Development of Subcutaneous Implants of Controlled Release Formulations of Carvedilol for Sustained Blood Pressure Reduction in Experimental Models of Hypertension

espanolObjetivo: El objetivo del presente estudio fue el desarrollo y la evaluacion farmacocinetica y farmacodinamica de la liberacionin vivo de implantes subcutaneos de carvedilol capaces de aportar niveles tisulares estables en modelos experimentales dehipertension arterial.La incorporacion del polimero hidrofilico SoluPlus (SP) en los implantes PCL:SP 150:150 y 50:250 favorece un incrementode la liberacion de carvedilol dado que aporta concentraciones plasmaticas en el rango de 100-200 ng/mL durante 2 semanas,lo que tiene como resultado una reduccion sostenida de la presion arterial sistolica indirecta en animales SHR.Material y metodos: Se prepararon implantes subcutaneos de poli (epsilon-caprolactona) (PCL) con diferentes proporcionesdel polimero hidrofilico SoluPlus (300:0; 250:50; 150:150 y 50:250 mg) cargados con 100 mg de carvedilol. Se evaluo el perfilplasmatico y el efecto sobre la presion arterial sistolica (PAS) luego del implante de cada formulacion en el tejido subcutaneode ratas espontaneamente hipertensas (REH) macho.Resultados: Las formulaciones PCL:SP 50:250 y 150:150 aportaron niveles en el rango de 100-200 ng/mL. Las formulacionesPCL:SP 250:50 y 300:0 aportaron concentraciones inferiores de carvedilol comprendidas en el rango de los 0-100 ng/mL duranteel transcurso del tratamiento. Los animales espontaneamente hipertensos tratados con PCL:SP 50:250 y 150:150 experimentaronun descenso significativo de la presion arterial sistolica (PCL:SP 50:250: DPAS: –36,6 ± 2,0 mmHg; PCL:SP150:150:35,7 ± 2,2 mmHg; p EnglishObjective: The aim of this study was the development and pharmacokinetic/pharmacodynamic evaluation of the in vivo releaseof subcutaneous implants of carvedilol capable of providing stable tissue levels in experimental models of hypertension.Methods: The subcutaneous implants were prepared with poly (epsilon-caprolactone) (PCL) and different proportions of theSoluPlus (SP) hydrophilic polymer (300:0; 250:50; 150:150 and 50:250 mg) loaded with 100 mg carvedilol. The plasma profileand the effect on systolic blood pressure (SBP) after subcutaneous implantation of each formulation was evaluated in malespontaneously hypertensive rats (SHR).Results: The PCL:SP 50:250 and 150:150 formulations provided levels ranging from 100 to 200 ng/mL and the PCL:SP 250:50and 300:0 formulations provided lower concentrations of carvedilol ranging from 0 to 100 ng/mL during the treatment period.Spontaneously hypertensive animals treated with the PCL:SP 50:250 y 150:150 implants presented a significant decrease inSBP (PCL:SP 50:250: DPAS: –36.6 ± 2.0 mm Hg; PCL:SP150:150: -35.7 ± 2.2 mmHg; p

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