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Q. Ru, C. Li, S. Brocchini, P. Khaw, M. Zloh; Molecular Dynamics Simulation of Ocular Tissue Tablets. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2451.
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Implantable tissue tablets are being developed to inhibit scarring after glaucoma filtration surgery (GFS). As the subconjunctival space may result in so-called "non-sink" conditions for the tablet, it is important to predict tablet dissolution. We conducted computational simulations using molecular dynamics (MD) to evaluate tablets derived from a hydrophilic drug, 5-fluorouracil (5-FU) and from a hydrophobic drug, ilomastat.
MD simulations were performed using Desmond v2.2 with Maestro 8.5 as a molecular modeling graphical interface. Tablet fabrication was simulated at compression pressures from 1-100 bar. The simulation of the tablet dissolution was conducted in the presence of explicit water molecules for 4.8 ns at a constant volume (266966 ± 493.7 Å). The dissolution was monitored by calculating the change in the total molecular surface area. To simulate the liquid turnover of the aqueous humor in the subconjunctival space, the water and dissolved drug molecules were removed and replaced by new water molecules every 0.6 ns.
Simulation of the dissolution for tablets compressed at increasing pressures showed that on average, one ilomastat molecule forms more hydrogen bonds than 5-FU, which in conjunction with hydrophobic interactions might contribute to its lower solubility. As anticipated, all the tablets were found to dissolve faster at 310 K than at 300 K. At the end of the simulation, the total molecular surface area of ilomastat increased by approximately 15% whilst the total molecular surface area of 5-FU increased by about 100% as a result of tablet swelling and release of molecules into solution. The number of 5-FU molecules released into solution was at least 80 times higher than the number of ilomastat molecules during the same period of simulation, qualitatively correlating to the ratio of their solubilities.
The tablet dissolution pattern shown in our MD simulations tends to correlate with experimental release profiles. Hence, the dissolution of ocular tissue tablets can be studied using MD calculations and may be used to predict the pharmacokinetics of ocular implants in development.
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