Mona M.A. Abdel-Mottaleb

Lipid nanocapsules for dermal application: A comparative study of lipid-based versus polymer-based nanocarriers

Lipid nanocapsules (LNC) are colloidal carriers providing controlled release profiles and improved bioavailability for many drug substances and diverse administration routes. However, they have not been explored before for transdermal application. Here, we study the behavior of LNC as a transdermal drug delivery system using ibuprofen as a model drug. A comparison to other lipid nanocarriers such as solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) and polymeric nanocarriers has been made. It was found that LNC could increase the flux rate of ibuprofen 21.9±0.5 compared to 5.8±0.4 μg/cm(2)h in case of drug solution. Similar flux rates were obtained for SLN and NLC with average values of 22.9±0.5 and 22.5±2.0 μg/cm(2)h, respectively. On the other side, comparison to polymeric nanoparticles showed that the polymer-based carriers of the same particle size had lower permeation-enhancing effect with a flux rate of 10.62±1.84 μg/cm(2)h. Polymeric carriers had fourfold higher accumulation in the skin compared to that of the LNC and twice the accumulation of SLN and NLC. These results would suggest that the LNC can be considered as efficient as SLN and NLC for the transdermal drug delivery while polymeric nanoparticles are more suitable for localized drug delivery to the skin.

Finite and infinite dosing: Difficulties in measurements, evaluations and predictions

Due to the increased demand for reliable data regarding penetration into and permeation across human skin, assessment of the absorption of xenobiotics has been gaining in importance steadily. In vitro experiments allow for determining these data faster and more easily than in vivo experiments. However, the experiments described in literature and the subsequent evaluation procedures differ considerably. Here we will give an overview on typical finite and infinite dose experiments performed in fundamental research and on the evaluation of the data. We will point out possible difficulties that may arise and give a short overview on attempts at predicting skin absorption in vitro and in vivo.

Standardized in vitro drug release test for colloidal drug carriers using modified USP dissolution apparatus I

Background: Recently the use of colloidal carriers as drug delivery systems is gaining more attention. Evaluation of the in vitro drug release is considered an important step during the development and quality control of such systems. Therefore, there is a need for a standard test technique to study in vitro drug release from colloidal systems. Methods: The glass basket dialysis method was performed by a modification to the USP dissolution apparatus I by replacing the baskets with glass cylinders closed at the lower end by dialysis membrane. This method was characterized for the essential test parameters and compared to the dialysis bags technique using different types of colloidal drug carriers, namely liposomes, polymeric, and lipid nanoparticles. Results: The method proved to be more discriminating than the conventional dialysis bag method and allowed for better comparison between different formulation parameters or experimental conditions. In general, the design is easy to perform, simple, and available in all pharmaceutical laboratories under the same setup. Conclusion: The described method is a step toward standardized dissolution tests on colloidal drug delivery systems and the possible comparability of results.

Nanoparticles enhance therapeutic outcome in inflamed skin therapy

Inflammatory reactions of the skin are a major therapeutic field; however, drug delivery is nowadays only related to the use of classical formulations like ointments and creams. Here, we report the behaviour of polymeric submicron particles (NP) for selective drug delivery to the inflamed skin. NPs of nominal diameters from 50 to 1000 nm were administered to an experimental dithranol-induced dermatitis inflammation model in mice ears. The results revealed that smaller particles had an around 3-fold stronger and deeper penetration tendency with a preferential accumulation in inflamed skin hair follicles and sebaceous glands (2.8 ± 0.6% and 2.3 ± 0.4% for NP100 and NP50 compared to 0.84 ± 0.04% and 0.92 ± 0.02% for the same sizes on healthy skin). Betamethasone loaded NP confirmed the size dependency by being therapeutically more efficient from histological examination and measurement of different inflammatory markers in the skin (myeloperoxidase activity of untreated control, 1.2 ± 0.4; NP1000, 1.0 ± 0.4; NP100, 0.5 ± 0.2, all U/mg). This approach holds a high potential for a selective therapy to the inflamed skin by increasing the local intradermal availability with simultaneous reduction in systemic adverse effects.

In vitro drug release mechanism from lipid nanocapsules (LNC)

Lipid nanocapsules are recently developed lipid nanocarriers for delivery of lipophilic drugs. Due to their small size and biocompatible nature, lipid nanocapsules (LNC) may be promising carriers for drug delivery with different routes of administration. The aim of this work was to study the effect of formulation variables on the in vitro drug release from LNC. Ibuprofen as a model drug was entrapped in the oily core while Cremophor A25 and Cremophor A6 were used as hydrophilic surfactants in different ratios ranging from 1:1 to 1:0. All the prepared LNC were of comparable particle sizes around 50nm. Varying Cremophor compositions as well as the presence of lecithin, cetyl or stearyl alcohol had no significant effect on the in vitro drug release profiles. However, drug release rates increased significantly with increasing the temperature from 4 to 50 degrees C, i.e. the flux increased from 1.5 to 7microg/(cm(2)min). This was explained by the increased ibuprofen-lipid interactions at reduced temperature where the increased viscosity of the lipid significantly slows down the drug diffusion to the external aqueous phase. In summary, the physicochemical properties of the drug as well as the oil phase have a high impact on the drug release rate while the surfactant type, composition or density exerted only a minor effect.

Surface-Charge-Dependent Nanoparticles Accumulation in Inflamed Skin

Polymeric nanoparticles (NPs) are interesting drug carriers for dermal application and drug targeting to certain skin structures. NP interactions with diseased skin and the associated benefits and risks have been hardly explored. Today, we study the behavior of polymeric NPs for selective drug delivery to inflamed skin. Neutral, cationic, and anionic NPs of nominal diameters around 100 nm were administered to an experimental dithranol-induced dermatitis inflammation model in mice ears. The results showed that the surface charge had an important influence on the penetration and accumulation tendency in the inflamed skin compared with the neutral and cationic (2.8 ± 0.3%, 2.1 ± 0.2%, and 1.9 ± 0.3% for anionic, neutral, and cationic particles, respectively). Confocal laser scanning microscopy showed that all particles were accumulated in the inflamed pilosebaceous units. Betamethasone-loaded NPs showed that both charged particles were therapeutically more efficient than the neutral ones. Treatment with anionic and cationic particles led to the reduction of the inflammatory enzyme alkaline phosphatase activity by 50.7 ± 2% and 57.7 ± 5%, respectively, in comparison with the inflamed control. Noncharged particles had a lower therapeutic impact where the activity was only reduced by a factor of 75%. Histological sections examination had also confirmed these results. Therefore, it was concluded that the presence of charge could enhance skin-NPs adhesion and interaction leading to higher therapeutic effect on inflamed skin.

Physically cross-linked polyvinyl alcohol for the topical delivery of fluconazole.

The aim of this study was to develop fluconazole in an ultrapure polyvinyl alcohol (PVA) hydrogel able to deliver the drug in a sustained release pattern for local treatment of skin fungal infections. The topical fluconazole hydrogels were prepared using PVA hydrogels physically cross-linked by freeze–thaw technique. Polyethylene glycol (PEG) was added as a hydrophilic excipient as a release enhancer of fluconazole. The effects of PVA molecular weight, PEG molecular weight, and PEG concentration were studied using a 2 × 4 × 2 factorially designed experiment. The selected fluconazole hydrogel proved to be physically stable over a period of 6 months and to be effective in the topical treatment of cutaneous candidiasis. Therefore, it could be concluded that the formula composed of 10% PVA 205000 and 1.5% PEG 4000 and 2% fluconazole and prepared by three cycles of freezing, and thawing is very promising in the local treatment of skin fungal infection as an alternative to the systemic use of fluconazole.

Stability of fluorescent labels in PLGA polymeric nanoparticles: Quantum dots versus organic dyes

Polymeric nanoparticles (NPs) are currently being investigated for various therapeutic, diagnostic and drug delivery applications. The study of their interactions and fate in biological systems is frequently performed via their fluorescent labeling and following them using fluorescent microscopy. Quantum dots are proposed as stable fluorescent label and compared to other organic dyes (Nile red and DiI) in terms of their entrapment, diffusion in different aqueous or lipophilic media and photostability. In vitro transfer to hydrophilic PBS solution showed that after 8h, 4.2±2.2, 15.5±2.0 and 0.9±0.02% was released from the QDs, NR and DiI nanoparticles, respectively. However, higher diffusion rates were observed in the lipophilic medium chain triglyceride and artificial sebum for all the dyes used. Fluorescent intensity of the three different markers was found to be stable over a period of 24h. Continuous illumination with laser beam using a confocal laser scanning microscopy indicated the superior stability of quantum dots compared to the other organic dyes. Skin permeation experiments have shown that QDs were the most representative marker for the polymeric nanoparticles skin penetration.

Nanomedicine strategies for targeting skin inflammation

Topical treatment of skin diseases is an attractive strategy as it receives high acceptance from patients, resulting in higher compliance and therapeutic outcomes. Recently, the use of variable nanocarriers for dermal application has been widely explored, as they offer several advantages compared with conventional topical preparations, including higher skin penetration, controlled and targeted drug delivery and the achievement of higher therapeutic effects. This article will focus on skin inflammation or dermatitis as it is one of the most common skin problems, describing the different types and causes of dermatitis, as well as the typical treatment regimens. The potential use of nanocarriers for targeting skin inflammation and the achievement of higher therapeutic effects using nanotechnology will be explored.

Composite chitosan-transfersomal vesicles for improved transnasal permeation and bioavailability of verapamil.

The creation of composite systems has become an emerging field in drug delivery. Chitosan has demonstrated several pharmaceutical advantages, especially in intranasal delivery. In this manuscript, a comparative study was conducted between regular vesicles (transfersomes and penetration enhancer vesicles) and composite vesicles (chitosan containing transfersomes and penetration enhancer vesicles) loaded with a model antihypertensive drug; verapamil hydrochloride VRP. Composite vesicles displayed larger particle size than regular vesicles owing to the coating potential of chitosan on the vesicular bilayer as displayed by transmission electron microscopy, with an increased viscosity of composite vesicles and a shift in the zeta potential values from negative to positive. The entrapment efficiency of VRP in the vesicles ranged from 24 to 64%, with best physical stability displayed with transfersomal vesicles prepared using sodium deoxycholate. Chitosan slowed the in vitro release of VRP from the selected formulation but managed to achieve high penetrability across sheep nasal mucosa as displayed by confocal laser microscopy. The chitosan composite transfersomal formulation exhibited absolute bioavailability of 81.83% compared to the oral solution which displayed only 13.04%. Findings of this manuscript highly recommend chitosan as a promising functional additive in vesicular formulations to improve the intranasal delivery of drugs with low oral bioavailability.