Compounding permeability

Nonpolar compounds, including the majority of xenobiotic chemicals and some metal complexes [249-252], generally diffuse passively through the lipid portions of the membrane by simple diffusion [21,246,253,254]. In this case, internalisation rates are reflected by compound permeability in the bilipid membrane [254,255] and can be predicted by Fick s law [254,256] ... 

Commercially available monolithic columns are based either on silica or organic polymer and are generally characterized as a polymeric skeleton with macropores, with a diameter of approximately 2 pm, and mesopores, with a diameter of approximately 13 nm. The role of the macropores (through-pores) is to provide channels with high compounds permeability, which permits the use of higher flow rates with respect to columns based on conventional particle size, and an extended surface area, which is comparable to conventional columns packed with 3 pm particles. 

While Franz-type diffusion cells are commonly used to assess in vitro penetration of compounds across the skin, they have also been used for the assessment of compound permeability across the buccal mucosa [19, 71, 104], In this system, buccal mucosa is sandwiched between two chambers, and compound solution is added to the donor chamber with compound-free buffer in the receptor chamber. The receptor chamber is then periodically sampled to assess the amount of compound that has permeated the tissue over time. 

The buccal mucosa does serve as an alternative route for administering compounds systematically however, to ensure particular compounds are candidates for delivery across this biological tissue, preclinical screening is essential. While in vivo human permeability studies are ideal, due to their costs and associated issues, it is necessary to perform such screening in vitro. Assessment of compound permeability across porcine buccal mucosa has been widely used and can provide the preclinical biopharmaceutical scientist with much information relating to permeability, routes of transport, and effects of various chemical penetration enhancers. 

At the beginning of the project, it is often difficult to have a precise idea of the projected therapeutic dose. Projects usually start with an estimated average potency of 1 mg/kg, once daily dose as an optimal approach. When initial pharmacokinetic/ pharmacodynamic (PK/PD) data becomes available one can better refine the TCP. Table 3.1 gives some guidelines on how to adjust the solubility requirement depending on the therapeutic dose and compound permeability. 

A variety of lipids have been shown to change the physical barrier function of the gut wall, and hence, to enhance permeability. For BCS class 2 compounds, permeability... 

Prognosis of a compounds permeability should be made stressing limitations of the model. There is no bioavailability prognosis from in vitro data - a cellular assay can provide only permeability potential through a biological membrane. The membrane, in most cases CACO-2 cells, is very similar to what we observe in vivo in the small intestine and resembles many characteristics to in vivo enterocytes. CACO-2 cells can be used for prediction of different pathways across intestinal cells. Best correlation occurs for passive transcellular route of diffusion. Passive paracellular pathway is less permeable in CACO-2 and correlations are rather qualitative than quantitative for that pathway. CACO-2 cells are an accepted model for identification of compounds with permeability problems, for ranking of compounds and selection of best compounds within a series. Carrier-mediated transport can be studied as well using careful characterization of transporters in the cell batch or clone as a prerequisite for transporter studies. 

R Wei, H Lee, LYT Li, JN Kryanos. Development of a high throughput analytical technique for compound permeability studies using Caco-2 Cells and HPLC/MS. Proceedings of the 47th American Society for Mass Spectrometry Conference, Dallas, TX, 1999. 

The permeability and PAMPA assays as described are robust and reproducible assays for determining passive, transcellular compound permeability. Permeability and PAMPA are automation compatible, relatively fast (4-16 hours), inexpensive, straightforward, and their results correlate with human drug absorption values from published methods. The PAMPA assay provides the benefits of a more biologically relevant system. It is also possible to tailor the lipophilic constituents so that they mimic specific membranes, such as the blood-brain barrier (BBB). Optimization of incubation time, lipid mixture, and lipid concentration will also enhance the assay s ability to predict compound permeability. 

Caco-2 cells are heterogeneous and their properties in final culture may differ based on the selection pressures of a particular laboratory. Direct comparison of compound permeability rates between laboratories is not possible unless the same Caco-2 cells and conditions are used. Therefore, transport rates and permeability classification ranges of specific drugs are expected to vary between reported studies. Most important is the ability to successfully classify compounds as low, medium, or high permeable drugs, and produce transport results that correlate to established human absorption values. 

Literature and knowledge on mass transfer of aroma compounds are few and no standard procedure is recommended. Methods developed for aroma compounds permeability measurements are commonly approached by isostatic or quasiisostatic methods and depend on the physical state (vapor or liquid) of the aroma compounds (Piringer and Baner 2000). 

Because butyl has the same permeability coefficient as bromobutyl mbber, blending it into a bromobutyl rubber compound does not alter the compound permeability as, for example, natural rubber would. 

The diffusivity D is a kinetic parameter related to polymer mobility, while the solubility coefficient is a thermodynamic parameter which is dependent upon the strength of the interactions in the polymer-penetrant mixture. Chemical modifications of polymers affect the coefficients of diffusion and of solubility. Changes in material structure have a greater effect on diffusion coefficient, whereas the solubility coefficient depends mainly on the character of the low-molecular-mass compound. Permeability is determined by factors such as the magnitude of the free volume, and crosslinking which reduces the segmental mobility and the free volume and diminishes the permeability coefficient. A reduction of interchain cohesion and of crystallinity increases the permeability coefficient. The transition from the amorphous to the crystaUine state usually decreases the permeability. A decrease in crystallinity may increase the permeability. The permeability of polymers is determined primarily by the amount of the amorphous phase [62,300, 301]. 

For each compound, a classical permeability mass transfer expression, which makes use of the compound permeability in the membrane material, P, is written ... 

---