Figure 7.8 (Continued)

7.2.4 Octanol-Impregnated Filters with Controlled Water Pores

Ghosh [548] used cellulose nitrate microporous filters (500 mm thick) as scaffold material to deposit octanol into the pores and then under controlled pressure conditions, displace some of the oil in the pores with water, creating a membrane with parallel oil and water pathways. This was thought to serve as a possible model for some of the properties of the outermost layer of skin, the stratum corneum. The relative proportions of the two types of channel could be controlled, and the properties of 5-10% water pore content were studied. Ibuprofen (lipophilic) and antipyr-ine (hydrophilic) were model drugs used. When the filter was filled entirely with water, the measured permeability of antipyrine was 69 (in 10~6 cm/s); when 90% of the pores were filled with octanol, the permeability decreased to 33; 95% octanol content further decreased permeability to 23, and fully octanol-filled filters indicated 0.9 as the permeability.


7.3.1 Egg Lecithin PAMPA Model (Roche Model)

Kansy et al. [547,550] from Hoffmann-La Roche published a widely read study of the permeation of drugs across phospholipid-coated filters, using a technique they coined as ''PAMPA,'' which stands for parallel artificial-membrane permeability assay. Their report could not have come at a better timeā€”just when the paradigm was shifting into screening for biopharmaceutic properties at high speeds, along side the biological screening.

In the commercial version of the PAMPA assay, a ''sandwich'' (Fig. 7.9) is formed from a specially-designed 96-well microtiter plate [pION] and a 96-well microfilter plate [several sources], such that each composite well is divided into two chambers: donor at the bottom and acceptor at the top, separated by a 125-mm-thick microfilter disk (0.45 mm pores, 70% porosity, 0.3 cm2 cross-sectional area), coated with a 10% wt/vol dodecane solution of egg lecithin (a mixed lipid containing mainly PC, PE, a slight amount of PI, and cholesterol), under conditions that multilamellar bilayers are expected to form inside the filter channels when the system contacts an aqueous buffer solution [543].

The Roche investigators were able to relate their measured fluxes to human absorption values with a hyperbolic curve, much like that indicated in Caco-2

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