Sorbitan Monolaurate-Containing Liposomes Enhance Skin Cancer Cell Cytotoxicity and in Association with Microneedling Increase the Skin Penetration of 5-Fluorouracil.

Squamous cell carcinoma (SCC) represents 20% of cases of non-melanoma skin cancer, and the most common treatment is the removal of the tumor, which can leave large scars. 5-Fluorouracil (5FU) is a drug used in the treatment of SCC, but it is highly hydrophilic, resulting in poor skin penetration in topical treatment. Some strategies can be used to increase the cutaneous penetration of the drug, such as the combination of liposomes containing penetration enhancers, for instance, surfactants, associated with the use of microneedling. Thus, the present work addresses the development of liposomes with penetration enhancers, such as sorbtitan monolaurate, span 20, for topical application of 5-FU and associated or not with the use of microneedling for skin delivery. Liposomes were developed using the lipid film hydration, resulting in particle size, polydispersity index, zeta potential, and 5-FU encapsulation efficiency of 88.08 nm, 0.169, -12.3 mV, and 50.20%, respectively. The presence of span 20 in liposomes potentiated the in vitro release of 5-FU. MTT assay was employed for cytotoxicity evaluation and the IC50 values were 0.62, 30.52, and 24.65 µM for liposomes with and without span 20 and 5-FU solution, respectively after 72-h treatment. Flow cytometry and confocal microscopy analysis evidenced high cell uptake for the formulations. In skin penetration studies, a higher concentration of 5-FU was observed in the epidermis + dermis, corresponding to 1997.71, 1842.20, and 2585.49 ng/cm2 in the passive penetration and 3214.07, 2342.84, and 5018.05 ng/cm2 after pretreatment with microneedles, for solution, liposome without and with span 20, respectively. Therefore, herein, we developed a nanoformulation for 5-FU delivery, with suitable physicochemical characteristics, potent skin cancer cytotoxicity, and cellular uptake. Span 20-based liposomes increased the skin penetration of 5-FU in association of microneedling. Altogether, the results shown herein evidenced the potential of the liposome containing span 20 for topical delivery of 5-FU.

Efficacy of topical Miltefosine formulations in an experimental model of cutaneous leishmaniasis.

Cutaneous leishmaniasis (CL) is a neglected tropical disease endemic in ~ 90 countries, with an increasing incidence. Presently available pharmacotherapy implies the systemic administration of moderately/very toxic drugs. Miltefosine (Milt) is the only FDA-approved drug to treat CL via the oral route (Impavido®). It produces side effects; in particular, teratogenic effects are of concern. A topical treatment would have the great advantage of minimising the systemic circulation of the drug, preventing side effects. We prepared dispersions containing Milt and liposomes of different compositions to enhance/modulate trans-epidermal penetration and evaluated in vitro and in vivo efficacy and toxicity, in vitro release rate of the drug and particles size stability with time. Treatments were topically administered to BALB/c mice infected with Leishmania (Leishmania) amazonensis. The dispersions containing 0.5% Milt eliminated 99% of the parasites and cured the lesions with a complete re-epithelisation, no visible scar and re-growth of hair. Fluid liposomes decreased the time to heal the lesion and the time needed to eliminate viable amastigotes from the lesion site. Relapse of the infection was not found 1 month after treatment in any case. Ultraflexible liposomes on the other hand had no significant in vitro effect but decreased in vivo efficacy. A topical Milt formulation including fluid liposomes seems a promising treatment against CL.

Development of monolithic matrix type transdermal patches containing cinnarizine: Physical characterization and permeation studies

To overcome the problems associated with bioavailability and systemic side effects of the drug by oral administration, monolithic matrix type transdermal patches containing cinnarizine (CNZ) were developed. For this purpose, films based on hydroxypropyl methylcellulose and polyvinylpyrrolidone as matrix-forming polymers were designed. Physical characteristics of transdermal films and drug-excipient compatibility were investigated. Factors affecting in vitro drug release and ex vivo skin penetration and permeation of the drug were studied. It was confirmed that films displayed sufficient flexibility and mechanical strength for application onto the skin for a long time period. Ex vivo penetration experiments gave satisfactory results for transdermal drug delivery through rat skin. The parameters determining good skin penetration were also evaluated. The highest drug permeation rate was obtained with incorporation of Transcutol® (0.102 mg/cm2/h) into the base CNZ formulation, followed by propylene glycol (0.063 mg/cm2/h), menthol (0.045 mg/cm2/h), and glycerin (0.021 mg/cm2/h) as penetration enhancers (p < 0.05). As a result, the developed transdermal patches of CNZ may introduce an alternative treatment for various conditions and diseases such as idiopathic urticarial vasculitis, Ménière's disease, motion sickness, nausea, and vertigo. Thus, the risk of systemic side effects caused by the drug can be reduced or eliminated

Development of Poly (Methyl vinyl ether-alt-maleic acid) Microneedles for Transdermal Delivery of Atorvastatin Calcium.

AIMS: Biodegradable polymeric microneedles containing atorvastatin calcium were developed in order to improve the percutaneous absorption of the drug, useful for the treatment of hypercholesterolemia. BACKGROUND: The use of physical enhancers like microneedles have shown good results to increase the delivery of drugs through the skin, the use of microneedles has very important advantages for transdermal drug delivery, for example, they are painless, easy to use and safe, they increase time interval of drug activity, dose, and reductions in adverse reactions, they also offer, the facility to remove the system instantly of the skin. OBJECTIVE: Develop polymer microneedles loaded with a calcium atorvastatin and evaluate them by Differential Scanning Calorimetry (DSC), Scanning Electron Microscopy (SEM), bioadhesion, postwetting- bioadhesion, breaking strength, drug release test and in vitro percutaneous absorption studies to demonstrate the use of microneedles atorvastatin is able to cross the skin. METHODS: The microneedles were made with poly (methyl vinyl ether-alt-maleic acid) as biodegradable polymer using the technique of casting in solution in a mold. After solidification these microneedles were characterized by Differential Scanning Calorimetry (DSC), Scanning Electron Microscopy (SEM), bioadhesion, post-wetting-bioadhesion, breaking strength, drug release test and in vitro percutaneous absorption studies. RESULTS: In general, the performances were satisfactory for optimal formulation in terms of DSC with no interactions between drug and excipients, SEM shows microneedles with a conical shape, bioadhesion of 1570 g.f, post wetting-bioadhesion of 1503.4 g.f, breaking strength of 1566.7g.f that is sufficient to disrupt Stratum corneum, good drug release and a flux of 33.4 µg/cm2*h with a tLag of 15.14 h for the in vitro percutaneous absorption. CONCLUSION: The results indicate that it is possible to generate microneedles to increase the percutaneous absorption of calcium atorvastatin transdermally, with the potential to be used as an alternative to the oral route for the treatment of dyslipidemias.

Recent Patents Concerning the use of Nanotechnology-based Delivery Systems as Skin Penetration Enhancers.

Nanotechnology-based delivery systems have been considered a promising approach for topical application, considering their characteristics of penetration into/across the skin. The present review aimed to evaluate the recent international scenario of patents concerning the use of nanotechnology- based delivery systems as skin penetration enhancers. A survey of recent patent documents was conducted by using the Espacenet patent database including the terms "skin" in the title and "promot* or enhanc* and penetrat* or absorp* or permeat*" and "nano*" with the truncation symbol (*) in the abstract of documents. A total of 110 patents were published from 2008 to 2018, with 94 technologies being considered. The results demonstrated an increase in innovations concerning nanotechnologybased delivery systems as skin penetration enhancers in recent years. Most patent applicants are from China (60.6%) and Korea (21.3%), and companies (68%) were the most prominent owners. The majority of patent applications (76%) were intended for cosmetic purposes; the types of products and nanostructures were also investigated. Overall results demonstrated the increased interest around the world in patenting products involving skin permeation promotion and nanotechnology for pharmaceutical and, mainly, for cosmetics purposes.

Is Vitamin D3 Transdermal Formulation Feasible? An Ex Vivo Skin Retention and Permeation.

Vitamin D3 supplementation is important to prevent and treat hypovitaminosis that is a worldwide public health issue. Most types of supplementation are by oral route or fortification foods. The alternative route must be investigated, as transdermal route, for people with fat malabsorption or other diseases that impair the absorption of vitamin D3. This study focused on verifying the feasibleness of vitamin D3 skin retention and permeation with the presence of chemical penetration enhancers (soybean lecithin, isopropyl palmitate, propylene glycol, ethoxydiglycol, and cereal alcohol) at different pharmaceutical forms (gel and cream) through a human skin. The integrity of skin was evaluated by transepidermal water loss (TEWL) during the skin retention and permeation test. The combination of chemical penetration enhancers presented in cream did not compromise the skin, different from the gel that association of cereal alcohol and propylene glycol compromised the skin in 24 h. Gel formulation showed vitamin D3 detection at stratum corneum in 4 h and at epidermis and dermis in 24 h. Vitamin D3 demonstrated an affinity with the vehicle in the cream formulation and was detected at the skin surface. No active was found at receptor fluid for both formulations. In conclusion, the vitamin D3 did not indicate feasibleness for transdermal use probably due to its physical-chemical characteristics such as high lipophilicity since it was not permeated through a human skin. Nevertheless, the transdermal route should be continuously investigated with less lipophilic derivates of vitamin D3 and with different combination of penetration enhancers.

Development of ciclopirox olamine topical formulations: evaluation of drug release, penetration and cutaneous retention.

With the aim of reducing system absorption and consequently, the side effects, and simultaneously select a penetration enhancing, three topical formulations with 0.5% ciclopirox olamine (CO) and 15% of propylene glycol (PG), ethoxydiglycol or oleic acid were developed and evaluated regarding the skin penetration and cutaneous retention of the drug using Franz diffusion cells. Release experiments were performed through synthetic membrane while dermatomed pig ear skin was used to evaluate CO skin penetration and skin retention. Retention studies were carried out applying tape stripping method and dosing CO in stratum corneum and in epidermis and dermis. A HPLC method was validated for quantifying CO. All formulations tested with synthetic membrane presented no retention of the drug. Permeation data suggested that there was no systemic absorption of ciclopirox olamine from the studied formulations, even when the skin penetration enhancers were applied. Higher concentrations of the drug were found in the stratum corneum (SC) and also in epidermis and dermis, for all of the developed formulations. The addition of enhancers improved the penetration and cutaneous retention of CO, and propylene glycol promoted higher concentrations in epidermis and dermis, probably because its cumulative effect on the skin and by an efficient solvent power.

Exploiting the buccal mucosa as an alternative route for the delivery of donepezil hydrochloride.

The potential of the buccal mucosa as an alternative route for the systemic delivery of donepezil (DPZ) hydrochloride, and the impact of various skin penetration enhancers on DPZ buccal permeability, was assessed using an in vitro model. DPZ was applied to porcine buccal mucosa in modified Ussing chambers either alone (20 µg/mL) or with different treatment protocols of various enhancers including Azone® (AZ), deoxycholic acid (DA), polyethylene glycol (PEG) 400, and oleic acid (OA)-PEG 400. DPZ permeated the buccal mucosa very rapidly with a permeability coefficient of 35.6 ± 4.9 × 10(-6) cm/s, which was not significantly affected by AZ pretreatment. Coapplication of DA 0.6% (w/w), but not DA 0.01% (w/w), reduced the buccal permeation of DPZ (3.5-fold), and PEG 400 reduced the absorption of DPZ in a dose-dependent manner (1.6- and 18.0-fold reduction at 5% and 50%, w/w, PEG 400, respectively). Coapplication of a combination of OA 1% (v/w) and PEG 400 5% (w/w) further reduced DPZ permeability (5.5-fold), which was demonstrated to result from excipient-induced DPZ precipitation as assessed by light microscopy analysis. These results confirm the feasibility of a novel buccal delivery system for Alzheimer's disease, and suggest various approaches that may be exploited for controlled buccal delivery of DPZ.