JP5212492B2 - 経鼻投与用医薬組成物 - Google Patents
経鼻投与用医薬組成物 Download PDFInfo
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- JP5212492B2 JP5212492B2 JP2011015623A JP2011015623A JP5212492B2 JP 5212492 B2 JP5212492 B2 JP 5212492B2 JP 2011015623 A JP2011015623 A JP 2011015623A JP 2011015623 A JP2011015623 A JP 2011015623A JP 5212492 B2 JP5212492 B2 JP 5212492B2
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Description
(a)配列番号1で表されるアミノ酸配列からなるペプチド。
(b)配列番号1で表されるアミノ酸配列のうち、1もしくは数個のアミノ酸が欠失、置換もしくは付加されたアミノ酸配列からなり、かつ鼻腔粘膜透過性を有するペプチド。
(c)(a)または(b)の逆配列で表されるアミノ酸配列からなり、鼻腔粘膜透過性を有するペプチド。
<方法>
インスリン(WAKO社)粉末を1.5mlチューブ(エッペンドルフ社)に一定量計りとり、0.1N、HClに溶解した後、同量の0.1N、NaOHを加えインスリン溶液を作製した。
投与後の血中インスリン濃度推移を図1に、血中グルコース濃度推移を図2に示す。インスリンのみを経鼻投与したラットでは血中のインスリン濃度上昇はほとんど確認出来ないのに対し、インスリンと共にペネトラチンまたはオリゴアルギニンを投与したラットでは投与直後よりインスリンの血中移行が認められ、最大血中濃度はL−ペネトラチンが最も高く、ついでD−ペネトラチン、D−オリゴアルギニン、L−オリゴアルギニンとなった(図1)。またインスリンの血中移行に伴う薬理活性である血糖値の低下も認められ、血中のインスリン濃度に対応する血糖値低下が確認された(図2)。
<方法>
実施例1と同様の方法を用い、実施例1で最も効率の良い吸収促進効果が認められたL体のペネトラチン(配列番号1)について、投与溶液に含まれる濃度として0.2mM、0.5mM、1mM、2mMに変更し、同様の評価を行った。
インスリン単独を投与した場合のバイオアベイラビリティが1.7%なのに対し、L体のペネトラチンを0.2mM、0.5mM、1mM、2mMで投与した場合のバイオアベイラビリティはそれぞれ15.1%、17.9%、28.4%、50.7%となり、ペネトラチンの濃度依存的にインスリンの吸収効率が向上した(図4)。
<方法>
蛍光標識デキストランであるFD−4(モルキュラープローブ社)をPBSで希釈し4mg/ml溶液とした。この溶液を40μl用い、実施例1と同じ手法を用いて評価を行った。血液中のFD濃度は蛍光光度法にて定量した。バイオアベイラビリティは同量のFD−4を静脈内投与した場合との比較により算出した。
FD−4単独を投与したラットのバイオアベイラビリティは4.9%、L体のペネトラチン17%、D体のペネトラチンを用いた場合は36%となった。またL体またはD体のオリゴアルギニンを投与したラットのバイオアベイラビリティはそれぞれ、12.4%、12.4%となり、オリゴアルギニンに比較し、ペネトラチンが高い吸収促進効果を示した(図5)。
<方法>
氷冷下、ヒト天然型インターフェロンβ(東レ株式会社製“フエロン”)にTween20添加PBSを1ml加え、6,000,000IU/mlとし、この溶液を100μl分取し、Tween20添加PBSを566μl加え900,000IU/ml溶液とした。D体およびL体のペネトラチン(配列番号1)をそれぞれ終濃度0.5mMまたは2mMになるように秤量しインターフェロンβ溶液40μlを添加して溶解し、インターフェロンβおよびペネトラチン混合溶液とし、実施例1と同じ手法を用いて評価を行った。インターフェロンβの濃度は株式会社鎌倉テクノサイエンス製“ヒトインターフェロンβELISAキット”により測定し、バイオアベイラビリティは同量のインターフェロンβを静脈内投与した場合との血漿中濃度の比較により算出した。
インターフェロンβと共にペネトラチンを添加することにより血中へのインターフェロンβ移行が認められた。バイオアベイラビリティは0.5mMのL体で6.1%、0.5mMのD体で11.0%、2mMのD体で22.0%であった(図6)。
<方法>
インスリン(WAKO社)粉末を1.5mlチューブ(エッペンドルフ社)に一定量計りとり、0.1N、HClに溶解した後、同量の0.1N、NaOHを加えインスリン溶液を作製した。
投与後の血中グルコース濃度推移を図7に血中インスリン濃度推移を図8に、評価結果より得られた各種パラメーターを表1に示す。インスリンのみを経鼻投与したラットでは血中のインスリン濃度上昇はほとんど確認出来ないのに対し、インスリンと共に配列番号1〜6のペプチドをそれぞれ投与することで、投与直後より血中へのインスリン移行が見られ、それに伴い、血中グルコース濃度の低下が確認された。血中インスリン濃度推移から算出したバイオアベイラビリティ(BA)はインスリンのみを投与したラットが2.3%だったのに対し、配列番号1〜6のペプチドでは4.4〜20.1%となった。また、血中グルコース濃度推移より算出した薬学的利用性(PA)はインスリンのみを投与した場合、4.7%であったのが、配列番号1〜6のペプチドでは15.7%〜37.5%となった。
Claims (7)
- 親水性生理活性ペプチドと下記(a)〜(c)のいずれかのペプチド(ただし、C末端がアミド化されたペプチドを除く。)を含有する経鼻投与用医薬組成物。
(a)配列番号1で表されるアミノ酸配列からなるペプチド。
(b)配列番号1で表されるアミノ酸配列のうち、1もしくは数個のアミノ酸が欠失、置換もしくは付加されたアミノ酸配列からなり、かつ鼻腔粘膜透過性を有するペプチド。
(c)(a)または(b)の逆配列で表されるアミノ酸配列からなり、鼻腔粘膜透過性を有するペプチド。 - 前記(b)のペプチドが、配列番号1で表されるアミノ酸配列のうち、1もしくは数個の塩基性アミノ酸が別の塩基性アミノ酸に置換、もしくは付加されたアミノ酸配列からなり、かつ鼻腔粘膜透過性を有するペプチドである、請求項1に記載の経鼻投与用医薬組成物。
- 前記(b)のペプチドが、配列番号3〜6のいずれかで表されるアミノ酸配列からなるペプチドである、請求項1または2に記載の経鼻投与用医薬組成物。
- 前記(c)のペプチドが、配列番号2で表されるアミノ酸配列からなるペプチドである、請求項1〜3のいずれかに記載の経鼻投与用医薬組成物。
- 前記(a)〜(c)のいずれかのペプチドを0.2〜2.0mMの濃度で含有する、請求項1〜4のいずれかに記載の経鼻投与用医薬組成物。
- 親水性生理活性ペプチドが、マイナスチャージを有するペプチドである、請求項1〜5のいずれかに記載の経鼻投与用医薬組成物。
- 前記(a)〜(c)のいずれかのペプチドの全アミノ酸配列がL体である、請求項6に記載の経鼻投与用医薬組成物。
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CA (1) | CA2716565C (ja) |
ES (1) | ES2671024T3 (ja) |
MX (1) | MX2010009148A (ja) |
PL (1) | PL2253326T3 (ja) |
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WO (1) | WO2009107766A1 (ja) |
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AU2010250452B2 (en) * | 2009-05-20 | 2014-06-05 | Toray Industries, Inc. | Cell membrane-permeable peptides |
WO2012024260A2 (en) * | 2010-08-16 | 2012-02-23 | The Trustees Of Columbia University In The City Of New York | Intranasal delivery of cell permeant therapeutics |
CN112313749A (zh) * | 2018-04-13 | 2021-02-02 | 香港理工大学 | 使用肽的数据存储 |
AU2019269590A1 (en) * | 2018-05-15 | 2020-12-03 | Dnalite Therapeutics, Inc. | Mucus-penetrating peptides, delivery vehicles and methods of therapy |
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Also Published As
Publication number | Publication date |
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BRPI0906045A2 (pt) | 2015-07-07 |
CN101959532B (zh) | 2013-02-27 |
US8895503B2 (en) | 2014-11-25 |
CA2716565C (en) | 2017-09-12 |
EP2253326A4 (en) | 2013-01-09 |
ES2671024T3 (es) | 2018-06-04 |
AU2009218060A1 (en) | 2009-09-03 |
WO2009107766A1 (ja) | 2009-09-03 |
JP4711013B2 (ja) | 2011-06-29 |
PL2253326T3 (pl) | 2018-09-28 |
KR20100135730A (ko) | 2010-12-27 |
JPWO2009107766A1 (ja) | 2011-07-07 |
BRPI0906045B1 (pt) | 2022-01-25 |
AU2009218060B2 (en) | 2014-08-28 |
CA2716565A1 (en) | 2009-09-03 |
US20110020280A1 (en) | 2011-01-27 |
EP2253326B1 (en) | 2018-04-04 |
KR101585046B1 (ko) | 2016-01-13 |
EP2253326A1 (en) | 2010-11-24 |
MX2010009148A (es) | 2010-12-06 |
JP2011084581A (ja) | 2011-04-28 |
RU2010139769A (ru) | 2012-04-10 |
RU2470666C2 (ru) | 2012-12-27 |
CN101959532A (zh) | 2011-01-26 |
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