Drug absorption boundary layers

Reduction of particle size increases the total specific surface area exposed to the solvent, allowing a greater number of particles to dissolve more rapidly. Furthermore, smaller particles have a small diffusion boundary layer, allowing faster transport of dissolved material from the particle surface [58]. These effects become extremely important when dealing with poorly water-soluble drugs, where dissolution is the rate-limiting step in absorption. There are numerous examples where reduction of particle size in such drugs leads to a faster dissolution rate [59-61], In some cases, these in vitro results have been shown to correlate with improved absorption in vivo [62-64]. 

RELEVANT TRANSVERSE ASPECTS TO DRUG ABSORPTION 1.4.1 Boundary Layers... 

Boundary layers also contribute to the effect of intestinal fluid hydrodynamics on drug absorption by both diffusional- and carrier-mediated processes. In a well-defined isolated in situ model such as perfused intestine of the rat, a good estimate of the gut wall permeability, which is the vector of convective diffusive mass transfer, passive diffusion and carrier-mediated transport, can be accomplished [99,100]. 

Aqueous Boundury (Diffusion) Luyer. The aqueous boundary layer (often referred to as the stagnant, unstirred, or aqueous diffusion layer) is an important hydrodynamic barrier that a drug must traverse before reaching the surface of the mucosal membrane. " Before a molecule in the intestinal lumen passes through the membrane, it must first cross the aqueous boundary layer located at the intestinal lumen and membrane interface (Fig. 2). The liquid in this layer, in reality, is not static, as the term unstirred implies, but represents a film at the surface where diffuse and natural convective mixing occurs. This unstirred layer can be a rate-limiting step for the absorption of hydro-phobic molecules. However, hydrophilic molecules such... 

The mechanism whereby drugs are absorbed from the GI tract is complex. Understanding the intestinal transport mechanism is crucial to the prediction of oral drug absorption. The physical model utilizes the basic principles of thermodynamics and mass transport. The physical model for the simultaneous passive and active membrane transport of drugs in the intestinal lumen is depicted in Fig. 7. The bulk aqueous solution with an aqueous boundary layer on the mucosal side is followed by a series of heterogeneous membranes consisting of parallel lipoidal and aqueous channel pathways for passive and active transport. Thereafter, a sink on the serosal side follows. 

For highly lipophilic drugs (-log PC >3.0), the absorption rate constant will be dependent on the diffusion rate across the aqueous boundary layer in front of the membrane, and is expressed by ... 

Many studies have been completed in order to assess the effect of bile salts on the bioavailability of poorly soluble drugs. Bile salts for example, have been shown to enhance the absorption of sulphaguanidine and urogastrone. Bile salts may also play a role in enhancing the transport of a compound from the lumen of the intestine to the systemic circulation. Such absorption involves overcoming the resistance of the aqueous boundary layer and the membrane epithelium to the passage of the drug. 

If the drug stratum corneum/product partition coefficient K is defined as Csc(o)/C)>, CJc is assumed to be much less than Csc(o), and the permeability coefficient (kp) is KD/h, equation 4 is equivalent to equation 3. The lag time is normally defined by Fick s law as h2/6D. The importance of equation 4 is well illustrated by the work of Rougier and Lotte (1993) in which it was shown that the in vivo percutaneous absorption (= Js) of a series of compounds was directly related to their concentration in stripped stratum corneum, irrespective of their structure, concentration or site of application. In theory, drug transport could go via a polar pathway, with a permeability coefficient kp pojar, as well as through the intercellular lipid pathway, with a permeability coefficient kp iipi(1, although the existence of a polar pathway remains controversial. As indicated previously, for lipophilic drugs, an aqueous boundary layer is likely to be present at the stratum corneum-viable epidermis interface... 

The rate and extent of intestinal permeation is dependent on the physicochemical properties of the compound (see Sections 16.1.2 and 16.4.3) and the physiological factors. Drugs are mainly absorbed in the small intestine due to its much larger surface area and less tight epithelium in comparison to the colon [17]. The permeation of the intestine may be affected by the presence of an aqueous boundary layer and mucus adjacent to cells, but for a majority of substances the epithelial barrier is the most important barrier to drug absorption. The lipoidal cell membrane restricts the permeability of hydrophilic and charged compounds, whereas large molecules are restricted by the ordered structure of the lipid bilayer. 

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