RESUMO
Ophthalmic conditions in which the retinal vasculature is obstructed generally lead to vision loss. Administration of the vasodilator L-lactate might offer a treatment strategy by restoring the blood flow, but unfortunately its effect after single intravitreal injection is short-lived. This study describes a concept in which the sustained release of L-lactic acid from a biodegradable copolymer system is investigated. The 50:50 (n/n) copolymer system, composed of L-lactic acid and L,D-2-hydroxyoctanoic acid, is a viscous injectable that will form an intravitreal drug depot. Hydrolysis of the copolymer will automatically lead to the release of L-lactic acid, which will convert to L-lactate at physiological pH, thereby providing a carrier and pro-drug in one. In vitro and ex vivo release studies demonstrate an L-lactic acid release over several weeks. Biocompatibility of the co-polymer and its degradation products is shown on a human retinal pigment epithelial cell line and on ex vivo retinal tissues. A low molecular weight copolymer (1200 g/mol) with low polydispersity has promising properties with a constant release profile, good biocompatibility and injectability.
Assuntos
Preparações de Ação Retardada/química , Portadores de Fármacos/química , Ácido Láctico/química , Poliésteres/química , Polímeros/química , Pró-Fármacos/química , Animais , Linhagem Celular , Preparações de Ação Retardada/administração & dosagem , Portadores de Fármacos/administração & dosagem , Humanos , Injeções Intravítreas , Ácido Láctico/administração & dosagem , Poliésteres/administração & dosagem , Polímeros/administração & dosagem , Pró-Fármacos/administração & dosagem , Oclusão da Artéria Retiniana/tratamento farmacológico , SuínosRESUMO
The in vitro stability of monoclonal antibodies used for age-related macular degeneration, ranibizumab and bevacizumab, was investigated. The aggregation profile of the antibodies was compared, alone and after association with dexamethasone sodium phosphate or triamcinolone acetonide. Commercial formulations of ranibizumab and bevacizumab were dialysed into three different buffers. After dialysis, samples were stored at 4°C, 25°C and 40°C during 35 days, alone and in combination with dexamethasone sodium phosphate, triamcinolone acetonide phosphate solution or triamcinolone acetonide suspension. Combined formulations based on both commercial formulations were investigated as well. The aggregation state of the antibodies was measured by multi-angle light scattering (MALS) after separation by asymmetrical flow field-flow fractionation (AFFF) or size-exclusion chromatography (SEC). Ranibizumab results to be more stable than bevacizumab, alone and in combination with dexamethasone sodium phosphate or triamcinolone acetonide. Elevation in concentration, pH and temperature causes a decrease in stability of both antibodies. The association of triamcinolone acetonide phosphate solution with either ranibizumab or bevacizumab is observed to be the least stable combination of all samples tested. Dexamethasone sodium phosphate was shown to have a stabilizing effect on bevacizumab, although this is not the case for its combination with the commercial formulation Avastin®. The results demonstrate that the in vitro association of either ranibizumab or bevacizumab with dexamethasone sodium phosphate or triamcinolone acetonide suspension does not decrease the stability of these antibodies. Although ranibizumab is more stable than bevacizumab in vitro, further research has to point out how this affects their mechanism of action in vivo.