Abstract
Ganciclovir and valganciclor are antiviral agents used for the treatment of cytomegalovirus retinitis. The conventional method for administering ganciclovir in cytomegalovirus retinitis patients is repeated intravitreal injections. In order to obviate the possible detrimental effects of repeated intraocular injections, to improve compliance and to eliminate systemic side-effects, we investigated the tuning of the ganciclovir pro-drug valganciclovir and the release from thin films of poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), or mixtures of both, as a step towards prototyping periocular valganciclovir implants. To investigate the drug release, we established and evaluated a high throughput fluorescence-based quantification screening assay for the detection of valganciclovir. Our protocol allows quantifying as little as 20 ng of valganciclovir in 96-well polypropylene plates and a 50× faster analysis compared to traditional HPLC measurements. This improvement can hence be extrapolated to other polyester matrix thin film formulations using a high-throughput approach. The acidic microenvironment within the polyester matrix was found to protect valganciclovir from degradation with resultant increases in the half-life of the drug in the periocular implant to 100 days. Linear release profiles were obtained using the pure polyester polymers for 10 days and 60 days formulations; however, gross phase separations of PCL and acid-terminated PLGA prevented tuning within these timeframes due to the phase separation of the polymer, valganciclovir, or both.
Highlights
The cytomegalovirus (CMV) is a member of the herpesviridae family and infects approximately 50%of the European population [1,2]
Our study demonstrates that the fluorescence of valganciclovir and ganciclovir is strongly pH-dependent and the fluorescence intensity improves with low pH
We show that the half-life of valganciclovir is prolonged from 10.6 hours in PBS buffer to approximately 100 days inside of 1:1 poly(lactic-co-glycolic acid) (PLGA) to PCL thin films
Summary
The cytomegalovirus (CMV) is a member of the herpesviridae family and infects approximately 50%. Of the European population [1,2]. CMV is characterized by lifelong persistence in the host [3,4]. Chronic infection of the host usually remains subclinical, as the virus count is actively kept under control by the immune system. In immunocompromised patients, such as HIV patients, latent cytomegalovirus may reactivate and become life threatening. Is the most common opportunistic AIDS-related ocular complication and occurs in 40% of all HIV patients with CD4 counts of less than 50 units [5]. Ganciclovir, an inhibitor of the viral DNA polymerase is the conventional drug to treat CMVR [6]
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