title: Development and in vivo evaluation of an innovative "Hydrochlorothiazide-in Cyclodextrins-in Solid Lipid Nanoparticles" formulation with sustained release and enhanced oral bioavailability for potential hypertension treatment in pediatrics.
abstract: An innovative pediatric oral formulation of hydrochlorothiazide (HCT) (2mg/mL), endowed with improved bioavailability and sustained release properties and suitable for the hypertension treatment in pediatric patients, was developed by combining the drug-cyclodextrin complexation and the incorporation of the complex into Solid Lipid Nanoparticles (SLN). Precirol®ATO5-based SLN, with two different surfactants (Pluronic®F68 and Tween®80) loaded with the drug as such or as binary system with hydroxypropyl-beta-cyclodextrin (HPβCd) and sulfobutyl-ether-beta-cyclodextrin (SBEβCd) both as physical mixture (P.M.) or coground product (GR), were prepared using the hot high-shear homogenization followed by ultrasonication method. Loading of the drug:HPβCd both as P.M. and GR gave rise to nanoparticle formation, differently from the HCT:SBEβCd ones, with an entrapment efficiency of about 65%. Such SLN formulations showed an improvement of the drug release rate compared both to the drug suspension and to the free drug-loaded SLN. In all cases the SLN containing the GR systems exhibited better performances than the corresponding with P.M. However, the presence of Tween®80 gave rise to the complete drug release after only 150min, without providing a sustained release, whereas Pluronic®F68-based SLN containing GR were able to assure a sustained release over the time achieving more than 75% drug released at the end of the test, maintaining a constant 1.8-fold increase respect to simple drug suspension. Pluronic®F68-based SLN showed a pharmaceutically acceptable stability up to three months. In vivo studies highlighted the effectiveness of such formulations, enabling a concomitant increased diuretic effect and a sustained drug release and, consequently, enhanced HCT oral bioavailability.
authors.affiliation: Department of Chemistry, School of Human Health Sciences, University of Florence, Via Schiff 6, Sesto Fiorentino I-50019, Florence, Italy. Electronic address: marzia.cirri@unifi.it.
authors.forename: Marzia
authors.initials: M
authors.lastname: Cirri
authors.affiliation: Department of Chemistry, School of Human Health Sciences, University of Florence, Via Schiff 6, Sesto Fiorentino I-50019, Florence, Italy.
authors.forename: Natascia
authors.initials: N
authors.lastname: Mennini
authors.affiliation: Department of Chemistry, School of Human Health Sciences, University of Florence, Via Schiff 6, Sesto Fiorentino I-50019, Florence, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Maestrelli
authors.affiliation: Department of Chemistry, School of Human Health Sciences, University of Florence, Via Schiff 6, Sesto Fiorentino I-50019, Florence, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Mura
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Pharmacology and Toxicology Section, University of Florence, Florence, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Ghelardini
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Pharmacology and Toxicology Section, University of Florence, Florence, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Di Cesare Mannelli
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D001682:Biological Availability; D003505:Cyclodextrins / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry; D004339:Drug Compounding; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006852:Hydrochlorothiazide / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism; D008055:Lipids; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D010372:Pediatrics / Q000379:methods; D020442:Poloxamer / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000959:Antihypertensive Agents; D003505:Cyclodextrins; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D008055:Lipids; D006852:Hydrochlorothiazide; D020442:Poloxamer
keywords: Cyclodextrin; Hydrochlorothiazide; Oral bioavailability; Pediatrics; Solid lipid nanoparticles; Sustained release