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.

Public Health Relevance

The proposed research is relevant to public health because new and innovative ways are needed to deliver poorly soluble active therapeutic agents by oral administration. [The proposed research will establish the basic physicochemical and biological principles that determine the utility of cocrystalline forms of drugs to enhance and modulate their solubility and absorption in vivo. Integration of these principles will allow cocrystalline drugs t mitigate pH dependent and food induced oral bioavailiability of weakly basic and lipophilic drugs.] This proposal is relevant to the part of NIH's mission that pertains to developing fundamental knowledge that will reduce the burdens of illness and extend health life using effective therapeutic agents to treat disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM107146-04
Application #
9392916
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Okita, Richard T
Project Start
2014-12-15
Project End
2018-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Chen, Yitian M; Rodríguez-Hornedo, Naír (2018) Cocrystals Mitigate Negative Effects of High pH on Solubility and Dissolution of a Basic Drug. Cryst Growth Des 18:1358-1366
Cao, Fengjuan; Amidon, Gordon L; Rodríguez-Hornedo, Naír et al. (2018) Mechanistic Basis of Cocrystal Dissolution Advantage. J Pharm Sci 107:380-389
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Kuminek, Gislaine; Cao, Fengjuan; Bahia de Oliveira da Rocha, Alanny et al. (2016) Cocrystals to facilitate delivery of poorly soluble compounds beyond-rule-of-5. Adv Drug Deliv Rev 101:143-166
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Lipert, Maya P; Roy, Lilly; Childs, Scott L et al. (2015) Cocrystal Solubilization in Biorelevant Media and its Prediction from Drug Solubilization. J Pharm Sci 104:4153-4163
Lipert, Maya P; Rodríguez-Hornedo, Naír (2015) Cocrystal Transition Points: Role of Cocrystal Solubility, Drug Solubility, and Solubilizing Agents. Mol Pharm 12:3535-46