JP2006503063A - 核酸コーティング粒子 - Google Patents
核酸コーティング粒子 Download PDFInfo
- Publication number
- JP2006503063A JP2006503063A JP2004539249A JP2004539249A JP2006503063A JP 2006503063 A JP2006503063 A JP 2006503063A JP 2004539249 A JP2004539249 A JP 2004539249A JP 2004539249 A JP2004539249 A JP 2004539249A JP 2006503063 A JP2006503063 A JP 2006503063A
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- Prior art keywords
- particles
- nucleic acid
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- group
- sucrose
- Prior art date
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- 239000011248 coating agent Substances 0.000 title description 5
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- 230000001404 mediated effect Effects 0.000 claims abstract description 35
- 229910052751 metal Inorganic materials 0.000 claims abstract description 32
- 239000002184 metal Substances 0.000 claims abstract description 32
- 229910021645 metal ion Inorganic materials 0.000 claims abstract description 27
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- 239000000203 mixture Substances 0.000 claims description 115
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- 150000003839 salts Chemical class 0.000 claims description 55
- 229930006000 Sucrose Natural products 0.000 claims description 44
- 239000005720 sucrose Substances 0.000 claims description 44
- 235000000346 sugar Nutrition 0.000 claims description 43
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 42
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 41
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- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 39
- ATHGHQPFGPMSJY-UHFFFAOYSA-N spermidine Chemical compound NCCCCNCCCN ATHGHQPFGPMSJY-UHFFFAOYSA-N 0.000 claims description 39
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- 239000003963 antioxidant agent Substances 0.000 claims description 13
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- 150000002016 disaccharides Chemical class 0.000 claims description 11
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 10
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 10
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 10
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- KIDHWZJUCRJVML-UHFFFAOYSA-N putrescine Chemical compound NCCCCN KIDHWZJUCRJVML-UHFFFAOYSA-N 0.000 claims description 10
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- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 claims description 9
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- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 8
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- PZZHMLOHNYWKIK-UHFFFAOYSA-N eddha Chemical compound C=1C=CC=C(O)C=1C(C(=O)O)NCCNC(C(O)=O)C1=CC=CC=C1O PZZHMLOHNYWKIK-UHFFFAOYSA-N 0.000 claims description 8
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- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 6
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Abstract
Description
−粒子介在送達装置からの送達に好適な粒子の製造方法において、
(i)核酸凝縮剤および金属イオンキレート剤の存在下に不活性金属キャリア粒子上に核酸を沈殿させる段階;および
(ii)得られた粒子を回収する段階
を有することを特徴とする方法;
−核酸免疫感作方法において、
(a)粒子介在送達装置からの送達に好適な粒子であって、核酸凝縮剤および金属イオンキレート剤の存在下に不活性金属キャリア粒子上に抗原をコードする核酸を沈殿させることで得ることができる粒子を提供する段階;および
(b)有効量の前記粒子を被験者に投与する段階
を有することを特徴とする方法;
−遺伝子治療方法において、
(a)粒子介在送達装置からの送達に好適な粒子であって、核酸凝縮剤および金属イオンキレート剤の存在下に不活性金属キャリア粒子上に治療用ポリペプチドをコードする核酸を沈殿させることで得ることができる粒子を提供する段階;および
(b)有効量の前記粒子を被験者に投与する段階
を有することを特徴とする方法;
−粒子介在送達装置からの送達に好適な粒子において、表面に核酸、金属イオンキレート剤ならびに
(i)核酸凝縮剤;
(ii)1以上の二糖類および/または三糖類;および
(iii)1以上の塩
のうちの1以上を有する不活性金属キャリア粒子を含むことを特徴とする粒子も提供する。
本発明を説明するにおいて、下記の用語を用いるが、それらは下記に示した定義を有するものである。
本発明は、核酸の粒子介在の送達に関するものである。詳細には本発明は、粒子介在送達装置からの送達に好適な粒子であって、核酸凝縮剤および金属イオンキレート剤の存在下に不活性金属キャリア粒子上に核酸を堆積させる段階を有するか、一部の実施形態では本質的にその段階からなる方法によって得ることができる粒子を提供する。
(i)核酸凝縮剤;
(ii)1以上の二糖類および/または三糖類糖;および
(iii)1以上の塩
のうちの1以上を有する不活性金属キャリア粒子を有するか場合によって本質的にそれからなる粒子が提供される。
(i)核酸凝縮剤および金属イオンキレート剤の存在下に不活性金属キャリア粒子上に核酸を沈殿させる段階;および
(ii)得られた粒子を回収する段階
を有するか、一部の実施形態では本質的にそれらの段階からなるものである。
以下に、本発明の方法を実行するための具体的な実施形態の例を示す。これら実施例は、例示のみを目的として提供されるものであって、いかなる形でも本発明の範囲を限定するものではない。使用の数字(例:量、温度など)に関しては正確さを確保するよう努力したが、当然のことながらわずかな実験的誤差および逸脱は許容されるべきである。
一連の実験を行って、3種類のDNA/金粒子製剤:「DSEP」(実験A)、「ポリArg」(実験B)および「改良スペルミジン」(実験C)における各種糖、キレート剤および他の賦形剤/添加剤の効果を評価した。これら各種粒子は、下記の基準のうちの1以上によって評価した。
以下の処方に従って、粒子を製造した。
被験糖は、モノラウリル酸ショ糖、マニトールトレハロース、乳糖、ラフィノースおよびモノカプリン酸ショ糖から選択した。被験塩は、酢酸カリウム、塩化カルシウム、塩化リチウム、酢酸ナトリウム、硝酸マグネシウム、クエン酸ナトリウム、リン酸ナトリウム、リン酸アルミニウム、塩化ナトリウム、硫酸ナトリウムおよび塩化マグネシウムから選択した。
糖:ショ糖〜モノラウリル酸ショ糖〜トレハロース〜乳糖〜ラフィノース>>>モノカプリン酸ショ糖(収率なし)
塩:酢酸カリウム〜塩化カルシウム〜塩化リチウム〜酢酸ナトリウム〜硝酸マグネシウム>クエン酸ナトリウム〜リン酸ナトリウム>>>リン酸アルミニウム
その他:ショ糖飽和エタノールによる洗浄によって、金粉末からDNAは除去されない。
糖:ショ糖>トレハロース>マニトール〜乳糖〜ラフィノース>モノラウリル酸ショ糖>モノカプリル酸ショ糖
塩:酢酸カリウム〜酢酸ナトリウム〜クエン酸ナトリウム〜リン酸ナトリウム>塩化ナトリウム>硫酸ナトリウム>塩化リチウム
その他:ショ糖飽和エタノールによる洗浄は安定性に寄与する。リン酸アルミニウムは沈殿を防止する。
糖:モノカプリル酸ショ糖<ラフィノース〜乳糖〜モノラウリル酸ショ糖<ショ糖〜トレハロース
塩:酢酸カリウム〜塩化リチウム〜リン酸ナトリウム〜クエン酸ナトリウム〜塩化ナトリウム〜硫酸ナトリウム<塩化カルシウム〜塩化マグネシウム<硝酸マグネシウム。
ショ糖/酢酸ナトリウム〜酢酸カリウム/ラフィノース〜ショ糖/硝酸マグネシウム〜酢酸カリウム/モノラウリル酸ショ糖。
室温で保存したリアルタイム経過製剤について、
3ヶ月目でショ糖/酢酸ナトリウム〜スペルミジン/CaCl2核酸粒子、
1ヶ月目でラフィノース/酢酸カリウム〜モノラウリル酸ショ糖/酢酸カリウム〜スペルミジン/CaCl2核酸粒子。
以下の処方に従って粒子を製造した。
被験糖はトレハロース、ショ糖およびラフィノースから選択した。被験キレート剤は、EDTA、DTPAおよびデスフェラール(DFO)から選択した。被験ポリアルギニンペプチドは、13000Mwポリアルギニン、(Arg)6および(Arg)4から選択した。糖、キレート剤およびポリアルギニンの各種組合せを調べた。
被験糖:トレハロース、ショ糖、ラフィノース
キレート剤:EDTA、DTPA、デスフェラール(DFO)
その他:ポリ-Argペプチドで、13,000Mw、(Arg)6、(Arg)4のいずれか。
糖:ショ糖>トレハロース>ラフィノース
キレート剤:EDTA>DTPA>デスフェラール(DFO)
その他:全てのポリ-Argペプチドが同様の安定性を与えた。
この製剤では問題はない。
トレハロース/EDTA/(Arg)4〜トレハロース/DTPA/(Arg)4
DNA、金粒子およびスペルミジンを用いて製造した粒子は、これらの製剤と同様のレベルの発現活性を示した。.
(v)マウス免疫効力
ショ糖/EDTA/(Arg)4>トレハロース/EDTA/(Arg)4〜トレハロース/DTPA/(Arg)4〜ショ糖/DTPA/(Arg)4。
粒子を以下の処方に従って製造した。
被験糖は、ショ糖、トレハロースおよびラフィノースから選択した。被験塩は、塩化マグネシウム、硝酸マグネシウム、塩化カルシウム、硫酸ナトリウム、硫酸カリウムおよび臭化ナトリウムから選択した。
糖:ラフィノース>トレハロース>ショ糖
塩:MgCl2〜MgNO3〜CaCl2>硫酸ナトリウム〜硫酸カリウム〜臭化ナトリウム
その他:スペルミジン濃度およびアルコール/水%も収率に影響する。
糖:ラフィノース>トレハロース>ショ糖
塩:MgCl2>MgNO3>CaCl2>硫酸ナトリウム〜硫酸カリウム〜臭化ナトリウム。
この製剤では問題はない。
各種比率の硫酸プロタミン、EDTA、水およびトレハロース、ショ糖または乳糖のうちの一つを用いて、コーティング粒子を製造した。粒子は、表1における10種類の製剤で示したように、10種類の異なる比率によって製造した。これら各比率に従って製造した粒子の安定性を、4℃および60℃ならびに0、7および14日の時間点で調べた。
各比率について、表1に従って管AおよびBを製造した。管AおよびBの内容物を、10秒間または各溶液が十分に混和するまで高速で渦撹拌した。管Aを中等度の速度で渦撹拌しながら、5mLのピペットマン(pipetman)を用いて管Bの内容物を滴下した。管Aをさらに15秒間渦撹拌し、内容物を5分間静置した。管Aにおける上清を除去し、残ったペレットを100%イソプロパノール1mLで1回洗浄した。管の内容物を渦撹拌し、ペレット化した。イソプロパノールを除去し、ペレットを窒素気流で乾燥させて粉末とした。
これら粒子製剤は、試験を通じて同様の安定性を示した。「比率4」に従って製造した粒子(処方4、表1)を選んでさらなる作業を行った。
粒子を、実施例2と同様に、そして表1における比率4に従って製造した。ただし相対的に量を多くし(金粒子350mg)、
(a)二糖類なし(対照);または
(b)トレハロース;または
(c)ショ糖;または
(d)乳糖
のいずれかを用いた。
いくつかの処方を試して各種長さのポリアルギニンがDNAを金微粒子上に沈殿させる能力を有することを確認した後、実験を計画して、収率および安定性を調べることでどのポリアルギニン長さを用いるべきかを検討した。さらに、以前の処方で安定性を高めることが明らかになっている糖およびキレート剤の選択も検討した。
天秤
渦撹拌器
超音波処理器
遠心器
2mlエッペンドルフ管
1mlおよび200μlピペットマン
空気流。
11.3mg/mlテトラアルギニン(ロット番号523352):重量0.8〜1.0mgテトラアルギニン。秤量mg当たりH2O 88.5μlを加える。それは異なる内容物のロットについては変わる。
管B:管Bを準備してから、エタノールおよびDNAを管Aに加える。キレート剤溶液、糖溶液、EtOHおよびテトラアルギニン溶液を加える。10秒間高渦撹拌する。
・渦撹拌しながら管Aに管Bを滴下する。
DNA:プラスミドおよびルシフェラーゼコードDNAの原液を1mg/mlで提供した。9SC1 8:1ルシフェラーゼ容量比で2種類のDNA溶液を混合する。
マスターAを注射器濾過する。
マスターBを注射器濾過する。
渦撹拌しながら管Bを管Aに滴下する。
マスター混合物を注射器濾過する。
金70mg
マスター混合物525μl
渦撹拌しながらEtOH 735μlを滴下
30秒間超音波処理し、10秒間渦撹拌する。
1.管AおよびBアプローチ。管AおよびBは、AがDNAを有し、Bがテトラアルギニンを有する以外は同じ組成を有する。いずれも十分に混合してから、BをAに滴下する。
Claims (67)
- 粒子介在送達装置からの送達に好適な粒子において、核酸凝縮剤および金属イオンキレート剤の存在下に不活性金属キャリア粒子上に核酸を沈殿させることで得られることを特徴とする粒子。
- 前記不活性金属キャリア粒子が金、タングステン、白金およびイリジウム粒子からなる群から選択される請求項1に記載の粒子。
- 前記不活性金属キャリア粒子が直径約1〜3μmを有する金粒子である請求項2に記載の粒子。
- 前記核酸が抗原をコードする請求項1〜3のいずれかに記載の粒子。
- 前記抗原がウィルス抗原、細菌抗原および真菌抗原からなる群から選択される請求項4に記載の粒子。
- 前記核酸が治療用ポリペプチドをコードする請求項1〜3のいずれかに記載の粒子。
- 前記核酸がDNAである請求項1〜6のいずれかに記載の粒子。
- 前記核酸凝縮剤がカチオン性ポリマーである請求項1〜7のいずれかに記載の粒子。
- 前記核酸凝縮剤がポリアミンである請求項8に記載の粒子。
- 前記ポリアミンが、プロタミン類、スペルミジン、スペルミン、プトレシンおよびそれらの生理的に許容される塩からなる群から選択される請求項9に記載の粒子。
- 前記ポリアミンがポリアルギニンまたはポリリジンである請求項9に記載の粒子。
- 前記ポリアルギニンが(Arg)4または(Arg)6であり請求項11に記載の粒子。
- 前記金属イオンキレート剤が、エチレンジアミン四酢酸(EDTA)、ジエチレントリアミン五酢酸(DTPA)、ニトリロ三酢酸(NTA)、イノシトール六リン酸、トリポリリン酸塩、ポリリン酸、コハク酸ナトリウム、コハク酸カリウム、コハク酸リチウム、リンゴ酸ナトリウム、リンゴ酸カリウム、リンゴ酸リチウム、デスフェラールおよびエチレンジアミン-ジ(o-ヒドロキシ-フェニル酢酸)(EDDHA)からなる群から選択される請求項1〜12のいずれかに記載の粒子。
- 1以上の二糖類および/または三糖類の存在下に沈殿を行う請求項1〜13のいずれかに記載の粒子。
- 前記1以上の糖が、トレハロース、ショ糖、乳糖およびラフィノースからなる群から選択される請求項14に記載の粒子。
- 前記1以上の糖がショ糖およびラフィノースの混合物である請求項15に記載の粒子。
- 1以上の塩の存在下に沈殿を行う請求項1〜16のいずれかに記載の粒子。
- 前記1以上の塩が、酢酸カリウム、塩化カルシウム、塩化リチウム、酢酸ナトリウム、硝酸マグネシウム、クエン酸ナトリウム、リン酸ナトリウムおよび塩化マグネシウムからなる群から選択される請求項17に記載の粒子。
- 得られた粒子を酸化防止剤と接触させる請求項1〜18のいずれかに記載の粒子。
- 前記酸化防止剤が、エタノール、ビタミンA、ビタミンCおよびビタミンEからなる群から選択される請求項19に記載の粒子。
- ポリアルギニン、EDTAおよびショ糖の存在下に金キャリア粒子上にDNAを沈殿させることで得られた請求項1に記載の粒子。
- 粒子介在送達装置用の投与容器において、核酸凝縮剤および金属イオンキレート剤の存在下に不活性金属キャリア粒子上に核酸を沈殿させることで得ることができる粒子を含むことを特徴とする容器。
- 核酸凝縮剤および金属イオンキレート剤の存在下に不活性金属キャリア粒子上に核酸を沈殿させることで得ることができる粒子を装填した粒子介在送達装置。
- 無針注射器である請求項23に記載の粒子介在送達装置。
- 粒子介在送達装置からの送達に好適な粒子の製造方法において、
(i)核酸凝縮剤および金属イオンキレート剤の存在下に不活性金属キャリア粒子上に核酸を沈殿させる段階;ならびに
(ii)得られた粒子を回収する段階
を有することを特徴とする方法。 - 段階(i)で、前記不活性金属キャリア粒子および前記核酸を含む混合物に前記核酸凝縮剤を加える請求項25に記載の方法。
- 前記不活性金属キャリア粒子が金、タングステン、白金およびイリジウム粒子からなる群から選択される請求項25または26に記載の方法。
- 前記不活性金属キャリア粒子が直径約1〜3μmを有する金粒子である請求項27に記載の方法。
- 前記核酸が抗原をコードする請求項25〜28のいずれかに記載の方法。
- 前記抗原がウィルス抗原、細菌抗原および真菌抗原からなる群から選択される請求項29に記載の方法。
- 前記核酸が治療用ポリペプチドをコードする請求項25〜28のいずれかに記載の方法。
- 前記核酸がDNAである請求項25〜31のいずれかに記載の方法。
- 前記核酸凝縮剤がカチオン性ポリマーである請求項25〜32のいずれかに記載の方法。
- 前記核酸凝縮剤がポリアミンである請求項33に記載の方法。
- 前記ポリアミンが、プロタミン類、スペルミジン、スペルミン、プトレシンおよびそれらの生理的に許容される塩からなる群から選択される請求項34に記載の方法。
- 前記ポリアミンがポリアルギニンまたはポリリジンである請求項34に記載の方法。
- 前記ポリアルギニンが(Arg)4または(Arg)6であり請求項36に記載の方法。
- 前記金属イオンキレート剤が、エチレンジアミン四酢酸(EDTA)、ジエチレントリアミン五酢酸(DTPA)、ニトリロ三酢酸(NTA)、イノシトール六リン酸、トリポリリン酸塩、ポリリン酸、コハク酸ナトリウム、コハク酸カリウム、コハク酸リチウム、リンゴ酸ナトリウム、リンゴ酸カリウム、リンゴ酸リチウム、デスフェラールおよびエチレンジアミン-ジ(o-ヒドロキシ-フェニル酢酸)(EDDHA)からなる群から選択される請求項25〜37のいずれかに記載の方法。
- 段階(i)をさらに1以上の二糖類および/または三糖類の存在下で行う請求項25〜38のいずれかに記載の方法。
- 前記1以上の糖が、トレハロース、ショ糖、乳糖およびラフィノースからなる群から選択される請求項39に記載の方法。
- 前記1以上の糖がショ糖およびラフィノースの混合物である請求項40に記載の方法。
- 段階(i)をさらに1以上の塩の存在下に行う請求項25〜41のいずれかに記載の方法。
- 前記1以上の塩が、酢酸カリウム、塩化カルシウム、塩化リチウム、酢酸ナトリウム、硝酸マグネシウム、クエン酸ナトリウム、リン酸ナトリウムおよび塩化マグネシウムからなる群から選択される請求項42に記載の方法。
- 段階(i)から得られた粒子を酸化防止剤と接触させる請求項25〜43のいずれかに記載の方法。
- 前記酸化防止剤が、エタノール、ビタミンA、ビタミンCおよびビタミンEからなる群から選択される請求項44に記載の方法。
- (i)ポリアルギニン、EDTAおよびショ糖の存在下に不活性金粒子上にDNAを沈殿させる段階;および
(ii)得られた粒子を回収する段階
を有する請求項25に記載の方法。 - 核酸免疫感作方法において、
(a)粒子介在送達装置からの送達に好適な粒子であって、核酸凝縮剤および金属イオンキレート剤の存在下に不活性金属キャリア粒子上に抗原をコードする核酸を沈殿させることで得ることができる粒子を提供する段階;ならびに
(b)有効量の前記粒子を被験者に投与する段階
を有することを特徴とする方法。 - 遺伝子治療方法において、
(a)粒子介在送達装置からの送達に好適な粒子であって、核酸凝縮剤および金属イオンキレート剤の存在下に不活性金属キャリア粒子上に治療用ポリペプチドをコードする核酸を沈殿させることで得ることができる粒子を提供する段階;ならびに
(b)有効量の前記粒子を被験者に投与する段階
を有することを特徴とする方法。 - 前記不活性金属キャリア粒子が金、タングステン、白金およびイリジウム粒子からなる群から選択される請求項47または48に記載の方法。
- 前記不活性金属キャリア粒子が直径約1〜3μmを有する金粒子である請求項49に記載の方法。
- 前記核酸がDNAである請求項47〜50のいずれかに記載の方法。
- 前記核酸凝縮剤がカチオン性ポリマーである請求項47〜51のいずれかに記載の方法。
- 前記核酸凝縮剤がポリアミンである請求項52に記載の方法。
- 前記ポリアミンが、プロタミン類、スペルミジン、スペルミン、プトレシンおよびそれらの生理的に許容される塩からなる群から選択される請求項53に記載の方法。
- 前記ポリアミンがポリアルギニンまたはポリリジンである請求項53に記載の方法。
- 前記ポリアルギニンが(Arg)4または(Arg)6であり請求項55に記載の方法。
- 前記金属イオンキレート剤が、エチレンジアミン四酢酸(EDTA)、ジエチレントリアミン五酢酸(DTPA)、ニトリロ三酢酸(NTA)、イノシトール六リン酸、トリポリリン酸塩、ポリリン酸、コハク酸ナトリウム、コハク酸カリウム、コハク酸リチウム、リンゴ酸ナトリウム、リンゴ酸カリウム、リンゴ酸リチウム、デスフェラールおよびエチレンジアミン-ジ(o-ヒドロキシ-フェニル酢酸)(EDDHA)からなる群から選択される請求項47〜56のいずれかに記載の方法。
- 沈殿を1以上の二糖類および/または三糖類の存在下で行う請求項47〜57のいずれかに記載の方法。
- 前記1以上の糖が、トレハロース、ショ糖、乳糖およびラフィノースからなる群から選択される請求項58に記載の方法。
- 前記1以上の糖がショ糖およびラフィノースの混合物である請求項59に記載の方法。
- 沈殿を1以上の塩の存在下に行う請求項47〜60のいずれかに記載の方法。
- 前記1以上の塩が、酢酸カリウム、塩化カルシウム、塩化リチウム、酢酸ナトリウム、硝酸マグネシウム、クエン酸ナトリウム、リン酸ナトリウムおよび塩化マグネシウムからなる群から選択される請求項61に記載の方法。
- 得られた粒子を酸化防止剤と接触させる請求項47〜62のいずれかに記載の方法。
- 前記酸化防止剤が、エタノール、ビタミンA、ビタミンCおよびビタミンEからなる群から選択される請求項63に記載の方法。
- (a)粒子介在送達装置からの送達に好適な粒子であって、ポリアルギニン、EDTAおよびショ糖の存在下に金粒子上に抗原をコードするDNAを沈殿させることで得られた粒子を提供する段階;および
(b)有効量の前記粒子を被験者に投与する段階
を有する請求項47に記載の方法。 - (a)粒子介在送達装置からの送達に好適な粒子であって、ポリアルギニン、EDTAおよびショ糖の存在下に金粒子上に治療用ポリペプチドをコードするDNAを沈殿させることで得られた粒子を提供する段階;および
(b)有効量の前記粒子を被験者に投与する段階
を有する請求項48に記載の方法。 - 粒子介在送達装置からの送達に好適な粒子において、表面に核酸、金属イオンキレート剤ならびに
(i)核酸凝縮剤;
(ii)1以上の二糖類および/または三糖類;および
(iii)1以上の塩
のうちの1以上を有する不活性金属キャリア粒子を含むことを特徴とする粒子。
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US9689028B2 (en) | 2008-12-22 | 2017-06-27 | University Of Utah Foundation | Monochrome multiplex quantitative PCR |
US9944978B2 (en) | 2014-12-30 | 2018-04-17 | Telomere Diagnostics, Inc. | Multiplex quantitative PCR |
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JP4793956B2 (ja) * | 2005-12-29 | 2011-10-12 | ニチコン株式会社 | アルミニウム電解コンデンサの駆動用電解液、およびこれを用いたアルミニウム電解コンデンサ |
GB0918679D0 (en) | 2009-10-23 | 2009-12-09 | Iqur Ltd | Influenza vaccine |
GB0918782D0 (en) | 2009-10-26 | 2009-12-09 | St Georges Hosp Medical School | A protein as an adjuvant for a vaccine |
US20160122420A1 (en) | 2013-06-06 | 2016-05-05 | Rowlands David J | Antibody display |
CN103736090B (zh) * | 2014-01-27 | 2016-03-02 | 中国医学科学院医学生物学研究所 | 甲磺酸去铁胺佐剂及含甲磺酸去铁胺佐剂的疫苗 |
EP3164156A1 (en) * | 2014-07-04 | 2017-05-10 | BioNTech AG | Stabilised formulations of rna |
TWI788643B (zh) * | 2019-09-29 | 2023-01-01 | 美洛生物科技股份有限公司 | 新穎三甲基甘胺醯甘油組成物及其發展抗癌症藥物及rna疫苗上的用途 |
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US9169516B2 (en) | 2003-01-24 | 2015-10-27 | University Of Utah Research Foundation | Methods of predicting mortality risk by determining telomere length |
US10227649B2 (en) | 2003-01-24 | 2019-03-12 | University Of Utah Research Foundation | Methods of predicting mortality risk by determining telomere length |
US9689028B2 (en) | 2008-12-22 | 2017-06-27 | University Of Utah Foundation | Monochrome multiplex quantitative PCR |
US11168359B2 (en) | 2008-12-22 | 2021-11-09 | University Of Utah Research Foundation | Monochrome multiplex quantitative PCR |
US9944978B2 (en) | 2014-12-30 | 2018-04-17 | Telomere Diagnostics, Inc. | Multiplex quantitative PCR |
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KR20050070008A (ko) | 2005-07-05 |
ZA200503380B (en) | 2007-11-28 |
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PL375782A1 (en) | 2005-12-12 |
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JP4791730B2 (ja) | 2011-10-12 |
CN100542605C (zh) | 2009-09-23 |
CA2500215A1 (en) | 2004-04-08 |
MXPA05003222A (es) | 2005-07-26 |
KR101152561B1 (ko) | 2012-06-01 |
GB2410497B (en) | 2006-11-22 |
PL212483B1 (pl) | 2012-10-31 |
EA010881B1 (ru) | 2008-12-30 |
CN1694721A (zh) | 2005-11-09 |
HK1073797A1 (en) | 2005-10-21 |
EA200500546A1 (ru) | 2005-10-27 |
IL167635A (en) | 2011-07-31 |
AU2003269213B2 (en) | 2008-11-13 |
BR0314751A (pt) | 2005-07-26 |
US20060153804A1 (en) | 2006-07-13 |
WO2004028560A1 (en) | 2004-04-08 |
US8349364B2 (en) | 2013-01-08 |
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