title: New formulation of an old drug in hypertension treatment: the sustained release of captopril from cyclodextrin nanoparticles.
abstract: Captopril (CAP) was the first angiotensin I-converting enzyme (ACE) inhibitor to be developed and is widely used in hypertension treatment. On the other hand, cyclodextrins (CDs) are cyclic oligosaccharides whose cone-shaped cavity allows formation of noncovalent inclusion complexes with appropriately sized guest molecules, thus modifying guest physical, chemical, and biological properties. Herein, the physicochemical characterization and in vivo ACE inhibition evaluation of seven CAP/CD complexes are reported. The inclusion complexes were prepared by spray-drying, freeze-drying, kneading, or lyophilization methods and characterized by nuclear magnetic resonance, Fourier-transformed infrared spectroscopy, X-ray diffraction, differential scanning calorimetry, and scanning electron microscopy techniques. In vivo assays compared CAP and CAP/CD complex administration (0.5 mg kg(-1) or 0.09 mg kg(-1), n = 4-7) to evaluate the ACE inhibition by continuous infusion of angiotensin I (30 ng 50 μL(-1) min(-1)) in conscious Wistar rats. The physicochemical analysis demonstrated complete amorphization and complexation between CAP and CDs, indicating the substitution of water molecules inside the CD cavity with CAP. During the infusion of angiotensin I, the administration of all CAP/CD complexes induced a reduction in mean arterial pressure similar to that observed upon CAP administration. The nanoparticles obtained by the kneading method (CAP/α-CD:KM) showed a potent and long-lasting inhibitory activity (∼22 hours) on the angiotensin I pressor effect. The results suggest that the inclusion complex of CAP and α-CD can function as a novel antihypertensive formulation that may improve therapeutic use of CAP by reducing its oral dose administration to once per day, thus providing better quality of life for almost 25% of the world's population who suffer from hypertension.
authors: Biopharmaceuticals and Hormones, Center of Biotechnology, Instituto de Pesquisas Energéticas e Nucleares, Sao Paulo, Brazil. mbmazevedo@ipen.br
authors: Mariangela de Burgos M
authors: Mde B
authors: de Azevedo
authors: Ljubica
authors: L
authors: Tasic
authors: Juliana
authors: J
authors: Fattori
authors: Fábio H S
authors: FH
authors: Rodrigues
authors: Fabiana C
authors: FC
authors: Cantos
authors: Leandro P
authors: LP
authors: Ribeiro
authors: Vanice
authors: V
authors: de Paula
authors: Danielle
authors: D
authors: Ianzer
authors: Robson A S
authors: RA
authors: Santos
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002152:Calorimetry, Differential Scanning; D002216:Captopril / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D003505:Cyclodextrins / Q000737:chemistry*; D003692:Delayed-Action Preparations; D004058:Diffusion; D008297:Male; D008855:Microscopy, Electron, Scanning; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D019906:Nuclear Magnetic Resonance, Biomolecular; D051381:Rats; D017208:Rats, Wistar; D017550:Spectroscopy, Fourier Transform Infrared; D014961:X-Ray Diffraction
chemical_list: D000959:Antihypertensive Agents; D003505:Cyclodextrins; D003692:Delayed-Action Preparations; D002216:Captopril