(586f) Validation of a Model Predicting the Influence of Cyclodextrins on Oral Bioavailability: Comparison with in Vitro and in Vivo Data

A model was developed predicting the influence of cyclodextrins (CD) on oral absorption of insoluble drugs. CDs are cyclic oligosaccharides which are known to help dissolution kinetics of insoluble drugs by forming inclusion complexes¹. In the model, the neutral form of the drug was considered to be delivered to the GI tract as a physical mixture with CD. Mathematical expressions for the key processes (dissolution and permeation through the intestinal mucous) affecting oral absorption of the drug were developed and incorporated into MATLAB®. Input parameters representing the physical and chemical properties of the drug, drug delivery device and biological environment were also included in the mathematical expressions. Simulations were made with different parameter values and post-dosing times to investigate the influence of CD on oral absorption of insoluble drugs. The neutral compound physical mixture (NCPM) model was also modified in order to predict the oral absorption of ionizable drugs considering pKa of the drug and intestinal pH. The purpose of this study is to validate the ability of the NCPM model to predict the effect of CDs on oral absorption by comparing simulations results with in vitro and in vivo data.

In vitro experiments were conducted to test the model predictions of the influence of CD on key processes in the GI tract environment. Dissolution and absorption kinetics of low solubility drugs that form complexes with CD²(Naproxen and Nifedipine) were tested in the presence and absence of CD (β-CD) in a simulated gastrointestinal environment (37ºC, well-mixed). Dissolution test results in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) fit simulation results with over 95% confidence. Absorption experiments were conducted with Naproxen, a weak acid, in a diffusion cell apparatus with a Caco-2 monolayer separating the two diffusion chambers. Due to its pKa (4.84), Naproxen is protonated in Kreb's buffer (pH = 7.4) and thus has higher solubility than the unionized form. NCPM model simulations predict that CD has a negative effect on absorption of high solubility drugs as it reduces the free drug concentration. In absorption experiments with Naproxen, the negative effect of CD on drug absorption was also observed. For a dose of 0.5 mgA/ml, the absorption of drug was reduced from 5.42 % in the absence of CD to 2.10 % in the presence of CD 2 hours post-dosing. To enable comparison of simulation predictions with in vivo drug bioavailability data obtained from the literature, a pharmacokinetic (PK) model was incorporated into the NCPM model. Comparison of model predictions with in vitro and in vivo data are being used to demonstrate the model's ability to predict the influence of CD on oral drug absorption and validate utility of modeling for rational dosage form design.

1. Stella VJ, Rajewski RA 1997. Cyclodextrins: their future in drug formulation and delivery. Pharmaceutical Research 14(5):556-567. 2. Erden N, Celebi N 1988. A study of the inclusion complex of naproxen with β-cyclodextrin. International Journal of Pharmaceutics 48(1-3):83-89.