JP2015533166A - 糖尿病性腎症および関連障害の処置のためのガラクトース分枝炭水化物化合物 - Google Patents
糖尿病性腎症および関連障害の処置のためのガラクトース分枝炭水化物化合物 Download PDFInfo
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Abstract
Description
本出願は、2012年10月10日出願の米国仮出願番号61/711,929の利益およびそれに対する優先権を主張し、その開示は引用によりその全体を本明細書に包含させる。
本発明の面は、医薬グレードのガラクトース分枝(pronged)多糖またはその医薬組成物を使用する糖尿病性腎症および関連障害の処置法に関する。
糖尿病性腎症は、腎糸球体の毛細血管の血管障害が原因である進行性腎疾患である。病理学的に汎発性糸球体硬化症として特徴付けられ、これはタンパク尿、ネフローゼ症候群、糸球体濾過率の進行性低下をもたらし、最終的に腎不全となる。
糖尿病性腎症は長年の糖尿病が原因であり、西洋諸国では透析の主適応症である。
本発明のある面は、糖尿病性腎症の処置おける適切なまたは増強された効果を有する治療剤に関する。ある態様において、本治療剤は、有効量のガラクトース分枝多糖化合物を含む。ある態様において、本治療剤は単独で投与しても、有効量の治療剤と混合してまたは一つのレジメンとして併用される。本製剤は、さらに、糖尿病性腎症もしくは糖尿病の処置用の併用治療剤を含んでもよく、または本製剤が粉末形態または液体形態であるときには添加物も含み得る。
本発明を、添付する図面を参照してさらに説明し、ここで、同じ構造は数枚の図を通して同じ数表示で引用する。示す図面は必ずしも縮尺どおりではなく、むしろ、本発明の原理を説明するための強調を含んでいる。
本発明の詳細な態様をここに記載するが、しかしながら、開示した態様は、種々の形態に具体化できる本発明の単なる説明例であると解釈されるべきである。さらに、本発明の種々の態様に関連して示す実施例の各々は説明的であり、限定的ではないことを意図する。さらに、図は必ずしも縮尺どおりではなく、ある特性を特定の要素の詳細を示すために誇張していることがある。さらに、図に示すあらゆる測定値、仕様などは説明的であり、限定的ではないことを意図する。それゆえに、ここに記載する具体的構造的および機能的詳細は限定ではなく、当業者に本発明を様々に用いることを教示するための代表的基板として解釈すべきである。
糖尿病(I型およびII型)患者の20%〜40%が最終的に糖尿病性腎症を発症する。糖尿病性腎症はまたキンメルスティール・ウィルソン症候群または結節性糖尿病性糸球体硬化症および毛細血管間糸球体腎炎としても知られ、腎糸球体における毛細血管の血管障害が原因の進行性腎疾患である。糖尿病性腎症は米国および他の西欧諸地域での慢性腎疾患の主原因であり、米国の全末期腎疾患の30〜40%の原因である。また糖尿病を有する個々の患者での罹病率および死亡率の点で最も顕著な長期合併症の一つでもある。
ある態様において、本ガラクトマンナン多糖組成物は、1.7:1のマンノース分子対ガラクトース分子比を有する。
下記は、治療的多糖の製造の説明的例であり、これは本発明を限定することを意味しない。この場合、ガラクトース分枝炭水化物化合物はガラクトアラビノ−ラムノガラクツロネートであり、本明細書では製品はGR−MD−02/001Bとラベルされている。
本実施例で使用した実験モデルは、糖尿病を誘発し、高脂肪餌を投与したマウスである。糖尿病は、生まれた直後のストレプトゾトシンの1回注射により誘発した。4週間後、マウスの高脂肪餌を開始した。
Claims (20)
- a. 医薬許容される担体中にガラクト−ラムノガラクツロネートを含む非経腸または経腸投与用組成物を得て、
b. 処置を必要とする対象に該組成物を、
タンパク尿の少なくとも10%減少またはタンパク尿の増加率の少なくとも10%減少、
糸球体濾過率の少なくとも10%増加または糸球体濾過率の低下率の少なくとも10%減少、
細胞外メサンギウム基質の少なくとも10%減少または少なくとも10%の増加率の少なくとも10%減少、
糸球体毛細管基底膜厚の少なくとも5%減少、
メサンギウムの体積比の少なくとも10%減少またはメサンギウムの体積比の増加率の少なくとも10%減少、
間質性尿細管体積の少なくとも10%減少または間質性体積の増加率の少なくとも10%減少、
間質性尿細管間隙におけるコラーゲン量の少なくとも10%減少または間質性尿細管間隙におけるコラーゲンの増加率の少なくとも10%減少、
糖尿病性腎症の血清バイオマーカーレベルの少なくとも10%の変化
の少なくとも一つを生じる有効量で投与することを含み、
ここで、処置を必要とする対象が原発性糸球体症疾患、二次性糸球体症疾患および尿細管間質性障害の少なくとも一つを有し、
有効量が0.1mg/kg〜9.99mg/kgの動物用量と同等である、
方法。 - ガラクト−ラムノガラクツロネートが、α−1,2−結合ラムノース残基およびα−1,4−結合GalA残基が交互に結合しているオリゴマーの分枝ヘテロポリマーに結合した1,4−結合ガラクツロン酸(GalA)およびガラクツロン酸メチル(MeGalA)残基主鎖を含み、該ラムノース残基が、1,4−β−D−ガラクトース残基のオリゴマーの一次分枝を有し得る、請求項1に記載の方法。
- ガラクト−ラムノガラクツロネートが、α−1,2−結合ラムノース残基およびα−1,4−結合GalA残基が交互に結合しているオリゴマーの分枝ヘテロポリマーに結合した1,4−結合ガラクツロン酸(GalA)残基主鎖を含み、該ラムノース残基が、1,4−β−D−ガラクトース残基のオリゴマーの一次分枝を有する、請求項1に記載の方法。
- ガラクト−ラムノガラクツロネートがさらにキシロース、グルコース、フコース残基またはこれらの組み合わせを含む、請求項1に記載の方法。
- ガラクト−ラムノガラクツロネートが、SEC−RIおよび/またはSEC−MALLS法により測定して、2,000〜80,000ダルトン、20,000〜70,000ダルトンまたは5,000〜55,000ダルトンの平均分子量分布を有する、請求項1に記載の方法。
- ガラクト−ラムノガラクツロネートが1,5−α−L−Ara残基を実質的に含まない、請求項1に記載の方法。
- 糖尿病性腎症の血清バイオマーカーが炎症性および血行力学性サイトカイン類、TNF−アルファ、TGF−ベータまたはIL−8、オステオポンチンまたは糖尿病性腎症の存在または重症度の指標である血清成分の代謝プロファイルを含む、請求項1に記載の方法。
- 組成物が1種以上のガレクチン阻害剤をさらに含む、請求項1に記載の方法。
- ガレクチン阻害剤がガレクチンの小有機阻害剤、モノクローナル抗体、RNA阻害剤、小結合ペプチド、タンパク質阻害剤またはこれらの組み合わせを含む、請求項9に記載の方法。
- 有効量が0.05〜0.49mg/kgの範囲である、請求項1に記載の方法。
- a. 医薬許容される担体中にガラクトアラビノ−ラムノガラクツロネートを含む非経腸または経腸投与用組成物を得て、
b. 処置を必要とする対象に該組成物を、
タンパク尿の少なくとも10%減少またはタンパク尿の増加率の少なくとも10%減少、
糸球体濾過率の少なくとも10%増加または糸球体濾過率の低下率の少なくとも10%減少、
細胞外メサンギウム基質の少なくとも10%減少または少なくとも10%の増加率の少なくとも10%減少、
糸球体毛細管基底膜厚の少なくとも5%減少、
メサンギウムの体積比の少なくとも10%減少またはメサンギウムの体積比の増加率の少なくとも10%減少、
間質性尿細管体積の少なくとも10%減少または間質性体積の増加率の少なくとも10%減少、
間質性尿細管間隙におけるコラーゲン量の少なくとも10%減少または間質性尿細管間隙におけるコラーゲンの増加率の少なくとも10%減少、
糖尿病性腎症の血清バイオマーカーレベルの少なくとも10%の変化有効量で投与する
の少なくとも一つを生じる有効量で投与することを含み、
ここで、処置を必要とする対象が原発性糸球体症疾患、二次性糸球体症疾患および尿細管間質性障害の少なくとも一つを有し、
有効量が0.1mg/kg〜1.99mg/kgの動物用量と同等である、
方法。 - ガラクト−ラムノガラクツロネートが、α−1,2−結合ラムノース残基およびα−1,4−結合GalA残基が交互に結合しているオリゴマーの分枝ヘテロポリマーに結合した1,4−結合ガラクツロン酸(GalA)およびガラクツロン酸メチル(MeGalA)残基主鎖を含むガラクトアラビノ−ラムノガラクツロネートであり、該ラムノース残基が、1,4−β−D−ガラクトース残基、1,5−α−L−アラビノース残基またはこれらの組み合わせのオリゴマーの一次分枝を有する、請求項11に記載の方法。
- 1,4−β−D−Gal残基、1,5−α−L−Ara残基およびこれらの組み合わせのモルパーセントが炭水化物の総モルの少なくとも8%である、請求項11に記載の方法。
- 1,4−β−D−Gal残基および1,5−α−L−Ara残基が1:1〜3:1の範囲の比で存在する、請求項11に記載の方法。
- ガラクトアラビノ−ラムノガラクツロネートが、SEC−RIおよび/またはSEC−MALLS法により測定して、2,000〜80,000ダルトン、20,000〜70,000ダルトンまたは5,000〜55,000ダルトンの平均分子量分布を有する、請求項11に記載の方法。
- ガラクトアラビノ−ラムノガラクツロネートが40〜70%の範囲のメトキシル化の程度を有する、請求項11に記載の方法。
- ガラクトアラビノ−ラムノガラクツロネートが、4:1〜7:1の範囲のガラクツロン酸メチル+ガラクツロン酸対ガラクトース比を有する、請求項11に記載の方法。
- 有効量が0.05〜0.19mg/kgの範囲である、請求項11に記載の方法。
- 糖尿病性腎症の処置に使用するための、許容される医薬担体中にガラクトアラビノ−ラムノガラクツロネート0.1mg/kg〜1.99mg/kgの動物用量と同等の有効量を含む組成物であって、ガラクトアラビノ−ラムノガラクツロネートが、α−1,2−結合ラムノース残基およびα−1,4−結合GalA残基が交互に結合しているオリゴマーの分枝ヘテロポリマーに結合した1,4−結合ガラクツロン酸(GalA)およびガラクツロン酸メチル(MeGalA)残基主鎖を含み、該ラムノース残基が、1,4−β−D−ガラクトース残基、1,5−α−L−アラビノース残基またはこれらの組み合わせのオリゴマーの一次分枝を有し得る、組成物。
- 糖尿病性腎症の処置に使用するための、許容される医薬担体中にガラクト−ラムノガラクツロネート.1mg/kg〜9.99mg/kgの動物用量と同等の有効量を含む組成物であって、ガラクト−ラムノガラクツロネートが、α−1,2−結合ラムノース残基およびα−1,4−結合GalA残基が交互に結合しているオリゴマーの分枝ヘテロポリマーに結合した1,4−結合ガラクツロン酸(GalA)残基主鎖を含み、該ラムノース残基が、1,4−β−D−ガラクトース残基のオリゴマーの一次分枝を有する、組成物。
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MX363178B (es) | 2019-03-13 |
KR102231732B1 (ko) | 2021-03-23 |
CA2926917A1 (en) | 2014-04-17 |
CN104822382A (zh) | 2015-08-05 |
IL238180A0 (en) | 2015-05-31 |
EP2906227A4 (en) | 2016-06-08 |
ES2698101T3 (es) | 2019-01-31 |
CN104822382B9 (zh) | 2019-01-18 |
BR112015007985A8 (pt) | 2019-08-27 |
CN104822382B (zh) | 2018-10-30 |
EP2906227B1 (en) | 2018-10-03 |
DK2906227T3 (en) | 2018-12-10 |
US20140099319A1 (en) | 2014-04-10 |
IL238180B (en) | 2020-03-31 |
AU2013329148B2 (en) | 2018-03-29 |
JP6055928B2 (ja) | 2016-12-27 |
EP2906227A1 (en) | 2015-08-19 |
MX2015004644A (es) | 2016-01-12 |
KR20150081431A (ko) | 2015-07-14 |
ZA201503042B (en) | 2016-01-27 |
US8828971B2 (en) | 2014-09-09 |
BR112015007985A2 (pt) | 2017-07-04 |
WO2014059135A1 (en) | 2014-04-17 |
CA2926917C (en) | 2021-01-05 |
AU2013329148A1 (en) | 2015-04-30 |
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