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

Miguel Allo, Camila Melody Boquete, Marcela Analía Morettón, Luciano Parola, Yanina SANTANDER PLANTAMURA, Facundo Martín Bertera, Diego Andrés Chiappetta, Christian HÖCHT

Abstract


Objective: 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 <0.05 vs. baseline values)Conclusions: The incorporation of the SoluPlus hydrophilic polymer in PC:SP 150:150 and 50:250 implants increases therelease of carvedilol, since it provides plasma concentrations ranging from 100 to 200 ng/ml, resulting in a sustained reductionof indirect SBP in SHR.

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