Elegant flexible vesicular nanocarriers for the efficient skin delivery of topically applied drugs-

Background: Skin diseases represent a major health concern worldwide and negatively impact patients’ quality of life. Despite the availability of various efficacious drugs, their therapeutic outcome is often limited due to shortcomings related to the formidable skin barrier and unfavorable physicochemical properties of drugs. Flexible nano-vesicles have shown tremendous potential to overcome these hurdles and improve the local therapeutic effect of these drugs. Objective: This review article is aimed to shed light on flexible nano-vesicular carriers as a means to combat skin diseases. Methods: The literature was reviewed using PubMed database using various keywords such as liposomes, flexible (deformable liposomes) (transferosomes), ethosomes, transethosomes, niosomes, and spanlastics. Results: Liposomes and niosomes were found effective for the loading and release of both hydrophilic and lipophilic drugs. However, their limited skin penetration led to drug delivery to the outermost layers of skin only. This necessitates the search for innovative vesicular carriers, including liposomes, flexible (deformable liposomes), ethosomes, transethosomes, and spanlastics. These flexible nano-vesicular carriers showed enhanced drug delivery and deposition across various skin layers, which was better than their corresponding conventional vesicles. This resulted in superior drug efficacy against various skin diseases such as skin cancer, inflammatory skin diseases, superficial fungal infections, etc. Conclusion: Flexible nano-vesicular carriers have proven themselves as efficient drug delivery systems that are able to deliver their cargo into the deep skin layers and thus, improve the therapeutic outcome of various skin diseases. However, there remain some challenges that need to be addressed before these nanocarriers can be translated from the lab to clinics.

Enhanced Skin Delivery of Therapeutic Peptides Using Spicule-Based Topical Delivery Systems

This study reports two therapeutic peptides, insulin (INS, as a hydrophilic model peptide) and cyclosporine A (CysA, as a hydrophobic one), that can be administrated through a transdermal or dermal route by using spicule-based topical delivery systems in vitro and in vivo. We obtained a series of spicules with different shapes and sizes from five kinds of marine sponges and found a good correlation between the skin permeability enhancement induced by these spicules and their aspect ratio L/D. In the case of INS, Sponge Haliclona sp. spicules (SHS) dramatically increased the transdermal flux of INS (457.0 ± 32.3 ng/cm2/h) compared to its passive penetration (5.0 ± 2.2 ng/cm2/h) in vitro. Further, SHS treatment slowly and gradually reduced blood glucose to 13.1 ± 6.3% of the initial level in 8 h, while subcutaneous injection resulted in a rapid blood glucose reduction to 15.9 ± 1.4% of the initial level in 4 h, followed by a rise back to 75.1 ± 24.0% of the initial level in 8 h. In the case of CysA, SHS in combination with ethosomes (SpEt) significantly (p < 0.05) increased the accumulation of CysA in viable epidermis compared to other groups. Further, SpEt reduced the epidermis thickness by 41.5 ± 9.4% in 7 days, which was significantly more effective than all other groups. Spicule-based topical delivery systems offer promising strategies for delivering therapeutic peptides via a transdermal or dermal route.

Topical Allopurinol-Loaded Nanostructured Lipid Carriers: A Novel Approach for Wound Healing Management

Nanostructured lipid carriers (NLC) have been widely studied as delivery systems for a variety of routes, including the skin. Their composition results in an imperfect lipid matrix, allowing increased drug encapsulation. Allopurinol (AP), a xanthine oxidase inhibitor, is characterized by low water solubility and high melting point, which has hampered its use through the topical route. In this work, AP was incorporated in a NLC formulation to enhance drug-carrier association and skin delivery as a topical approach to treat wounds. AP-NLC system was characterized in terms of size, charge, rheological behavior, and in vitro skin permeation. The in vitro cytotoxicity was evaluated using HaCaT cells. The wound healing efficacy of the AP-NLC formulation on animal skin lesions was evaluated in male Wistar rats. The AP-NLC presented a mean size of 193 ± 15 nm with a PdI of 0.240 ± 0.02, zeta potential values around −49.6 mV, and an encapsulation efficiency of 52.2%. The AP-NLC formulation presented an adequate profile to be used topically, since epidermal and dermal drug retention were achieved. No reduction in HaCaT cells viability was observed at the tested concentrations (AP < 10 μg/mL). The in vivo application of the AP-NLC formulation resulted in the regeneration of skin lesions when compared with non-treated controls.

Jabuticaba (Myrciaria jaboticaba) Peel as a Sustainable Source of Anthocyanins and Ellagitannins Delivered by Phospholipid Vesicles for Alleviating Oxidative Stress in Human Keratinocytes

The Brazilian berry scientifically known as jabuticaba is a fruit covered by a dark purple peel that is still rich in bioactives, especially polyphenols. Considering that, this work was aimed at obtaining an extract from the peel of jabuticaba fruits, identifying its main components, loading it in phospholipid vesicles specifically tailored for skin delivery and evaluating their biological efficacy. The extract was obtained by pressurized hot water extraction (PHWE), which is considered an easy and low dissipative method, and it was rich in polyphenolic compounds, especially flavonoids (ortho-diphenols and condensed tannins), anthocyanins (cyanidin 3-O-glucoside and delphinidin 3-O-glucoside) and gallic acid, which were responsible for the high antioxidant activity detected using different colorimetric methods (DPPH, FRAP, CUPRAC and metal chelation). To improve the stability and extract effectiveness, it was incorporated into ultradeformable phospholipid vesicles (transfersomes) that were modified by adding two different polymers (hydroxyethyl cellulose and sodium hyaluronate), thus obtaining HEcellulose-transfersomes and hyaluronan-transfersomes. Transfersomes without polymers were the smallest, as the addition of the polymer led to the formation of larger vesicles that were more stable in storage. The incorporation of the extract in the vesicles promoted their beneficial activities as they were capable, to a greater extent than the solution used as reference, of counteracting the toxic effect of hydrogen peroxide and even of speeding up the healing of a wound performed in a cell monolayer, especially when vesicles were enriched with polymers. Given that, polymer enriched vesicles may represent a good strategy to produce cosmetical and cosmeceutical products with beneficial properties for skin.

Influence of Stabilizer on the Development of Luteolin Nanosuspension for Cutaneous Delivery: An In Vitro and In Vivo Evaluation

Luteolin is a natural drug used as an antioxidant and anti-inflammatory, but unfortunately, it possesses low water solubility, which hinders its delivery via the skin. The main objective of this study was to prepare a luteolin-loaded nanosuspension by the antisolvent precipitation/sonication technique and study the effects of four stabilizers (two nonionic stabilizers, Pluronic F127 and Tween 80, and two polymeric stabilizers, HPMC and alginate) on the physicochemical properties of the prepared formulations. The selected formulations were incorporated into a gel base to evaluate their skin permeability and anti-inflammatory efficacy. The particle size was in the nanosize range (in the range from 468.1 ± 18.6 nm to 1024.8 ± 15.9 nm), while the zeta potential was negative and in the range from −41.7 ± 6.3 mV to −15.3 ± 1.9 mV. In particular, alginate-stabilized nanosuspensions showed the smallest particle size, the highest zeta potential value, and excellent stability due to the dual stabilizing effects (electrostatic and steric effects). The DSC results revealed a less crystalline structure of luteolin in lyophilized NS2 and NS12. Formulations stabilized by 1% Pluronic (NS2) and 2% alginate (NS12) were incorporated into a carbopol 940 gel base and showed good organoleptic character (homogenous with no evidenced phase separation or grittiness). In vitro dissolution studies showed that NS12 enhanced luteolin release rates, indicating the effect of particle size on the drug release pattern. On the other hand, NS2 showed enhanced skin permeability and anti-inflammatory effect in a carrageenan-induced paw edema model, revealing the surface activity role of the stabilizers. In conclusion, while alginate increased the nanosuspension stability by means of dual stabilizing effects, Pluronic F127 improved the skin delivery and pharmacodynamic efficacy of luteolin.

Oleuropein multicompartment nanovesicles enriched with collagen as a natural strategy for the treatment of skin wounds connected with oxidative stress

Aim: Collagen-enriched transfersomes, glycerosomes and glytransfersomes were specifically tailored for skin delivery of oleuropein. Methods: Vesicles were prepared by direct sonication and their main physicochemical and technological properties were measured. Biocompatibility, protective effect and promotion of the healing of a wounded cell monolayer were tested in vitro using fibroblasts. Results: Vesicles were mainly multicompartment, small (∼108 nm), slightly polydispersed (approximately 0.27) and negatively charged (~-49 mV). Oleuropein was incorporated in high amounts (approximately 87%) and vesicles were stable during four months of storage. In vitro studies confirmed the low toxicity of formulations (viability ≥95%), their effectiveness in counteracting nitric oxide generation and damages caused by free oxygen radicals, especially when collagen glytransfersomes were used (viability ~100%). These vesicles also promoted the regeneration of a wounded area by promoting the proliferation and migration of fibroblasts. Conclusion: Collagen-enriched vesicles are promising formulations capable of speeding up the healing of the wounded skin.

Lamellar Lyotropic Liquid Crystal Phases as a Carrier for Skin Delivery of Morus alba Stem Extract

Morus alba stem extract possesses several biological activities. However, skin delivery of the extract is limited by the stratum corneum. In this study, lamellar lyotropic liquid crystal (LLC) was investigated for the potential application in the skin delivery of M. alba stem extract. The four formulations were developed and incorporated with M. alba stem extract at 3% w/w. These formulations were stored at room temperature in light-protected containers for 3 months. The optical pattern under polarized light microscope, viscosity and remaining of the extract were determined. The skin penetration enhancing property of the formulations was investigated using excised porcine ear skin model. The results showed that all formulations remained stable after 3-month storage. The two formulations exhibiting good penetration enhancing properties were F3 consisting of PEG-7 glyceryl cocoate/n-Dodecane/Water/extract (55.29/19.40/22.31/3.00 %w/w) and F4 consisting of mixed Surfactant/n-Dodecane/Water/extract (48.50/4.85/43.65/3.00 %w/w). The mixed surfactant composed of PEG-7 glyceryl cocoate/PEG-40 hydrogenated castor oil/Glyceryl oleate (40/33.24/26.76 %w/w). It can be concluded that the lamellar LLC formulations developed in this study can be used as a carrier for delivering of M. alba stem extract. The components of the formulations which play important roles are the oil and the surfactant.