Amorphous Solid Solutions in Glassy Hydrogels for Enhancing the Delivery of Poorly Soluble Drugs

玻璃状水凝胶中的无定形固溶体增强难溶性药物的递送

• 批准号: RGPIN-2019-05459
• 负责人: Lee, Ping
• 金额: $ 2.04万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=738310
• 关键词: Amorphous; Solid; Solutions; Glassy; Hydrogels

One major challenge in oral drug delivery has been the low bioavailability of many crystalline compounds exhibiting poor solubility characteristics. Traditional methods for solubility enhancement involving solubilizing agents (e.g. co-solvents & surfactants) and particle size reduction have not always been successful. On the other hand, the creation of solid solutions (molecular dispersions) in soluble polymers has shown potential to be effective in enhancing the dissolution and oral bioavailability due to the higher solubility of the amorphous drug (supersaturation). However, the mechanisms of drug dissolution and release from amorphous solid solutions and their effect on the overall time evolution of supersaturation during dissolution are not well understood and have not been fully explored. In addition, physical instability of these systems during storage such as crystallization on aging has limited their success in commercial applications. Furthermore, no criterion exists in determining the threshold drug loading level above which crystallization may occur in these soluble polymers. Despite the ongoing interest in hydrogels as biomaterials and carriers for controlled drug release, the novel application of cross-linked glassy hydrogels for stabilizing the loaded drug in an amorphous state has not been fully investigated. Cross-linked hydrogels are more advantageous than soluble polymers in this regard since the three-dimensional network in the glassy state is more effective in preventing the crystallization of loaded amorphous drug. Experimental evidence suggests that solid solutions based on hydrogels can also avoid peaks and valleys in the kinetic solubility profiles normally associated with solid solutions based on soluble polymers, thereby achieving a more sustained drug supersaturation than conventional systems based on soluble polymers. We therefore propose to conduct an in-depth investigation of this hydrogel-based system and identify the optimal range of design parameters that can effectively inhibit the crystallization of loaded drug and maximize the supersaturation maintenance to enhance the delivery of poorly soluble drugs.

口服药物递送的一个主要挑战是许多表现出不良溶解度特性的结晶化合物的低生物利用度。涉及增溶剂（例如助溶剂和表面活性剂）和减小粒度的传统溶解度增强方法并不总是成功的。另一方面，在可溶性聚合物中形成固溶体（分子分散体）已显示出由于无定形药物的较高溶解度（过饱和）而有效提高溶出度和口服生物利用度的潜力。然而，药物从无定形固体溶液中溶解和释放的机制及其对溶解过程中过饱和度的总体时间演变的影响还没有很好地理解，也没有得到充分的探索。此外，这些体系在储存期间的物理不稳定性，例如老化时的结晶，限制了它们在商业应用中的成功。此外，没有标准存在于确定阈值载药量水平，高于该阈值载药量水平，在这些可溶性聚合物中可能发生结晶。尽管水凝胶作为生物材料和载体用于控制药物释放的持续的兴趣，交联的玻璃态水凝胶用于稳定无定形状态的负载药物的新应用尚未被充分研究。在这方面，交联水凝胶比可溶性聚合物更有利，因为玻璃态的三维网络在防止负载的无定形药物结晶方面更有效。实验证据表明，基于水凝胶的固溶体还可以避免通常与基于可溶性聚合物的固溶体相关的动力学溶解度曲线中的峰和谷，从而实现比基于可溶性聚合物的常规系统更持续的药物过饱和。因此，我们建议进行深入的调查，这种水凝胶为基础的系统，并确定最佳范围的设计参数，可以有效地抑制装载的药物的结晶，并最大限度地维持过饱和，以提高交付的难溶性药物。