Secretan Philippe-Henri, Vieillard Victoire, Thirion Olivier, Annereau Maxime, Yayé Hassane Sadou, Astier Alain, Paul Muriel, Damy Thibaud, Do Bernard
Matériaux et Santé, Université Paris-Saclay, 91400 Orsay, France.
Department of Pharmacy, Henri Mondor Hospital, AP-HP, 94000 Créteil, France.
Antioxidants (Basel). 2023 Feb 9;12(2):424. doi: 10.3390/antiox12020424.
In vitro studies have shown that epigallocatechin gallate (EGCG), the most potent antioxidant of the green tea polyphenol catechins, is able to effectively prevent the formation of amyloid plaques and induce their clearance. However, its high chemical reactivity promotes high chemical instability, which represents a major obstacle for the development of pharmaceutical forms containing solubilized EGCG, an essential condition for a better systemic passage via the oral route. After discovering that EGCG forms a deep eutectic with choline chloride, we exploited this property to formulate and patent liquid-filled capsules containing 200-800 mg of soluble EGCG in easy-to-administer sizes. The gelatin envelopes used are of the conventional type and their filling has been achieved using 3D printing technology. Not only did the EGCG-choline complex allow the formulation of hydrophilic solutions with a high concentration of active substance but it also contributed significantly to its chemical stability, since after at least 18 months of storage at 25 °C/60% RH and one year at 40 °C/75% RH, the capsules show unchanged hardness, chromatographic profiles and antioxidant activity compared to T0. Preclinical studies in monkeys showed that bioavailability was increased by a factor of 10 compared to marketed capsules comprising EGCG powder. This pharmaceutical development was conducted in the context of upcoming clinical trials to evaluate EGCG alone or in combination when treating transthyretin and light-chain cardiac amyloidosis.
体外研究表明，表没食子儿茶素没食子酸酯（EGCG）是绿茶多酚类儿茶素中最有效的抗氧化剂，能够有效防止淀粉样斑块的形成并促使其清除。然而，其高化学反应活性导致化学稳定性较差，这对开发含有可溶解EGCG的药物剂型构成了重大障碍，而可溶解EGCG是实现更好的口服全身吸收的必要条件。在发现EGCG与氯化胆碱形成低共熔物后，我们利用这一特性研发并申请了专利，制备了易于给药规格的、含有200 - 800毫克可溶性EGCG的液囊。所使用的明胶外壳为常规类型，其填充采用了3D打印技术。EGCG - 胆碱复合物不仅能够制备出含有高浓度活性物质的亲水性溶液，还对其化学稳定性有显著贡献，因为在25℃/60%相对湿度下储存至少18个月以及在40℃/75%相对湿度下储存一年后，与初始状态（T0）相比，胶囊的硬度、色谱图谱和抗氧化活性均未改变。在猴子身上进行的临床前研究表明，与市售的含EGCG粉末胶囊相比，生物利用度提高了10倍。这项药物研发是在即将开展的临床试验背景下进行的，旨在评估单独使用EGCG或其与其他药物联合使用治疗转甲状腺素蛋白和轻链心脏淀粉样变性的效果。
