JP2012500254A - タンパク質の経口投与用の方法および組成物 - Google Patents
タンパク質の経口投与用の方法および組成物 Download PDFInfo
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- WBWWGRHZICKQGZ-GIHLXUJPSA-N taurocholic acid Chemical compound C([C@@H]1C[C@H]2O)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@H](O)C1 WBWWGRHZICKQGZ-GIHLXUJPSA-N 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
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Abstract
【選択図】図1
Description
例1:インスリン、SNAC、および、プロテアーゼインヒビター経口製剤
材料および実験方法
製剤
投与のX[挙げてください]日前、(1)[正確な担体であるもの]中の6mgのインスリン、250mgのSNAC、125mgのSBTI、(2)[正確な担体であるもの]中の6mgのインスリン、250mgのSNAC、2.5mgのアプロチニン、125mgのSBTI、(3)[正確な担体であるもの]中の6mgのインスリン、250mgのSNAC、2.5mgのアプロチニン、125mgのSBTI、(4)[正確な担体であるもの]中の6mgのインスリン、250mgのSNACを含有する製剤を調製した。製剤を投与まで冷蔵庫(4℃)で保管した。
次の実験では、「製剤」の章で記載した製剤を、3人の健康なヒト被験体に経口摂取させた。図1に示すように、製剤(1)および(3)で処置したヒト被験体では、血糖値は著しく減少し、安定した。このような結果は、プロテアーゼインヒビターとSNACの組み合わせを含む製剤がSNACのみを含む製剤よりも優れていることを示している。具体的に、SNACとSBTIとの組み合わせは、用いられた他のいずれの製剤よりも優れている。インスリンと単一のプロテアーゼインヒビターからなる製剤は血糖値降下作用を有しておらず、血糖値の低下の違いは、単一のプロテアーゼインヒビター(SBTIまたはアプロチニン)を含む同じ製剤を用いた以前の実験では何も観察されなかったことから、SNACとプロテアーゼインヒビターの効果は相乗的であることに着目することが肝要である。したがって、インスリンとSNACと少なくとも1つのプロテアーゼインヒビターの組み合わせとを用いた血糖値の低下に関する結果は、予想外のものであった。SNACとSBTIを含む製剤は、血糖値を低下させる相乗的で最大限の効果を有している。
オメガ3脂肪酸(例えば、明細書で先に挙げたもの)の様々なオメガ3脂肪酸またはオメガ3脂肪酸源を、本発明の方法および組成物における経口投与後のインスリン保存能力に関して比較する。インスリンが魚油の代わりに代替源中で溶解するということを除いて、インスリン錠またはカプセルを上記例で記載されたように処方する。オメガ3脂肪酸の最も効果的な供給源を、以下の例で用いる。
様々なプロテアーゼインヒビター(無毒性か、または、許容可能な毒性特性を有するもの。例えば、明細書で先に挙げたもの)を、本発明の方法および組成物における経口投与後のインスリン保存能力に関して比較する。代替的なプロテアーゼインヒビターをSBTIおよび/またはアプロチニンの代わりにするということを除いて、インスリンまたはエクセナチド錠またはカプセルを上記例で記載されたように処方する。最適な量を決めるために、プロテアーゼインヒビターの量も変化させる。最も効果的なプロテアーゼインヒビター/その量を、以下の例で用いる。
様々なエンハンサー(例えば、明細書で先に挙げたもの)を、本発明の方法および組成物における経口投与後のインスリンの吸収を促進する能力に関して比較する。代替的なエンハンサーをEDTAの代わりにするということを除いて、インスリン錠またはカプセルを上記例で記載されたように処方する。最適な量を決めるために、エンハンサーの量も変化させる。最も効果的なエンハンサー/その量を、以下の実験で用いる。
例1:インスリン、SNAC、および、プロテアーゼインヒビター経口製剤
材料および実験方法
製剤
(1)6mgのインスリン、250mgのSNAC、125mgのSBTI、(2)6mgのインスリン、250mgのSNAC、2.5mgのアプロチニン、125mgのSBTI、(3)6mgのインスリン、250mgのSNAC、2.5mgのアプロチニン、125mgのSBTI、(4)6mgのインスリン、250mgのSNACを含有する製剤を調製した。製剤を投与まで冷蔵庫(4℃)で保管した。
Claims (31)
- 最大100000ダルトンの分子量を有するタンパク質と、
プロテアーゼインヒビターと、および、
吸収エンハンサーとを含む組成物であって、
前記吸収エンハンサーは、腸管粘膜バリアを介して前記タンパク質の吸収を高めることを特徴とする組成物。 - 前記組成物が経口医薬組成物であることを特徴とする請求項1記載の組成物。
- 前記吸収エンハンサーが、N−(8−[2−ヒドロキシベンゾイル]アミノ)カプリル酸(SNAC)、ナトリウムN−(10−[2−ヒドロキシベンゾイル]アミノ)デカン酸(SNAD)、または、それらの組み合わせであることを特徴とする請求項1記載の組成物。
- 前記タンパク質が、インスリン、グルカゴン、インターフェロン・ガンマ、インターフェロン・アルファ、成長ホルモン、エリスロポエチン、GLP−1、GLP−1アナログ、または、顆粒球コロニー刺激因子(G−CSF)であることを特徴とする請求項1記載の組成物。
- 前記プロテアーゼインヒビターが、セルピン、自殺阻害剤、遷移状態阻害剤、タンパク質プロテアーゼインヒビター、キレート剤、システインプロテアーゼインヒビター、トレオニンプロテアーゼインヒビター、アスパラギン酸プロテアーゼインヒビター、または、メタロプロテアーゼインヒビターであることを特徴とする請求項1記載の組成物。
- 前記セルピンがトリプシンインヒビターであることを特徴とする請求項5記載の組成物。
- 前記トリプシンインヒビターが、リママメトリプシンインヒビター、アプロチニン、大豆トリプシンインヒビター(SBTI)、または、オボムコイドであることを特徴とする請求項6記載の組成物。
- オメガ3脂肪酸をさらに含むことを特徴とする請求項1記載の組成物。
- EDTAまたはその塩をさらに含むことを特徴とする請求項1記載の組成物。
- 前記吸収エンハンサーが胆汁酸またはそのアルカリ金属塩であることを特徴とする請求項1記載の組成物。
- 被験体の胃において前記組成物の消化を抑制するコーティング、腸内コーティング、または、ゼラチンコーティングをさらに含むことを特徴とする請求項1記載の組成物。
- 最大100000ダルトンの分子量を有するタンパク質を被験体に経口投与するための方法であって、
前記タンパク質のかなりの割合が前記被験体の腸管粘膜バリアを介した吸収後もその活性を維持し、
前記方法はさらに、
前記タンパク質、プロテアーゼインヒビター、および、吸収エンハンサーを含む医薬組成物を前記被験体に経口投与する工程を含み、
これによって、前記吸収エンハンサーは腸管粘膜バリアを介した前記タンパク質の吸収を高めることを特徴とする方法。 - 前記吸収エンハンサーは、N−(8−[2−ヒドロキシベンゾイル]アミノ)カプリル酸(SNAC)、ナトリウムN−(10−[2−ヒドロキシベンゾイル]アミノ)デカン酸(SNAD)、または、それらの組み合わせであることを特徴とする請求項12記載の方法。
- 前記タンパク質が酵素であることを特徴とする請求項12記載の方法。
- 前記タンパク質が、インスリン、グルカゴン、インターフェロン・ガンマ、インターフェロン・アルファ、成長ホルモン、エリスロポエチン、GLP−1、GLP−1アナログ、または、顆粒球コロニー刺激因子(G−CSF)であることを特徴とする請求項12記載の方法。
- 前記組成物がオメガ3脂肪酸をさらに含むことを特徴とする請求項12記載の方法。
- 前記プロテアーゼインヒビターが、セルピン、自殺阻害剤、遷移状態阻害剤、タンパク質プロテアーゼインヒビター、キレート剤、システインプロテアーゼインヒビター、トレオニンプロテアーゼインヒビター、アスパラギン酸プロテアーゼインヒビター、または、メタロプロテアーゼインヒビターであることを特徴とする請求項12記載の方法。
- 前記セルピンがトリプシンインヒビターであることを特徴とする請求項17記載の方法。
- 前記トリプシンインヒビターが、リママメトリプシンインヒビター、アプロチニン、大豆トリプシンインヒビター(SBTI)、または、オボムコイドであることを特徴とする請求項18記載の方法。
- EDTAまたはその塩をさらに含むことを特徴とする請求項12記載の方法。
- 前記吸収エンハンサーが胆汁酸またはそのアルカリ金属塩であることを特徴とする請求項12記載の方法。
- 被験体の胃において前記組成物の消化を抑制するコーティング、腸内コーティング、または、ゼラチンコーティングをさらに含むことを特徴とする請求項17記載の方法。
- 被検体の真性糖尿病を処置する方法であって、
前記方法は、
インスリンと、エクセナチドと、またはそれらの組み合わせと、プロテアーゼインヒビターと、および、吸収エンハンサーとを含む医薬組成物を、前記被検体に経口投与する工程を備え、
前記吸収エンハンサーは腸管粘膜バリアを介した前記タンパク質の吸収を高め、
これによって真性糖尿病を処置することを特徴とする方法。 - 前記タンパク質が酵素であることを特徴とする請求項23記載の方法。
- 前記吸収エンハンサーは、N−(8−[2−ヒドロキシベンゾイル]アミノ)カプリル酸(SNAC)、ナトリウムN−(10−[2−ヒドロキシベンゾイル]アミノ)デカン酸(SNAD)、または、それらの組み合わせであることを特徴とする請求項23記載の方法。
- 前記組成物がオメガ3脂肪酸をさらに含むことを特徴とする請求項23記載の方法。
- 前記プロテアーゼインヒビターが、セルピン、自殺阻害剤、遷移状態阻害剤、タンパク質プロテアーゼインヒビター、キレート剤、システインプロテアーゼインヒビター、トレオニンプロテアーゼインヒビター、アスパラギン酸プロテアーゼインヒビター、または、メタロプロテアーゼインヒビターであることを特徴とする請求項23記載の方法。
- 前記セルピンがトリプシンインヒビターであることを特徴とする請求項23記載の方法。
- EDTAまたはその塩をさらに含むことを特徴とする請求項23記載の方法。
- 前記吸収エンハンサーが胆汁酸またはそのアルカリ金属塩であることを特徴とする請求項23記載の方法。
- 被験体の胃において前記組成物の消化を抑制するコーティング、腸内コーティング、または、ゼラチンコーティングをさらに含むことを特徴とする請求項23記載の方法。
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CN102123697A (zh) | 2011-07-13 |
JP5981575B2 (ja) | 2016-08-31 |
US20180280292A1 (en) | 2018-10-04 |
CA2734442C (en) | 2016-08-16 |
US9186412B2 (en) | 2015-11-17 |
CN102123697B (zh) | 2015-06-10 |
EP2331072A4 (en) | 2013-12-18 |
NZ591497A (en) | 2012-11-30 |
US10010503B2 (en) | 2018-07-03 |
JP5740689B2 (ja) | 2015-06-24 |
US20190380953A1 (en) | 2019-12-19 |
US20110142800A1 (en) | 2011-06-16 |
RU2011108334A (ru) | 2012-09-27 |
CA2734442A1 (en) | 2010-02-25 |
EP2331072B1 (en) | 2020-07-22 |
US11246827B2 (en) | 2022-02-15 |
US20160058699A1 (en) | 2016-03-03 |
AU2009283821A1 (en) | 2010-02-25 |
WO2010020978A1 (en) | 2010-02-25 |
US20220151919A1 (en) | 2022-05-19 |
RU2646828C2 (ru) | 2018-03-07 |
ES2823233T3 (es) | 2021-05-06 |
US10420721B2 (en) | 2019-09-24 |
EP3741359A1 (en) | 2020-11-25 |
JP6124095B2 (ja) | 2017-05-10 |
RU2013130611A (ru) | 2015-01-10 |
JP2015107990A (ja) | 2015-06-11 |
EP2331072A1 (en) | 2011-06-15 |
JP2016185970A (ja) | 2016-10-27 |
EP2331072B8 (en) | 2020-08-26 |
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