title: Nanoemulsions for dermal controlled release of oleanolic and ursolic acids: In vitro, ex vivo and in vivo characterization.
abstract: The aim of the present study was to design and optimize a nanoemulsion for dermal administration of mixtures of natural or synthetic pentacyclic triterpenes with recognized anti-inflammatory activity. The composition of the developed nanoemulsions was obtained from pseudo-ternary phase diagrams, composed of castor oil as the oil phase, labrasol as the surfactant, transcutol-P as co-surfactant and propylene glycol as the aqueous phase. Different ratios of surfactant/co-surfactant mixture (Smix) (4:1, 3:1, 2:1, 1:1, 1:2 and 1:4) were produced, and Smix 4:1 was chosen based on the greater area of optimal nanoemulsion conditions. Two different nanoemulsions of mean droplet size below 600 nm were produced, loading mixtures of natural or synthetic pentacyclic triterpenes, respectively. The viscosity of nanoemulsion containing natural pentacyclic triterpenes was 51.97±4.57 mPas and that loaded with synthetic mixtures was 55.33±0.28 mPas. The studies of release and skin permeation were performed using Franz diffusion cells, adjusting the release kinetics of both formulations to Korsmeyer-Peppas model. No significant differences in permeation parameters between the two nanoemulsions were observed. The amount of drug retained in the skin was higher than the amount of drug that has permeated, favoring a local action. The results of the in vivo tests demonstrated that the developed formulations were not toxic and not irritant to the skin. The formulation loading a mixture of natural triterpenes showed greater ability to inhibit inflammation than that loading the synthetic mixture. The findings clearly corroborate the added value of o/w nanoemulsions for dermal delivery of pentacyclic triterpenes.
authors.affiliation: Department of Biopharmacy and Pharmacology, Faculty of Pharmacy, University of Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain; Department of Physical Chemistry, Faculty of Pharmacy, University of Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain.
authors.forename: H L
authors.initials: HL
authors.lastname: Alvarado
authors.affiliation: Department of Biopharmacy and Pharmacology, Faculty of Pharmacy, University of Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain; Department of Physical Chemistry, Faculty of Pharmacy, University of Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Abrego
authors.affiliation: Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra (FFUC), Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; Center for Neuroscience and Cell Biology & Institute for Biomedical Imaging and Life Sciences (CNC-IBILI), University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal. Electronic address: ebsouto@ff.uc.pt.
authors.forename: E B
authors.initials: EB
authors.lastname: Souto
authors.affiliation: Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Av. Universidad No. 1001, Col Chamilpa, Cuernavaca, Morelos, Mexico.
authors.forename: M L
authors.initials: ML
authors.lastname: Garduño-Ramirez
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Granada, Campus de Cartuja s/n, 18071 Granada, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Clares
authors.affiliation: Department of Physical Chemistry, Faculty of Pharmacy, University of Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain.
authors.forename: M L
authors.initials: ML
authors.lastname: García
authors.affiliation: Department of Biopharmacy and Pharmacology, Faculty of Pharmacy, University of Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain. Electronic address: anacalpena@ub.edu.
authors.forename: A C
authors.initials: AC
authors.lastname: Calpena
mesh_terms: D000279:Administration, Cutaneous; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems / Q000379:methods; D004355:Drug Stability; D004655:Emulsions; D006801:Humans; D007700:Kinetics; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000737:chemistry / Q000648:ultrastructure; D009828:Oleanolic Acid / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D012867:Skin / Q000378:metabolism*; D012869:Skin Absorption; D012995:Solubility; D013696:Temperature; D014315:Triterpenes / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D014783:Viscosity; D000097245:Ursolic Acid
chemical_list: D003692:Delayed-Action Preparations; D004655:Emulsions; D009828:Oleanolic Acid; D014315:Triterpenes; D000097245:Ursolic Acid
keywords: Anti-inflammatory activity; Nanoemulsion; Oleanolic acid; Topical administration; Ursolic acid