Antioxidant-containing monoolein aqueous dispersions: a preliminary study.

The present study describes a preliminary study on the use of monoolein aqueous dispersions (MADs) as delivery systems for antioxidant molecules, namely, ascorbyl palmitate (AP) and alpha-tocopherol (AT). MAD, produced by emulsifying monoolein (4.5% w/w) in water and poloxamer 407 (0.5% w/w) as emulsifier, was characterized in terms of size, morphology, and antioxidant activity by mean of PCS, cryo-TEM, and (2,2-diphenyl-1-picrylhydrazyl) assay. MAD-AP or MAD-AT gave rise to a bimodal size distribution with mean size around 200 nm. All the preparations stored at 25 °C showed quite stable size at least up to 90 days. Cryo-TEM images confirmed MAD size distribution and indicated different MAD morphologies as a function of the loaded antioxidant molecule. Indeed, in the case of MAD-AP, vesicles and cubosomes with the typical inner cubic structure were observed, while vesicles and hexosomes were shown for MAD-AT. The encapsulation efficiency of both antioxidants reached more than 90% with respect to the total amount of drug used for MAD preparation. Moreover, AP and AT antioxidant activity was retained after encapsulation, and in vitro Franz cell experiments showed that the MAD enabled to better control the drug release. These preliminary results suggest that MAD formulations could be further investigated as a potential delivery system for antioxidant supplementation in dietary or cosmetic fields.

Ethosomes for Coenzyme Q10 Cutaneous Administration: From Design to 3D Skin Tissue Evaluation.

Ethosome represents a smart transdermal vehicle suitable for solubilization and cutaneous application of drugs. Coenzyme Q10 is an endogenous antioxidant whose supplementation can counteract many cutaneous disorders and pathologies. In this respect, the present study describes the production, characterization, and cutaneous protection of phosphatidylcholine based ethosomes as percutaneous delivery systems for coenzyme Q10. CoQ10 entrapment capacity in ethosomes was almost 100%, vesicles showed the typical 'fingerprint' structure, while mean diameters were around 270 nm, undergoing an 8% increase after 3 months from production. An ex-vivo study, conducted by transmission electron microscopy, could detect the uptake of ethosomes in human skin fibroblasts and the passage of the vesicles through 3D reconstituted human epidermis. Immunofluorescence analyses were carried on both on fibroblasts and 3D reconstituted human epidermis treated with ethosomes in the presence of H2O2 as oxidative stress challenger, evaluating 4-hydroxynonenal protein adducts which is as a reliable biomarker for oxidative damage. Notably, the pretreatment with CoQ10 loaded in ethosomes exerted a consistent protective effect against oxidative stress, in both models, fibroblasts and in reconstituted human epidermis respectively.

Nanomedicines to Treat Skin Pathologies with Natural Molecules.

The skin and mucous membranes are subjected to many disorders and pathological conditions. Nature offers a wide range of molecules with antioxidant activity able to neutralize, at least in part, the formation of free radicals and therefore to counteract the phenomena of cellular aging. Since synthetic drugs for the treatment of skin diseases can induce resistance, it is particularly interesting to use compounds of plant origin, transporting them in pharmaceutical forms capable of controlling their release and absorption. This review provides an overview of new findings about the use of lipid-based nanosystems for the delivery of natural molecules useful on the topical treatment of skin disorders. Several natural molecules encapsulated in lipid nanosystems have been considered in the treatment of some skin pathologies or diseases. Particularly, the use of rosemary and eucalyptus essential oil, saffron derivatives, curcumin, eugenol, capsaicin, thymol and lycopene has been reported. The molecules have been alternatively encapsulated in viscous systems, such as the organogels, or in liquid systems, such as ethosomes, transferosomes, solid lipid nanoparticles and monoolein based dispersions thickened by inclusion in carbomer gels. The nanostructured forms have been in vitro and in vivo investigated for the treatment of skin disorders due to dehydration, inflammation, melanoma, wound healing, fungal infections or psoriasis. The data reported in the different studies have suggested that the cutaneous application of lipid nanosystems allows a deep interaction between lipid matrix and skin strata, promoting a prolonged release and efficacy of the loaded natural molecules. This review suggests that the application of natural molecules onto the skin by lipid-based nanosystems can provide numerous clinician benefits in dermatology and cosmetics.

New Strategies for the Delivery of Some Natural Anti-oxidants with Therapeutic Properties.

Nature offers tremendous potential in the medicine field. Natural antioxidant molecules inhibit or quench free radical reactions and delay or inhibit cellular damage. In the last few years, researchers have been focusing on the health benefits of natural products. Particularly some dietary nutrients, such as curcumin, crocin, resveratrol, quercetin, coenzyme Q10, vitamin C, as well as some polysaccharides have been evaluated for their numerous and unique therapeutic properties. This review focuses on examples of pharmaceutical applications of natural anti-oxidants, with special regards to their encapsulation in micro- and nano- delivery systems. In vitro and in vivo studies have been conducted to investigate the physicochemical and pharmacological properties of different delivery systems containing antioxidant molecules. For instance, ethosomes, organogels, monoolein aqueous dispersions and solid lipid nanoparticle have been considered. It was found that micro and nanoencapsulation strategy can improve the solubility of lipophilic molecules and the chemical stability of labile antioxidants, thus prolonging their efficacy. In vitro and in vivo studies have highlighted that antioxidant encapsulation prolongs release kinetics, bioavailability and antioxidant effects. Noticeably, some encapsulated antioxidants effectively inhibit cancer cell proliferation, cell migration and colony formation, thus suppressing cancer progression.

Cubic Phases, Cubosomes and Ethosomes for Cutaneous Application.

Cutaneous administration represents a good strategy to treat skin diseases, avoiding side effects related to systemic administration. Apart from conventional therapy, based on the use of semi-solid formulation such as gel, ointments and creams, recently the use of specialized delivery systems based on lipid has been taken hold. This review provides an overview about the use of cubic phases, cubosomes and ethosomes, as lipid systems recently proposed to treat skin pathologies. In addition in the final part of the review cubic phases, cubosomes and ethosomes are compared to solid lipid nanoparticles and lecithin organogel with respect to their potential as delivery systems for cutaneous application. It has been reported that lipid nanosystems are able to dissolve and deliver active molecules in a controlled fashion, thereby improving their bioavailability and reducing side-effects. Particularly lipid matrixes are characterized by skin affinity and biocompatibility allowing their application on skin. Indeed, after cutaneous administration, the lipid matrix of cubic phases and cubosomes coalesces with the lipids of the stratum comeum and leads to the formation of a lipid depot from which the drug associated to the nanosystem can be released in the deeper skin strata in a controlled manner. Ethosomes are characterized by a malleable structure that promotes their interaction with skin, improving their potential as skin delivery systems with respect to liposomes. Also in the case of solid lipid nanoparticles it has been suggested a deep interaction between lipid matrix and skin strata that endorses sustained and prolonged drug release. Concerning lecithin organogel, the peculiar structure of this system, where lecithin exerts a penetration enhancer role, allows a deep interaction with skin strata, promoting the transdermal absorption of the encapsulated drugs.

Lipid nanocarriers containing a levodopa prodrug with potential antiparkinsonian activity.

This paper describes the production, characterization and in vivo activity of lipid nanocarriers (LN) containing a levodopa prodrug (LD-PD) with therapeutic potential in Parkinson's disease. LD is the mainstay of the pharmacotherapy of Parkinson's disease. However, after a good initial response, motor fluctuations, dyskinesia and loss of efficacy, develop over time, partly due to oscillations in plasma and brain levels of the drug. LD-PD was produced with the aim of prolonging the pharmacological activity of LD. To improve solubility, and simultaneously provide a long lasting release and therapeutic efficacy, the prodrug was formulated in tristearin/lecithin LN. The obtained formulation was homogeneous in particle size and remained stable for up to 2months from preparation. For the three different tested LD concentrations, namely 1.25, 2.5 and 5.0mg/ml, the morphological characterization revealed no substantial differences between unloaded and LD-PD loaded LN. The calorimetric test showed an interaction between the lipid phase and the loaded prodrug. In vitro studies using the dialysis method and enzymatic degradation procedure showed that the LD-PD loaded LN provided a controlled prodrug release. Finally, two behavioural tests specific to akinesia (bar test) or akinesia/bradykinesia (drag test) performed in 6-hydroxydopamine hemilesioned mice (a model of Parkinson's disease) demonstrated that the LD-PD loaded LN attenuated parkinsonian disabilities, showing a slightly reduced maximal efficacy but a longer lasting action (up to 24h) than an equal dose of LD. We conclude that LD-PD loaded LN may represent a future LD formulation useful in Parkinson's disease therapy.

Effect of nanostructured lipid vehicles on percutaneous absorption of curcumin.

The present study describes the production and characterization of monoolein aqueous dispersions (MAD) and lecithin organogels (ORG) as percutaneous delivery systems for curcumin (CUR). In particular, MAD stabilized by sodium cholate/poloxamer and w0 3 ORG lipid carriers, both in the presence and absence of CUR, have been considered: MAD morphology and dimensional distribution have been investigated by Cryogenic Transmission Electron Microscopy (cryo-TEM) and Photon Correlation Spectroscopy (PCS), while the inner structure of MAD and ORG has been studied by X-ray scattering techniques. As a general result, CUR chemical stability has been found to be better controlled by MAD, probably because CUR is more protected in the case of CUR-MAD with respect to CUR-ORG. To investigate the performance of differently composed lipid formulations as CUR delivery system, in vitro studies, based on Franz cell and stratum corneum-epidermis (SCE) membranes, and in vivo studies, based on skin reflectance spectrophotometry and tape stripping, were then performed. The results indicated that ORG induces a rapid and intense initial penetration of CUR probably due to a strong interaction between the peculiar supramolecular aggregation structure of phospholipids in the vehicle and the lipids present in the stratum corneum. Conversely, CUR incorporated into MAD can be released in a controlled fashion possibly because of the formation of a CUR depot in the stratum corneum. In this respect ORG could be employed in pathologies requiring rapid CUR action, while MAD could be proposed for assuring a prolonged CUR activity.

Design and characterization of fenretinide containing organogels.

The stable, transparent, organogels, which are prepared by adding a minute amount of water to a solution of lecithin in biocompatible oil, are here studied as matrices for solubilization and percutaneous delivery of fenretinide (4 hydroxypropyl phenyl retinamide, 4HPR), a retinoic acid derivative. The influence of different types of oil, content of water and presence of hyaluronic acid was studied on gel properties. Rheology studies were carried out in order to detect the effect of these variables on gel viscosity. 4HPR diffusion from the different organogels was determined by in vitro Franz cell. It was found that diffusion coefficients (Jn) of 4HPR incorporated in organogels are about five fold lower than Jn of 4HPR in organic solution. Stability and shelf life stability studies demonstrate that 4HPR incorporated in organogels does not degrade and that organogels maintain 90% of 4HPR stability for periods up to 4 months.

Cellulose acetate butyrate-pH/thermosensitive polymer microcapsules containing aminated poly(vinyl alcohol) microspheres for oral administration of DNA.

The aim of this work is to safely transport bioadhesive microspheres loaded with DNA to intestine and to test their bioadhesive properties. Poly(vinyl alcohol) (PVA) microspheres were prepared by dispersion reticulation with glutaraldehyde and further aminated. These microspheres were firstly loaded with plasmid DNA by electrostatic interactions and then entrapped in cellulose acetate butyrate (CAB) microcapsules for gastric protection. The entrapped PVA microspheres do not have enough force by swelling to produce the rupture of CAB shell, therefore the resistance of microcapsules was weakened by incorporating different amount of the pH/thermosensitive polymer (SP) based on poly(N-isopropylacrylamide-co-methyl methacrylate-co-methacrylic acid) (NIPAAm-co-MM-co-MA). This polymer is insoluble in gastric juice at pH 1.2 and 37 degrees C, but quickly solubilized in intestinal fluids (pH 6.8 and pH 7.4). Therefore, DNA loaded PVA microspheres were not expelled in acidic media but were almost entirely discharged in small intestine or colon. The integrity of DNA after entrapment was tested by agarose gel electrophoresis indicating that no DNA degradation occurs during encapsulation. The percentage of adhered microspheres on the mucus surface of everted intestinal tissue was 65+/-18% for aminated PVA microspheres without DNA and almost 50+/-15% for those loaded with DNA. Non-aminated PVA microspheres display the lowest adhesive properties (33+/-12%). In conclusion DNA loaded microspheres were progressively discharged in intestine. The integrity of DNA was not modified after entrapment and release, as proved by agarose gel electrophoresis. Both loaded and un-loaded aminated microspheres display good bioadhesive properties.

Effect of charge and lipid concentration on in-vivo percutaneous absorption of methyl nicotinate from liposomal vesicles.

We have investigated the influence of charge and lipid concentration on the in-vivo percutaneous absorption of a model compound, methyl nicotinate (MN), from liposomal vesicles. MN-loaded liposomes were produced by the reverse-phase evaporation method (REV) using different concentrations of phosphatidyl choline (PC), in association with surfactants such as dioctadecyl dimethyl ammonium bromide (DDAB18) and dicetyl phosphate (DCP), which impart a positive or negative charge to the systems, respectively. The liposomal suspensions were then processed to hydrogels and used to study in-vivo the MN permeation profile. MN was chosen as the model compound since it was capable of causing cutaneous erythema, the intensity and duration of which was proportional to the amount entering the living epidermis over time. The extent of the erythema was monitored by reflectance spectrophotometry, a non-invasive technique. In-vivo findings showed an interesting MN delayed release, which was proportional to the amount of phospholipids in each liposomal formulation. Furthermore, it could be noted that the erythematous effect was more prolonged when MN was delivered from neutral or negatively-charged liposomal forms.