、
(4)得られるリセドロン酸亜鉛アジュバントが4.0~11.4の粒子ゼロ電荷点を有すること、
(5)得られるリセドロン酸亜鉛アジュバントが60%超のタンパク質吸着率を有し、好ましくは、タンパク質がウシ血清アルブミンを含むこと、
の1つ以上を特徴とする、請求項4に記載の方法。 - 請求項1~3のいずれか一項に記載のリセドロン酸亜鉛マイクロ/ナノ粒子アジュバントを含むワクチンアジュバント、医薬組成物又は免疫原性組成物。
- 抗原と請求項1~3のいずれか一項に記載のリセドロン酸亜鉛マイクロ/ナノ粒子アジュバントとを含むワクチン組成物であって、好ましくは該抗原が水痘帯状疱疹ウイルスgE糖タンパク質抗原等のタンパク質抗原を含む、ワクチン組成物。
- ワクチンアジュバント、医薬組成物、薬物送達ビヒクル、免疫原性組成物又はワクチン組成物の製造における請求項1~3のいずれか一項に記載のリセドロン酸亜鉛マイクロ/ナノ粒子アジュバントの使用であって、好ましくは該ワクチンが水痘帯状疱疹ウイルス組み換えタンパク質ワクチン等のタンパク質ワクチンを含む、使用。
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