An empirical relationship between physicochemical properties and sublingual absorption of the model drugs

Abstract

Sublingual drug delivery offers a non-invasive alternative to oral administration, allowing drugs to be rapidly absorbed while bypassing the first-pass effect. The purpose of this study was to compare the pharmacokinetics of model drugs following sublingual and oral administration in healthy human subjects and to explore the empirical relationship between sublingual drug-absorption parameters and the physicochemical properties of the model compounds. Orally disintegrating tablets and oral tablets of five model drugs atenolol, caffeine, naproxen, propranolol, and verapamil were administered to healthy human subjects via both sublingual and oral routes. Sublingual administration resulted in faster absorption (shorter T max ) and higher C max and AUC for all drugs except naproxen. Sublingual absorption rate constants (K a ) were estimated via deconvolution using the Wagner–Nelson or Loo–Riegelman method, depending on drug kinetics. Multiple linear regression (MLR) identified molecular weight (MW), number of rotatable bonds (nRB), and LogD 7.4 as empirically associated with 65% of the variability in K a (R 2 = 0.65). The resulting model is expressed as the following equation: K a = -4.05 + 0.04 x MW −0.70 x NRB – 0.89 x LogD 7.4. Drugs with lower lipophilicity and molecular flexibility exhibited faster sublingual absorption. These findings help to highlight the important physicochemical properties that may influence sublingual absorption.