title: Passive and active strategies for transdermal delivery using co-encapsulating nanostructured lipid carriers: in vitro vs. in vivo studies.
abstract: This work aimed at designing a formulation based on nanostructured lipid carriers (NLC) for transdermal co-administration of olanzapine and simvastatin, using passive and active strategies in a combined in vitro/in vivo development approach. NLC were prepared by two distinct methods, namely solvent emulsification-evaporation (SE/E) and high pressure homogenization (HPH). HPH was selected on the basis of a better performance in terms of drug loading and in vitro permeation rate. Several mathematical models were used to elucidate the release mechanisms from lipid nanoparticles. In vitro release kinetics was shown to be driven by diffusion, but other mechanisms were also present, and supported the feasibility of using NLC for sustained drug delivery. The in vitro skin studies showed that the chemical penetration enhancers, limonene and ethanol, added to the NLC formulations, promoted a synergistic permeation enhancement of both drugs, with olanzapine exhibiting a higher permeation than simvastatin. Transdermal administration to rats resulted in steady-state levels reached at around 10h and maintained for 48h, again with olanzapine exhibiting a better permeation rate. The pharmacokinetic parameters indicated that the NLC dispersion displayed a better in vivo performance than the gel, which was consistent with the in vitro results. These differences were, however, negligible in the flux values, supporting the use of gel as a final, more convenient, formulation. The in vivo experiments in rats correlated well with in vitro findings and revealed that the combined use of ethanol and limonene, incorporated in the NLC formulation, provided the main driving force for drug permeation. The Dermaroller® pretreatment did not significantly enhance drug permeation, supporting the use of passive methods as suitable for a transdermal delivery system. Furthermore, this work may provide a promising proof-of-concept for further clinical application in the treatment of schizophrenia and associated disorders, combined with dyslipidemia.
authors: Centro de Estudos Farmacêuticos (CEF), University of Coimbra, Coimbra, Portugal.
authors: Carla
authors: C
authors: Vitorino
authors: Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), University of Lisbon, Lisbon, Portugal.
authors: António
authors: A
authors: Almeida
authors: Centro de Estudos Farmacêuticos (CEF), University of Coimbra, Coimbra, Portugal.
authors: João
authors: J
authors: Sousa
authors: INSERM, U 1070, Poitiers, France; Université de Poitiers, Faculté de Médecine et de Pharmacie, Poitiers, France.
authors: Isabelle
authors: I
authors: Lamarche
authors: INSERM, U 1070, Poitiers, France.
authors: Patrice
authors: P
authors: Gobin
authors: INSERM, U 1070, Poitiers, France; Université de Poitiers, Faculté de Médecine et de Pharmacie, Poitiers, France; CHU de Poitiers, Poitiers, France.
authors: Sandrine
authors: S
authors: Marchand
authors: INSERM, U 1070, Poitiers, France; Université de Poitiers, Faculté de Médecine et de Pharmacie, Poitiers, France; CHU de Poitiers, Poitiers, France.
authors: William
authors: W
authors: Couet
authors: INSERM, U 1070, Poitiers, France; Université de Poitiers, Faculté de Médecine et de Pharmacie, Poitiers, France.
authors: Jean-Christophe
authors: JC
authors: Olivier
authors: Chemistry Department, University of Coimbra, Coimbra, Portugal. Electronic address: pais@qui.uc.pt.
authors: Alberto
authors: A
authors: Pais
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D001569:Benzodiazepines / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D002626:Chemistry, Pharmaceutical / Q000379:methods; D053138:Cyclohexenes / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry* / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods; D005782:Gels / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D000077222:Limonene; D008055:Lipids / Q000008:administration & dosage* / Q000737:chemistry*; D008297:Male; D049329:Nanostructures / Q000008:administration & dosage* / Q000737:chemistry*; D000077152:Olanzapine; D010316:Particle Size; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D012867:Skin / Q000378:metabolism*; D012869:Skin Absorption; D013552:Swine; D013729:Terpenes / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism
chemical_list: D053138:Cyclohexenes; D004337:Drug Carriers; D005782:Gels; D008055:Lipids; D013729:Terpenes; D001569:Benzodiazepines; D000077222:Limonene; D019821:Simvastatin; D000077152:Olanzapine
keywords: Microneedles; Nanostructured lipid carriers; Olanzapine; Permeation enhancers; Pharmacokinetics; Simvastatin; Transdermal delivery