RESUMEN
In this study we present the development of an injectable polymeric drug delivery system for subconjunctival treatment of primary open angle glaucoma. The system consists of hyaluronic acid sodium salt (HA), which is commonly used in ophthalmology in anterior segment surgery, and an isocyanate-functionalized 1,2-ethylene glycol bis(dilactic acid) (ELA-NCO). The polymer mixtures with different ratios of HA to ELA-NCO (1/1, 1/4, and 1/10 (v/v)) were investigated for biocompatibility, degradation behavior and applicability as a sustained release system. For the latter, the lipophilic latanoprost ester pro-drug (LA) was incorporated into the HA/ELA-NCO system. In vitro, a sustained LA release over a period of about 60days was achieved. In cell culture experiments, the HA/ELA-NCO (1/1, (v/v)) system was proven to be biocompatible for human and rabbit Tenon's fibroblasts. Examination of in vitro degradation behavior revealed a total mass loss of more than 60% during the observation period of 26weeks. In vivo, LA was continuously released for 152days into rabbit aqueous humor and serum. Histological investigations revealed a marked leuko-lymphocytic infiltration soon after subconjunctival injection. Thereafter, the initial tissue reaction declined concomitantly with a continuous degradation of the polymer, which was completed after 10months. Our study demonstrates the suitability of the polymer resulting from the reaction of HA with ELA-NCO as an injectable local drug delivery system for glaucoma therapy, combining biocompatibility and biodegradability with prolonged drug release.
Asunto(s)
Conjuntiva , Glaucoma de Ángulo Abierto/tratamiento farmacológico , Animales , Humor Acuoso/metabolismo , Materiales Biocompatibles , Células Cultivadas , Preparaciones de Acción Retardada , Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Ojo/patología , Glaucoma de Ángulo Abierto/patología , Humanos , Ácido Hialurónico/administración & dosificación , Ácido Hialurónico/uso terapéutico , Inyecciones , Latanoprost , Fármacos Neuroprotectores/administración & dosificación , Fármacos Neuroprotectores/uso terapéutico , Polímeros , Profármacos/administración & dosificación , Prostaglandinas F Sintéticas/administración & dosificación , Prostaglandinas F Sintéticas/uso terapéutico , ConejosRESUMEN
Drug-coated balloons (DCB), which have emerged as a therapeutic alternative to drug-eluting stents in percutaneous cardiovascular intervention, are well described with regard to clinical efficacy and safety within a number of clinical studies. In vitro studies elucidating the correlation between coating additive and DCB performance are however rare but considered important for the understanding of DCB requirements and the improvement of established DCB. In this regard, we examined three different DCB-systems, which were developed in former studies based on the ionic liquid cetylpyridinium salicylate, the body-own hydrogel hyaluronic acid and the pharmaceutically well-established hydrogel polyvinylpyrrolidone, considering coating morphology, coating thickness, drug-loss, drug-transfer to the vessel wall, residual drug-concentration on the balloon surface and entire drug-load during simulated use in an in vitro vessel model. Moreover, we investigated particle release of the different DCB during simulated use and determined the influence of the three coatings on the mechanical behavior of the balloon catheter. We could show that coating characteristics can be indeed correlated with the performance of DCB. For instance, paclitaxel incorporation in the matrix can reduce the drug wash-off and benefit a high drug transfer. Additionally, a thin coating with a smooth surface and high but delayed solubility can reduce drug wash-off and decrease particle burden. As a result, we suggest that it is very important to characterize DCB in terms of mentioned properties in vitro in addition to their clinical efficacy in order to better understand their function and provide more data for the clinicians to improve the tool of DCB in coronary angioplasty.
Asunto(s)
Antineoplásicos Fitogénicos/química , Materiales Biocompatibles Revestidos/química , Stents Liberadores de Fármacos , Hidrogel de Polietilenoglicol-Dimetacrilato/química , Líquidos Iónicos/química , Paclitaxel/química , Angioplastia Coronaria con Balón , Materiales Biocompatibles Revestidos/síntesis química , Ácido Hialurónico/química , Líquidos Iónicos/síntesis química , Microscopía Confocal , Microscopía Electrónica de Rastreo , Modelos Biológicos , Povidona/química , Propiedades de SuperficieRESUMEN
Drug-coated balloons (DCB), which have emerged as therapeutic alternative to drug-eluting stents in percutaneous cardiovascular intervention, are well described with regard to clinical efficiency and safety within a number of clinical studies. In vitro studies elucidating the correlation of coating method and composition with DCB performance are however rare but considered important for the understanding of DCB requirements and the improvement of established DCB. In this context, we evaluated the applicability of a pipetting, dip-coating, and spray-coating process for the establishment of DCB based on paclitaxel (PTX) and the ionic liquid cetylpyridinium salicylate (Cetpyrsal) as novel innovative additive in three different compositions. Among tested methods and compositions, the pipetting process with 50 wt.% PTX resulted in most promising coatings as drug load was less controllable by the other processes and higher PTX contents led to considerable drug crystallization, as visualized by electron microscopy, accelerating PTX loss during short-term elution. Applying these conditions, homogeneous coatings could be applied on balloon catheter, whose simulated use in an in vitro vessel model revealed percental drug losses of 36 and 28% during transit and percental drug transfers of 12 and 40% under expansion for coatings applied in expanded and folded balloon condition, respectively. In comparison to literature values, these results support the high potential of Cetpyrsal as novel DCB matrix regarding low drug loss and efficient drug transfer.