JP5459827B2 - 慢性閉塞性肺疾患改善剤 - Google Patents
慢性閉塞性肺疾患改善剤 Download PDFInfo
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- JP5459827B2 JP5459827B2 JP2009061075A JP2009061075A JP5459827B2 JP 5459827 B2 JP5459827 B2 JP 5459827B2 JP 2009061075 A JP2009061075 A JP 2009061075A JP 2009061075 A JP2009061075 A JP 2009061075A JP 5459827 B2 JP5459827 B2 JP 5459827B2
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Description
そこで本発明者は、かかる考え方に立脚して、先に提案している細胞親和性の高いレシチン化スーパーオキサイドジスムターゼ(PC−SOD)についてCOPDへの適用を検討した結果、このPC−SODがCOPDの症状改善に極めて効果的であることを確認して、本発明を完成させるに至った。
下記一般式(I):
SOD’(Q−B)m (I)
(式中、SOD’はスーパーオキサイドジスムターゼの残基を表し、Qは化学的架橋を表し、Bはグリセロールの2位に水酸基を有するリゾレシチンにおけるその水酸基の水素原子を除いた残基を表し、mはスーパーオキサイドジスムターゼ1分子に対するリゾレシチンの平均結合数であって、1以上の整数を表す)
で表されるレシチン化スーパーオキサイドジスムターゼを有効成分とすることを特徴とするCOPD改善剤である。
これまで効果的なCOPD改善剤が存在しなかった状況下において、特異的なPC−SODを投与することにより、その症状の改善を行える点で、その医療上の効果は極めて特異的なものである。
SOD’(Q−B)m (I)
(式中、SOD’はスーパーオキサイドジスムターゼの残基を表し、Qは化学的架橋を表し、Bはグリセロールの2位に水酸基を有するリゾレシチンにおけるその水酸基の水素原子を除いた残基を表し、mはスーパーオキサイドジスムターゼ1分子に対するリゾレシチンの平均結合数であって、1以上の整数を表す)
で表すことができる。
したがって、特開平9−117279号公報に記載されるヒトCu/Zn SODの調製は、本明細書の一部を構成し、本発明で使用するPC−SODは、これらのヒトCu/Zn SODを素材として得ることができる。
−O−CH(CH2OR)[CH2OP(O)(O−)(OCH2CH2N+(CH3)3)]
(II)
(式中、Rは脂肪酸残基(アシル基)である)
で表される。
なお、上記化学的架橋の残基においてnとしては2以上の整数であり、好ましくは2〜10の整数である。
なお、本発明において1U(ユニット)とは、pH7.8/30℃の条件下でNBT(ニトロブルーテトラゾリウム)を用いてJ. Biol. Chem., vol.244, No.22 6049-6055 (1969) に記載の方法に準じて測定し、NBTの還元速度を50%阻害するPC−SODの酵素量を表す。
かかる吸入剤とは、気管、気管支、肺等へ到達させるための医薬組成物を意味し、好適には、点鼻剤又は経鼻若しくは経肺投与に適した組成物であり、特に経肺投与に適した組成物である。
[方法]
6〜8週齢のBALB/cマウスに、ブタ脾臓エステラーゼを、マウス1匹あたり50μg経気道投与し、肺傷害を作成させた。
各濃度(1.5及び3.0kU/kg)のPC−SODを一日一回静脈内投与し、3日後に肺胞洗浄液を回収し、全細胞数をカウントした。
また、細胞をディフクイック法により染色し、各炎症性細胞数をカウントした。
更に、マウスを安楽死させ、肺組織の切片を作成し、H&E染色を行い、電子顕微鏡撮影により染色像(×40)を得た。
そのH&E染色像より、平均肺胞径(Mean Linear Intercept:μm)を測定した。
1.肺胞洗浄液中の全細胞数を図1に示した。
図中の結果から判明するように、ブタ脾臓エステラーゼ投与により、全細胞数は上昇し、炎症性細胞の増加が予測された。また、この上昇はPC−SODにより減弱したことから、PC−SODが抗炎症作用を発揮することが予測された。
2.各炎症性細胞数を図2〜図4に示した。
図2は肺胞マクロファージの結果を、図3は好中球の結果を、図4はリンパ球の結果を示した。
図中の結果からも判明するように、PC−SODの1.5及び3.0kU/kg静脈投与で、炎症性細胞の減少が見られ、有意に抗炎症作用を示していることが判明する。
各図中に示した結果からも判明するように、PC−SODの1.5及び3.0kU/kg静脈投与は、エラスターゼ依存の平均肺胞径の延長を抑制し、肺傷害を抑制していることが判明する。
[方法]
6〜8週齢のBALB/cマウスに、ブタ脾臓エステラーゼを、マウスあたり50μg経気道投与し、肺傷害を作成させた。
各濃度(30及び60kU/Chamber)のPC−SODを含有する吸入剤を一日一回吸入投与し、3日後に肺胞洗浄液を回収し、全細胞数をカウントした。
また、細胞をディフクイック法により染色し、各炎症性細胞数をカウントした。
更に、マウスを安楽死させ、肺組織の切片を作成し、H&E染色を行い、電子顕微鏡撮影により染色像(×40)を得た。
そのH&E染色像より、平均肺胞径(Mean Linear Intercept:μm)を測定した。
1.肺胞洗浄液中の全細胞数を図7に示した。
図中の結果から判明するように、ブタ脾臓エステラーゼ投与依存によって上昇した全細胞数はPC−SODにより減弱したことから、PC−SODが抗炎症作用を発揮したことが予測された。
2.各炎症性細胞数を図8〜図10に示した。
図8は肺胞マクロファージの結果を、図9は好中球の結果を、図10はリンパ球の結果を示した。
図中の結果からも判明するように、PC−SODの30及び50kU/Chamber)のPC−SODを含有する吸入剤の吸入投与(経肺投与)は、有意に抗炎症作用を示していることが判明する。
各図中に示した結果からも判明するように、PC−SODの30及び50kU/Chamber)のPC−SODを含有する吸入剤の吸入(経肺)投与は、エラスターゼ依存の平均肺胞径の延長を抑制し、肺傷害を抑制していることが判明する。
PC−SOD1%(w/w)、シュークロース10%(w/w)、塩化ベンザルコニウム0.05%(w/w)を5%キシリトール水溶液に溶解した後、凍結乾燥した。得られた凍結乾燥剤に、別にバイアル充填した0.5%カルメロースあるいは注射用水を加えることにより静脈注射用剤を得た。
吸入用液剤(1)
PC−SOD1%(w/w)、シュークロース10%(w/w)、塩化ベンザルコニウム0.05%(w/w)を5%キシリトール水溶液に溶解し、吸入用液剤を調製する。
PC−SOD1%(w/w)、シュークロース10%(w/w)、塩化ベンザルコニウム0.05%(w/w)、ポリエチレングリコール10%(w/w)、プロピレングリコール20%(w/w)、残部精製水で吸入用液剤を調製する。
PC−SODが5%(w/w)、残部シュークロース(微細粉末状)で吸入用散剤を調製する。
Claims (10)
- 下記一般式(I):
SOD’(Q−B)m (I)
(式中、
SOD’はスーパーオキサイドジスムターゼの残基を表し、
Qは−C(O)−(CH 2 ) n −C(O)−(式中、nは2〜10の整数を表す)の化学的架橋を表し、
Bはグリセロールの2位に水酸基を有するリゾレシチンにおけるその水酸基の水素原子を除いた残基を表し、
mはスーパーオキサイドジスムターゼ1分子に対するリゾレシチンの平均結合数であって、1〜12の整数を表す)
で表されるレシチン化スーパーオキサイドジスムターゼを有効成分とすることを特徴とする慢性閉塞性肺疾患改善剤。 - SOD’が、ヒトのスーパーオキサイドジスムターゼの残基であることを特徴とする請求項1に記載の慢性閉塞性肺疾患改善剤。
- SOD’が、ヒトのスーパーオキサイドジスムターゼのアミノ酸配列における111位のアミノ酸がS−(2−ヒドロキシエチルチオ)システインとなったスーパーオキサイドジスムターゼ修飾体の残基であることを特徴とする請求項1または2に記載の慢性閉塞性肺疾患改善剤。
- スーパーオキサイドジスムターゼが、活性中心に銅と亜鉛を含むスーパーオキサイドジスムターゼであることを特徴とする請求項2または3に記載の慢性閉塞性肺疾患改善剤。
- さらに安定化剤を含有することを特徴とする請求項1ないし4のいずれか1項に記載の慢性閉塞性肺疾患改善剤。
- 安定化剤が、糖であることを特徴とする請求項5に記載の慢性閉塞性肺疾患改善剤。
- 糖が、シュークロースであることを特徴とする請求項6に記載の慢性閉塞性肺疾患改善剤。
- シュークロースが、活性炭処理されたシュークロースであることを特徴とする請求項7に記載の慢性閉塞性肺疾患改善剤。
- 注射剤の形態にあることを特徴とする請求項1に記載の慢性閉塞性肺疾患改善剤。
- 吸入剤の形態にあることを特徴とする請求項1に記載の慢性閉塞性肺疾患改善剤。
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CN201510546801.2A CN105126112A (zh) | 2009-03-13 | 2010-03-02 | 卵磷脂化超氧化物歧化酶作为有效成分在制备慢性阻塞性肺疾病改善剂中的应用 |
US13/254,242 US20120034202A1 (en) | 2009-03-13 | 2010-03-02 | Ameliorating agent for chronic obstructive pulmonary disease |
CN2010800112435A CN102348465A (zh) | 2009-03-13 | 2010-03-02 | 慢性阻塞性肺疾病改善剂 |
PCT/JP2010/053317 WO2010103959A1 (ja) | 2009-03-13 | 2010-03-02 | 慢性閉塞性肺疾患改善剤 |
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EP10750713.9A EP2407176B1 (en) | 2009-03-13 | 2010-03-02 | Ameliorating agent for chronic obstructive pulmonary disease |
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US20120034202A1 (en) | 2012-02-09 |
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KR101654959B1 (ko) | 2016-09-06 |
KR20110138372A (ko) | 2011-12-27 |
WO2010103959A1 (ja) | 2010-09-16 |
CN105126112A (zh) | 2015-12-09 |
CA2755116A1 (en) | 2010-09-16 |
US20140023629A1 (en) | 2014-01-23 |
CN102348465A (zh) | 2012-02-08 |
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