title: Development of liposomal and microemulsion formulations for transdermal delivery of clonazepam: effect of randomly methylated β-cyclodextrin.
abstract: Transdermal administration of clonazepam, a poorly water-soluble benzodiazepine, is an interesting strategy for overcoming the drawbacks of its oral administration. With this aim, two nano-carrier formulations, based on ultra-deformable liposomes and microemulsions, have been developed to favour clonazepam transdermal delivery. Considering the solubilizing power of methyl-βcyclodextrin (Me-βCD) toward clonazepam and its potential positive influence on transdermal drug delivery, the effect of its addition to these formulations was investigated. Artificial lipophilic membranes simulating the skin allowed a rapid evaluation of the drug permeation properties from the systems, compared with those from an aqueous drug suspension, with or without Me-βCD. The best formulations were further characterized by permeation through excised rabbit ear skin. All the formulations increased drug permeability, ranging from 2-fold (liposomes without Me-βCD), up to over 4-fold (microemulsions containing Me-βCD). The different formulations allowed for pointing out different possible permeation enhancing mechanisms of Me-βCD: increase in drug solubility and thermodynamic activity in the vehicle, when added to the drug aqueous suspension; interactions with the vesicle bilayer, in case of liposomal formulations; interactions with the skin membrane lipids, as evidenced in experiments with excised rabbit ear for microemulsions containing Me-βCD, that were then selected for further in vivo studies.
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 Chemistry, School of Human Health Sciences, University of Florence, Via Schiff 6, Sesto Fiorentino I-50019, Florence, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Bragagni
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: 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. Electronic address: francesca.maestrelli@unifi.it.
authors.forename: Francesca
authors.initials: F
authors.lastname: Maestrelli
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002998:Clonazepam / Q000008:administration & dosage / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry; D004655:Emulsions / Q000008:administration & dosage / Q000737:chemistry*; D008081:Liposomes / Q000008:administration & dosage / Q000737:chemistry*; D008563:Membrane Lipids / Q000378:metabolism; D010539:Permeability; D011817:Rabbits; D012867:Skin / Q000378:metabolism; D012869:Skin Absorption; D012995:Solubility; D047392:beta-Cyclodextrins / Q000008:administration & dosage / Q000737:chemistry*
chemical_list: D004337:Drug Carriers; D004655:Emulsions; D008081:Liposomes; D008563:Membrane Lipids; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D002998:Clonazepam
keywords: Clonazepam; Liposomes; Microemulsions; Permeation enhancers; Randomly methylated β-cyclodextrin; Transdermal delivery