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: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=682081
• 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.

口服给药的一个主要挑战是许多晶体化合物的生物利用度低，具有较差的溶解度。提高溶解度的传统方法涉及增溶剂（如助溶剂和表面活性剂）和减小粒径并不总是成功的。另一方面，由于非晶态药物的高溶解度（过饱和），在可溶性聚合物中创建固溶体（分子分散体）已显示出在增强溶解和口服生物利用度方面有效的潜力。然而，药物在非晶态固溶体中的溶解和释放机制及其对溶解过程中过饱和总体时间演变的影响尚不清楚，也没有得到充分的探讨。此外，这些系统在储存过程中的物理不稳定性，如结晶和老化，限制了它们在商业应用中的成功。此外，在确定这些可溶性聚合物中可能发生结晶的阈值药物负荷水平时，没有标准存在。尽管人们一直对水凝胶作为生物材料和药物控释载体感兴趣，但交联玻璃水凝胶在将载药稳定在无定形状态方面的新应用尚未得到充分研究。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更有效地防止负载非晶态药物的结晶。实验证据表明，基于水凝胶的固溶体也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谱中的峰和谷，从而实现比基于可溶性聚合物的传统体系更持久的药物过饱和。因此，我们建议对这种基于水凝胶的系统进行深入的研究，并确定最佳的设计参数范围，以有效地抑制负载药物的结晶，最大限度地保持过饱和度，以增强难溶性药物的递送。