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furosemide limited the drug concentration in the control solution. The Caco-2 monolayer
integrity was not compromised during the permeability experiments.
A clear pH effect was also observed in the studies. The determined pKa values for
furosemide are pKa1 3.70 ± 0.04 and pKa2 9.93 ± 0.09. The logD values were estimated
according to the Eq. (2) as logDpH5.5 = 0.54 and logDpH7.4 = 0.03. Due to the high acidic
strength, the lipophilicity of furosemide decreases with increasing pH, which does not
favor absorption. This explains the pH effect in the permeability results of furosemide.
Also, the pH gradient from 5.5 to 7.4 across the cell monolayers provided favorable
conditions for drug permeation via enhanced sink conditions. The overall permeability of
furosemide was at the highest when loaded in the particles at apical pH 5.5 (Papp = 18.0 ±
1.3 ×10 -6 cm/s, Table 6), and diminished with increasing pH. The effect was more
pronounced with solutions, where the apparent permeability was dramatically decreased
from 12.2 to 0.93 × 10 -6 cm/s, due to the change of the apical pH from 5.5 to 6.8.
Probably, due to the dissolution improving effects of TCPSi the change in Papp was less
steep, despite clear, in the microparticle studies (Table 6). The highest relative increase
(4.6 times) in the drug permeability from drug-loaded TCPSi compared to the drug
solution was detected at apical pH 7.4, where the drug solution concentration was high,
but the drug permeability from the solution was the poorest. Even the small increase in
drug solubility provided by TCPSi formulation seemed to have a distinctive effect on the
permeation of furosemide.
Table 6. Apparent permeabilities (Papp × 10 -6 cm/s; means ± SD) of furosemide across
Caco-2 monolayers from pre-dissolved furosemide (control solutions) and
estimates for furosemide-loaded TCPSi microparticles.
Apical pH Control solutions TCPSi-loaded 1
Conc (µg/ml) Papp × 10 -6 cm/s Conc (µg/ml) Papp × 10 -6 cm/s
pH 5.5 150 12.2 ± 1.0 520 18.0 ± 1.3 1.5
pH 6.8 600 0.93 ± 0.38 840 4.1 ± 0.5 4.4
pH 7.4 650 0.30 ± 0.01 670 1.38 ± 0.05 4.6
43
Papp TCPSi /
solution
1 The apparent permeability coefficients were estimated using C0 values based on the complete dissolution
of the full dose contained in the TCPSi particles.