JP2012509291A - 部位特異的にモノ抱合化されたインスリン分泌性のglp−1ペプチド - Google Patents
部位特異的にモノ抱合化されたインスリン分泌性のglp−1ペプチド Download PDFInfo
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- JP2012509291A JP2012509291A JP2011536815A JP2011536815A JP2012509291A JP 2012509291 A JP2012509291 A JP 2012509291A JP 2011536815 A JP2011536815 A JP 2011536815A JP 2011536815 A JP2011536815 A JP 2011536815A JP 2012509291 A JP2012509291 A JP 2012509291A
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Abstract
Description
a)ヒトのGLP−1またはその類似体のアシル化された誘導体、例えば、その中のアシル部分がin vivoで血清アルブミン結合を促進し、効力の減少なく約13〜15時間まで半減期を延長する、リラグルチド、すなわち、{Arg28−Lys20−N−[ε−(γ−Glu{N−α−ヘキサデカノイル})]−GLP−1}[非特許文献12]。
c)持続したかつ制御された放出速度でGLP−1を送達するための徐放性製剤として働く生分解性ポリマー中へのGLP−1ペプチドの包括によって[非特許文献14]。
タンパク質−CONH2+R−NH2→タンパク質−CONHR+NH3
式中、−CONH2は、アシル供与体として作用する、タンパク質を結合したグルタミン残基のγ−カルボキサミド基であり、かつR−NH2はアシル受容体として作用する多様な第一級アミン(タンパク質鎖中のリシン残基のε−アミノ基を含む)を表す。現在知られている真核生物のトランスグルタミナーゼとしては、とりわけ、血液凝固因子XIIIa、ケラチノサイトTgase(1型Tgase)および遍在性の組織型Tgase(2型Tgase)などが挙げられる。多様な真核生物のTgaseは、いくつかのサブユニットからなりかつ高度な配列類似性および機能特性の双方を共有している1種のファミリーのアイソザイムに属し、約75〜90kDaの分子量および同様なCa2+依存的な触媒の作用機序を有する[非特許文献23]。
酵素による直接的な、GLP−1−アミドおよびエクセナチドのモノペグ化のいくつかの実験的研究の結果を表1および表2にまとめる。
a) GLP−1−ペプチドの受容体結合に関与しない、すなわち、受容体結合に重要な1、4、6、7、9、13、15、22、23および26番目の部位にあるもの[非特許文献3:非特許文献4]以外の任意の残基
b) グルタミン置換を、M−Tgaseに触媒される直接的なトランスグルタミナーゼ反応においてそれがアシル供与体として作用することが可能な部位に有する。
GLP−1ペプチドを、10mM、pH8.0のクエン酸二水素ナトリウム溶液に、約150μMの濃度に相当する、0.5mgペプチド/mlの濃度で溶解する。次いで、このペプチド溶液に20kDaのm−PEG−アミン(メトキシポリエチレングリコールアミン20000、Iris Biotech)を添加して、20:1のPEG:GLP−1モル比を達成する。次いで、この反応混合物に、微生物のトランスグルタミナーゼ(Activa WM、味の素)を、0.25U/mlの最終濃度まで、添加する。撹拌下、室温で16時間反応させる。
S12Q/Q17N−GLP−1−アミドを、10mM、pH8.0のクエン酸二水素ナトリウム溶液に、約150μMの濃度に相当する、0.5mgペプチド/mlの濃度で溶解する。
Q17N/A24Q−GLP−1−アミドを、10mM、pH8.0のクエン酸二水素ナトリウム溶液に、約150μMの濃度に相当する、0.5mgペプチド/mlの濃度で溶解する。
リン酸緩衝食塩水中、(ペプチド含有量を等しいものとして計算した)0.1mg/mlの濃度のGLP−1−アミド、モノペグ化されたGLP−1−アミドまたはモノペグ化されたGLP−アミドの変異体もしくは類似体の溶液を、DPP−IV(ブタ腎臓由来のジペプチジルペプチダーゼIV、Sigma)、5U/mlのペプチド溶液と混合し、37℃でインキュベートした。各時点で一定分量の反応混合物を回収し、DPP−IVによって除去されたN末端ジペプチドHis−AlaをRP−HPLC分析によって検出してGLP−1−ペプチドの分解を測定した。例えば図1に示したように、酵素分解を各試料のHis−Alaタイトルから算出した
ポロキサマー407の27%溶液を、このポリマーを0.2Mの酢酸緩衝液pH4.0に4℃でゆっくりと溶解することによって調製した。GLP−1−アミド−Q17 PEG 20kDaを添加して最終濃度0.3mg/mlのGLP−1−アミド−Q17 PEG 20kDaおよび22%のポロキサマーを得て、この溶液を4℃で保存した。
Claims (19)
- アルキルアミノ官能化されたポリマーに共有結合で結合されたグルタミン残基を有する、インクレチン模倣ペプチドのモノ抱合化された誘導体であって、前記インクレチン模倣ペプチドと前記ポリマーとが直接結合されていることを特徴とする誘導体。
- 前記インクレチン模倣ペプチドはグルカゴン様ペプチド−1であることを特徴とする、請求項1に記載のモノ抱合化された誘導体。
- 前記アルキルアミノ官能化されたポリマーは直鎖状または分枝状のモノメトキシ−ポリ(エチレングリコール)であることを特徴とする、請求項1に記載のモノ抱合化された誘導体。
- 前記直鎖状または分枝状のモノメトキシ−ポリ(エチレングリコール)は第一級アミノ基で官能化されていることを特徴とする、請求項3に記載のモノ抱合化された誘導体。
- 前記第一級アミノ基で官能化されている直鎖状または分枝状のモノメトキシ−ポリ(エチレングリコール)は2から50kDaまで、好ましくは5から40kDaまでの分子量を有することを特徴とする、請求項4に記載のモノ抱合化された誘導体。
- 前記第一級アミノ基で官能化されている直鎖状または分枝状のモノメトキシ−ポリ(エチレングリコール)は10から30kDaまで、好ましくは15から25kDaまで、より好ましくは約20kDaの分子量を有することを特徴とする、請求項5に記載のモノ抱合化された誘導体。
- 前記インクレチン模倣ペプチドはGLP−1(7−36)アミド(配列番号1)、グリシンで伸長されたGLP−1(7−37)(配列番号2)、エキセディン−3(exendin-3)およびエキセディン−4(exendin-4)から選択されることを特徴とする、請求項1に記載のモノ抱合化された誘導体。
- 前記GLP−1(7−36)アミド(配列番号1)またはグリシンで伸長されたGLP−1(7−37)(配列番号2)の17番目の部位にあるグルタミン残基は前記アルキルアミノ官能化されたポリマーに共有結合で結合されていることを特徴とする、請求項1および7に記載のモノ抱合化された誘導体。
- 糖尿病、好ましくは2型糖尿病を治療するためのものであることを特徴とする、請求項1から8に記載のモノ抱合化された誘導体。
- 糖尿病、好ましくは2型糖尿病を患っている患者において高血糖を低減するためのものであることを特徴とする、請求項1から9に記載のモノ抱合化された誘導体。
- 請求項1から8に記載のモノ抱合化された誘導体を少なくとも1種の薬学的に許容される賦形剤,および/またはアジュバントと共に含有することを特徴とする製剤。
- 請求項1から8に記載のモノ抱合化された誘導体をポリマーおよび/または脂質のナノ粒子およびマイクロ粒子と共に含有することを特徴とする製剤。
- 請求項1から8に記載のモノ抱合化された誘導体を温度応答性ポリマーと共に含有することを特徴とする製剤。
- 前記インクレチン模倣ペプチドを前記アルキルアミノ官能化されたポリマーとトランスグルタミナーゼの存在下で反応させるステップを含むことを特徴とする、請求項1から8に記載のモノ抱合化された誘導体の調製のための方法。
- 前記トランスグルタミナーゼは微生物のトランスグルタミナーゼであることを特徴とする、請求項14に記載の方法。
- グルカゴン様ペプチド−1とアルキルアミノ官能化されたポリマーのモル比は、1:1から1:100の間、好ましくは1:5から1:35の間、より好ましくは、1:15から1:25の間に含まれることを特徴とする、請求項14および15に記載の方法。
- 前記反応を4から9の間、好ましくは5から8の間のpHの緩衝液中で行うことを特徴とする、請求項14から16に記載の方法。
- 前記トランスグルタミナーゼを0.1U/mlから2U/mlの間、好ましくは0.2U/mlから1U/mlの間の範囲の量で使用することを特徴とする、請求項14から17に記載の方法。
- 前記反応を10℃から50℃の間、好ましくは15℃から30℃の間の温度で行うことを特徴とする、請求項14から18に記載の方法。
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ITMI2008A002066A IT1392655B1 (it) | 2008-11-20 | 2008-11-20 | Site-specific monoconjugated insulinotropic glp-1 peptides. |
PCT/EP2009/064599 WO2010057774A1 (en) | 2008-11-20 | 2009-11-04 | Site-specific monoconjugated insulinotropic glp-1 peptides |
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