title: Supramolecular interactions between losartan and hydroxypropyl-β-CD: ESI mass-spectrometry, NMR techniques, phase solubility, isothermal titration calorimetry and anti-hypertensive studies.
abstract: In this work, low soluble supramolecular complex between the losartan potassium (Los) and hydroxypropil-β-cyclodextrin (HPβCD) were characterized throughout phase-solubility, NMR techniques ((1)H and 2D-ROESY) and isothermal titration calorimetry (ITC) in order to attain physical-chemical knowledge of the system. In addition, the hypertensive effect of composition Los/HPβCD was evaluated aiming to obtain a more efficient oral pharmaceutical composition. ESI mass spectrometry and ITC blank experiment demonstrate the presence of Los clusters at 30 mM pure solution. Phase-solubility experiments showed a "Bs" type system, due to the formation of a less soluble complex than pure Los. NMR demonstrated the short distance interactions between the Los and the cyclodextrin, where several possibilities of interactions were observed. ITC data suggest an average 1:1 stoichiometry of Los and the cyclodextrin. The complex demonstrated efficiency in hypertension control, presenting antagonist action on the pressure effect of angiotensin II within 30 h, as compared to Los alone, 6h, indicating that inclusion of Los in HPβCD enhanced the extent and duration of its antagonistic action. In this work, a model of interaction between Los and HPβCD was proposed based on dissociation of self-assembled Los followed by complexation with HPβCD.
authors.affiliation: Laboratório de Encapsulamento Molecular e Biomateriais, Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, Av Antônio Carlos 6627, Belo Horizonte 31270-901, MG, Brazil.
authors.forename: Washington X
authors.initials: WX
authors.lastname: de Paula
authors.forename: Angelo M L
authors.initials: AM
authors.lastname: Denadai
authors.forename: Marcelo M
authors.initials: MM
authors.lastname: Santoro
authors.forename: Aline N G
authors.initials: AN
authors.lastname: Braga
authors.forename: Robson A S
authors.initials: RA
authors.lastname: Santos
authors.forename: Rubén D
authors.initials: RD
authors.lastname: Sinisterra
mesh_terms: D000284:Administration, Oral; D000804:Angiotensin II; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002151:Calorimetry; D002626:Chemistry, Pharmaceutical; D004195:Disease Models, Animal; D004337:Drug Carriers; D004339:Drug Compounding; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D007700:Kinetics; D019808:Losartan / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D021241:Spectrometry, Mass, Electrospray Ionization; D013678:Technology, Pharmaceutical / Q000379:methods*; D047391:alpha-Cyclodextrins / Q000737:chemistry*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D004337:Drug Carriers; D047391:alpha-Cyclodextrins; C479658:hydroxypropyl-alpha-cyclodextrin; D000804:Angiotensin II; D019808:Losartan