JP5390059B2 - 無菌ポリヌクレオチド系薬剤の製造方法 - Google Patents
無菌ポリヌクレオチド系薬剤の製造方法 Download PDFInfo
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- JP5390059B2 JP5390059B2 JP2004565151A JP2004565151A JP5390059B2 JP 5390059 B2 JP5390059 B2 JP 5390059B2 JP 2004565151 A JP2004565151 A JP 2004565151A JP 2004565151 A JP2004565151 A JP 2004565151A JP 5390059 B2 JP5390059 B2 JP 5390059B2
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Images
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- C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C219/14—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to a carbon atom of a six-membered aromatic ring
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C211/62—Quaternary ammonium compounds
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C219/06—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having the hydroxy groups esterified by carboxylic acids having the esterifying carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms of an acyclic saturated carbon skeleton
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Description
本発明は、(1)配合物を滅菌する低温濾過プロセス、及び(2)溶液が曇り点を通してサイクル処理されることを必要としない製造方法を提供することにより、当業者のニーズに対処し、そしてこれを満たす。この方法の結果、前述の配合物と同様の粒子サイズ及び表面電荷(ゼータ電位)を有する複合体が生じる。
本明細書中で使用された「PBS」とは、--リン酸緩衝生理食塩水--を意味する。
(i) カチオン性界面活性剤;
(ii) ブロック・コポリマー;及び
(iii)ポリヌクレオチド
を、前記ブロック・コポリマーの曇り点未満の温度で混合することにより、混合物を形成することを含む。本発明の適切な成分は本明細書中に発表されている。
PBS(1, 10及び100μg/mL)中のネイクドVR4700プラスミドDNAに対する用量応答、及び熱サイクルプロセス及び濾過プロセスを使用してポロキサマーCRL-1005(7.5mg/ml)及び塩化ベンザルコニウム(0.3mM)と配合されたVR4700(5mg/ml)に対する用量応答を下記に示す。配合物を濃縮原液として解凍し、次いで所要濃度に希釈することによって、希釈されたポロキサマー配合物の粒度を維持した。ネイクドVR4700プラスミドDNA、又はCRL-1005及びBAKと配合されたVR4700を増量しながらワクチン接種されたマウスの平均CD4+及びCD8+T細胞応答を、下記表3に示す。
上記一般手順を用いて、in vivoポロキサマー(CRL-1005)用量応答試験を、塩化ベンザルコニウムなしで、DNA濃度を固定した状態で、熱サイクルプロセス及び濾過プロセスを採用して行った。CRL-1005を増量しながら、そしてVR4700プラスミドDNAを用量固定した状態で、これらをワクチン接種されたマウスの平均CD4+及びCD8+T細胞応答を、下記表5に示す。
Claims (8)
- 無菌配合物の製造方法であって、
(a)(i)塩化ベンザルコニウム(BAK)、(±)−N−(ベンジル)−N,N−ジメチル−2,3−ビス(ヘキシルオキシ)−1−プロパンアミニウムブロミド(Bn−DHxRIE)、(±)−N−(2−アセトキシエチル)−N,N−ジメチル−2,3−ビス(ヘキシルオキシ)−1−プロパンアミニウムブロミド(DHxRIE−OAc)、(±)−N−(2−ベンゾイルオキシエチル)−N,N−ジメチル−2,3−ビス(ヘキシルオキシ)−1−プロパンアミニウムブロミド(DHxRIE−OBz)、及び(±)−N−(3−アセトキシプロピル)−N,N−ジメチル−2,3−ビス(オクチルオキシ)−1−プロパンアミニウムクロリド(Pr−DOctRIE−OAc)からなる群から選択されるカチオン性界面活性剤;
(ii)ポロキサマーCRL−1005であるブロック・コポリマー;及び
(iii)DNA溶液、プラスミド、及びVR4700プラスミドDNAからなる群から選択されるポリヌクレオチド;
を、前記ブロック・コポリマーの曇り点未満の温度で混合することにより、混合物を形成し;そして、
(b)該混合物を低温濾過することにより、無菌配合物を生成し;
ただし、前記ブロック・コポリマーの曇り点を上回って該混合物の温度を上昇させることを含まず、該混合物の温度は前記ブロック・コポリマーの曇り点未満である
ことを含む、無菌配合物の製造方法。 - さらに、前記配合物を好適な容器内にアリコートすることを含む、請求項1に記載の方法。
- 前記混合が、−2℃〜8℃の温度で実施される、請求項1又は2に記載の方法。
- 前記低温濾過が、−2℃〜8℃の温度で実施される、請求項1〜3のいずれか1項に記載の方法。
- 前記低温濾過が、孔サイズ0.01マイクロ〜2マイクロのフィルターを使用して行われる、請求項1〜4のいずれか1項に記載の方法。
- 前記配合物中に存在する前記カチオン性界面活性剤の最終濃度が、0.01mM〜5mMである、請求項1〜5のいずれか1項に記載の方法。
- 前記配合物中に存在する前記ブロック・コポリマーの最終濃度が、1mg/mL〜50mg/mLである、請求項1〜6のいずれか1項に記載の方法。
- 前記配合物中に存在する前記ポリヌクレオチドの最終濃度が、1ng/mL〜10mg/mLである、請求項1〜7のいずれか1項に記載の方法。
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US20040162256A1 (en) | 2004-08-19 |
US8435557B2 (en) | 2013-05-07 |
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