title: Nanocarriers for optimizing the balance between interfollicular permeation and follicular uptake of topically applied clobetasol to minimize adverse effects.
abstract: The treatment of various hair disorders has become a central focus of good dermatologic patient care as it affects men and women all over the world. For many inflammatory-based scalp diseases, glucocorticoids are an essential part of treatment, even though they are known to cause systemic as well as local adverse effects when applied topically. Therefore, efficient targeting and avoidance of these side effects are of utmost importance. Optimizing the balance between drug release, interfollicular permeation, and follicular uptake may allow minimizing these adverse events and simultaneously improve drug delivery, given that one succeeds in targeting a sustained release formulation to the hair follicle. To test this hypothesis, three types of polymeric nanocarriers (nanospheres, nanocapsules, lipid-core nanocapsules) for the potent glucocorticoid clobetasol propionate (CP) were prepared. They all exhibited a sustained release of drug, as was desired. The particles were formulated as a dispersion and hydrogel and (partially) labeled with Rhodamin B for quantification purposes. Follicular uptake was investigated using the Differential Stripping method and was found highest for nanocapsules in dispersion after application of massage. Moreover, the active ingredient (CP) as well as the nanocarrier (Rhodamin B labeled polymer) recovered in the hair follicle were measured simultaneously, revealing an equivalent uptake of both. In contrast, only negligible amounts of CP could be detected in the hair follicle when applied as free drug in solution or hydrogel, regardless of any massage. Skin permeation experiments using heat-separated human epidermis mounted in Franz Diffusion cells revealed equivalent reduced transdermal permeability for all nanocarriers in comparison to application of the free drug. Combining these results, nanocapsules formulated as an aqueous dispersion and applied by massage appeare to be a good candidate to maximize follicular targeting and minimize drug penetration into the interfollicular epidermis. We conclude that such nanotechnology-based formulations provide a viable strategy for more efficient drug delivery to the hair follicle. Moreover, they present a way to minimize adverse effects of potent glucocorticoids by releasing the drug in a controlled manner and simultaneously decreasing interfollicular permeation, offering an advantage over conventional formulations for inflammatory-based skin/scalp diseases.
authors.affiliation: Department of Pharmacy, Saarland University, Saarbrücken, Saarland, Germany. Electronic address: christiane.mathes@mx.uni-saarland.de.
authors.forename: C
authors.initials: C
authors.lastname: Mathes
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, University of Valencia, Valencia, Spain. Electronic address: ana.melero@uv.es.
authors.forename: A
authors.initials: A
authors.lastname: Melero
authors.affiliation: Department of Pharmacy, Saarland University, Saarbrücken, Saarland, Germany; Department of Pharmacy and Pharmaceutical Technology, University of Valencia, Valencia, Spain; Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. Electronic address: pmconrad@googlemail.com.
authors.forename: P
authors.initials: P
authors.lastname: Conrad
authors.affiliation: Department of Dermatology, Saarland University Hospital, Homburg, Saar, Germany. Electronic address: thomas.vogt@uks.eu.
authors.forename: T
authors.initials: T
authors.lastname: Vogt
authors.affiliation: Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. Electronic address: lucasrigo1@gmail.com.
authors.forename: L
authors.initials: L
authors.lastname: Rigo
authors.affiliation: Department of Pharmacy, Saarland University, Saarbrücken, Saarland, Germany; Scientific Consilience GmbH, Saarbrücken, Germany. Electronic address: d.selzer@scientific-consilience.com.
authors.forename: D
authors.initials: D
authors.lastname: Selzer
authors.affiliation: Departamento de Química Orgânica, Instituto de Química, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. Electronic address: will_ap20@hotmail.com.
authors.forename: W A
authors.initials: WA
authors.lastname: Prado
authors.affiliation: Department of Drug Delivery, Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz-Center for Infection Research (HZI), Saarbrücken, Germany. Electronic address: chiara.derossi@helmholtz-hzi.de.
authors.forename: C
authors.initials: C
authors.lastname: De Rossi
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, University of Valencia, Valencia, Spain. Electronic address: Teresa.Garrigues@uv.es.
authors.forename: T M
authors.initials: TM
authors.lastname: Garrigues
authors.affiliation: Department of Drug Delivery, Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz-Center for Infection Research (HZI), Saarbrücken, Germany. Electronic address: hansen@vakzine-manager.de.
authors.forename: S
authors.initials: S
authors.lastname: Hansen
authors.affiliation: Departamento de Química Orgânica, Instituto de Química, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. Electronic address: silvia.guterres@ufrgs.br.
authors.forename: S S
authors.initials: SS
authors.lastname: Guterres
authors.affiliation: Departamento de Química Orgânica, Instituto de Química, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. Electronic address: adriana.pohlmann@ufrgs.br.
authors.forename: A R
authors.initials: AR
authors.lastname: Pohlmann
authors.affiliation: Departamento de Química Orgânica, Instituto de Química, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. Electronic address: ruy.beck@ufrgs.br.
authors.forename: R C R
authors.initials: RCR
authors.lastname: Beck
authors.affiliation: Department of Pharmacy, Saarland University, Saarbrücken, Saarland, Germany; Department of Drug Delivery, Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz-Center for Infection Research (HZI), Saarbrücken, Germany. Electronic address: claus-michael.lehr@helmholtz-hzi.de.
authors.forename: C-M
authors.initials: CM
authors.lastname: Lehr
authors.affiliation: Department of Pharmacy, Saarland University, Saarbrücken, Saarland, Germany. Electronic address: ufs@mx.uni-saarland.de.
authors.forename: U F
authors.initials: UF
authors.lastname: Schaefer
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D002990:Clobetasol / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D065546:Drug Liberation; D018859:Hair Follicle / Q000378:metabolism*; D006801:Humans; D020100:Hydrogels; D053769:Nanocapsules / Q000008:administration & dosage*; D010812:Physical Stimulation; D011091:Polyesters / Q000737:chemistry; D013552:Swine
chemical_list: D000893:Anti-Inflammatory Agents; D020100:Hydrogels; D053769:Nanocapsules; D011091:Polyesters; C016240:polycaprolactone; D002990:Clobetasol
keywords: Hair follicle; Inflammation; Nanoparticle; Skin permeation; Sustained release