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

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，过饱和积累速率对溶解过程中过饱和的总体时间演变的影响还没有得到很好的理解，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稳定溶解药物的无定形状态和提高难溶性药物的溶解性和生物利用度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阻止了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。提出的研究的长期目标是阐明基于玻璃亲水聚合物的固溶体（分子分散体）产生过饱和的演变，以及控制这种非晶态固溶体在固体状态下在玻璃水凝胶中的稳定的潜在机制。我们的直接目标是深入了解溶解药物在水凝胶相中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，以及在非沉降溶解过程中产生过饱和的机制，以及影响其持续过饱和行为的参数。我们拟对难溶性药物在交联水凝胶中的固溶体进行深入的机理和实验研究，包括：(1)载药效应及其对聚合物基质（无定形或结晶）中药物状态的影响，以及药物释放机制；(2)聚合物水化对药物结晶动力学的影响是温度、吸水量、载药量和聚合物性质的函数；(3)难溶性药物固溶体在玻璃状水凝胶中过饱和的演变。我们希望建立这些参数的标准和限制范围，以有效抑制载药在玻璃状水凝胶中的成核和结晶，并产生最佳过饱和速率，使动力学溶解度浓度-时间剖面的曲线下面积（AUC）最大化。这些方面对于玻璃状水凝胶中稳定的非晶态固溶体/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.