JP2019500423A - 糖尿病性神経損傷及びその関連疾患を予防または治療するための方法 - Google Patents
糖尿病性神経損傷及びその関連疾患を予防または治療するための方法 Download PDFInfo
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Abstract
Description
「糖尿病」は遺伝的要素、免疫機能の乱れ、微生物感染及びその毒素、フリーラジカル毒素、精神要因などの各種病気誘発因子が生体に作用することによる、インスリン減退、インスリン抵抗などによって引き起こされる糖、タンパク質、脂肪、水及び電解質等の一連の代謝に乱れが生じる症候群であり、臨床的には高血糖を主な特徴とする。
分数X/Y×100
プラスミノゲンは自然界から分離及び精製され、さらに治療の用途に用いられるものであり、さらには標準的な化学ペプチド合成技術によって合成することができる。化学的手法によりポリペプチドを合成する際、液相または固相で合成を行うことができる。固相ポリペプチド合成(SPPS)(配列のC末端アミノ酸を不溶性支持体に附着させ、順番に配列中の残りのアミノ酸を添加する)はプラスミノゲンの化学的合成に適したものである。各種形式のSPPS、例えばFmoc及びBocは、プラスミノゲンの合成に用いることができる。固相合成に用いられる技術は以下に記載されている:Barany及びSolid−Phase Peptide Synthesis;3−284ページ、The Peptides:Analysis,Synthesis,Biology.第二巻:Special Methods in Peptide Synthesis,Part A.,Merrifield,tら J.Am.Chem.Soc.,85:2149−2156(1963);Stewartら,Solid Phase Peptide Synthesis,2nd ed.Pierce Chem.Co.,Rockford,Ill.(1984);及びGanesan A.2006Mini Rev.Med Chem.6:3−10及びCamarero JAら 2005Protein Pept Lett.12:723−8。簡単に言えば、その上にペプチド鎖が構築された機能性ユニットにより不溶性の多孔ビーズを処理する。カップリング/脱保護の繰り返し循環後に、附着した固相の遊離N末端アミンと単一のN保護を受けているアミノ酸ユニットをカップリングさせる。それから、該ユニットを脱保護させ、他のアミノ酸と連結する新しいN末端アミンを露出させる。ペプチドを固相上に固定したままにし、それからそれを切除する。
必要とする純度のプラスミノゲンと選択可能な薬用担体、賦形剤、または安定剤(Remington’s Pharmaceutical Sciences,第16版,Osol,A.ed.(1980))を混合して凍結乾燥製剤または水溶液を形成して治療用配合剤を得る。許容可能な担体、賦形剤、安定剤は所要の用量及び濃度下において被験者に対して毒性がなく、さらに例えばリン酸塩、クエン酸塩及びその他の有機酸などの緩衝剤を含む。抗酸化剤はアスコルビン酸和メチオニンを含む;防腐剤(例えばベンジルジメチルステアリルアンモニウムクロリド水和物;塩化ヘキサメチレンジアミン;塩化ベンザルコニウム(benzalkonium chloride)、ベンゼトニウムクロリド;フェノール、ブタノールまたはベンジルエタノール;アルキルパラヒドロキシ安息香酸エステル、例えばメチルまたはプロピルのパラヒドロキシ安息香酸エステル;ピロカテコール;レソルシノール;シクロヘキサノール;3−ペンチルエタノール;m−クレゾール);低分子量ポリペプチド(少なくとも10個の残基を有するもの);タンパク質例えば血清アルブミン、ゼラチン、または免疫グロブリン;親水性重合体、例えばポリゼニールピロリドン;アミノ酸、例えばグリシン、グルタミン、アスパラギン酸、ヒスチジン、アルギニンまたはリジンである;単糖、二糖及びその他の炭水化物はブドウ糖、マンノース、またはデキストリンを含む;キレート剤は例えばEDTAである;糖類は例えばショ糖、マンニトール、フコースまたはソルビトールである;塩形成イオン、例えばナトリウム;金属複合体(例えば亜鉛−タンパク複合体);及び/または非イオン界面活性剤、例えばTWEENTM、PLURONICSTMまたはポリエチレングリコール(PEG)である。好ましくは凍結乾燥された抗−VEGF抗体配合剤であり、WO 97/04801に記載されているとおりであり、本明細書において参考とされるものである。
異なる方式、例えば静脈内、腹膜内、皮下、頭蓋骨内、髄腔内、動脈内(例えば頸動脈)、筋肉内、鼻内、体表または皮内投与または脊髄または脳内輸送により本発明の薬物組成物の投与を実現できる。エアロゾル製剤例えば鼻噴霧製剤は活性剤を含有する精製した水性またはその他の溶液及び防腐剤と等張剤を含有する。このような製剤を鼻粘膜と許容し得るpH及び等張状態に調整する。
本発明の一つの実施形態はプラスミノゲンを用いて被験者を治療した後、治療効力及び治療安全性に対して判断を行うことに係る。
0点:痛みがない;
3点以下:軽微な痛みがあるが、我慢できる;
4−6点:被験者が痛みを感じて且つ睡眠に影響しているが、まだ我慢できる;
7−10点:被験者には強い痛みがあり、痛みが我慢しづらく、食欲と睡眠に影響を及ぼす。
本発明の一つの実施形態は製品または薬物キットに係るものであり、本発明のプラスミノゲン/プラスミンを含有する。前記製品は好ましくは一つの容器、ラベルまたはパンフレットを含む。適切な容器はボトル、小瓶、注射器などである。容器は各種材料例えばガラスまたはプラスチックから作られることができる。前記容器は組成物を含有し、前記組成物は本発明の疾患または症状を有効に治療し且つ無菌の入口を有する(例えば前記容器は静脈輸液用パックまたは小瓶であり、皮下注射針によって貫通される栓を含む)。前記組成物中の少なくとも一種類の活性化剤がプラスミノゲン/プラスミンである。前記容器上にあるまたは添付されているラベルは前記組成物を本発明の前記糖尿病神経損傷の治療に用いられると説明するものである。前記製品はさらに薬用緩衝液を含有する第二容器を含み、前記薬用緩衝液は例えばリン酸塩緩衝の食塩水、リンガー溶液及びブドウ糖溶液である。さらには商業及び使用者の角度から見ると必要とされるその他の物質、即ちその他の緩衝液、希釈剤、濾過物、針及び注射器を含むことができる。また、前記製品は使用説明を有するパンフレットを含み、これは例えば前記組成物の使用者にプラスミノゲン組成物及び疾患の治療に伴うその他の薬物を患者に投与することを指示するものである。
実験結果は以下を示している。0及び4日目に、プラスミノゲン投与グループ及び溶媒PBS投与対照グループはアセトン刺激に対して顕著な差異がなく、7日目から顕著な差異が観察され、16日目に極めて顕著な差異が観察され、P値<0.0001である(図7)。これは投薬から15日後に、糖尿病マウスは冷刺激に対する反応がほとんど完全に回復していることを回復し、これは、プラスミノゲンは極めて顕著に糖尿病末期マウスの冷刺激に対する刺激損傷を修復していることを示している。
Claims (14)
- 被験者に有効量のプラスミノゲンを投与することを含む、糖尿病性神経損傷を修復するための方法。
- 前記糖尿病性神経損傷は神経組織損傷及び神経の炎症を含むことを特徴とする、請求項1に記載の方法。
- 被験者に有効量のプラスミノゲンを投与することを含む、糖尿病性神経損傷の関連疾患を治療及び/または予防するための方法。
- 前記糖尿病性神経損傷の関連疾患は体の痛み、感覚減退、痺れ、熱さ、冷たさ、及び糖尿病性神経疼痛を含み、当該糖尿病性神経疼痛は糖尿病合併症によって引き起こされる自発性疼痛、痛覚減退、痛覚過敏を含むがこれに限られないことを特徴とする、請求項3に記載の方法。
- 前記プラスミノゲンは配列2、6、8、10または12と少なくとも80%、85%、90%、95%、96%、97%、98%または99%の配列同一性を有し、且つ依然としてプラスミノゲン活性を有するものであることを特徴とする、請求項1〜4のいずれかに記載の方法。
- 前記プラスミノゲンはプラスミノゲン活性フラグメントを含み、且つ依然としてプラスミノゲン活性を有するタンパク質であることを特徴とする、請求項1〜5のいずれかに記載の方法。
- 前記プラスミノゲンはGlu−プラスミノゲン、Lys−プラスミノゲン、ミニプラスミノゲン、マイクロプラスミノゲン、δ(delta)−プラスミノゲンまたはその任意の組み合わせから選択されるものであることを特徴とする、請求項1〜6のいずれかに記載の方法。
- 前記プラスミノゲンは例えば、体表、静脈内、筋肉内、皮下、吸入、椎管内、局所注射、関節内注射または直腸投与によって全身または局所にて投与されることを特徴とする、請求項1〜7のいずれかに記載の方法。
- 前記プラスミノゲンは他の薬物または療法と組み合わせて施用できることを特徴とする、請求項1〜8のいずれかに記載の方法。
- 前記他の薬物または療法は神経栄養薬、鎮痛系薬、糖尿病治療薬、抗感染薬、血圧降下薬、高脂血症治療薬、物理療法を含み、前記物理療法は例えば電磁療法、赤外線療法であることを特徴とする、請求項9に記載の方法。
- 糖尿病性神経損傷を修復、治療及び/または予防するための製品であって、有効用量のプラスミノゲンを含有する容器、及び被験者の糖尿病性神経損傷を修復、治療及び/または予防することにおける製品の投与を指導するプロトコルを含むことを特徴とする、前記製品。
- さらに一種類または複数種類の他の薬物の容器を含むことを特徴とする、請求項11に記載の製品。
- 前記他の薬物は神経栄養薬、鎮痛系薬、糖尿病治療薬、抗感染薬、血圧降下薬、高脂血症治療薬であることを特徴とする、請求項12に記載の製品。
- 前記プロトコルはさらに前記プラスミノゲンは前記他の薬物の投与の前、投与と同時、及び/または後に投与できることを説明するものであることを特徴とする、請求項12または13に記載の製品。
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JP2019500422A (ja) * | 2015-12-18 | 2019-01-10 | タレンゲン インターナショナル リミティッドTalengen International Limited | 急性及び慢性血栓を予防または治療することに用いる方法 |
US10864257B2 (en) | 2015-12-18 | 2020-12-15 | Talengen International Limited | Method for prevention or treatment of acute and chronic thrombosis |
US11207387B2 (en) | 2016-12-15 | 2021-12-28 | Talengen International Limited | Method and drug for preventing and treating obesity |
US11389515B2 (en) | 2016-12-15 | 2022-07-19 | Talengen International Limited | Method for mitigating heart disease |
US11478535B2 (en) | 2016-12-15 | 2022-10-25 | Talengen International Limited | Method for preventing and treating fatty liver |
US11547746B2 (en) | 2016-12-15 | 2023-01-10 | Talengen International Limited | Method for treating coronary atherosclerosis and complications thereof |
JP2023515916A (ja) * | 2020-01-17 | 2023-04-17 | タレンゲン インターナショナル リミテッド | 神経損傷及び関連障害を治療するための方法 |
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WO2017101867A1 (zh) | 2017-06-22 |
JP2020090543A (ja) | 2020-06-11 |
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TW201722465A (zh) | 2017-07-01 |
US20180369345A1 (en) | 2018-12-27 |
US11400142B2 (en) | 2022-08-02 |
EP3395353A1 (en) | 2018-10-31 |
TWI653981B (zh) | 2019-03-21 |
CA3008694C (en) | 2022-11-29 |
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CA3008694A1 (en) | 2017-06-22 |
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