Gerald S Rork

Controlled drug delivery devices for experimental ocular studies with timolol 2. Ocular and systemic absorption in rabbits

Controlled drug delivery was tested as a means to decrease the potentially dangerous systemic drug concentrations which are associated with timolol eyedrop therapy. l-Tumolol (125 μg) was administered in 0.5% eyedrops (25 μl, pH 6.86) and in controlled release silicone tubing devices (dose 57.6 μ;g; release rate 7.2 μgh for 8 h) in the eyes of pigmented rabbits. [3H]Timolol tracer was used in ocular absorption studies and unlabeled timolol dosage forms in systemic absorption studies. [3H]Timolol concentrations were determined in ocular tissues and tear fluid. Beta blocking activity in plasma was determined using a radioreceptor assay. Comparable timolol concentrations were achieved in the iris-ciliary body with silicone tubing devices (57.6 μg) and with eyedrops (125 μg). The relative ocular timolol bioavailability after controlled drug delivery was about 2-fold greater than from eyedrops. In plasma, peak beta-blocking activity was much higher after eyedrop administration (17.16 ± 2.40 ng/ml) than during controlled timolol delivery (< 1.0 ngml). The results indicate that controlled drug delivery is a viable alternative in improving the therapeutic index of glaucoma therapy with timolol.

Controlled drug delivery devices for experimental ocular studies with timolol 1. In vitro release studies

Abstract Controlled drug delivery devices which can be easily tailored and conveniently prepared to release ocular drugs at specified controlled rates can be useful in studies of ocular drug delivery and drug response. The devices were fabricated by injecting 6.0, 9.0 or 12.5 μl of aqueous borate buffered solutions of timolol (2.5–20.0 mg ml ) into end-plugged pieces of silicone tubing and the release of timolol was studied in vitro. An initial lag in timolol release was avoided by storing the devices for an appropriate time (3–9 h) after filling the devices. The appropriate storage time was dependent on the steady-state flux of timolol, indicating that timolol was binding to the silica filler in the silicone tubing. Timolol was released at a constant rate (0.7–7.2 μg h ) for 8 h from the devices when the initial core pH was 8.64 and when the devices were stored for an appropriate time before an experiment. The steady-state release rate of timolol was increased 2.4-fold when the pH inside the device was increased from 8.34 to 9.24, As expected, the observed release rate increased with increased drug concentration in the device core and with increased length of the device. The permeability of timolol in the silicone membrane walls was 2.48−6.03 × 10 −9 cm 2 s −1 depending on the composition of the inner core solution. Thickness of the end-plugs (0.5 or 3.5 mm) did not affect timolol release from the devices, when the volume of timolol solution in the devices was 12.5 μl.

Tableting of controlled release multiparticulates, the effect of millisphere size and protective overcoating

Controlled release enalapril millispheres of different diameters were prepared and tableted with excipients in a 1:1 ratio on a Carver press. Drug release rate profiles showed that the microporous coating on the millispheres was severely damaged during the compression process. Overcoating of the microporous coating with hydroxypropyl methylcellulose E5 (HPMC E5) protects the microporous coating during compression by absorbing and dissipating the compressional forces. This protection becomes more pronounced as the size of the millispheres is reduced. A novel investigation of individual millisphere strength was conducted to identify the most favorable coating and size combination which would preserve the controlled release properties of the millispheres.