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R. A. Wassel, D. Chen, D. J. Nuno, A. B. Quiambao, J. L. Chodnicki, Y. Hu, P. Margaron, J.-X. Ma, R. Farjo; Pharmacokinetic Measurements of a Sustained Drug Delivery System. Invest. Ophthalmol. Vis. Sci. 2009;50(13):5952.
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The purpose of this study was to measure the drug concentration of CLT-003, a proprietary small molecule inhibitor of Hif1-, as it was released from polylactic-co-glycolic acid nanoparticles and microparticles in Dutch belted rabbits after intravitreal injection as well as in an in-vitro release model.
Dutch Belted Rabbits were given an intravitreal injection of nanoparticles or microparticles containing CLT-003. Plasma was collected at multiple time points following administration and vitreous humor and retina were collected at 6 weeks post-injection. CLT-003 was extracted from the tissues with chloroform and measured via LC/MS. For the in-vitro model; various CLT-003 PLGA formulations were dialyzed against 60 ml of PBS (pH 7.4) at 37 ºC. Samples were collected at various time points and analyzed by HPLC.
The concentration of CLT-003 in plasma was minimal, as expected following local delivery. A therapeutic concentration of CLT-003 could be detected in the vitreous for 6 weeks, suggesting a depot for the drug in the vitreous. CLT-003 was also detected in the retina. Some of this drug was most likely from CLT-003 that was released from the nanoparticles/microparticles in the vitreous and diffused into the retina, as well as CLT-003 that was released from nanoparticles or microparticles intracellularly in the target retinal cells. The in-vitro model showed that for the majority of formulations (nanoparticles and microparticles) tested, at least 50% of the drug was still inside the nanoparticles after 60 days. Further time points are being collected and processed.
CLT-003 PLGA-based formulations have demonstrated the ability to release the drug over a 6 week period. These results suggest these formulations may be developed into a suitable sustained release therapeutic that can be dosed intravitreally 1-3 times per year.
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