Enhanced Oral Delivery of Low Solubility Drugs using Cocrystal Design

描述（由申请人提供）：开发新的口服活性治疗剂以治疗许多人类疾病的主要障碍是这些药物在肠道的水性环境中的溶解度差。共晶体（活性治疗剂与良性分子复合的化学计量分子复合物）代表了一种潜在的有吸引力的新方法，可用于修改和调整溶解度和溶出特性，以增强和[调节]生物利用度。共晶固体已经显示出显著增加水溶性。然而，仍然有一个显着缺乏了解的关键的物理化学和生物学因素，影响在体内性能的共晶体，如差异增溶共晶体成分的生理相关的表面活性剂，和差异吸收的活性成分和共形成物。因此，迫切需要开发基于机制的策略来指导共晶表征、选择和配制，从而优化口服递送。在强有力的初步数据的指导下，长期目标是开发新的和有效的策略，以增强基于共晶体提供的固体和溶液化学控制的水不溶性药物的口服给药。本申请的主要目的是建立决定共晶增溶、溶解和吸收的基本物理化学原理，并建立可用于准确预测体外和体内共晶行为的定量数学关系。核心假设是，定量的、基于科学的 可以建立数学关系[代表描述共晶体、药物和共形成物行为的相关物理化学过程]，以预测共晶体在生理学相关介质中的溶解度和溶出度，并且应用这些知识将允许进行准确的体内吸收和生物利用度预测。为了检验中心假设并实现本项目的目标，将追求三个特定目标：1）确定预测共晶在生理相关介质中溶解度的关键分子和理化参数，2）开发共晶在生理相关介质中溶解的预测扩散/反应模型，并在相关体外溶出系统中进行测试，3） 评价共晶药物的体内外口服吸收机制。这项研究具有创新性，因为它代表了与当前研究的新的实质性背离，当前研究专门关注固态和简单水溶液中的物理和化学性质。这种方法将有效地整合生物学相关组分，如表面活性剂与药物和组成共晶的相关共形成物的重要口服吸收考虑。这种综合的物理化学和生物学模型可以预期导致更有效和更准确的预测共晶口服吸收率，并最终改进药物输送系统的发展，以治疗人类疾病。

DESCRIPTION (provided by applicant): A major impediment to the development of new, orally active therapeutic agents to treat many human diseases is the poor solubility of such agents in the aqueous environment of the intestinal tract. Cocrystals (stoichiometric molecular complexes of an active therapeutic agent complexed with a benign molecule) represent a potentially attractive and new approach that can be used to modify and tailor solubility and dissolution properties to enhance and [modulate] bioavailability. Cocrystalline solids have been shown to profoundly increase aqueous solubility. However, there remains a significant lack of understanding of the key physicochemical and biological factors that influence in vivo performance of cocrystals such as differential solubilization of cocrystal components by physiologically relevant surfactants, and differential absorption of the active ingredient and coformer. There is, therefore, a critical need to develop mechanistic-based strategies to guide cocrystal characterization, selection, and formulation leading to optimized oral delivery. Guided by strong preliminary data, the long-term goal is to develop novel and efficient strategies to enhance the oral delivery of water insoluble drugs based on the solid and solution chemistry control that cocrystals provide. The primary objective in this application is to establish the basi physicochemical principles that dictate cocrystal solubilization, dissolution and absorption, and to establish quantitative mathematical relationships that can be used to accurately predict cocrystal behavior in vitro and in vivo. The central hypothesis is that quantitative, science-based mathematical relationships [that represent the relevant physicochemical processes describing cocrystal, drug and coformer behavior] can be developed to predict cocrystal solubility and dissolution in physiologically relevant media, and application of this knowledge will allow accurate in vivo absorption and bioavailability predictions to be made. To test the central hypothesis and achieve the objectives of this project, three Specific Aims will be pursued: 1) identify key molecular and physicochemical parameters that predict cocrystal solubility in physiologically relevant media, 2) develop predictive diffusion/reaction models of cocrystal dissolution in physiologically relevant media and test in relevant in vitro dissolution systems, 3) assess the oral absorption mechanisms of cocrystal drugs in vitro and in vivo. This research is innovative because it represents a new and substantial departure from current research which focuses exclusively on the physical and chemical properties in the solid state and in simple aqueous solutions. This approach will be effective in integrating biologically relevant components such as surfactants with important oral absorption considerations of both the drug and the associated coformer that make up the cocrystal. This integrated physicochemical and biological model can be expected to lead to more effective and accurate predictions of cocrystal oral absorption rates and ultimately to the development of improved drug delivery systems to treat human diseases.