INVESTIGADORES
RAMIREZ RIGO Maria Veronica
congresos y reuniones científicas
Título:
Polyelectrolyte-lisinopril complexes: pharmaceutical and biopharmaceutical properties
Autor/es:
RAMÍREZ RIGO M V; LUCIANI GIACOBBE LC; ARDUSSO M; OLIVERA ME; MANZO RH
Lugar:
Córdoba
Reunión:
Congreso; Reunión Internacional de Ciencias Farmacéuticas; 2010
Institución organizadora:
Departamento de Farmacia. Facultad de Ciencias Químicas. Universidad Nacional de Córdoba
Resumen:
INTRODUCTION. Lisinopril (LS) is a peptide-mimetic drug, angiotensin-converting enzyme inhibitor, used for the treatment of hypertension and congestive heart failure and to alleviate strain on heart damage as a result of a heart attack. LS is absorbed in the first segment of the intestine, by PEPT 1 and 2 transporters. It is slowly and incompletely absorbed after oral administration, with a bioavailability of 25-30%.In a R&D project on drug delivery systems, LS was selected to be associated to polyelectrolyte carriers (PE). Besides, its amphoteric nature allows the interaction of LS with acid and basic PEs.The aim of this work was to study some pharmaceutical and biopharmaceutical properties of PE-LS complexes.Lisinopril (LS) is a peptide-mimetic drug, angiotensin-converting enzyme inhibitor, used for the treatment of hypertension and congestive heart failure and to alleviate strain on heart damage as a result of a heart attack. LS is absorbed in the first segment of the intestine, by PEPT 1 and 2 transporters. It is slowly and incompletely absorbed after oral administration, with a bioavailability of 25-30%.In a R&D project on drug delivery systems, LS was selected to be associated to polyelectrolyte carriers (PE). Besides, its amphoteric nature allows the interaction of LS with acid and basic PEs.The aim of this work was to study some pharmaceutical and biopharmaceutical properties of PE-LS complexes. MATERIALS AND METHODS. Alginic acid (polyanion model), Eudragit E100 (polycation model) and LS were used to obtain new materials as solid at various drug-to-polymer weight ratios by a wet granulation method, and drying at 40°C in an oven. Similarly, LS loaded hydrogels with the same composition were prepared by dispersing the obtained solids in water. The complexes were studied in solid state (DSC, PXRD and FTIR) as well as in dispersion (release in Franz cells) to establish affinity and type of interactions. Drug permeation was evaluated by the rat everted gut sac technique from LS-Eudragit E100 dispersions, at a concentration of LS of 20 and 40 mg/250 ml, to simulate concentrations of LS after oral administration at the lowest and highest recommended dose. RESULTS. The PE-LS materials were easily prepared as solid particulates by mixing the powders with small proportions of hydroalcoholic solutions. No residues of crystalline or unreacted LS were present in the solids, regardless of the PE. In solid state, the amine group of LS is ionically linked to the carboxylic groups of alginic acid. Likewise, one of the carboxylic groups of LS is ionically linked to the dimethyl amine groups of Eudragit E100. The aqueous dispersions are physically stable and clear when the functional groups of the PEs are 50% neutralized with LS and the remaining 50% with NaOH (in alginic acid) or HCl (in Eudragit E100). Final pH of the formulations were in the range of 4-6. The PE-LS dispersions show in Franz cells slow and prolonged release when the receptor medium is water. Release rate is increased upon contact with physiologic simulated fluid, indicating the reversibility of the interaction. Data fits the fickian kinetic model. Interestingly, the release in water from both PEs was faster than previously studied monofunctional drug-PE dispersions (1, 2). This fact can be explained by the zwitterionic nature of LS, which in dispersion appears as a bipolar ion able to migrate from the electrical gradient of polyelectrolyte. LS intestinal permeation, at the both concentrations tested, was not affected by the presence of neither of the PE.The PE-LS materials were easily prepared as solid particulates by mixing the powders with small proportions of hydroalcoholic solutions. No residues of crystalline or unreacted LS were present in the solids, regardless of the PE. In solid state, the amine group of LS is ionically linked to the carboxylic groups of alginic acid. Likewise, one of the carboxylic groups of LS is ionically linked to the dimethyl amine groups of Eudragit E100. The aqueous dispersions are physically stable and clear when the functional groups of the PEs are 50% neutralized with LS and the remaining 50% with NaOH (in alginic acid) or HCl (in Eudragit E100). Final pH of the formulations were in the range of 4-6. The PE-LS dispersions show in Franz cells slow and prolonged release when the receptor medium is water. Release rate is increased upon contact with physiologic simulated fluid, indicating the reversibility of the interaction. Data fits the fickian kinetic model. Interestingly, the release in water from both PEs was faster than previously studied monofunctional drug-PE dispersions (1, 2). This fact can be explained by the zwitterionic nature of LS, which in dispersion appears as a bipolar ion able to migrate from the electrical gradient of polyelectrolyte. LS intestinal permeation, at the both concentrations tested, was not affected by the presence of neither of the PE. CONCLUSIONS. The ionic interaction between alginic acid or Eudragit E100 and LS modulates the release rate. This attribute could be beneficial to develop long acting formulations to circumvent problems related to LS current treatment, not only for oral but also for transdermal administration.The ionic interaction between alginic acid or Eudragit E100 and LS modulates the release rate. This attribute could be beneficial to develop long acting formulations to circumvent problems related to LS current treatment, not only for oral but also for transdermal administration.