A comparison between direct determination of in vivo dissolution and the deconvolution technique in humans

Abstract

Aim. The primary objective of this study was to investigate the in vivo dissolution of carbamazepine in humans and to compare it with the dissolution estimated by deconvolution of plasma concentrations as well as the in vitro dissolution.

Methods. The in vivo study included six healthy volunteers, and consisted of two sequential parts. In part 1 the dissolution was measured by perfusing a semi-open segment in the proximal jejunum in humans. In part 2 the volunteers were given a solution of carbamazepine orally. In both parts of the study, plasma samples were collected up to 48 h after administration of the dose. The in vitro dissolution was measured in a flow-through cell using dissolution medium with and without the addition of bile acids (3 mM).

Results. The direct measured in vivo dissolution profile of carbamazepine and the deconvoluted profile were found to be similar. The two dissolution profiles of carbamazepine obtained in vitro were statistically lower than the two in vivo dissolution profiles. The higher in vivo dissolution rate is probably due to efficient sink conditions as a consequence of the high permeability of carbamazepine and more pronounced intestinal motility.

Conclusion. The jejunal perfusion system was successfully used for in vivo dissolution measurements of carbamazepine and agreed with the deconvoluted plasma profile regarding rate and extent of dissolution. Single-pass perfusion is therefore a meaningful tool for further studies of in vivo dissolution.

Introduction

A prerequisite for intestinal drug absorption is dissolution of drugs in the gastrointestinal (GI) fluids. The dissolution rate for solid particles can be described by the following equation (Dressman et al., 1998):

$$\text{d}\text{X}\text{d}\text{t}\text{=}\text{AD}\text{δ}\text{C}{}_{\mathrm{<mtext>s</mtext>}}\text{−}\text{Xd}\text{V}$$

where dX/dt is the dissolution rate in terms of mass X per unit time t, A is the available surface area of the solid drug, D is the diffusion coefficient, δ is the effective diffusion boundary layer thickness, C_s is the saturated solubility of the drug in the intestinal luminal contents, Xd is the amount of drug already in solution and V is the volume of fluid in the lumen available for dissolution. The bioavailability of poorly soluble drugs may in some cases be limited by the dissolution rate in the gastrointestinal fluids. The dissolution rate is affected by physicochemical properties of the drug and gastrointestinal factors. Crucial gastrointestinal factors are composition, volume and hydrodynamics of the luminal fluids (Charman et al., 1997). The physical chemistry of the fluid in the GI tract is complex and depends on the nutritional status (Hernell et al., 1990, Staggers et al., 1990, Lindahl et al., 1997). For example, the concentration of amphiphilic bile components in the small intestine is significantly different between the fasted and the fed state, and affects the solubility and dissolution of drugs (Charman et al., 1997). If the transit time of the drug in the absorptive part of the GI tract is too short or the amount of intestinal fluid is less than required for complete dissolution, the concentration of dissolved drug available for permeation over the intestinal mucosa will be dissolution rate limited (Amidon et al., 1995).

In the design and development of oral dosage forms containing poorly soluble drug substances it is important to evaluate the in vivo dissolution process. Furthermore, it is crucial to develop a reproducible and predictable in vitro dissolution test to be used for optimisation of the oral dosage form. It is also important to establish an IVIV correlation, which is possible for poorly soluble and highly permeable drugs (Amidon et al., 1995). Until recently the only means to evaluate the in vivo dissolution profile was to utilize indirect methods such as deconvolution methods of plasma profiles (Hanano, 1967, Langenbucher, 1982, Gillespie and Veng Pedersen, 1985, Nicklasson et al., 1987).

A new approach for direct determination of in vivo dissolution profiles in humans was presented recently (Bønløkke et al., 1997). The method is based on the perfusion technique Loc-I-Gut® which has been used extensively for studies of jejunal permeability, transport mechanisms and first-pass effects (Knutson et al., 1989, Lennernäs et al., 1992, Lindahl et al., 1996).

The aim of the present study was to use this new direct in vivo perfusion method to examine the effective in vivo dissolution of carbamazepine in the proximal small intestine of healthy human subjects. Moreover, to compare the effective in vivo dissolution profile with dissolution profiles obtained by the deconvolution of plasma data and in vitro dissolution studies.