Implantable disks for glaucoma treatment were prepared by blending poly(ε-caprolactone), PCL, poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) and dorzolamide. Their in vivo performance was assessed by their capacity to decrease intraocular pressure (IOP) in normotensive and hypertensive eyes. Drug mapping showed that release was complete from blend disks and the low molecular weight (MW) PCL after 1 month in vivo. The high MW PCL showed non-cumulative release rates above the therapeutic level during 3 months in vitro. In vivo, the fibrous capsule formation around the implant controls the drug release, working as a barrier membrane. Histologic analysis showed normal foreign body reaction response to the implants. In normotensive eyes, a 20 % decrease in IOP obtained with the disks during 1 month was similar to Trusopt R eyedrops treatment. In hypertensive eyes, the most sustained decrease was shown by the high MW PCL (40 % after 1 month, 30 % after 2 months). It was shown that the implants can lower IOP in sustained manner in a rabbit glaucoma model.

Implantable dorzolamide-loaded discs were prepared by blending poly(ε-caprolactone), PCL, with poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide), Lu. By blending, crystallinity, water uptake and mass loss were modified relative to the pure polymers. Burst was diminished by coating the discs with a PCL shell. All samples presented burst release except PCL-coated samples that showed controlled release during 18 days. For PCL-coated samples, barrier control of diffusion coupled with partition control from the core slowed down the release, while for 50/50 Lu/PCL-coated samples, the enhancement in the porosity of the core diminished partition control of drug release. Nonlinear regression analysis suggested that a degradation model fully describes the release curve considering a triphasic release mechanism: the instantaneous diffusion (burst), diffusion and polymer degradation stages. The MTT test indicated that the materials are not cytotoxic for corneal endothelial cells. A good in vitro-in vivo correlation was obtained, with similar amounts of drug released in vitro and in vivo. The discs decreased intraocular pressure (IOP) in normotensive rabbit eyes by 13.0% during 10 days for PCL-coated and by 13.0% during 4 days for 50/50 Lu/PCL-coated samples. The percentages of IOP decrease are similar to those obtained by dorzolamide eyedrop instillation (11.0%).

The purpose of this work was to study ‘in vivo’ the vascular responses of retinal vessels of New Zealand white rabbits to substance P (SP), neurokinin A (NKA), neurokinin B (NKB), senktide, capsaicin (CAPS), and calcitonin gene related peptide (CGRP) before and after selective antagonist administration. We examined the effects of these neuropeptides on the normal circulation in the optic nerve head of the rabbit. Drugs were injected via pars plana through a micropipette system. Ten minutes before perivascular injection of 10 nmol/l sumatriptan (to contract the vessel), a selective antagonist or its solvent was administered. Then, cumulative injection of the agonist was performed. The other eye was used as control. Direct measurement of retinal arteriole diameters was performed using digital angiography. The quantification of the relaxing effect is expressed as percentage related to the precontracted vascular diameter. Microinjection of SP (NK1 receptor agonist) up to 10 nmol/l induced a dose-dependent arteriolar dilating effect [E_max (mean ± SEM) 21.3 ± 2.3%]. After the perivascular preinjection of 1 nmol/l L-668,169 or 1 nmol/l L-733,060 (NK1 receptor antagonists), the SP dose-response curve was shifted to the right. The same results were obtained with NKA (NK2 receptor agonist) which induced the most potent effect of all neuropeptides (E_max 53.3±2.5%). The NK2 receptor antagonists L-659,877 and GR 159897 (1 nmol/l) strongly inhibited this arteriolar vasodilation. As for CGRP, doses up to 10 nmol/l induced a marked vasodilation (E_max 41.1±0.4%) which decreased after microinjection of the selective antagonist CGRP8-37. The NK3 receptor agonists (senktide and NKB) showed a minor vasodilating effect (E_max 5.1±1.2 and 8.0±0.9%, respectively). On the contrary, CAPS showed a marked dose-dependent vasodilating effect (E_max 43.2±2.9%), antagonized by the tachykinin receptor antagonists and CGRP8-37. These results suggest, for the first time, the presence of NK1, NK2, and CGRP receptors on the retinal arteriolar wall of the rabbit.

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