University of Coimbra - Faculty of Pharmacy - Department of Pharmaceutical Technology University of Santiago de Compostela - Faculty of Pharmacy - Department of Pharmaceutical Technology
Abstract: Ophthalmic delivery of α-tocopherol (TOC), which is the most active and cost/effective form of vitamin E, is receiving increasing attention as a way of preventing and treating glaucoma, cataracts, and dry eye syndrome, among other ocular pathologies. The aim of this work was to elucidate the possibility of using poly(propylene oxide) (PPO) and poly(ethylene oxide) (PEO) block copolymers of poloxamine family (namely, Tetronic(®) 1107) to develop polymeric micelles that can host TOC, enhance the apparent solubility and sustain the release of this vitamin in lachrymal fluid. The interactions of Tetronic 1107 with TOC were analyzed at the air-water interface recording the π-A isotherms at various temperatures, indicating favorable interactions as temperature increased from 10 to 29°C. In 0.9% NaCl aqueous medium, a sharp increase in TOC solubility was observed when T1107 surpasses the critical micellar concentration (CMC); the apparent solubility in 20% T1107 being more than 600-fold and 6000-fold that observed in the absence of copolymer at 4 and 25°C, respectively. Micelles were characterized before and after loading by means of dynamic light scattering (DLS) and transmission electronic microscopy (TEM). TOC sustained release profiles were recorded in Franz-Chien diffusion cells. After storage for 3 months at 4°C, TOC-loaded T1107 10% micellar system retained 84% TOC solubilized, which maintained the antioxidant activity. Furthermore, the rheological properties of the micellar systems were not altered either; the viscoelastic parameters being dependent on T1107 concentration, which opens the possibility of developing from free-flowing eye-drops to in situ gelling systems.
Abstract: Polymeric micelles of single and mixed poloxamines (Tetronic) were evaluated regarding their ability to host the antiglaucoma agent ethoxzolamide (ETOX) for topical ocular application. Three highly hydrophilic varieties of poloxamine (T908, T1107 and T1307) and a medium hydrophilic variety (T904), possessing a similar number of propylene oxide units but different contents in ethylene oxide, were chosen for the study. The critical micellar concentration and the cloud point of mixed micelles in 0.9 per cent NaCl were slightly greater than the values predicted from the additive rule, suggesting that the co-micellization is hindered. Micellar size ranged between 17 and 120 nm and it was not altered after the loading of ETOX (2.7-11.5 mg drug g(-1) poloxamine). Drug solubilization ability ranked in the order: T904 (50-fold increase in the apparent solubility) > T1107 is approximately equal to T1307 > T908. Mixed micelles showed an intermediate capability to host ETOX but a greater physical stability, maintaining almost 100 per cent drug solubilized after 28 days. Furthermore, the different structural features of poloxamines and their combination in mixed micelles enabled the tuning of drug release profiles, sustaining the release in the 1-5 days range. These findings together with promising hen's egg test-chorioallantoic membrane biocompatibility tests make poloxamine micelles promising nanocarriers for carbonic anhydrase inhibitors in the treatment of glaucoma.
Abstract: Hydrogels with high affinity for carbonic anhydrase (CA) inhibitor drugs have been designed trying to mimic the active site of the physiological metallo-enzyme receptor. Using hydroxyethyl methacrylate (HEMA) as the backbone component, zinc methacrylate, 1- or 4-vinylimidazole (1VI or 4VI), and N-hydroxyethyl acrylamide (HEAA) were combined at different ratios to reproduce in the hydrogels the cone-shaped cavity of the CA, which contains a Zn(2+) ion coordinated to three histidine residues. 4VI resembles histidine functionality better than 1VI, and, consequently, pHEMA-ZnMA(2) hydrogels bearing 4VI moieties were those with the greatest ability to host acetazolamide or ethoxzolamide (2 to 3 times greater network/water partition coefficient) and to sustain the release of these antiglaucoma drugs (50% lower release rate estimated by fitting to the square root kinetics). The use of acetazolamide as template during polymerization did not enhance the affinity of the network for the drugs. In addition to the remarkable improvement in the performance as controlled release systems, the biomimetic hydrogels were highly cytocompatible and possessed adequate oxygen permeability to be used as medicated soft contact lenses or inserts. The results obtained highlight the benefits of mimicking the structure of the physiological receptors for the design of advanced drug delivery systems.
