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，这些化合物表现出较差的溶解特性。使用增溶剂(如共溶剂和表面活性剂)和减小颗粒尺寸的传统增溶方法并不总是成功的。另一方面，由于无定形药物(过饱和)的较高溶解度，在可溶聚合物中形成固体溶液(分子分散体)在提高药物的溶出度和口服生物利用度方面具有潜在的潜力。然而，过饱和累积速率对溶解过程中过饱和总体时间演化的影响还不是很清楚，也没有得到充分的研究。此外，这些体系在储存过程中的物理不稳定性，如老化结晶，限制了它们在商业应用中的成功。此外，在确定这些可溶聚合物中可能发生结晶的阈值载药量水平方面没有标准。尽管水凝胶作为生物材料和药物控制释放的载体一直受到人们的关注，但用于稳定非晶态溶解药物和提高难溶药物的溶出度和生物利用度的交联玻璃水凝胶的新应用还没有得到充分的研究。在这方面，交联水凝胶比可溶性聚合物更有优势，因为玻璃态的三维网络在防止初始成核和随后的晶体生长方面更有效。初步证据表明，基于水凝胶的固溶体还可以避开通常与基于可溶聚合物的固溶体相关的动力学溶解度分布中的峰和谷，从而实现比基于可溶聚合物的传统体系更持久的药物过饱和。本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)产生过饱和度的演化以及控制这种无定形固溶体在玻璃态水凝胶中稳定的潜在机制。我们的近期目标是深入了解药物在水凝胶相中的成核和结晶动力学随载药量、湿度和聚合物特性的变化，以及扩散控制的玻璃水凝胶体系在非沉淀式溶解过程中产生过饱和的机理和影响其持续过饱和行为的参数。我们建议从力学和实验两方面深入研究难溶药物在交联水凝胶中的固溶体：(1)载药效应及其对药物在聚合物基质(无定形或晶态)中的状态的影响，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，作为温度、吸水率、载药量和聚合物性质的函数；以及(3)难溶药物在玻璃水凝胶中固溶体产生的过饱和度的演化。我们希望建立这些参数的标准和限制范围，能够有效地抑制载药在玻璃水凝胶中的成核和结晶，并产生最优的过饱和速率，使动力学溶解度浓度-时间分布的曲线下面积(AUC)最大化。这些方面对于设计玻璃水凝胶中稳定的无定形固体溶液/分散体及其增强难溶药物输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.