Pharmaceutical Technology: Controlled Drug Release, Volume 2

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CH. 14] COMPARISON OF TIMOLOL MALEATE RELEASE 157 Buffered matrices containing disodium phosphate (2.11 mmol) were prepared as above with the following exception. The salt was first dissolved in a small amount of distilled water, then methanol-polymer mixture and the drug were added. The amount of salt in the matrices was 12.5% or 12.9% (w/w). Studies of in vitro release The release of timolol from isopropyl PVM-MA matrices used the rotating disk method [5]. The dissolution medium was 100 ml of pH 7.42 mM phosphate buffer at 32°C. Ionic strength was adjusted to 0.5 with sodium chloride. Samples of volume 3.0 ml were withdrawn and replaced by dissolution medium. Timolol concentrations were analysed with a UV spectrophotometer at 294 nm and the pH was measured. <strong>Release</strong> rates (%/min) were calculated from the best fits of released drug vs. time plots. The slopes (k) of the log(released drug) vs. log(time) plots were calculated from the linear leastsquares regression lines. A slope of 0.5 in the log-log plot indicates diffusional, square root of time, dependence and a slope of 1.0 indicates zero-order release kinetics [6]. Times of 50% drug release (t50%) were calculated from the best fits of drug released vs. time plots. In vivo studies Matrices of monoisopropyl ester of PVM-MA were carefully applied in the lower conjunctival sac of rabbits. Inserts did not cause any irritation in rabbit eyes. Plasma and tear fluid samples were collected at different times during a period of 8 h. Blood samples were taken from the cannulated ear artery. Plasma was separated by centrifuging (2000 g, 4min) and kept at −20°C until analysed. Tear fluid samples (1 µl) were collected with microcapillaries at 30, 120, 240 and 480 min after application of the matrices. Tear fluid samples were diluted in 5 ml of phosphate buffer. Timolol concentration in plasma and tear fluid samples was measured using a modified radioreceptor assay [7]. In the assay, displacement of a β-antagonist, (–)- 3 H-CGP-12177, from β- receptors of rat reticulocyte membranes by timolol was measured. Rat reticulocyte membranes were obtained as described by Wellstein et al. [7]. In a total volume of 300 µl, 50µl reticulocyte membranes in phosphate buffer (500 µg protein) were incubated for 60 min at 25°C with 50 µl (30 nCi) of (−)-3H-CGP-12177, 180 µl of plasma and 20µ1 of 310 mOsm sodium phosphate buffer (pH 7.4). Standard curves were run for each rabbit separately in order to avoid errors due to possible differences in protein binding. To generate the standard curves, blank plasma was used and incubated in the presence of 1–20 nM timolol. For the determination of non-specific binding, incubation in a 10 −5 M propranolol solution was used. Timolol concentration in tear fluid samples was measured in the same way, but 200 µl of the diluted tear fluid in phosphate buffer were used instead of 180 µl plasma. After incubation, bound and free radioligand were separated by vacuum filtration through Whatman GF/F glass fibre filters. Filters were washed three times with 10 ml ice-cold 310 mOsm phosphate buffer, dried and counted for retained radioactivity in 5 ml of Lipoluma-Lumasolve-water (10:1:0.2) mixture using
158 OPHTHALMIC FORMULATION [CH. 14 Table 1—<strong>Release</strong> of timolol from buffered and unbuffered matrices of monoisopropyl ester of PVM-MA in 2 mM phosphate buffer solution (pH 7.40) at 32°C Means ± SEM of n experiments are shown. a Slope of log(released timolol) vs. log(time) plot. b pH at the end of the release experiment. c-d p
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PHARMACEUTICAL TECHNOLOGY Controlle
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3 TABLET MACHINE INSTRUMENTATION IN
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First published in 1991 by ELLIS HO
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7 10 Controlled delivery of theophy
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Slow and steady wins the race Poems
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1 Influence of drug solubility in t
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CH. 1] INFLUENCE OF DRUG SOLUBILITY
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24 MATRIX FORMULATIONS [CH. 2 MATER
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26 MATRIX FORMULATIONS [CH. 2 Fig.
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28 MATRIX FORMULATIONS [CH. 2 Table
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30 MATRIX FORMULATIONS [CH. 2 The e
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34 CH. 3] THE FORMULATION OF SUSTAI
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4 Statistical optimization of a con
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MATRIX FORMULATIONS [CH. 4 45 (4) G
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MATRIX FORMULATIONS [CH. 4 47 Fig.
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Columns 1-4 lead to the matrix of e
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MATRIX FORMULATIONS [CH. 4 51 Table
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MATRIX FORMULATIONS [CH. 4 53 Fig.
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Fig. 5—Linearization of the relea
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58 MATRIX FORMULATIONS [CH. 5 Pevik
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60 MATRIX FORMULATIONS [CH. 5 The d
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6 Controlled release matrix tablets
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CH. 6] CONTROLLED RELEASE MATRIX TA
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7 A new ibuprofen pulsed release or
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CH. 7] A NEW IBUPROFEN PULSED RELEA
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90 CH. 8] TOPICAL RELEASE AND PERME
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Page 133 and 134: 132 CH. 12] BIODEGRADABLE POLYMERS
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Page 185 and 186: 184 CH. 17] SILICON MATRIX SYSTEMS
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Page 195 and 196: 194 INDEX dry granulation, 43 elect
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Pharmaceutical Technology: Controlled Drug Release, Volume 2

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