Pharmaceutical Technology: Controlled Drug Release, Volume 2

CH. 14] COMPARISON OF TIMOLOL MALEATE RELEASE 159
Fig. 3—Timolol concentration (µg/ml) in plasma after application of one buffered (■) or unbuffered (□) matrix in each
eye of a rabbit. Means±SEM of 5–9 rabbits are shown.
approximately doubled. The phosphate did not affect the bulk pH in the end of experiment
(Table 1). Consequently, the faster release rate of timolol from matrices with disodium phosphate
is due to the higher pH on the polymer surface. Higher pH increases the rate of polymer
dissolution and as a consequence drug release is accelerated.
The peak timolol concentration (7.0±1.5 ng/ml) in plasma occurred at 60 min with the buffered
matrices (Fig. 3). After administration of unbuffered matrix a steady state level of 1.0±0.1 ng/ml
in plasma was achieved at 3 h (Fig. 3).
The concentration profiles in tear fluid (Fig. 4) resemble the profiles in plasma (Fig. 3). Compared
with unbuffered matrix (c max =45.2±9.4µg/ml) administration of timolol in polymer matrix with
disodium phosphate resulted in a higher peak (91.5±13.7 µg/ml) in tear fluid (Fig. 4). With the
unbuffered matrices, the peak levels of timolol in tear fluid were seen much later than with
buffered matrices (Fig. 4).
Timolol concentrations in the tear fluid and plasma suggest that compared with unbuffered
matrices timolol is released more rapidly from the isopropyl ester of PVM-MA matrices with
disodium phosphate in vivo. During the experiment, the buffered matrices also dissolved more
rapidly in the tear fluid than the unbuffered matrices.
In vivo results correspond quite well to those of the in vitro experiments although the effect of a
basic additive seems to be greater in vivo. It is possible to increase the dissolution rate of PVM-
MA esters in tear fluid by adding disodium phosphate or possibly other basic salts to the matrices.
With basic additives it may be possible to modify drug release and polymer dissolution also in the
case of other polyacids.