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G. Hsiue, R. Chang, J. Lai, C. Wang, S. Lee; Development of In-situ Thermo-sensitive Ophthalmic Drug Delivery System for Glaucoma Therapy . Invest. Ophthalmol. Vis. Sci. 2003;44(13):4418.
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Purpose: The thermo-sensitive polymeric vehicles with enhancing drug bioavailability were prepared to entrap the epinephrine and investigated for glaucoma therapy. Methods: Poly-N-isopropylacrylamide (PNIPAAm) is a well-known reversible thermo-sensitive polymer. To improve the biocompatibility and mechanical strength, chemical modification of PNIPAAm was conducted by grafting of Poly-2-hydroxyethyl methacrylate (PHEMA). The cross-linked gel particles and linear polymers of PNIPAAm-g-PHEMA were obtained via respective synthetic pathways. The combination of 10% linear PNIPAAm-g-PHEMA and 2% of their cross-linked gel particles were used for drug vehicles. The epinephrine and PNIPAAm-g-PHEMA vehicles were uniformly dissolved in PBS to yield the desired drug solution served as eyedrop-mimetics. For in vitro controlled drug release measurements, the samples were obtained periodically and radioactivity of 3H-epinephrine counted following the addition of EcoscientTM H. The 2.5-3 kg New Zealand adult albino rabbits for animal experiments were divided into two groups. In experimental groups, the drug solution composed of 0.2% epinephrine/saline and PNIPAAm-g-PHEMA vehicles was dropped into right eye while PNIPAAm-g-PHEMA vehicles dissolved in PBS was dropped into left eye for each rabbit. In controlled groups, 0.2% epinephrine/saline and PBS were dropped into right and left eye respectively. The intraocular pressure (IOP) was measured by pneumo-tonometer per hour after topical application of tested solution described in each group. The statistical analysis was conducted with Student's t-test. Results: For controlled drug release, the polymeric drug vehicles composed of the linear PNIPAAm-g-PHEMA and their gel particles could prolong drug bioavailability and the pharmacokinetics was close to the Fickian diffusion model. The results for animal experiments showed the IOP rapidly decreased to maximum of -3.6 mmHg (p<0.05) at 1st hr, and gradually returned to baseline at 8th hours in controlled groups while the maximal IOP-reducing effect was reached at 2nd hr, and persist more than 26th hours. The eyedrop-mimetics containing polymeric vehicles were more than 3 times effective in reducing the IOP over traditional eyedrops. Conclusions: It was successfully demonstrated that the thermo-sensitive polymeric drug vehicles exhibited great potential in controlled release for glaucoma therapy.
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