JP2005519905A - Dnaの製剤 - Google Patents
Dnaの製剤 Download PDFInfo
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- JP2005519905A JP2005519905A JP2003561574A JP2003561574A JP2005519905A JP 2005519905 A JP2005519905 A JP 2005519905A JP 2003561574 A JP2003561574 A JP 2003561574A JP 2003561574 A JP2003561574 A JP 2003561574A JP 2005519905 A JP2005519905 A JP 2005519905A
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- dna
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- pharmaceutical preparation
- dna pharmaceutical
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- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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Abstract
Description
A. 10mMメチオニンおよび2.9%エタノール
B. 3.7%エタノールおよび1mM EDTA
C. 100mM Tris、1mM EDTAならびに10mMメチオニンおよび2.9%エタノール
D. 100mM Tris、1mM EDTAおよび10mMメチオニン
E. 100mM Tris、1mM EDTAおよび2.9%エタノールである。
糖、DNA、金粒子を含む溶液を混合し、ガラスバイアル中に満たす。これらのバイアルに半分栓をして、凍結乾燥機に取り付ける。その後、庫内温度を-45℃に低下させ、バイアル内の生成物を凍結させる。すべてのバイアルを凍結させた後、冷却器を-60℃以下の温度に冷やす。その後、約100 mTの真空をかけながら庫内温度を約-30℃に上昇させることによって、一次乾燥を行う。一次乾燥の間に、形成された氷の結晶からの水が昇華する。一次乾燥が完了した後、庫内温度を室温より高く上昇させ、最大の真空にかける。二次乾燥は強固に結合したすべての水を除去し、長期安定性を達成するために粉末を乾燥させる。
噴霧乾燥は、連続的な給液の噴霧によって作られた分散液滴を蒸発させるために、熱い気流(通常は空気)による熱を利用する脱水方法である。その結果生じる粉末生成物は数秒以内に乾燥し、細かい粒子となる。治療用タンパク質粉末の生成に対する噴霧乾燥の実現可能性は、十分に実証されている((Broadhead, J., Rouan, S.K.E., Hau, I.,および Rhodes, C.T. 1994. J. Pharm. Pharmacol. 46: 458-467.; Mumenthaler, M., Hsu, C.C.,およびPearlman, R. 1994. Pharm. Res. 11: 12-20))。我々の製剤混合物へのこのような応用では、調剤されたDNA、金粒子および糖溶液は、50~150℃の範囲の一般的な注入温度で、通常0.1〜10 mL/minの間の流速で、噴霧乾燥機に供給されるであろう。その結果生じる粉末は乾燥され、コレクションチャンバーに回収される。
噴霧凍結乾燥は、DNA、金粒子および糖を含む溶液をドライアイスまたは液体窒素を入れたトレイ上に噴霧する方法である。これは液滴の瞬間的な凍結を引き起こす。その後、トレイを凍結乾燥機に取り付け、そこで粒子を上述の方法に従って凍結乾燥させる。
1.1プラスミドの調製および製剤
この検討に使用したプラスミドは図1に示される。
糖(1〜40%の間のスクロースまたはトレハロース)、DNAプラスミド、金粒子を含む溶液を混合し、ガラスバイアル中を満たす。これらのバイアルに半分栓をして、凍結乾燥機に取り付ける。その後、庫内温度を-45℃に低下させ、バイアル内の生成物を凍結させる。すべてのバイアルを凍結させた後、冷却器を-60℃以下の温度に冷やす。その後、約100 mTの真空をかけながら庫内温度を約-30℃に上昇させることによって、一次乾燥を行う。一次乾燥の間に、形成された氷の結晶からの水が昇華する。一次乾燥が完了した後、庫内温度を室温より高く上昇させ、最大の真空にかける。二次乾燥は強固に結合したすべての水を除去し、長期安定性を達成するために粉末を乾燥させる。
噴霧乾燥は、連続的な給液の噴霧によって作られた分散液滴を蒸発させるために、熱い気流(通常は空気)による熱を利用する脱水方法である。その結果生じる粉末生成物は数秒以内に乾燥し、細かい粒子となる。治療用タンパク質粉末の生成に対する噴霧乾燥の実現可能性は、十分に実証されている((Broadhead, J., Rouan, S.K.E., Hau, I.,および Rhodes, C.T. 1994. J. Pharm. Pharmacol. 46: 458-467.; Mumenthaler, M., Hsu, C.C.,およびPearlman, R. 1994. Pharm. Res. 11: 12-20))。我々の製剤混合物へのこのような応用では、調製されたDNA、金粒子および糖溶液は、50〜150℃の範囲の一般的な注入温度で、通常0.1〜10 mL/minの間の流速で、噴霧乾燥機に供給されるであろう。その結果生じる粉末は乾燥され、コレクションチャンバーに回収される。
噴霧凍結乾燥は、DNA、金粒子および糖を含む溶液をドライアイスまたは液体窒素を入れたトレイ上に噴霧する方法である。これは液滴の瞬間的な凍結を引き起こす。その後、トレイを凍結乾燥機に取り付け、そこで粒子を上述の方法に従って凍結乾燥させる。
製剤に用いられるスクロースの量または糖の種類のいずれかを変化させた、一連の異なるDNA製剤のプラスミドDNA安定性の比較を行った。既にDNAの安定性および放出に最適であることが見いだされている他のすべての賦形剤は、すべての製剤中に存在させた(すなわち、100mM TrisHCl pH8.0、1mM EDTA、10mMメチオニンおよび2.9%エタノール)。針を被覆および凍結乾燥後、37℃で1ヶ月まで保存し、それらのスーパーコイルプラスミドDNAを安定化させる能力について、製剤を比較した(促進DNA安定性試験)。その後、標準的な手法でプラスミドDNA(pVAC1.OVA)を溶出、回収し、インターカレート剤の非存在下でアガロースゲル電気泳動(100V、100mAで2時間)を行った(Sambrook, J.ら、上述)。その後、エチジウムブロマイドによる染色およびUV光の下で可視化した後、溶出したプラスミドDNAの完全性を観察した。UVP Bioimaging system上のLabworks 4.0画像解析ソフトウェアを用いた画像強度として、これらのサンプルからのスーパーコイル単量体および二量体のプラスミド型ならびにまた直鎖型および開環型の比率を測定した。
示差走査熱量測定(DSC)による凍結乾燥したプラスミドDNA製剤の解析
40%スクロース中にプラスミドDNA(pVAC1.OVA)(10mg/ml)を含む凍結乾燥DNA/スクロース製剤のサンプルを調製し、また、付加的に100mM TrisHCl pH8.0、1mM EDTA、10mMメチオニンおよび2.9%エタノールを含む凍結乾燥サンプルを調製した。サンプルを分割し、1時間または24時間のいずれかの凍結乾燥サイクルに供した。その後、固体の状態を決定するために、サンプルを示差走査熱量測定(DSC)による解析に供した。これは、20ml/minの流速で、パージガスとして窒素を用い、25℃〜300℃の温度範囲に渡って、TA Instruments DSC2920 machineで行われた。サンプルパンの種類はピンホールアルミニウムであり、サンプル重量は解析の当日にMettler M3 balanceで測定された。
上述のDSC解析のために調製した凍結乾燥プラスミドDNA/スクロース(±賦形剤)サンプルを、偏光顕微鏡によって解析した。対照サンプルは1時間および24時間サイクルで凍結乾燥した40%スクロースのみで調製され、また、スクロースならびに主要な固体賦形剤、すなわち、メチオニン、Tris HClおよびEDTAの結晶サンプルもまた解析された。これは、比較のため、および製剤中に存在するあらゆる結晶性物質の出現に留意するためであった。液浸油中に備え付け、被覆したサンプルを用いて、Zeiss STD16-444111偏光顕微鏡で解析を行った。
上述のような賦形剤を含むプラスミドDNA製剤中に存在するポリオール/糖の性質が、凍結乾燥によって非晶性ガラスを生成するこのような製剤の能力に影響を与えるかを決定するために、ポリオールを変化させた。存在するポリオールのみが異なる多数の同様な製剤を作成し、凍結乾燥し、偏光顕微鏡によって解析した。この場合にはOlympus BX51偏光顕微鏡を使用したこと以外、これは実施例3に記載されたものと同様の方法で行われた。
本研究の目的は金粒子を含む3つの糖を基材とするDNA製剤を凍結乾燥することである。製剤は以下に示すように形成された。
試験の間のDNA構造の変化を決定するために、安定性サンプルについて0.6%アガロースゲル電気泳動を行った。各凍結乾燥サンプルを蒸留水中で再構成させ、以下のサンプル、ローディングバッファーおよび蒸留水の組合せを用いて、アガロースゲルの各ウェルに添加した:2μlのサンプル+16μlの蒸留水+2μlのローディングバッファー。
1週間および3週間のサンプルを含有しているゲルの写真を図6および7に示す。図6は25℃で1週間保存したサンプルのDNAプロフィールを示す(左側がレーン1)。:レーン1 - 1キロベースラダー;レーン2-25℃で1週間保存した後の凍結乾燥サンプル(製剤1);レーン3 - 5℃で1週間保存後の凍結乾燥サンプル(製剤1) - 対照;レーン4 - 25℃で1週間保存した後の凍結乾燥サンプル(製剤2);レーン5 - 5℃で1週間保存した後の凍結乾燥サンプル(製剤2);レーン6 - 25℃で1週間保存した後の凍結乾燥サンプル(製剤3);レーン7 - 5℃で1週間保存した後の凍結乾燥サンプル(製剤3);レーン8 - 凍結乾燥前の5℃での液体製剤1;レーン9 - 凍結乾燥前の5℃での液体製剤2;レーン10 - 凍結乾燥前の5℃での液体製剤3;レーン11 - 調剤されていないプラスミド、GW700561X (batch A01B30);レーン12 - DNAプラスミドを含まない製剤1の希釈剤+金ビーズで構成される、凍結乾燥された製剤1の陰性対照。
本研究において我々は、糖/金を基材とするDNA製剤をDNA構造の有意な変化なしに凍結乾燥させることが可能であることを実証した。更に我々は、その結果生じる凍結乾燥ビーズが25℃で3週間安定であることを示した。
Claims (24)
- DNA薬剤を含む固形の貯蔵媒体で被覆された高密度核成分を有する、DNA医薬製剤。
- フリーラジカルの分解効果を阻害する安定化剤をさらに含む、請求項1記載のDNA医薬製剤。
- 安定化剤が金属イオンキレート剤およびフリーラジカルスカベンジャーの一方または両方である、請求項2記載のDNA医薬製剤。
- 金属イオンキレート剤が、イノシトール6リン酸、トリポリリン酸塩、コハク酸、リンゴ酸、エチレンジアミン四酢酸(EDTA)、トリス(ヒドロキシメチル)アミノメタン(TRIS)、デスフェラール、ジエチレントリアミン五酢酸(DTPA)およびエチレンジアミンジヒドロキシフェニル酢酸(EDDHA)から成る群より選択される、請求項3記載のDNA医薬製剤。
- 非還元フリーラジカルスカベンジャーが、エタノール、メチオニンまたはグルタチオンから成る群より選択される、請求項3記載のDNA医薬製剤。
- フリーラジカルの分解効果を阻害する安定化剤が(a)メチオニンもしくはEDTAと組み合わせたリン酸緩衝エタノール溶液、または(b)メチオニンもしくはエタノール(またはメチオニンおよびエタノールの併用)と組み合わせたTris緩衝EDTAである、請求項3記載のDNA医薬製剤。
- 固形の貯蔵媒体が非晶性ポリオールである、請求項1〜6のいずれか1項に記載のDNA医薬製剤。
- ポリオールが安定化ポリオールである、請求項7記載のDNA医薬製剤。
- 固形の生分解性貯蔵媒体が糖である、請求項1〜8のいずれか1項に記載のDNA医薬製剤。
- 糖が、ラクトース、グルコース、スクロース、ラフィノースまたはトレハロースから選択される、請求項9記載のDNA医薬製剤。
- 固形の貯蔵媒体がガラス形態である、請求項1〜10のいずれか1項に記載のDNA医薬製剤。
- 固形の貯蔵媒体が糖ガラス形態である、請求項11記載のDNA医薬製剤。
- DNAがスーパーコイルプラスミドDNAである、請求項1〜12のいずれか1項に記載のDNA医薬製剤。
- 37℃での4週間の保存後に50%以上のDNAがそのスーパーコイル型を維持するように、スーパーコイルプラスミドDNAが安定化されている、請求項13記載のDNA医薬製剤。
- 放出される際の単量体:二量体スーパーコイル型の比率が0.8:1.2の範囲内であるように、DNAが安定化されている、請求項13記載のDNA医薬製剤。
- 薬剤がワクチンである、請求項1〜15のいずれか1項に記載のDNA医薬製剤。
- 固形の貯蔵媒体がワクチンアジュバント、トランスフェクション促進剤、DNA分解酵素阻害剤または結晶阻害剤を更に含有する、請求項1〜16のいずれか1項に記載のDNA医薬製剤。
- アジュバントがCpG、合成イミダゾキノリン、ツセラゾール(tucerasol)、サイトカイン、MPL、QS21、QS7および水中油型エマルジョンから成る群より選択される、請求項17記載のDNA医薬製剤。
- 高密度核成分が0.5〜10μmの平均粒径のマイクロビーズである、請求項1記載のDNA医薬製剤。
- 高密度核成分が金またはタングステンマイクロビーズである、請求項19記載のDNA医薬製剤。
- DNA薬剤、貯蔵媒体、およびフリーラジカルの分解効果を阻害する安定化剤からなる溶液を溶媒中で調製する工程、続いて、該溶液で少なくとも1つの高密度核成分を被覆する工程、ならびに、溶媒を除去して薬剤およびフリーラジカルの分解効果を阻害する薬剤を含有する固形の貯蔵媒体を形成する工程を含む、請求項1記載のDNA医薬製剤の製造方法。
- 貯蔵媒体が糖である、請求項21記載のDNA医薬製剤の製造方法。
- 支持構材上での乾燥前の糖濃度が20〜40%w/vの範囲である、請求項22記載のDNA医薬製剤の製造方法。
- 溶媒が工程の前に脱金属されている、請求項23記載のDNA医薬製剤の製造方法。
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GBGB0201736.6A GB0201736D0 (en) | 2002-01-25 | 2002-01-25 | DNA dosage forms |
PCT/GB2003/000336 WO2003061629A2 (en) | 2002-01-25 | 2003-01-23 | Dna dosage forms |
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CA (1) | CA2473717A1 (ja) |
DE (1) | DE60312645T2 (ja) |
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JP2007063265A (ja) * | 2005-08-02 | 2007-03-15 | Santen Pharmaceut Co Ltd | 熱的に不安定な薬物の分解抑制方法 |
JP2011057717A (ja) * | 2005-08-02 | 2011-03-24 | Santen Pharmaceut Co Ltd | イソプロピルウノプロストンの分解抑制方法 |
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WO2004014322A2 (en) * | 2002-08-12 | 2004-02-19 | Dynavax Technologies Corporation | Immunomodulatory compositions, methods of making, and methods of use thereof |
AU2002951692A0 (en) * | 2002-09-23 | 2002-10-17 | Vital Biotech (Hong Kong) Limited | Improvements in or relating to vaccines |
GB0423681D0 (en) * | 2004-10-26 | 2004-11-24 | Sec Dep For Environment Food & | Vaccine and nucleic acids |
US8512679B2 (en) | 2011-03-04 | 2013-08-20 | Elwha Llc | Glassy compositions |
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DK28792D0 (da) * | 1992-03-04 | 1992-03-04 | Novo Nordisk As | Nyt enzym |
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2003
- 2003-01-23 DE DE60312645T patent/DE60312645T2/de not_active Expired - Fee Related
- 2003-01-23 WO PCT/GB2003/000336 patent/WO2003061629A2/en active IP Right Grant
- 2003-01-23 EP EP03700947A patent/EP1467711B1/en not_active Expired - Lifetime
- 2003-01-23 JP JP2003561574A patent/JP2005519905A/ja active Pending
- 2003-01-23 ES ES03700947T patent/ES2285087T3/es not_active Expired - Lifetime
- 2003-01-23 CA CA002473717A patent/CA2473717A1/en not_active Abandoned
- 2003-01-23 AT AT03700947T patent/ATE357219T1/de not_active IP Right Cessation
- 2003-01-23 US US10/502,290 patent/US20050085434A1/en not_active Abandoned
-
2007
- 2007-06-01 US US11/756,817 patent/US20080095854A1/en not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2001213807A (ja) * | 1989-06-26 | 2001-08-07 | Powderject Vaccines Inc | 動物の体細胞の粒子媒介形質転換 |
JPH08510639A (ja) * | 1993-04-19 | 1996-11-12 | メディソーブ・テクノロジーズ・インターナショナル・リミテッド・パートナーシップ | 細胞取込みと遺伝子発現の促進と標的化をもたらす接合体と核酸のカプセル化 |
WO1997040839A1 (en) * | 1996-04-26 | 1997-11-06 | Merck & Co., Inc. | Dna vaccine formulations |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2007063265A (ja) * | 2005-08-02 | 2007-03-15 | Santen Pharmaceut Co Ltd | 熱的に不安定な薬物の分解抑制方法 |
JP2011057717A (ja) * | 2005-08-02 | 2011-03-24 | Santen Pharmaceut Co Ltd | イソプロピルウノプロストンの分解抑制方法 |
JP2012140459A (ja) * | 2005-08-02 | 2012-07-26 | R Tec Ueno:Kk | イソプロピルウノプロストンの分解抑制方法 |
Also Published As
Publication number | Publication date |
---|---|
US20080095854A1 (en) | 2008-04-24 |
DE60312645T2 (de) | 2007-11-29 |
EP1467711A2 (en) | 2004-10-20 |
CA2473717A1 (en) | 2003-07-31 |
ES2285087T3 (es) | 2007-11-16 |
US20050085434A1 (en) | 2005-04-21 |
EP1467711B1 (en) | 2007-03-21 |
DE60312645D1 (de) | 2007-05-03 |
ATE357219T1 (de) | 2007-04-15 |
WO2003061629A2 (en) | 2003-07-31 |
WO2003061629A3 (en) | 2003-10-02 |
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