Attempt to Design Continuous Dissolution–Absorption System Using Everted Intestine Segment for In Vitro Absorption Studies of Slow Drug Release Formulations

Abstract

INTRODUCTION Amajor objective of the pharmaceutical industry is to develop drugs with good oral bioavailability. Administration of drug as a solid or liquid unit provides more convenient dosing and better patient compliance than painful and inconvenient iv dosage regimens. Good oral bioavailability occurs when the drug has maximum permeability and maximum solubility at the site of absorption (1). The extent of absorption of drug in vivo,thus,could be predicted based on permeability and solubility measurements (2). Hence,the intestinal permeability represents one essential part in the prediction of oral bioavailability (3). The intestinal permeability data can be used in preformulation studies to evaluate the effects of various pharmaceutical excipients on drug absorption (4). A number of in vitro methods for assessing the intestinal permeability of a given drug have been developed and reviewed recently (5). In the last decade,the use of Caco-2 cell monolayers has gained popularity as an in vitro absorption screening tool. Nevertheless,the Caco-2 cell-based assay has some disadvantages. It is labor intensive, time consuming,has a high cost per assay,and requires a 21-day growth period and regular maintenance feeding for the preparation of stable monolayers. An alternative to the use of cultured cells is an in vitro absorption procedure based on in situ perfusion and isolated sacs from animal intestines (5). One of the major drawbacks of the in situ perfusion method is that it is unsuitable for screening a large number of compounds. In vitro absorption (permeability) studies based on isolated intestinal sacs are routinely performed. The advantages of this model are that it contains all the types of cells and mucus layer, is relatively fast and inexpensive,and can be used for preformulation studies (5). This kind of model is suitable for measuring kinetic parameters with high reliability and reproducibility (6). Several animal species including rat, rabbit,pig,dog,and monkey have been used in permeability studies based on isolated intestinal sacs (7). To the best of our knowledge, in vitro absorption studies using chicken intestine have never been reported. The chicken small intestine could be a useful model (8) for intestinal absorption based on the assumption that membrane permeability of drugs is not species-dependant, since the composition of plasma membrane of intestinal epithelial cells is similar across the species. Thus the permeability across the chicken intestinal segment could be expected to be the same. The aim of the current work was two-fold: to develop an in vitro continuous dissolution–absorption system using the chicken intestinal sac to predict a dissolution–absorption relationship for ABSTRACT Reliable and predictive in vitro methods to quantify drug transport across the intestinal epithelium are required at an early stage in the drug development process for oral solid dosage forms. Also,the method should be useful for evaluating the effects of formulations on the transport. Several approaches have been used to obtain the most representative model of the intestinal epithelium. The everted and perfused intestine model presents many advantages relative to other methods. In this work,an attempt has been made to develop an in vitro continuous dissolution–absorption system to study the effect of slow drug release formulation variables on drug absorption. The dissolution studies were conducted on free drug and on two slow-release metformin hydrochloride (marketed) formulations. The studies yielded a dissolution–absorption relationship that can be used to predict dissolution or permeation-rate-limited absorption for two marketed formulations. The system also predicted permeation-rate-limited absorption for free metformin HCl,which is a highly permeable and aqueous soluble drug. Thus,the dissolution–absorption system may prove to be a valuable tool in formulation development. Broader evaluation of such a system is warranted.