RESUMO
Intravitreal injections are the standard procedure in the treatment of retinal pathologies, such as the administration of the anti-VEGF antibodies in age-related macular degeneration. The aim of this study is to evaluate the intraocular and blood pharmacokinetics after an intravitreal injection of 89Zr-labelled bevacizumab and 89Zr-labelled aflibercept in Sprague-Dawley rats using Positron Emission Tomography. First, both antibodies were radiolabelled to zirconium-89 with a maximum specific activity of 15 Mbq/mg for bevacizumab and 10 Mbq/mg for aflibercept. Four µL containing 1-1.2 Mq of 89Zr-labelled compound were injected into the vitreous through a 35 G needle. A microPET acquisition was carried out immediately after the injection and at different time points through a 12-day study and blood samples were obtained through the tail vein. Radiolabelling was successfully performed with a radiochemical purity after ultrafiltration above 95% for both agents. Both antibodies ocular curves followed a two-compartment model in which an intraocular elimination half-life of 16.44 h was found for 89Zr-bevacizumab and 4.51 h for 89Zr-aflibercept, considering the alpha phase as the elimination phase. Regarding the beta phase, a half-life of 3.23 days for 89Zr-bevacizumab and 4.69 days for 89Zr-aflibercept were observed. With regards to blood concentration, 89Zr-bevacizumab showed a blood half-life of 7.08 days, whereas 89Zr-aflibercept's was 3.18 days, by a one-compartment model with first-order absorption kinetics. In conclusion, this study shows for the first time the ocular and blood pharmacokinetic analysis after intravitreal injection of aflibercept and bevacizumab in rats.
Assuntos
Bevacizumab/metabolismo , Olho/metabolismo , Injeções Intravítreas/métodos , Tomografia por Emissão de Pósitrons/métodos , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/sangue , Inibidores da Angiogênese/metabolismo , Animais , Bevacizumab/administração & dosagem , Bevacizumab/sangue , Olho/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Receptores de Fatores de Crescimento do Endotélio Vascular/sangue , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/sangueRESUMO
Age-related macular degeneration is the most common cause of vision loss in elderly people in developed countries. Nowadays, in clinical practice, three anti-VEGF drugs are commonly used (bevacizumab, aflibercept and ranibizumab), requiring repeated intravitreal injections. In order to minimise the number of injections, research on intravitreal drug delivery systems (DDSs) is needed. In this review, the DDSs developed up to date regarding intravitreal anti-VEGF drugs have been summarised, which include systems as hydrogels, liposomes, microparticles, nanoparticles or implants. Most of the studies have focused on the extended in vitro release behaviour of the developed DDSs, but data as antibody bioactivity, biocompatibility or in vivo stability is sometimes scarce. Moreover, as DDS development relies on in vivo pharmacokinetic analyses to evaluate the extended drug release, all the information regarding anti-VEGF intravitreal pharmacokinetics in different animal species have been compiled.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Sistemas de Liberação de Medicamentos , Degeneração Macular/tratamento farmacológico , Idoso , Inibidores da Angiogênese/farmacocinética , Inibidores da Angiogênese/farmacologia , Animais , Bevacizumab/administração & dosagem , Liberação Controlada de Fármacos , Humanos , Injeções Intravítreas , Degeneração Macular/fisiopatologia , Ranibizumab/administração & dosagem , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
Ocular cystinosis is a rare disease characterised by the deposit of cystine crystals on the corneal surface, which hinder patients' eyesight. Oral cysteamine is given as cysteamine; however, it does not reach the cornea due to the lack of corneal vascularization making necessary its administration by the topical ocular route. The aim of the present study is to determine the stability of an ophthalmic hydrogel of cysteamine, which can be potentially prepared at hospital pharmacy departments, under different preservation conditions during a follow-up of 30 days. Different physical and chemical parameters were evaluated: osmolality, pH and cysteamine concentration, which has been measured by a method of ultra performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS). Descriptive assays were also performed, such as transparency measurement and microbiological assays in order to verify its sterility. The obtained results allow us to conclude that the cysteamine hydrogel is stable during 30 days, being recommendable its preservation in refrigerated conditions.
La cistinosis ocular es una enfermedad rara que se caracteriza por el depósito de cristales de cistina a nivel corneal, los cuales dificultan la visión de los pacientes. La cisteamina oral se administra en forma de cisteamina, pero esta no alcanza la córnea debido a la falta de vascularización corneal, por lo que es necesaria la aplicación tópica ocular. El objetivo del presente trabajo es determinar la estabilidad de un hidrogel oftálmico de cisteamina, potencialmente formulable en servicios de farmacia hospitalaria, conservado este bajo diferentes condiciones de almacenamiento durante un periodo de 30 días. Los parámetros físicos y químicos evaluados han sido la osmolalidad, el pH y la concentración de cisteamina, siendo esta última valorada mediante un método de cromatografía líquida de ultra alta presión, empleando un detector de masas en tándem (UPLC-MS/MS). Los ensayos descriptivos se han basado en la medición de la transparencia y los ensayos microbiológicos en la realización de pruebas de esterilidad. Los resultados obtenidos permiten concluir que el hidrogel de cisteamina es estable durante un periodo de 30 días, recomendándose que su conservación sea en nevera.
Assuntos
Cisteamina/administração & dosagem , Cisteamina/uso terapêutico , Cistinose/tratamento farmacológico , Oftalmopatias/tratamento farmacológico , Hidrogel de Polietilenoglicol-Dimetacrilato/administração & dosagem , Hidrogel de Polietilenoglicol-Dimetacrilato/uso terapêutico , Soluções Oftálmicas/administração & dosagem , Soluções Oftálmicas/uso terapêutico , Administração Tópica , Química Farmacêutica , HumanosRESUMO
Cystinosis is a rare autosomal recessive disorder in which cystine crystals accumulate within the lysosomes of various organs, including the cornea. Ocular treatment is based on the administration of cysteamine eye drops, requiring its instillation several times per day. We have introduced the cysteamine in two types of previously developed ocular hydrogels (ion sensitive hydrogel with the polymers gellan gum and kappa-carrageenan and another one composed of hyaluronic acid), aiming at increasing the ocular retention in order to extend the dosing interval. The biopermanence studies (direct measurements and PET/CT) show that these formulations present a high retention time on the ocular surface of rats. From the in vitro release study we determined that both hydrogels can control the release of cysteamine over time, showing a zero order kinetics during four hours. At the same time, these hydrogels could act as corneal absorption promoters, as they allow a higher permeation of cysteamine through bovine cornea compared to a solution. HET-CAM test and cytotoxicity assays show no irritation on the ocular surface. These results demonstrate that the developed formulations present a high potential as vehicles for the topical ocular administration of cysteamine.