Modeling the influence of cyclodextrins on oral absorption of low-solubility drugs: I. Model development.

The ability to quantitatively predict the influence of a solubilization technology on oral absorption would be highly beneficial in rational selection of drug delivery technology and formulation design. Cyclodextrins (CDs) are cyclic oligosaccharides which form inclusion complexes with a large variety of compounds including drugs. There are many studies in the literature showing that complexation between CD and drug enhances oral bioavailability and some demonstrating failure of CD in bioavailability enhancement, but relatively little guidance regarding when CD can be used to enhance bioavailability. A model was developed based upon mass transport expressions for drug dissolution and absorption and a pseudo-equilibrium assumption for the complexation reaction with CD. The model considers neutral compound delivered as a physical mixture with CD in both immediate release (IR) and controlled release (CR) formulations. Simulation results demonstrated that cyclodextrins can enhance, have no effect, or hurt drug absorption when delivered as a physical mixture with drug. The predicted influence depends on interacting parameter values, including solubility, drug absorption constant, binding constant, CD:drug molar ratio, dose, and assumed volume of the intestinal lumen. In general, the predicted positive influence of dosing as a physical mixture with CD was minimal, alluding to the significance of dosing as a preformed complex. The model developed enabled examination of which physical and chemical properties result in oral absorption enhancement for neutral drug administered as a physical mixture with CD, demonstrating the utility of modeling the influence of a drug delivery agent (e.g., CD) on absorption for rational dosage form design.

Modeling the influence of cyclodextrins on oral absorption of low solubility drugs: II. Experimental validation.

A model was developed for predicting the influence of cyclodextrins (CDs) delivered as a physical mixture with drug on oral absorption. CDs are cyclic oligosaccharides which form inclusion complexes with many drugs and are often used as solubilizing agents. The purpose of this work is to compare the simulation predictions with in vitro as well as in vivo experimental results to test the model's ability to capture the influence of CD on key processes in the gastrointestinal (GI) tract environment. Dissolution and absorption kinetics of low solubility drugs (Naproxen and Nifedipine) were tested in the presence and absence of CD in a simulated gastrointestinal environment. Model predictions were also compared with in vivo experimental results (Glibenclamide and Carbamazepine) from the literature to demonstrate the model's ability to predict oral bioavailability. Comparisons of simulation and experimental results indicate that a model incorporating the influence of CD (delivered as a physical mixture) on dissolution kinetics and binding of neutral drug can predict trends in the influence of CD on bioavailability. Overall, a minimal effect of CD dosed as a physical mixture was observed and predicted. Modeling may aid in enabling rational design of CD containing formulations.

Predicting the effect of fed-state intestinal contents on drug dissolution.

PURPOSE: There are several endogenous and exogenous species in the gastrointestinal (GI) tract which can act as solubilizing agents and thereby affect drug dissolution. The purpose of this study is to understand food effects on drug dissolution and provide insight into their anticipated overall effect on absorption and bioavailability. METHODS: Dissolution kinetics of 15 drugs of variable logP, charge, and molecular weight were tested in simulated intestinal environment. The ability of a film-equilibrium-based model to predict the influence of a simulated intestinal environment on drug dissolution was examined. RESULTS: The most significant improvement in dissolution kinetics and solubility (up to 6-fold) was evident with highly hydrophobic compounds (logP > 4). Improvement in solubility did not always constitute improvement in dissolution kinetics on a relevant time scale. Comparison of simulation and experimental results indicates that a model considering micelle partitioning as a pseudo-equilibrium process can predict trends in the influence of food-related solubilizing agents on drug dissolution kinetics. CONCLUSIONS: The significance of food-related solubilizing agents to drug dissolution is not always obvious, as it depends on multiple physicochemical parameters; however, simple modeling may provide insight into food effects on dissolution and, ultimately, overall absorption and bioavailability of compounds considered for oral formulation.

Materials and Microenvironments for Engineering the Intestinal Epithelium.

The barrier functions of the gastrointestinal tract rely in large part on a single layer of columnar intestinal epithelial cells. These epithelial cells are mediators of intestinal homeostasis, regulating and communicating biochemical signals between underlying stromal cells and luminal cues. The development of representative in vitro models to recapitulate the gastrointestinal epithelium is crucial to understanding cell-cell interactions during intestinal homeostasis and dysfunction. Ideally, models would contain microbiota/immune cells, polarized intestinal architecture, multilayered cellular complexity, extracellular matrix, biochemical cues, and mechanical deformation. This review focuses on historical and state of the art biomaterials and substrates used in the field to establish static and fluidic models of the intestinal epithelium. A discussion of conventional adenocarcinoma colon cancer cell lines, primary intestinal epithelial cells derived from organoids, and stromal support cells such as enteric neurons, myofibroblasts, and immune cells, as well as the importance of increasing cellular complexity and future outlook is included.

Drug salts and solubilization: modeling the influence of cyclodextrins on oral absorption.

Substantial effort and resources are spent for the oral delivery of low solubility compounds using drug delivery technologies. Complexation using cyclodextrins (CDs) is one popular strategy used to enhance drug dissolution kinetics and solubility. In addition to delivery technologies, another common method of improving dissolution kinetics of a low solubility compound is to dose it as a salt. It is not often possible to anticipate how effective a technology such as CD will be in a certain formulation in improving drug absorption, leading to a trial-and-error based formulation process; simultaneous use of salt and complexation technologies increases the complexity of the system. A simple dynamic, systems-based model was developed for predicting the influence of CDs on oral absorption of a salt form of low solubility drug administered as a physical mixture with CD, and validated by in vitro experiments. Model predictions indicate that while CD is generally considered a solubilization technology, CD can enhance overall absorption of salt form drug mainly by decreasing the driving force for precipitation through binding free drug in solution. Modeling enabled examination of which physical and chemical properties result in oral absorption enhancement or decrement for drug salt administered as a physical mixture with CD.