Elka Touitou

This review focuses on nanovesicular carriers for enhanced delivery of molecules into and across the skin, from their design to recent emerging technologies. During the last four decades, several approaches have been used aiming to design new nanovesicles, some of them by altering the properties of the classic phospholipid vesicle, the liposome. Phospholipid nanovesicular systems, including the phospholipid soft vesicles as well as the non-phospholipid vesicular carries, are reviewed. The altered nanovesicles have served in the manufacture of various cosmetic products and have been investigated and used for the treatment of a wide variety of skin conditions. The evolution and recent advances of these nanovesicular technologies are highlighted in this review.

We have investigated delivery systems that can form a structured matrix film on the skin after their application. In a previous work, we have shown that Weblike film forming systems (also called Pouches Drug Delivery Systems, PDDS) enable enhanced skin delivery of the incorporated molecules. These delivery systems are composed of one or more phospholipids, a short-chain alcohol, a polymer and optionally water. In this work, we continue the investigation and characterization of Weblike carriers focusing on some factors affecting the delivery properties such as components concentration and mode of application on the skin. Upon non-occluded application on the skin, the systems dry rapidly, forming a web-like structured film. Lidocaine, Ibuprofen, FITC and Cannabidiol are molecules with various physico-chemical properties that were incorporated in the carrier. The systems were tested in a number of in vitro and in vivo experiments. Results of the in vitro permeation of Ibuprofen through porcine skin indicated two-fold delivery through the skin of Ibuprofen when applied from our Weblike system in comparison with a nanovesicular carrier, the ethosome. We also have investigated weblike systems containing hemp seed oil (HSO). This addition enhanced the film’s ability to deliver lipophilic molecules to the deeper skin layers, leading to an improved pharmacodynamic effect. In analgesic tests carried out in a pain mice model following one hour application of CBD in Weblike system with and without HSO, the number of writhing episodes was decreased from 29 in the untreated animals to 9.5 and 18.5 writhes, respectively. The results of our work open the way towards a further investigation of Weblike film forming systems containing drugs for improved dermal and transdermal treatment of various ailments.

Pomegranate seed oil (PSO) is currently administrated orally as a food supplement for improving memory. However, the efficiency of the oral dosage forms for such purposes is low, mainly due to the blood brain barrier impeding a good delivery to brain. In this work, we designed and characterized a PSO phospholipid oily gel for nasal administration. We tested the performance of the new PSO delivery system in animal models for impaired memory and locomotor activity. The experimental results indicated a statistically significant improvement (p < 0.05) of more than 1.5 fold in the behavior of animals treated nasally, in comparison to those treated with orally administrated oil. Furthermore, in multiphoton microscopy and near infrared imaging studies, the nasal administration of fluorescent probes, fluorescein isothiocyanate (FITC), and indocyanine green (ICG) incorporated in the PSO system showed enhanced delivery to the brain. Results of the histopathologic examination of the nasal cavity and mucosa, as carried out by a pathologist, indicated the safety of the PSO phospholipid oily gel. In conclusion, the results of this work encourage further investigation of the phospholipid oily gel composition as a new way of PSO administration.

This review focuses on the improved topical treatment of various medical skin conditions by the use of drugs delivered from carriers containing phospholipid soft vesicles. Topical drug delivery has many advantages over other ways of administration, having increased patient compliance, avoiding the first-pass effect following oral drug administration or not requesting multiple doses administration. However, the skin barrier prevents the access of the applied drug, affecting its therapeutic activity. Carriers containing phospholipid soft vesicles are a new approach to enhance drug delivery into the skin and to improve the treatment outcome. These vesicles contain molecules that have the property to fluidize the phospholipid bilayers generating the soft vesicle and allowing it to penetrate into the deep skin layers. Ethosomes, glycerosomes and transethosomes are soft vesicles containing ethanol, glycerol or a mixture of ethanol and a surfactant, respectively. We review a large number of publications on the research carried out in vitro, in vivo in animal models and in humans in clinical studies, with compositions containing various active molecules for treatment of skin medical conditions including skin infections, skin inflammation, psoriasis, skin cancer, acne vulgaris, hair loss, psoriasis and skin aging.

Nasal nanovesicular delivery systems (NVS) containing the noncontrolled analgesic drugs Ketoprofen, Butorphanol or Tramadol, incorporated in a phospholipid nanovesicular carrier, were designed and investigated. The systems were first characterized for their physicochemical properties. Due to their composition, comprising propylene glycol as a lipid bilayers fluidizer, these systems contain soft vesicles. Pharmacokinetic profiles of Tramadol in plasma and brain and of Ketoprofen in plasma were also assessed. The analgesic effect of each of the three tested drugs was evaluated in the acetic acid mice model for pain. One important result obtained in this work is that the concentration of Tramadol in rats’ plasma and brain increased rapidly after administration, reaching a peak value 10 min after administration with a C_max of 2 to 5 folds greater than that for the oral or nasal non-vesicular treatments, respectively. In the case of Ketoprofen, the peak of the drug level in plasma was measured 10 min post nasal administration in NVS. The C_max was three-fold higher relative to oral administration of this drug. In the experiment testing analgesia, a rapid and improved analgesia was observed for the tested drugs when delivered nasally in the nanocarrier. On the other hand, a weaker analgesic effect was observed for oral and nasal control systems. This new approach suggests that nasal delivery of non-controlled drugs in soft nanovesicles may open the way for better and noninvasive treatment of severe pain.

The stratum corneum, the most superficial layer of the skin, protects the body against environmental hazards and presents a highly selective barrier for the passage of drugs and cosmetic products deeper into the skin and across the skin. Nanomaterials can effectively increase the permeation of active molecules across the stratum corneum and enable their penetration into deeper skin layers, often by interacting with the skin and creating the distinct sites with elevated local concentration, acting as reservoirs. The flux of the molecules from these reservoirs can be either limited to the underlying skin layers (for topical drug and cosmeceutical delivery) or extended across all the sublayers of the epidermis to the blood vessels of the dermis (for transdermal delivery). The type of the nanocarrier and the physicochemical nature of the active substance are among the factors that determine the final skin permeation pattern and the stability of the penetrant in the cutaneous environment. The most widely employed types of nanomaterials for dermal and transdermal applications include solid lipid nanoparticles, nanovesicular carriers, microemulsions, nanoemulsions, and polymeric nanoparticles. The recent advances in the area of nanomaterial-assisted dermal and transdermal delivery are highlighted in this review.

This is a comprehensive review on the use of phospholipid nanovesicles for dermal/transdermal and nasal drug administration. Phospholipid-based vesicular carriers have been widely investigated for enhanced drug delivery via dermal/transdermal routes. Classic phospholipid vesicles, liposomes, do not penetrate the deep layers of the skin, but remain confined to the upper stratum corneum. The literature describes several approaches with the aim of altering the properties of these vesicles to improve their penetration properties. Transfersomes and ethosomes are the most investigated penetration-enhancing phospholipid nanovesicles, obtained by the incorporation of surfactant edge activators and high concentrations of ethanol, respectively. These two types of vesicles differ in terms of their structure, characteristics, mechanism of action and mode of application on the skin. Edge activators contribute to the deformability and elasticity of transfersomes, enabling them to penetrate through pores much smaller than their own size. The ethanol high concentration in ethosomes generates a soft vesicle by fluidizing the phospholipid bilayers, allowing the vesicle to penetrate deeper into the skin. Glycerosomes and transethosomes, phospholipid vesicles containing glycerol or a mixture of ethanol and edge activators, respectively, are also covered. This review discusses the effects of edge activators, ethanol and glycerol on the phospholipid vesicle, emphasizing the differences between a soft and an elastic nanovesicle, and presents their different preparation methods. To date, these differences have not been comparatively discussed. The review presents a large number of active molecules incorporated in these carriers and investigated in vitro, in vivo or in clinical human tests.

The aim of this work was to design and characterize a new nanovesicular nasal delivery system (NDS) containing buspirone, and investigate its efficiency in an animal model for the treatment of hot flushes. The presence of multilamellar vesicles with a mean size distribution of 370 nm was evidenced by transition electron microscopy (TEM), cryo-scanning electron microscopy (Cryo-SEM), and dynamic light scattering (DLS) tests. Pharmacodynamic evaluation of the nasal treatment efficacy with the new system was carried out in ovariectomized (OVX) rat—an animal model for hot flushes—and compared with other treatments. We found that the nasal administration of a buspirone NDS resulted in a significant reduction in tail skin temperature (TST). This effect was not observed in the control buspirone-treated groups. Buspirone levels in the plasma and brain of nasally-treated normal rats were quantified and compared with those of rats that had received oral administration by a LC-MS/MS assay. A significantly higher bioavailability was achieved with the new treatment relative to an oral administration of the same drug dose. No pathological changes in the nasal cavity were observed following sub-chronic nasal administration of buspirone NDS. In conclusion, the data of our investigation show that buspirone in the new nanovesicular nasal carrier could be considered for further studies for the development of a treatment for the hot flushes ailment.