(656f) Model Prediction of Oral Bioavailability of Saltform Drug Administered with Cyclodextrins: Comparison with in Vitro and in Vivo Experiments

A model was developed predicting the influence of cyclodextrins (CD) on oral absorption of low solubility drugs. CDs are cyclic oligosaccharides which form inclusion complexes with many drugs and are often used as solubilizing agents¹. Since many insoluble drugs are formulated as saltforms of active compounds, the model was designed to predict the influence of CD dosed with saltform drug as a physical mixture. The Saltform Compound Physical Mixture (SCPM) model was based on another model developed to predict the oral absorption of neutral drug administered as a physical mixture with CD². Mathematical expressions for key processes (dissolution, precipitation and permeation through the intestinal membrane) 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 purpose of this study is to validate the ability of the model to predict the effect of CDs on oral absorption by comparing simulation results with in vitro and in vivo data.

In vitro experiments were conducted to test model predictions of the influence of CD on key processes in the gastrointestinal (GI) tract environment. Dissolution, precipitation and absorption kinetics of low solubility drug that forms complexes with CD (Naproxen Sodium) was 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. In the model, precipitation is represented as a first-order process, and the first-order precipitation constant of Naproxen Sodium was measured and used as model input. Absorption experiments were conducted in a diffusion cell apparatus with a Caco-2 monolayer separating the two diffusion chambers. The model predicts that β-CD will actually have no overall effect on absorption of Naproxen sodium, and either a negative or no effect on overall absorption of saltform drugs in general when dosed as a physical mixture (rather than a pre-formed complex) for most drug and GI parameter values tested. In absorption experiments with Naproxen Sodium, CD shows no significant effect on absorption of the drug. For a dose of 0.5 mgA/ml, the absorption of drug was 4.0 % in the absence of β-CD and 4.3 % in the presence of β-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 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, V. J.; Rajewski, R. A., Cyclodextrins: their future in drug formulation and delivery. Pharmaceutical Research 1997, 14, (5), 556-567. 2. Gamsiz, D. E., Miller, L.A., Thombre, A.G., Carrier, R.L.,Predicting the Ability of Cyclodextrin to Enhance Intestinal Absorption in Controlled Release Delivery: Comparison with Immediate Release, Controlled Release Society Annual Meeting, Miami, FL, 2005.