Drug delivery technologies such as cyclodextrins, lipid-based systems, and polymers have been used to deliver drugs with low oral bioavailability. Low oral bioavailability is often caused by poor absorption in the gastrointestinal (GI) tract. Dissolution and permeation of the drug through the intestinal membrane are the key processes affecting drug absorption in the GI tract environment. Predicting the influence of a drug delivery technology on oral bioavailability of an insoluble drug would be highly beneficial in selection of drug delivery technology and device design. Cyclodextrins (CD) 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 cyclodextrin 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.

Four models were developed considering oral delivery of insoluble drug (either neutral form or saltform) in the presence of CD in different dosing schemes (physical mixture vs. pre-formed complex). These models describe: 1. dosing neutral compound as a physical mixture with cyclodextrin (NCPM), 2. dosing a saltform of a drug as a physical mixture with cyclodextrin (SCPM), 3. dosing a neutral compound as a pre-formed complex (NCC) and 4. dosing a saltform of a compound as a pre-formed complex (SCC). In these models, dissolution is described by the Noyes-Whitney equation and absorption is considered as a first-order process. Complexation between drug and CD is considered to be in pseudo-equilibrium. Precipitation is described by first-order kinetics proportional to supersaturation. Simulations were run for different ranges of parameter values reflecting the physical and chemical properties of drug, CD and the GI tract environment. Simulations results were analyzed using statistical software to understand which parameter combinations are effective in enhancing drug absorption. In order to predict the oral bioavailability of insoluble drugs, a pharmacokinetic (PK) model was incorporated into each model.

In order to test the ability of the models to predict the oral absorption of insoluble drugs, in vitro tests (dissolution, precipitation and absorption) were performed for each key process as well as combinations of the processes. In the experiments, insoluble drugs such as Naproxen, Nifedipine and Spironolactone were tested either in neutral form or saltform depending on the model being validated. For example, for NCC model validation pre-formed complex of Naproxen with Β-CD was prepared, and dissolution, precipitation and absorption in simulated intestinal fluids were tested. Simulation results accurately predicted the in vitro experimental results for all four models.

Simulations were run to compare predictions with in vivo experimental results taken from the literature to assess the ability of the models to predict oral bioavailability of insoluble drugs. For example, in vivo experimental results for Carbamazepine delivered in the presence of HP-Β-CD in rats were compared with NCPM/PK model predictions. Carbamazepine was orally administered as a physical mixture with HP-Β-CD to rats¹. NCPM/PK model results agreed with in vivo experimental results for Carbamazepine in both the presence and absence of CD. The results showed no influence of CD on drug bioavailability. Depending on the physical and chemical properties of drug, CD and biological environments, the models indicate the positive, negative or lack of effect of the drug delivery technology on oral bioavailability of insoluble drugs. The information obtained from the models would be highly useful in the process of formulation design.

1. Choudhury S, Nelson KF 1992. Improvement of oral bioavailability of carbamazepine by inclusion in 2-hydroxypropyl-b-cyclodextrin. International Journal of Pharmaceutics 85(1-3):175-180.