Cristina Padula

Bioadhesive film for the transdermal delivery of lidocaine: in vitro and in vivo behavior

The aim of this work was to study, in vitro and in vivo, the behavior of a skin bioadhesive film containing lidocaine. The film characterization included drug transport studies through skin in vitro and in vivo tape stripping with and without iontophoresis. We studied the effect of drug loading in order to identify the release mechanism. Finally, the release rate was compared with a lidocaine commercial gel, to assess the therapeutic value. From the data obtained it can be concluded that the monolayer film acts as a water-permeable transdermal/dermal patch on application to the skin. The permeation kinetics across the skin was not linear, but the patch acted as a matrix controlling drug delivery. Additionally, the permeation rate increased with drug loading. The in vivo experiments with tape stripping indicated that the presence of water during film application is essential to achieve not only the proper adhesion but also an effective accumulation. The application of electric current to the patch can further increase the amount of drug accumulated in the stratum corneum.

Different approaches for improving skin accumulation of topical corticosteroids

The aim of this paper was to evaluate the effect of vehicle, chemical enhancer and iontophoresis on the skin accumulation of clobetasol propionate (CP) and mometasone furoate (MF). In vitro permeation experiments were performed using pig ear skin as barrier and HPLC as quantification method. The formulations tested were chitosan gels, sodium-deoxycholate gels and commercial creams of CP and MF. The results obtained indicate that Na-DOC gel had an enhancing effect on the skin accumulation of both active agents. This effect was more evident with CP especially in the stratum corneum and epidermis which are the target sites of topical steroidal treatment. Two terpene derivatives (D-limonene and nerolidol) and Transcutol P were evaluated as chemical penetration enhancers. Nerolidol produced considerable increase in the amount of CP and MF accumulated without any permeation across the skin. The application of electric current (anodal iontophoresis) to the gels improved the accumulation of MF while it did not effect the accumulation of CP. Due to the best accumulation results of nerolidol, the enhancement effect in combination with iontophoresis was also investigated. It was shown that, the combination of anodal iontophoresis and chemical enhancer (nerolidol) produced no further enhancement for both active agents.

In-vitro permeation of bevacizumab through human sclera: effect of iontophoresis application

Objectives  Bevacizumab (Avastin) is a recombinant humanized monoclonal antibody used in ophthalmology (off‐label) for the treatment of neovascularization in diseases such as diabetic retinopathy and age‐related macular degeneration (wet form). Bevacizumab is currently administrated by repeated intravitreal injection, which can cause severe complications; a non‐invasive delivery route is therefore desirable. The passive permeation of bevacizumab through isolated human sclera was evaluated and the iontophoretic technique was explored as a method to enhance its transscleral transport in vitro.

Characterization of Rabbit Ear Skin as a Skin Model for in vitro Transdermal Permeation Experiments: Histology, Lipid Composition and Permeability

Aim: The aim of this work was to characterize rabbit ear skin in view of its use in transdermal permeation experiments. Method: The characterization included histological analysis of the tissue, qualitative and quantitative analysis of stratum corneum (SC) lipids, differential scanning calorimetry and permeation experiments (caffeine, nicotinamide, progesterone). As a reference, pig ear skin was used. Results: The results obtained show that rabbit ear skin has a similar SC thickness compared to pig skin although the viable epidermis has a different structure. The lipid composition of rabbit SC was similar to pig SC but was characterized by a lower content of ceramides and a higher content of cholesterol esters and triglycerides. In terms of permeability, rabbit ear skin was 4–7 times less permeable to hydrophilic compounds, probably because of the higher lipophilicity of its SC. The permeability to progesterone was comparable between isolated pig epidermis and rabbit ear skin. Conclusion: Overall, the results obtained in this work support the usefulness of rabbit ear skin as barrier for skin penetration studies, for both lipophilic and hydrophilic permeants.

Ex vivo models to evaluate the role of ocular melanin in trans-scleral drug delivery.

Trans-scleral delivery is nowadays considered as a possible way to deliver drugs to the posterior segment of the eye. Despite the potentiality of this administration route, there is a lack of fundamental knowledge on the role of the numerous barriers involved. The aim of this work was to develop an easy and cheap ex vivo method to evaluate the barrier properties of the choroid-Bruchs layer and in particular to estimate the role of melanin in drug diffusion through ocular tissues. In vitro binding studies were performed to estimate drug affinity for melanin; model molecules used were methylene blue, propranolol, levofloxacin and methylprednisolone sodium succinate. The ex vivo model set up is based on porcine eye bulbs with light blue iris or brown iris. While the choroid of brown eyes is dark, the choroid of blue eyes is transparent, due to the absence of melanin. Permeation experiments using pigmented and not-pigmented porcine tissues gave the opportunity to discriminate between the barrier role of choroid-Bruchs membrane as such and the barrier role of melanin. Ex vivo permeation experiments can be performed using isolated choroid-Bruchs or the sclera-choroid-Bruchs layer. In this last case, it is possible to take into account also the barrier role of the sclera that tends to decrease the drug concentration at the sclera/choroid interface, thus amplifying the effect of melanin. The data obtained in this paper indicate that for some drugs melanin can really represent a barrier and the effect can imply a lower drug flux or simply a longer lag time depending on the kind of drug and the concentration applied. However, it is a saturable barrier, thus its effect can probably be overtaken by high doses or multiple administrations. The ex vivo model set up can help to refine computational models, to better evaluate the interplay among static, dynamic and metabolic barriers. Additionally, since human eyes display a full range of pigmentation, the model could also be useful to investigate the possible influence of pigmentation phenotype on trans-scleral delivery.

Bioadhesive films containing benzocaine: correlation between in vitro permeation and in vivo local anesthetic effect.

ABSTRACTPurposeThe aim of this work was to develop anesthetic bioadhesive films containing benzocaine and study their in vitro skin permeation and in vivo performance, in comparison with commercial formulations.MethodsFilms containing 3% and 5% w/w of benzocaine were prepared and characterized by weight, drug content, thickness and morphology. In vitro permeation assays were performed in vertical diffusion cells using full-thickness pig ear skin as barrier. Intensity and duration of analgesia were evaluated in rats by tail-flick test, and skin histological analysis was carried out.ResultsTail-flick test showed that the duration of benzocaine-induced analgesia was significantly prolonged with the films compared to commercial creams, in agreement with the higher in vitro permeation. Histological analysis of the rat tail skin did not reveal morphological tissue changes nor cell infiltration signs after application of the commercial creams or films.ConclusionsResults from our study indicate that the films developed in this work can be considered as innovative dermal/transdermal therapeutic systems for benzocaine local delivery.

Strategies for delivering local anesthetics to the skin: focus on liposomes, solid lipid nanoparticles, hydrogels and patches

Introduction: Dermal and transdermal drug delivery systems offer the possibility to control the release of the drug for an extended period of time. In particular, skin-delivery of local anesthetics (LA) is one of the most important strategies to increase the local drug concentration and to reduce systemic adverse reactions. Areas covered: During the development phase of new formulations for skin-delivery of LA one should consider a set of desirable features such providing suitable adhesion, easy application/removal and also to be biocompatible, biodegradable and non-toxic. This review emphasizes the main strategies for skin-delivery of LA considering those features in relation to the composition of the delivery systems described. The topics highlight the relationships between physico-chemical studies and pharmaceutical applications for liposomes and solid lipid nanoparticles as well as the formulation and clinical applications for hydrogels and patches. Expert opinion: The development of LA skin-delivery systems using hydrogels and different permeation enhancers, liposomes or lipid nanoparticles (as isolated carrier systems or as their dispersion in a gel-base) and patches have been explored as alternatives to commercial formulations, modifying the release rate of LA, increasing bioadhesive properties and reducing toxicity, resulting in an improved therapeutic efficacy. This review should provide to the reader a special emphasis on four delivery-systems, comprising the group of liposomes and lipid nanoparticles, hydrogels and patches technologies looking forward their application for skin anesthesia.

Innovative formulations for the delivery of levothyroxine to the skin

The aim of this work was to realize innovative transdermal formulations containing sodium levothyroxine in view of topical administration. Permeation experiments were performed in vitro, using rabbit ear skin as barrier. At the end of the permeation experiments levothyroxine retained in the skin was extracted and quantified by HPLC. Formulations tested were microemulsions and transdermal films. Microemulsions containing isopropyl myristate and isobutanol were shown to be able to increase levothyroxine solubility by the inclusion in reverse micelles. However, the inclusion in reversed micelles reduced the drug release to a significant extent, and consequently skin retention, compared to aqueous solutions. When the microemulsion was included in the transdermal film, drug retention was increased, probably for the enhancer effect of its excipients. The transdermal film proposed in this work could be an interesting alternative to semisolid formulations for the ease of use and the control in the amount of active applied. Additional benefit can be obtained if the film is used in occlusive conditions.

Physical Characterization of a New Skin Bioadhesive Film

Physical properties (roughness, gloss, mechanical, surface topography and adhesive) of a bioadhesive film for the transdermal delivery of drugs and its interactions with a skin model surface were studied. Roughness is a measurement of the small-scale variations in the height of a physical surface. No significant differences in Ra between the “x” and “y” dimensions for both the skin model and patch were detected, due to uniformity in their production. Scanning electron microscope pictures showed small particles projected from the film. Those particles resulted in increasing roughness and surface area. For the patch, gloss values measured at 20° were 6.0 ± 0.9 and at 60°, 32.2 ± 2.2 gloss units, respectively, indicating a semi-gloss material. Concerning the mechanical properties, the tensile strength of the film resulted four- to sevenfold greater than the peel force from the model skin used, indicating the suitability of the film for skin application. The adhesion to skin model depended on the amount of water used for film application and on the elapsed time between film application and removal. Finally, the model skin that was invented by Charkoudian can be used as an alternative to costly and highly variable human skin substrates since it possesses human topography.

Effect of formulation factors on the trans-scleral iontophoretic and post-iontophoretic transports of a 40 kDa dextran in vitro

The aim of the work was to study in vitro, across isolated porcine sclera and across the trilayer sclera-choroid-Bruchs membrane (SCB), the effect of iontophoresis on the permeation of a 40 kDa dextran (FD-40), chosen as model compound of high molecular weight neutral drugs. In particular, the effect of vehicle composition (in terms of buffering agent and ionic strength) and current intensity (from 0.3 to 4.2 mA, corresponding to 0.5-7 mA cm(-2)) was investigated. Additionally the post-iontophoretic transport of FD-40 through SCB was studied. The results obtained in the present paper confirm the importance of formulation parameters during transscleral iontophoresis of a neutral high molecular weight hydrophilic compound transported by electroosmosis. In particular, ionic strength seems to be the more relevant parameter, while the buffering agent (phosphate vs HEPES) is not relevant. The enhancement obtained increases--although in a stepwise way--with current intensity, after a threshold value of approximately 1.5 mA. However, the real variable to be considered is probably current density (threshold value 2.5 mA cm(-2)) more than intensity, in analogy with transdermal iontophoresis. The inclusion of further static barriers besides the sclera, such as choroid and Bruchs membrane, reduces, as expected, the permeation of FD-40, but iontophoresis is able to significantly promote FD-40 transport also through this more complex barrier, without altering its permeability. Finally, the study of the post-iontophoretic transport highlights the formation of a pronounced FD-40 reservoir inside the sclera. This reservoir permits to obtain in vitro a sustained transscleral flux up to 3 h after current stop. This result could be of interest in the case of a real application, prolonging the enhancement effect also after iontophoresis stop.