JP6076902B2 - 新規な持続型グルカゴン結合体およびこれを含む肥満の予防および治療用薬学的組成物 - Google Patents
新規な持続型グルカゴン結合体およびこれを含む肥満の予防および治療用薬学的組成物 Download PDFInfo
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- JP6076902B2 JP6076902B2 JP2013520654A JP2013520654A JP6076902B2 JP 6076902 B2 JP6076902 B2 JP 6076902B2 JP 2013520654 A JP2013520654 A JP 2013520654A JP 2013520654 A JP2013520654 A JP 2013520654A JP 6076902 B2 JP6076902 B2 JP 6076902B2
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- 206010036067 polydipsia Diseases 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
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- 238000002360 preparation method Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
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- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
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- 239000000243 solution Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
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- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
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- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000002435 venom Substances 0.000 description 1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
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Description
薬の製造のための使用を提供することである。
本発明による製造方法は:
1)化学式4のグルカゴン誘導体を、両末端にアルデヒドを有するPEGとpH9.0で反応させるステップと、
流速:2.0mL/分
勾配:溶出液A0%→溶出液B50%(A:20mMクエン酸、pH3.0、B:A+1M KCl)で50分間溶出
流速:7.0mL/分
勾配:溶出液A100%→0%(A:20mMトリス、pH7.5+2M NaCl)
で60分間溶出
流速:2.0mL/分
勾配:溶出液A0%→溶出液B20%(A:20mMトリス、pH9.0、B:A+1M NaCl)で70分間溶出
流速:2.0mL/分
勾配:溶出液A 0%→溶出液B20%(A:20mMトリス、pH9.0、B:A+
1M NaCl)で70分間溶出
流速:2.0mL/分
勾配:溶出液A0%→溶出液B50%(A:20mMクエン酸、pH3.0、B:A+
1M KCl)で50分間溶出
流速:2.0mL/分
勾配:溶出液A0%→溶出液B20%(A:20mMトリス、pH9.0、B:A+1M NaCl)で70分間溶出
流速:7.0mL/分
勾配:溶出液A100%→0%60分(A:20mMトリス、pH7.5+1.5M硫酸アンモニウム)で60分間溶出
Claims (42)
- グルカゴン誘導体が、非ペプチドリンカーによって重合体キャリアに共有的に連結された、持続型グルカゴン結合体であって、
前記グルカゴン誘導体が、天然型グルカゴンのN末端の1番目のアミノ酸であるヒスチジン残基のアルファ炭素またはそれに結合されたアルファアミン基が置換、修飾または除去されたものである、持続型グルカゴン結合体。 - 前記グルカゴン誘導体が、天然型グルカゴンの一番目のN末端ヒスチジン残基のアミン基が除去された誘導体、その一番目のN末端ヒスチジン残基のアミン基がヒドロキシル基(hydroxyl group)に置換された誘導体、その一番目のN末端ヒスチジン残基のアミン基が2個のメチル基で修飾された誘導体およびその一番目のN末端ヒスチジン残基のアルファ炭素およびアルファ炭素に結合されたアミン基が除去された誘導体からなる群より選択されるものである、請求項1に記載の持続型グルカゴン結合体。
- 前記グルカゴン誘導体が、下記化学式1〜4で表示される誘導体からなる群より選択されるものである、請求項2記載の持続型グルカゴン誘導体:
- 前記非ペプチドリンカーの一方の末端がグルカゴン誘導体に、他方の末端は重合体キャリアに共有的に連結されるものである、請求項1に記載の持続型グルカゴン結合体。
- 前記非ペプチドリンカーが、ポリエチレングリコール(PEG)、ポリプロピレングリコール、エチレングリコールとプロピレングリコールとの共重合体、ポリオキシエチル化ポリオール、ポリビニルアルコール、ポリサッカライド、デキストラン、ポリビニルエチルエーテル、生分解性高分子、脂質重合体、キチン、ヒアルロン酸およびこれらの組み合わせからなる群より選択されるものである、請求項1に記載の持続型グルカゴン結合体。
- 前記非ペプチドリンカーが、1〜100kDaの範囲の分子量を有するものである、請求項1に記載の持続型グルカゴン結合体。
- 前記非ペプチドリンカーが、両末端にそれぞれグルカゴンまたはその誘導体および重合体キャリアと共有的に連結できる官能基を有するものである、請求項1に記載の持続型グルカゴン結合体。
- 前記官能基がアルデヒド基、プロピオンアルデヒド基、ブチルアルデヒド基、マレイミド基、スクシンイミジルプロピオン酸、ヒドロキシスクシンイミジルカルボキシメチルおよびスクシンイミジルカーボネートからなる群より選択される官能基を有するものである、請求項7に記載の持続型グルカゴン結合体。
- 前記非ペプチドリンカーが、両末端にアルデヒド基を有するものである、請求項8に記載の持続型グルカゴン結合体。
- 前記非ペプチドリンカーが、両末端にアルデヒド基を有するポリエチレングリコール(PEG)である、請求項9に記載の持続型グルカゴン結合体。
- 前記重合体キャリアが、ポリエチレングリコール(PEG)、ポリアミノ酸、アルブミン、ゼラチン、兔疫グロブリン断片、デキストラン、脂肪酸、ポリサッカライドおよび高分子重合体からなる群より選択されるものである、請求項1に記載の持続型グルカゴン結合体。
- 前記重合体キャリアが、兔疫グロブリンFc断片である、請求項11に記載の持続型グルカゴン結合体。
- 前記兔疫グロブリンFc断片が、非糖鎖化されたものである、請求項12に記載の持続型グルカゴン結合体。
- 前記兔疫グロブリンFc断片が、CH1、CH2、CH3およびCH4ドメインからなる群より選択される1個〜4個のドメインからなるものである、請求項12に記載の持続型グルカゴン結合体。
- 前記兔疫グロブリンFc断片が、ヒンジ領域をさらに含むものである、請求項12に記載の持続型グルカゴン結合体。
- 前記兔疫グロブリンFc断片が、IgG、IgA、IgD、IgEおよびIgMからなる群より選択された兔疫グロブリンに由来するものである、請求項12に記載の持続型グルカゴン結合体。
- 前記兔疫グロブリンFc断片が、IgG4Fc断片である、請求項12に記載の持続型グルカゴン結合体。
- 前記兔疫グロブリンFc断片が、非糖鎖化したヒトIgG4Fc断片である、請求項17に記載の持続型グルカゴン結合体。
- 下記化学式5で表示される構造を有する、請求項1記載の持続型グルカゴン結合体:
R2は、−NH2、−OHおよびリシン(Lys)からなる群より選択され、
Xは、SQGTFTSDYSKYLDSRRAQDFVQWLMNTであり、
Yは、ポリエチレングリコール(PEG)であり、
Zは、兔疫グロブリンFc断片である。 - 下記のステップを含む請求項1による持続型グルカゴン結合体の製造方法:
1)グルカゴン誘導体を、両末端に官能基を有する非ペプチドリンカーと反応させるステップと、
2)ステップ1)の反応混合物から、非ペプチドリンカーの一方の末端にグルカゴン誘導体が共有的に連結された複合体を分離するステップと、
3)ステップ2)で分離された複合体を重合体キャリアと反応させるステップと、
4)ステップ3)の反応混合物から、非ペプチドリンカーの一方の末端にはグルカゴン誘導体が、他方の末端には重合体キャリアが共有的に連結された持続型グルカゴン結合体を分離するステップ。 - ステップ1)において、グルカゴン誘導体と非ペプチドリンカーとの反応が、1:5〜1:50の反応モル比で、pH7.5〜10.0の条件で行われるものである、請求項20に記載の製造方法。
- ステップ1)において、グルカゴン誘導体と非ペプチドリンカーとの反応が、還元剤の存在下で行われるものである、請求項20に記載の製造方法。
- 前記還元剤が、ナトリウムシアノボロハイドライド(NaCNBH3)、水素化ホウ素ナトリウム、ジメチルアミンホウ酸塩およびピリジンホウ酸塩からなる群より選択されるものである、請求項22に記載の製造方法。
- ステップ2)で分離された複合体が、グルカゴン誘導体のN末端以外のアミノ酸残基に非ペプチドリンカーの一方の末端が共有的に連結された、グルカゴン−非ペプチドリンカーの構造を有するものである、請求項20に記載の製造方法。
- 前記アミノ酸残基が、グルカゴン誘導体の12番目のリシン残基である、請求項24に記載の製造方法。
- ステップ3)において、複合体と重合体キャリアの反応が、1:2〜1:10の反応モル比で、pH5.0〜8.0で行われるものである、請求項20に記載の製造方法。
- ステップ3)において、複合体と重合体キャリアの反応が、還元剤の存在の下に行われるものである、請求項20に記載の製造方法。
- 還元剤が、ナトリウムシアノボロハイドライド(NaCNBH3)、水素化ホウ素ナトリウム、ジメチルアミンホウ酸塩およびピリジンホウ酸塩からなる群より選択されるものである、請求項27に記載の製造方法。
- ステップ4)で分離された持続型グルカゴン結合体が、グルカゴン−非ペプチドリンカー−重合体キャリアの構造を有するものである、請求項20に記載の製造方法。
- 下記のステップを含むものである、請求項20に記載の製造方法:
1)天然型グルカゴンのN末端ヒスチジン残基のアルファ炭素およびアルファ炭素に結合されたアミン基が除去されたイミダゾアセチルグルカゴンを両末端にアルデヒドを有するPEGとpH9.0で反応させるステップ:
2)ステップ1)の反応混合物から、グルカゴン誘導体の12番目のリシン残基にPEGの一方の末端が共有的に連結されたグルカゴン−PEG複合体を分離するステップ;
3)ステップ2)で分離されたグルカゴン誘導体−PEG複合体を兔疫グロブリンFc断片と反応させるステップ;および
4)ステップ3)の反応混合物から、PEGの一方の末端にはグルカゴン誘導体が、他方の末端には兔疫グロブリンFc断片が共有的に連結された持続型グルカゴン結合体を分離するステップ。 - 有効成分として請求項1記載の持続型グルカゴン結合体、抗肥満薬物および薬学的に許容可能な担体を含む、肥満の予防または治療用薬学的組成物。
- 前記抗肥満薬物が、GLP−1作動剤、レプチン(Leptin)作動剤、DPP−IV阻害剤、Y5受容体拮抗剤(antagonist)、メラニン濃縮ホルモン(melanin−concentrating hormone、MCH)拮抗剤、Y2/3作動剤、MC3/4作動剤、胃/膵臓リパーゼ(gastric/pancreatic lipase)阻害剤、5HT2c作動剤、β3A作動剤、アミリン(amylin)作動剤、グレリン(ghrelin)拮抗剤およびこれらの組み合わせからなる群より選択されるものである、請求項31に記載の薬学的組成物。
- 前記GLP−1作動剤が、エキセンディン−4、エキセンディン−4誘導体およびこれらの持続型結合体である、請求項32に記載の薬学的組成物。
- 前記エキセンディン−4誘導体が、天然型エキセンディン−4の1番目のN末端ヒスチジン残基のアミン基が除去された誘導体、その一番目のN末端ヒスチジン残基のアミン基がヒドロキシル基に置換された誘導体、その一番目のN末端ヒスチジン残基のアミン基が2個のメチル基で修飾された誘導体およびその一番目のN末端ヒスチジン残基のアルファ炭素およびアルファ炭素に結合されたアミン基が除去された誘導体からなる群より選択されるものである、請求項33に記載の薬学的組成物。
- 前記持続型エキセンディン−4結合体が、非ペプチドリンカーを介してエキセンディン−4またはその誘導体と兔疫グロブリンFc断片が共有的に連結された構造を有するものである、請求項33に記載の薬学的組成物。
- 前記持続型エキセンディン−4結合体が、非ペプチドリンカーの一方の末端にはエキセンディン−4誘導体が、他方の末端には兔疫グロブリンFc断片が共有的に連結された構造を有するものである、請求項35に記載の薬学的組成物。
- 請求項1記載の持続型グルカゴン結合体及び抗肥満薬物の組み合わせの、肥満の予防または治療用薬の製造のための使用。
- 前記抗肥満薬物が、GLP−1作動剤、レプチン(Leptin)作動剤、DPP−IV阻害剤、Y5受容体拮抗剤(antagonist)、メラニン濃縮ホルモン(melanin−concentrating hormone、MCH)拮抗剤、Y2/3作動剤、MC3/4作動剤、胃/膵臓リパーゼ(gastric/pancreatic lipase)阻害剤、5HT2c作動剤、βA作動剤、アミリン(amylin)作動剤、グレリン(ghrelin)拮抗剤およびこれらの組み合わせからなる群より選択されるものである、請求項37に記載の使用。
- 前記GLP−1作動剤が、エキセンディン−4、エキセンディン−4誘導体およびこれらの持続型結合体である、請求項38に記載の使用。
- 前記エキセンディン−4誘導体が、天然型エキセンディン−4一番目のN末端ヒスチジン残基のアミン基が除去された誘導体、その一番目のN末端ヒスチジン残基のアミン基がヒドロキシル基に置換された誘導体、その一番目のN末端ヒスチジン残基アミン基が2個のメチル基で修飾された誘導体およびその一番目のN末端ヒスチジン残基のアルファ炭素およびアルファ炭素に結合されたアミン基が除去された誘導体からなる群より選択されるものである、請求項39に記載の使用。
- 前記持続型エキセンディン−4結合体が、非ペプチドリンカーを介してエキセンディン−4またはその誘導体と兔疫グロブリンFc断片が共有的に連結された構造を有するものである、請求項39に記載の使用。
- 前記持続型エキセンディン−4結合体が、非ペプチドリンカーの一方の末端にはエキセンディン−4誘導体が、他方の末端には兔疫グロブリンFc断片が共有的に連結された構造を有し、前記エキセンディン−4誘導体がその一番目のN末端ヒスチジン残基のアルファ炭素およびアルファ炭素に結合されたアミン基が除去されたものである、請求項41に記載の使用。
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PCT/KR2011/005375 WO2012011752A2 (en) | 2010-07-21 | 2011-07-21 | Novel long-acting glucagon conjugate and pharmaceutical composition comprising the same for the prevention and treatment of obesity |
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