| Wei Gang (Specialty: Pharmaceutics) Dissertation supervisor: Prof. Zheng Junmin and Li SanmingAs one of the important fields of controlled release, ophthalmic drug delivery has received extensive interests during the last two decades. The sensitivity and protection mechanisms of the eye promote more effective drug delivery systems with better compliancy to be developed, however, the applications of numerous pharmaceutical methods are limited simultaneously, which presents great challenge in designing ophthalmic dosage forms. In situ gels refer to the polymer solutions can be administrated as liquid, which undergo a phase transition to a non-crosslinked semisolid gel upon exposure to physiological environments. Most of the applications of the in situ gels are concerned with ophthalmic disease treatment for its convenient administration combined with the favorable ocular residence time, hi this dissertation, timolol maleate (TM) was selected as a model drug, and a series of relative researches were carried out, during which many novel techniques and methods have been used, including the drug permeability across isolated cornea, in vitro evaluation of the precorneal residence of water soluble polymers, development of in situ gels with modulated phase transition temperature, characterization of gelation process by dynamic rheological method, analyzing the states of the thermosetting vehicles under physiological and non-physiological conditions, drug release and diffusion, the dynamics of precorneal clearance and the pharmacokinetics in aqueous humor after the in situ gels applied topically.The diffusion behaviors of TM across isolated rabbit cornea possessed zero-order kinetic characteristic. At neutral media (pH 7.65), an apparent permeation coefficient of 1.43×10-5 cm.s-1 was found. When the pH varied from 6.65 to 9.20, the accumulative amount for timolol transcorneal penetration increased 1.3 times and the lag time shortened more than 19-folds. The calculated permeability coefficients of ionized and un-ionized timolol were 1.29×10-5 cm.s-1 and 4.22×10-5 cm.s-1, respectively. Penetration enhancers, which accelerate the drug transporting by intracellular pathway, showed significantly promoting activity. 0.05% sodium deoxycholate and 1% poloxamer 188 (P188) improved the apparent permeability of TM as much as 1.88 and 1.55 folds, respectively, without irritancy observed, but further increasing P188 concentration led to lower permeability. Azone caused corneal tissue damage although has showed maximum permeation enhancing effect. EDTA, a calcium ion chelator, may loosen tight intercellular junctions, however, no improvement was found for TM transcornealpermeation. The result indicated that timolol mainly penetrated corneal membrane as freebase by intracellular pathway, and comeal epithelium was the rate-limiting barrier.For the purpose of comparing the capability of some water soluble polymers to adhere to the ocular surface and evaluating the effect of solution viscosity on precomeal residence, captive bubble technique was used, with the consecutive change of contact angle interpreted as an indication of desorption process, to study the residence of those polymers on freshly enucleated rabbit eyes under physiological conditions. It was evidenced that the contact angle on mucin-coated corneal surface was 38.2?.6?measured by sessile bubble method, and sodium hyaluronate (HA-Na) had the most appropriate corneal wettability although not decreasing the surface tension. Significant difference in the corneal retentive capabilities was observed between five polymers. Carbopol and HA-Na, which adsorbed to isolated ocular surface more than 15 min, showed the optimum bioadhesive properties. When the solution viscosity increased from 12 mPa.s to 50 mPa.s, the residence times of Carbopol and HA-Na were prolonged by 10 min and 7 min, respectively, but that of sodium carboxymethylcellulose was not affected. The result suggested that moderately higher viscosity is beneficial to improve the ocular residence...
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