Evolution of Supersaturation Generated from Amorphous Solid Solutions of Poorly Soluble Drugs in Glassy Hydrogels

口服药物递送的一大挑战是许多表现出较差溶解度特性的结晶化合物的生物利用度低。涉及增溶剂（例如共溶剂和表面活性剂）和减小粒径的传统增强溶解度的方法并不总是成功。另一方面，由于无定形药物（过饱和）的溶解度较高，在可溶性聚合物中形成固溶体（分子分散体）已显示出有效增强溶出度和口服生物利用度的潜力。然而，过饱和度形成速率对溶解过程中过饱和度总体时间演化的影响尚不清楚，也尚未得到充分探索。此外，这些系统在储存过程中的物理不稳定性（例如老化结晶）限制了它们在商业应用中的成功。此外，在确定阈值药物负载水平方面不存在标准，高于该阈值药物负载水平可能在这些可溶性聚合物中发生结晶。尽管人们对水凝胶作为生物材料和控制药物释放的载体一直感兴趣，但交联玻璃状水凝胶用于将溶解的药物稳定在无定形状态以及提高难溶性药物的溶解和生物利用度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初始成核和随后的晶体生长。初步证据表明，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传统系统更持久的药物过饱和度。拟议研究的长期目标是阐明基于玻璃状亲水性聚合物的固溶体（分子分散体）产生过饱和度的演变以及控制玻璃状水凝胶中此类无定形固溶体稳定的基本机制在固态。我们的近期目标是深入了解水凝胶相中溶解药物的成核和结晶动力学，作为药物负载、湿度水平和聚合物特性的函数，以及这种扩散控制玻璃状水凝胶系统非下沉溶解过程中过饱和产生的机制以及影响其持续过饱和行为的参数。我们建议从机械和实验方面对交联水凝胶中难溶性药物的固溶体进行深入研究，包括（1）载药量的影响及其对聚合物基质中药物状态（无定形或结晶）的影响以及对药物释放机制的影响； (2) 聚合物水合对药物结晶动力学的影响，作为温度、吸水量、载药量和聚合物性质的函数； (3)难溶性药物在玻璃状水凝胶中的固溶体产生的过饱和度的演变。我们希望建立这些参数的标准和限制范围，以有效抑制玻璃状水凝胶中负载药物的成核和结晶，并产生最佳的过饱和率，使动力学溶解度浓度-时间曲线的曲线下面积（AUC）最大化。这些方面对于玻璃水凝胶中稳定的无定形固溶体/分散体的设计及其增强难溶性药物递送的能力具有重要意义。

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 effect of rate of supersaturation build-up on the overall time evolution of supersaturation during dissolution is not well understood and has 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 dissolved drug in an amorphous state and for enhancing the dissolution and bioavailability of poorly soluble drugs has not been fully investigated. Cross-linked hydrogels are more advantageous than soluble polymers in this regard as the three-dimensional network in the glassy state is more effective in preventing the initial nucleation and subsequent crystal growth. Preliminary 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.The long-term objective of the proposed research is to elucidate the evolution of supersaturation generation from solid solutions (molecular dispersions) based on glassy hydrophilic polymers and the underlying mechanisms governing governing the stabilization of such amorphous solid solutions in glassy hydrogels in the solid state. Our immediate objective is aimed at gaining an in-depth understanding of the kinetics of nucleation and crystallization of dissolved drug in the hydrogel phase as a function of drug loading, humidity level, and polymer characteristics, as well as the mechanism of supersaturation generation during nonsink dissolution from such diffusion-controlled glassy hydrogel systems and parameters that affect their sustained supersaturation behavior. We propose to conduct an in-depth investigation of solid solutions of poorly soluble drugs in cross-linked hydrogels, both mechanistically and experimentally, in terms of (1) effect of drug loading and its influence on the state of drug in the polymer matrix (amorphous or crystalline), and on the mechanisms of drug release; (2) the effect of polymer hydration on the drug crystallization kinetics as a function of temperature, water uptake, drug loading and polymer properties; and (3) the evolution of supersaturation generated from solid solutions of poorly soluble drugs in glassy hydrogels . We hope to establish criteria and limiting ranges of these parameters that can effectively inhibit the nucleation and crystallization of loaded drug in glassy hydrogels as well as generate an optimal supersaturation rate which maximizes the area-under-the-curve (AUC) of the kinetic solubility concentration-time profile. These aspects are of significant importance to the design of stable amorphous solid solutions/dispersions in glassy hydrogels and their ability to enhance the delivery of poorly soluble drugs.