Enhanced intestinal permeability and oral bioavailability of enalapril maleate upon complexation with the cationic polymethacrylate Eudragit E100.
The low bioavailability of enalapril maleate associated to its instability in solid state motivated the development of a polyelectrolyte-drug complex between enalapril maleate and the cationic polymethacrylate Eudragit E100. The solid complexes were characterized by DSC-TG, FT-IR and X-ray diffraction. Their aqueous dispersions were evaluated for drug delivery in bicompartimental Franz cells and electrokinetic potentials. Stability in solid state was also evaluated using an HPLC-UV stability indicating method. Absorption of enalapril maleate was assessed thorough the rat everted gut sac model. In addition, urinary recovery after oral administration in rats was used as an indicator of systemic exposition. The solid materials are stable amorphous solids in which both moieties of enalapril maleate are ionically bonded to the polymer. Their aqueous dispersions exhibited controlled release over more than 7h in physiologic saline solution, being ionic exchange the fundamental mechanism that modified the extent and rate of drug release. Intestinal permeation of enalapril maleate was 1.7 times higher in the presence of the cationic polymer. This increase can be related with the capacity to adhere the mucosa due to the positive zeta potential of the complexes. As a consequence bioavailability was significantly improved (1.39 times) after oral administration of the complexes. In addition, no signs of chemical decomposition were observed after a 14months period. The results indicated that the products are new chemical entities that improve unfavorable properties of a useful drug.
Planta Piloto de Ingeniería Química (PLAPIQUI CONICET - Universidad Nacional del Sur), Camino la Carrindanga Km 7, 8000 Bahía Blanca, Argentina. Electronic address: vrrigo@plapiqui.edu.ar.
María V
MV
Ramírez-Rigo
Departamento de Farmacia, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba (UNC), Unidad de Tecnología Farmacéutica (UNITEFA, CONICET - UNC), Ciudad Universitaria, 5000 Córdoba, Argentina.
María E
ME
Olivera
Instituto de Investigaciones Farmacológicas (ININFA, CONICET - Universidad de Buenos Aires), Junín 956, 1113 Buenos Aires, Argentina.
Modesto
M
Rubio
Departamento de Farmacia, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba (UNC), Unidad de Tecnología Farmacéutica (UNITEFA, CONICET - UNC), Ciudad Universitaria, 5000 Córdoba, Argentina. Electronic address: rubmanzo@fcq.unc.edu.ar.
Ruben H
RH
Manzo
D000179:Acrylates / Q000737:chemistry*; D000268:Adhesiveness; D000284:Administration, Oral; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D001682:Biological Availability; D002152:Calorimetry, Differential Scanning; D002412:Cations; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D004355:Drug Stability; D004656:Enalapril / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D010539:Permeability; D011108:Polymers / Q000737:chemistry*; D033362:Powder Diffraction; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D017550:Spectroscopy, Fourier Transform Infrared; D013678:Technology, Pharmaceutical / Q000379:methods; D013818:Thermogravimetry
D000179:Acrylates; D000806:Angiotensin-Converting Enzyme Inhibitors; D002412:Cations; D003692:Delayed-Action Preparations; D004337:Drug Carriers; C477020:Eudragit E100; D011108:Polymers; D004656:Enalapril
Bioavailability enhancement; Drug delivery; Intestinal permeation; Ionic complexes; Polymethacrylate; Urinary excretion