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Over the last three decades, research in the field of phospholipid nanocarriers as tools to improve dermal and transdermal drug delivery has grown substantially. In particular, liposomes have been the target of studies aimed at reformulating vesicles with a greater ability to deliver drugs trans-dermally. A number of additives with varied physicochemical properties have been combined with traditional components of liposomes. These novel modification processes have produced new classes of vesicles with the potential to enhance the treatment of both dermatological disorders and systemic pathologies. Development of the first deformable and elastic phospholipid vesicles has highlighted the key role of vesicle composition in promoting release of vesicle content into and through the skin. This paper discusses the key vesicle properties and mechanisms of delivery by which newly developed phospholipid vesicles can improve percutaneous drug delivery., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In this study, the active components of grape pomaces were first extracted by maceration in ethanol and propylene glycol, then in extra virgin olive oil. The main components of the hydrophilic extractive solutions were flavonoids, while monounsaturated fatty acids were the most abundant constituents of the extractive oil, with high levels of oleic acid, which were identified by HPLC/DAD and GC/MS, respectively. The hydrophilic extractive solutions and the lipophilic extractive oil were used to prepare phospholipid vesicles, avoiding the energetically and economically expensive steps required to obtain solid matrixes or pure compounds. The obtained grape bioactive enriched penetration enhancer containing vesicles (PEVs) were multilamellar, around 200nm in size, and more viscous than the corresponding solutions. The antioxidant activity, evaluated by the Folin-Ciocalteu and DPPH assays, was potentiated when the extractive solutions were loaded in PEVs. Further, the grape enriched PEVs were able to ensure an optimal protection against oxidative stress in an ex vivo human erythrocytes-based model., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In the present work, quercetin and resveratrol, natural polyphenols with strong antioxidant and anti-inflammatory properties, were co-loaded in polymer-associated liposomes conceived for oral delivery, by exploiting the potential of pH-sensitive succinyl-chitosan. Chitosan was succinylated, characterized by Nuclear Magnetic Resonance spectroscopy and Gel Permeation Chromatography, and used to form a protective shell on the surface of liposomes. The physico-chemical properties of the succinyl-chitosan liposomes were assessed by light scattering, zeta potential, cryogenic transmission electron microscopy, and small angle X-ray scattering. Small, spherical, uni- and bilamellar vesicles were produced. The succinyl-chitosan shell increased not only the physical stability of the vesicular system, as demonstrated by accelerated stability tests, but also the release of the polyphenols to a greater extent at pH 7.0, mimicking the intestinal environment. The proposed approach based on polyphenol vesicular formulations may be of value in the treatment of pre-cancerous/cancerous intestinal conditions associated with inflammation and oxidative stress., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

New biocarriers, named santosomes, were formulated using Santolina insularis essential oil and hydrogenated phosphatidylcholine. They were modified by adding propylene glycol, a hydrophylic penetration enhancer, and loaded with phycocyanin, a protein found in cyanobacteria, which possesses antioxidant and antiinflammatory properties. The essential oil was expected to modify the bilayer structure and improve the delivery and efficacy of the protein due to a synergistic effect of the phospholipid and S. insularis terpenes. Santosomes were small in size (∼118nm), unilamellar and with polyhedral shape. SAXS patterns showed that phycocyanin strongly interacted with the polar heads of the vesicle bilayer. Phycocyanin-loaded vesicles did not show any toxic effect in vitro: cell viability was ∼100% in endothelial cells and ∼120% in keratinocytes, at all the concentrations tested. In addition, phycocyanin-loaded vesicles protected the cells against free radical damage. In vivo studies were performed to evaluate the ability of santosomes to inhibit chemically-induced oedema and inflammation in mice. Results demonstrated that the application of phycocyanin-loaded santosomes produced an evident amelioration of the skin lesion, confirming their great potential for wound healing., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Liquorice extract, obtained by percolation in ethanol of Glycyrrhiza glabra L. roots, was incorporated in liposomes and hyalurosomes, new phospholipid-sodium hyaluronate vesicles, and their protective effect against oxidative stress skin damages was probed. As a comparison, raw glycyrrhizin was also tested. All the vesicles were small in size (≤ 100 nm), with a highly negative zeta potential ensuring long-term stability, and able to incorporate a high amount of the extract. In vitro tests showed that the liquorice extract loaded in vesicles was able to scavenge DPPH free radical (80% inhibition) and to protect 3T3 fibroblasts against H2O2-induced oxidative stress, restoring the normal conditions. By contrast, glycyrrhizin showed poor antioxidant activity, and was not able to efficiently counteract the oxidative effect of H2O2. In addition, the incorporation of the liquorice extract into the vesicular systems promoted the proliferation and migration of 3T3 fibroblasts, favouring the closure of the scratched area. In vivo anti-inflammatory tests on mice confirmed the ability of the proposed nanosystems to improve the local efficacy of the extract, favouring the re-epitelization process., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Biocompatible quercetin nanovesicles were developed by coating polyethylene glycol-containing vesicles with chitosan and nutriose, aimed at targeting the colon. Uncoated and coated vesicles were prepared using hydrogenated soy phosphatidylcholine and quercetin, a potent natural anti-inflammatory and antioxidant drug. Physicochemical characterization was carried out by light scattering, cryogenic microscopy and X-ray scattering, the results showing that vesicles were predominantly multilamellar and around 130 nm in size. The in vitro release of quercetin was investigated under different pH conditions simulating the environment of the gastrointestinal tract, and confirmed that the chitosan/nutriose coating improved the gastric resistance of vesicles, making them a potential carrier system for colon delivery. The preferential localization of fluorescent vesicles in the intestine was demonstrated using the In Vivo FX PRO Imaging System. Above all, a marked amelioration of symptoms of 2,4,6-trinitrobenzenesulfonic acid-induced colitis was observed in animals treated with quercetin-loaded coated vesicles, favoring the restoration of physiological conditions. Therefore, quercetin-loaded chitosan/nutriose-coated vesicles can represent a valuable therapeutic tool for the treatment of chronic intestinal inflammatory diseases, and presumably a preventive system, due to the synergic action of antioxidant quercetin and beneficial prebiotic effects of the chitosan/nutriose complex., (Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Purpose: To develop quercetin-loaded phospholipid vesicles, namely liposomes and PEVs (Penetration Enhancer-containing Vesicles), and to investigate their efficacy on TPA-induced skin inflammation., Methods: Vesicles were made from a mixture of phospholipids, quercetin and polyethylene glycol 400 (PEG), specifically added to increase drug solubility and penetration through the skin. Vesicle morphology and self-assembly were probed by Cryo-Transmission Electron Microscopy and Small/Wide Angle X-ray Scattering, as well as the main physico-chemical features by Light Scattering. The anti-inflammatory efficacy of quercetin nanovesicles was assessed in vivo on TPA-treated mice dorsal skin by the determination of two biomarkers: oedema formation and myeloperoxidase activity. The uptake of vesicles by 3T3 fibroblasts was also evaluated., Results: Small spherical vesicles were produced. Their size and lamellarity was strongly influenced by the PEG content (0%, 5%, 10% v/v). The administration of vesicular quercetin on TPA-inflamed skin resulted in an amelioration of the tissue damage, with a noticeable attenuation of oedema and leukocyte infiltration, especially using 5% PEG-PEVs, as also confirmed by confocal microscopy. In vitro studies disclosed a massive uptake and diffusion of PEVs in dermal fibroblasts., Conclusions: The proposed approach based on quercetin vesicular formulations may be of value in the treatment of inflammatory skin disorders.

In this work we studied various nanoformulations of resveratrol in phospholipid vesicles. Conventional phophatidylcholine liposomes were prepared and characterized in parallel with PEVs (Penetration Enhancer-containing Vesicles) obtained by adding one of eight selected amphiphilic penetration enhancers (PEs; 0.2% w/v; HLB range 1-16) to the composition. All vesicles were around 100 nm, negatively charged (∼-30 mV) and able to incorporate resveratrol in good yields (>74%). The structure and the lamellar self-organization of the vesicles were investigated by Transmission Electron Microscopy (TEM) and Small and Wide Angle X-ray Scattering (SWAXS). These analyses showed that the lamellarity of the vesicles depended on the formulation composition. This work also addressed the stability of our colloidal dispersions, which was measured by means of the analytical centrifuge LUMiSizer(®): this procedure disclosed the absence of any demixing phenomena and estimated a 3- to 6-month shelf-life. Moreover, the antioxidant activity of resveratrol was determined by assessing its ability to scavenge free radicals (DPPH assay), and showed that it was not affected by the vesicular formulation., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objectives: The ex-vivo percutaneous absorption of the natural antioxidant resveratrol in liposomes and niosomes was investigated. The influence of vesicle composition on their physicochemical properties and stability was evaluated. Liposomes containing resveratrol were formulated using soy phosphatidylcholine (Phospholipon90G). Innovative niosomes were formulated using mono- or diglycerides: glycerol monooleate (Peceol) and polyglyceryl-3 dioleate (Plurol OleiqueCC), respectively, two suitable skin-compatible oleins used in pharmaceutical formulations as penetration enhancers., Methods: Small, negatively charged vesicles with a mean size of approximately 200 nm were prepared. The accelerated stability of vesicles was evaluated using Turbiscan Lab Expert, and the bilayer deformability was also assessed. Ex-vivo transdermal experiments were carried out in Franz diffusion cells, on newborn pig skin, to study the influence of the different vesicle formulations on resveratrol skin delivery., Key Findings: Results indicated a high cutaneous accumulation and a low transdermal delivery of resveratrol, especially when Peceol niosomes were used., Conclusions: Overall, niosomes formulated with Plurol oleique or Peceol showed a better behaviour than liposomes in the cutaneous delivery of resveratrol., (© 2013 Royal Pharmaceutical Society.)

Diclofenac-loaded phospholipid vesicles, namely conventional liposomes, ethosomes and PEVs (penetration enhancer-containing vesicles) were developed and their efficacy in TPA (phorbol ester) induced skin inflammation was examined. Vesicles were made from a cheap and unpurified mixture of phospholipids and diclofenac sodium; Transcutol P and propylene glycol were added to obtain PEVs, and ethanol to produce ethosomes. The structure and lamellar organization of the vesicle bilayer were investigated by transmission electron microscopy and small and wide angle X-ray scattering, as well as the main physico-chemical features. The formulations, along with a diclofenac solution and commercial Voltaren Emulgel, were tested in a comparative trial for anti-inflammatory efficacy on TPA-treated mice dorsal skin. Vesicles were around 100 nm, negatively charged, able to encapsulate diclofenac in good yields, and disclosed different lamellarity, as a function of the formulation composition. Vesicular formulations promoted drug accumulation and reduced the permeation. Administration of vesicular diclofenac on TPA-inflamed skin resulted in marked attenuation of oedema and leucocyte infiltration, especially using PEVs. Histology confirmed the effectiveness of vesicles, since they provided an amelioration of the tissual damage induced by TPA. The proposed approach based on vesicular nanocarriers may hold promising therapeutic value for treating a variety of inflammatory skin disorders., (Copyright © 2013 Elsevier B.V. All rights reserved.)

This study was aimed to characterize the microstructure and the performance of gelatin microspheres (GMs) cross-linked by two different cross-linkers viz. d-glucose and glutaraldehyde. New formulations were obtained, suspending the GMs in a thermoreversible Pluronic F127 (PF127) liquid-crystalline gel. Lysozyme was used as a model biomacromolecular drug to evaluate release features. Both types of cross-linked GMs were prepared by thermal gelation method. The lysozyme-loaded microspheres were characterized by scanning electron microscopy (SEM) for size distribution, shape, and surface texture. SEM revealed that both types of lysozyme-loaded GMs were spherical in shape and that the surface of glutaraldehyde cross-linked GMs was smoother than that of the glucose cross-linked GMs. The degree of cross-linking of microspheres was investigated using ATR-FTIR technique. The prepared GMs were suspended in 20% w/v aqueous PF127 gel for which the usual sol-gel transition temperature of 22 °C did not change in the presence of GMs, as indicated by rheological measurements. SAXS study of the PF127 gel confirmed the occurrence of a discrete cubic liquid-crystalline phase of the Fm3m type whose lattice parameter slightly decreased as a result of GMs addition. The in vitro release of lysozyme from both types of cross-linked GMs was successfully controlled when they were suspended in PF127 gel, thus suggesting the potential use of this new combined formulation as a drug-depot system.

The ability of a recently developed novel class of liposomes to promote dermal delivery of tretinoin (TRA) was evaluated. New penetration enhancer-containing vesicles (PEVs) were prepared adding to conventional phosphatidylcholine vesicles (control liposomes) different hydrophilic penetration enhancers: Oramix NS10 (OrNS10), Labrasol (Lab), Transcutol P (Trc), and propylene glycol (PG). Vesicles were characterized by morphology, size distribution, zeta potential, incorporation efficiency, stability, rheological behaviour, and deformability. Small, negatively charged, non-deformable, multilamellar vesicles were obtained. Rheological studies showed that PEVs had fluidity higher than conventional liposomes. The influence of the obtained PEVs on (trans)dermal delivery of tretinoin was studied by ex vivo diffusion experiments through new born pig skin using formulations having the drug both inside and outside the vesicles, having TRA only inside, in comparison with non-incorporated drug dispersions of the same composition used to produce the studied vesicles. Main result of these experiments was an improved cutaneous drug accumulation and a reduced transdermal TRA delivery (except for PG-PEVs). TRA deposition provided by PEVs was higher for dialysed than for non-dialysed vesicles. Further, the accumulation increased in the order: control liposomes

A comparative study between archaeosomes, lipid lamellar vesicles made from archaea polar lipids, and conventional phospholipids liposomes was carried out, aiming at evaluating the properties and the potential of archaeosomes as novel colloidal carriers for effective drug delivery to the skin. Betamethasone dipropionate (BMD)-loaded archaeosomes and conventional liposomes were prepared by the thin-lipid film and sonication procedures, using, respectively, archaeal lipids extracted from archaea Halobacterium salinarum and enriched soy phosphatidylcholine. Vesicular formulations were characterized by assessing vesicle size, zeta potential, incorporation efficiency, and morphology. In order to investigate the effect of the incorporation in the two different colloidal carrier systems on the (trans)dermal delivery of BMD, in vitro drug permeation studies through full-thickness pig skin were carried out by using Franz diffusion vertical cells by testing both archaeal and liposomal dispersions. Interestingly, archaeosomes appeared to be the most effective carriers for the model drug, achieveing a major drug penetration and accumulation in the skin strata, especially in the epidermis. This can, presumably, be due to the enhanced archaeosomal bilayer fluidity, as indicated by the rheological studies that provided insight into the viscoelastic properties of all the studied systems. The available data suggest that suitably developed archaeosomes may hold great promise as delivery vehicles for topical applications.