JP2006515855A - 核酸/ブロックコポリマー/陽イオン性界面活性剤複合体を凍結乾燥する方法 - Google Patents
核酸/ブロックコポリマー/陽イオン性界面活性剤複合体を凍結乾燥する方法 Download PDFInfo
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- JP2006515855A JP2006515855A JP2004565150A JP2004565150A JP2006515855A JP 2006515855 A JP2006515855 A JP 2006515855A JP 2004565150 A JP2004565150 A JP 2004565150A JP 2004565150 A JP2004565150 A JP 2004565150A JP 2006515855 A JP2006515855 A JP 2006515855A
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- block copolymer
- mixture
- cationic surfactant
- crystalline
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- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical group [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 39
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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 29
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- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 claims description 4
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Abstract
Description
本発明は、一般に、ポリヌクレオチド、ブロックコポリマー及び陽イオン性界面活性剤を含んで成る製剤をフリーズドライさせることに関連する。抗凍結剤又は増量剤の存在下で、製剤をフリーズドライすることができ、それによって、当該乾燥した製剤を再生するに際し、微粒子がそれらの至適サイズを維持し、そして凝集又は融合が避けられる。
非イオン性コポリマーの、ポリヌクレオチドベースの医薬中での、アジュバントとしての使用は、従来技術において述べられてきた。ポリヌクレオチド、ブロックコポリマー及び陽イオン性界面活性剤を含んで成るポリヌクレオチド複合体は、in vivo免疫反応を増強することが証明されてきた。いくつかの場合において、使用直前に、水性系へと再生されて良い粉末形態においてこれらの複合体の懸濁を提供することが望ましい又は必須である。水性媒体を乾燥する1つの方法は、媒体を凍結させて水を真空下で昇華させることによって抽出する凍結乾燥による方法である。もし前記水性媒体が微粒子の懸濁を含んでいれば、これらの粒子は、結晶化領域が伝播することが理由により凍結乾燥過程の最初の凍結段階の間にクラスターになる傾向がある。往々にして、微粒子は不変的に凝集し、そして再生させる場合に再度分散することはなく、多分散性サイズ分布を伴う集団が生じる。
1つの観点において、本発明は、凍結乾燥組成物を調製するための方法を供し当該方法は、ブロックコポリマーとある集団のポリヌクレオチド分子、陽イオン性界面活性剤、及び非晶質抗凍結剤もしくは増量剤もしくはそれらの任意の組み合わせを、当該ブロックコポリマーの曇り点未満の温度で混合し、混合物を形成させることを含んで成る。この混合物を再生に際し、粒子サイズ及び集団多分散性が維持される。
定義
本明細書中、「PBS」とは--リン酸緩衝塩類溶液--を意味する。
HO(C2H4O)x(C3H6O)y(C2H4O)xH
(式中、yは疎水性POP部分(C3H6O)の分子量が最大で約20,000Daであるような数を表し、そしてxは親水性POE部分(C2H4O)の%が約1%〜50重量%であるような数を表す)。
HO(C2H4O)x(C3H6O)y(C2H4O)xH
(式中、yは疎水性物質(C3H6O)の分子量が約9,000Da〜15,000Daであるような数を表し、そしてxは親水性物質(C2H4O)の%が約3%〜35重量%であるような数を表す)。
HO(C2H4O)x(C3H6O)y(C2H4O)xH
(式中、yは疎水性物質(C3H6O)の分子量が約9,000〜15,000Daであるような数を表し、そしてxは親水性物質(C2H4O)の%が約3%〜10重量%であるような数を表す)。
HO(C2H4O)x(C3H6O)y(C2H4O)xH
(式中、yは疎水性物質(C3H6O)の分子量が約12,000Daであるような数を表し、そしてxは親水性物質(C2H4O)の%が約5%であるような数を表す)。CLS-1005の場合、xは約7、±1であり、そしてyはおよそ12,000Da、約207ユニット、±7である。
HO(C2H4O)x(C3H6O)y(C2H4O)xH
(式中、yは疎水性物質(C3H6O)の分子量が約9,000Daであるような数を表し、そしてxは親水性物質(C2H4O)の%が約3〜5重量%であるような数を表す)。
HO(C2H4O)x(C3H6O)y(C2H4O)xH
(式中、yは疎水性物質(C3H6O)の分子量が約9,000Daであるような数を表し、そしてxは親水性物質(C2H4O)の%が約3重量%であるような数を表す)。
HO(C3H6O)y(C2H4O)x(C3H6O)xH
(式中、yは疎水性POP部分(C3H6O)の分子量が最大約20,000Daであるような数を表し、そしてxは親水性POE部分(C2H4O)の%が約1重量%〜約50重量%であるような数を表す)。これら「リバース」ブロックコポリマーは構造POP-POE-POPを有し、そして米国特許第5,656,611号及び6,359,054号に記載されている。
HO(C3H6O)y(C2H4O)x(C3H6O)yH
(式中、yは疎水性物質(C3H6O)の分子量が約9,000Da〜15,000であるような数を表し、そしてxは親水性物質(C2H4O)の%が約3重量%〜35重量%であるような数を表す)。
HO(C3H6O)y(C2H4O)x(C3H6O)yH
(式中、yは疎水性物質(C3H6O)の分子量が約9,000Da〜15,000Daであるような数を表し、そしてxは親水性物質(C2H4O)の%が約3重量%〜10重量%であるような数を表す)。
HO(C3H6O)y(C2H4O)x(C3H6O)yH
(式中、yは疎水性物質(C3H6O)の分子量が約12,000Daであるような数を表し、そしてxは親水性物質(C2H4O)の%が約5重量%であるような数を表す)。
HO(C3H6O)y(C2H4O)x(C3H6O)yH
(式中、yは疎水性物質(C3H6O)の分子量が約9,000Daであるような数を表し、そしてxは親水性物質(C2H4O)の%が約3〜5重量%であるような数を表す)。
HO(C3H6O)y(C2H4O)x(C3H6O)yH
(式中、yは疎水性物質(C3H6O)の分子量が約9,000Daであるような数を表し、そしてxは親水性物質(C2H4O)の%が約3%であるような数を表す)。
実施例1
目的:DNA/ポロキサマー/BAK製剤(5mg/mlのDNA、7.5mg/mLのCRL-1005、0.3mMのBAK)を10%スクロース、10mMのリン酸ナトリウムビヒクル中で調製し、そして当該製剤を凍結乾燥させ、そしてこの方法の粒子サイズに対する効果を特定する。
例1にあるように、10%スクロース、10mMのリン酸ナトリウム溶液中で調製した場合、凍結乾燥させたある試料を、注射のために960μlの滅菌水中で再生し、そして手動により穏やかに撹拌し、そして15分に渡りベンチトップ上に置いた。次いで、この溶液の20μlアリコートを15、60、120、240、360分間隔で取り出し、2mlのろ過(0.2μm)した10%スクロース、10mMのリン酸ナトリウム中で希釈した。この粒子のZ平均中項粒子及び多分散性を、上記のように、Malvern 3000HS Zetasizerを使用して測定した(図1A及び1B)。
DNA、CRL-1005及び他のポロキサマー、そして陽イオン性脂質(例えば、8.5%スクロース中の塩化ベンザルコニウムが挙げられるがそれに限定されない)を本明細書中に記載の通りに調製できうる。次いで、この混合物を凍結乾燥させ、そして再生させた場合、これらの製剤を、免疫源性研究において使用して良い。上記製剤を注射した動物のT-細胞反応をIFN-γ ELISpotアッセイによって測定でき、そして抗原特異的抗体をELISAによって測定できうる。データから、有利な生理的又は医薬的特性を有する生物学的に活性を有する製剤及び/又は生物学的活性が増強された製剤を同定できる。
Claims (28)
- 凍結乾燥させた組成物を調製する方法であって:
(a)(i)ポリオキシエチレン(POE)及びポリオキシプロピレン(POP)のブロックコポリマー;
(ii)ポリヌクレオチド;
(iii)陽イオン性界面活性剤;及び
(iv)非晶質抗凍結剤又は結晶質増量剤、
を、当該ブロックコポリマーの曇り点より下の温度で混合して混合物を形成させ;そして、
(b)当該混合物を凍結乾燥させる、
ことを含んで成る方法。 - 前記ブロックコポリマーが一般式:
HO(C2H4O)x(C3H6O)y(C2H4O)xH
(式中、yは疎水性POP部分(C3H6O)の分子量が最大で約20,000Daであるような数を表し、そしてxは親水性POE部分(C2H4O)の%が約1重量%〜50重量%であるような数を表す)
である、請求項1に記載の方法。 - 前記ブロックコポリマーが一般式:
HO(C3H6O)y(C2H4O)x(C3H6O)y H
(式中、yは疎水性POP部分(C3H6O)の分子量が最大で約20,000Daであるような数を表し、そしてxは親水性POE部分(C2H4O)の%が約1重量%〜50重量%であるような数を表す)
である、請求項1に記載の方法。 - 冷却ろ過段階を更に含んで成る、請求項1に記載の方法。
- 前記混合段階(a)を約−2℃〜約−8℃の温度で行っている、請求項1に記載の方法。
- 前記冷却ろ過段階を約−2℃〜約−8℃の温度で行っている、請求項4に記載の方法。
- 前記冷却ろ過段階を、孔径約0.01ミクロン〜約2ミクロンを有するフィルターを使用して行っている、請求項4に記載の方法。
- 前記ブロックコポリマーがCRL-1005である、請求項2に記載の方法。
- 前記陽イオン性界面活性剤が、塩化ベンザルコニウム(BAK)、塩化ベネトニウム、セトリミド(cetrimide)、塩化セチルピリジニウム、塩化アセチルトリエチルアンモニウム、(±)−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ている、請求項1に記載の方法。
- 前記混合物が非晶質抗凍結剤を1種類以上含んで成る、請求項1に記載の方法。
- 前記非晶質抗凍結剤がスクロースである、請求項10に記載の方法。
- 前記混合物が、結晶質増量剤を1種類以上含んで成る、請求項1に記載の方法。
- 前記混合物が、前記非晶質抗凍結剤又は結晶質増量剤を約1%〜約20%(w/v)含んで成る、請求項1に記載の方法。
- スクロースの最終濃度が約10%(w/v)である、請求項11に記載の方法。
- 前記混合物が更に、pH安定化生理的緩衝剤を含んで成る、請求項1に記載の方法。
- 前記生理的緩衝剤が、塩類溶液、PBS、HEPES、MOPS、BIS-TRIS、リン酸ナトリウム、リン酸カリウム、二塩基性リン酸ナトリウム(Na2HPO4)、一塩基性リン酸ナトリウム(NaH2PO4)、一塩基性リン酸カリウム(NaKHPO4)、リン酸マグネシウム(Mg3(PO4)2・4H2O)、又はD(+)−α−ナトリウムグリセロフォスフェート(HOCH2CH(OH)CH2OPO3Na2)からなる群から選択されている、請求項15に記載の方法。
- 前記生理的緩衝剤がリン酸ナトリウムである、請求項16に記載の方法。
- 前記混合物中、前記生理緩衝剤の濃度が約5mM〜約25mMである、請求項15に記載の方法。
- 前記リン酸ナトリウムが約5mM〜約25mMの濃度である、請求項17に記載の方法。
- 前記混合物中に存在する前記陽イオン性界面活性剤の最終濃度が約0.01mM〜約5mMである、請求項1に記載の方法。
- 前記混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約1mg/mL〜約50mg/mLである、請求項1に記載の方法。
- 前記混合物中に存在する前記ポリヌクレオチド分子の最終濃度が約1ng/mL〜約10mg/mLである、請求項1に記載の方法。
- 請求項1の方法によって生産した製品。
- 請求項23に記載の製品を水性溶液により再生することによって生産した、安定な、単分散性製品。
- 請求項4の方法によって生産した製品。
- 請求項25に記載の製品を水性溶液により再生することによって生産した、安定な、単分散性製品。
- 請求項15の方法によって生産した製品。
- 請求項27に記載の製品を水性溶液により再生することによって生産した、安定な、単分散性製品。
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Also Published As
Publication number | Publication date |
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US20090181919A1 (en) | 2009-07-16 |
WO2004060059A2 (en) | 2004-07-22 |
AU2003293195A1 (en) | 2004-07-29 |
CA2508279A1 (en) | 2004-07-22 |
EP1578193A4 (en) | 2011-06-15 |
WO2004060059A3 (en) | 2005-12-22 |
US7521187B2 (en) | 2009-04-21 |
JP4917263B2 (ja) | 2012-04-18 |
EP1578193A2 (en) | 2005-09-28 |
US20040157789A1 (en) | 2004-08-12 |
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