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D. Nishizaka, H. Suzuki, S. Kageyama, T. Wada, M. Takeuchi, H. Hirata, T. Oguma, E. Shirasawa; Improved Timolol Drug Delivery With a Novel Thermosetting Gel Formulation. Invest. Ophthalmol. Vis. Sci. 2009;50(13):5998.
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The intraocular pressure (IOP) lowering response to timolol is limited by its residence time on the ocular surface. To deal with this limitation, we used a methylcellulose (MC) thermosetting gel for prolonging timolol exposure to the anterior surface. However, in its unmodified form the MC sol-gel transition only occurs at 50 to 55 C. A better MC formulation for extending drug exposure would be one in which this transition occurs closer to body temperature. We report here on the properties of a modified MC solution containing timolol (TGO) in which its transition temperature was lowered to that of the ocular surface without altering its rheological properties.
Viscosity of MC solutions (1.4% w/w) diluted with sodium citrate (0 to 5% w/w) and polyethylene glycol (PEG) (0 to 5% w/w) was measured at various temperatures with a B-type viscometer either in the presence or absence of timolol. Gamma scintigraphy determined the timolol precorneal residence time in TGO vehicle and MC solution (1.4% w/w). These media were radiolabeled by the inclusion of technetium-99m-labeled diethylenetriaminepentaacetic acid. Timolol penetration kinetics from TGO into rabbit iris ciliary body for up to 3 days were compared with those resulting from timolol eyedrop application. The duration of IOP lowering effects induced by TGO application was determined in ocular hypertensive rabbits.
MC sol-gel transition temperature was progressively lowered as a function of increases in sodium citrate and PEG concentration. Retention of TGO vehicle was greater than in MC solution. The buildup of timolol concentration in the iris ciliary body was larger during 24 h than that resulting from its application in eyedrops. TGO application in rabbits resulted in IOP declines lasting for 18 h.
A protocol was developed for lowering the sol-gel transition temperature of TGO to levels that are expected not to cause patient discomfort without altering rheological properties. Clinical usage of this modified gel may also improve patient compliance and prolong hypotensive responses to timolol. Furthermore, this novel delivery system may also improve responses to other drugs besides timolol.
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