Development and Evaluation of an In Silico Dermal Absorption Model Relevant for Children

The higher skin surface area to body weight ratio in children and the prematurity of skin in neonates may lead to higher chemical exposure as compared to adults. The objectives of this study were: (i) to provide a comprehensive review of the age-dependent anatomical and physiological changes in pediatric skin, and (ii) to construct and evaluate an age-dependent pediatric dermal absorption model. A comprehensive review was conducted to gather data quantifying the differences in the anatomy and physiology of child and adult skin. Maturation functions were developed for model parameters that were found to be age-dependent. A pediatric dermal absorption model was constructed by updating a MoBi implementation of the Dancik et al. 2013 skin permeation model with these maturation functions. Using a workflow for adult-to-child model extrapolation, the predictive performance of the model was evaluated by comparing its predicted rates of flux of diamorphine, phenobarbital and buprenorphine against experimental observations using neonatal skin. For diamorphine and phenobarbital, the model provided reasonable predictions. The ratios of predicted:observed flux in neonates for diamorphine ranged from 0.55 to 1.40. For phenobarbital, the ratios ranged from 0.93 to 1.26. For buprenorphine, the model showed acceptable predictive performance. Overall, the physiologically based pediatric dermal absorption model demonstrated satisfactory prediction accuracy. The prediction of dermal absorption in neonates using a model-based approach will be useful for both drug development and human health risk assessment.

Nanostructured-lipid carriers-Chitosan hydrogel beads carrier system for loading of resveratrol: A new method of topical application

The aim of this study was to develop nanostructured-lipid carriers (NLC) encapsulated by Chitosan hydrogel beads for the efficient topical carrier. Dynamic light scattering (DLS), X-ray diffraction (XRD), Differential scanning calorimetry (DSC), and attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) were conducted to study the influence of the encapsulation on the characteristic of resveratrol-loaded NLC, and the results showed that there was no impact on resveratrol-loaded NLC. Chitosan hydrogel beads could significantly improve the physical stability of resveratrol-loaded NLC. In vitro release study revealed that resveratrol-loaded NLC-Chitosan hydrogel beads had a more significant sustained-release effect on resveratrol. In vitro transdermal studies suggested that the skin permeation of resveratrol was promoted by the effect of Chitosan hydrogel beads and increased resveratrol distribution in the skin. In vitro cytotoxicity showed that resveratrol-loaded NLC-Chitosan hydrogel beads did not exert a hazardous effect on L929 cells. Hence, NLC-Chitosan hydrogel beads might be a promising method for topical applications of resveratrol.

OPTIMIZATION OF RIVASTIGMINE CHITOSAN NANOPARTICLES FOR NEURODEGENERATIVE ALZHEIMER; IN VITRO AND EX VIVO CHARACTERIZATIONS

Objective: In an attempt to optimize the anti-Alzheimer effect, rivastigmine-loaded chitosan nanoparticles were developed in order to target of brain through skin permeation. Methods: Rivastigmine-loaded chitosan-tripolyphosphate nanoparticles were prepared by modified ionic gelation method using tween 80 surfactants in different batches with variable chitosan/cross-linker ratios, desirability factors were applied to choose the optimal Nanocarrier and (F15) was selected. Different rivastigmine concentrations were loaded and the highest encapsulation efficiency formulae chosen for further study and evaluated by scanning electron microscopy (SEM), transmission electron microscopy (TEM) and differential scanning calorimetric (DSC). Further, drug loading, Ex-vivo skin permeation of Nano-gel, and kinetic studies were carried out in addition to stability along three months under different temperature. Results: Particle size and polydispersity index showed average 291.6±7.70 to 490.6±7.42 d. nm. and 0.333±0.04 to 0.570±0.023 respectively. The nanoparticles were spherical in shape. Drug concentrations 4% w/w showed the highest drug entrapment efficiency (89.80%) and drug loading (40.81). Ex vivo studies shows that gel formulae of rivastigmine loaded chitosan nanoparticles was not irritant to rat skin had better skin permeation than chitosan nanoparticles aqueous dispersion also capable of releasing the drug in a sustained manner, and follow kinetic diffusion model. Optimum formula F15 was physical and chemical stable. Conclusion: The experimental results showed the suitability of chitosan nanoparticles coated with a surfactant as a potential carrier for permeation through skin and brain, providing sustained delivery of rivastigmine.

Fluconazole and Curcumin Loaded Nanoemulsion Against Multiple Drug Resistance Dermatophytes

Purpose: Topical nanoemulsion comprising of fluconazole and curcumin was developed to target multiple drug resistance dermatophytes infection and to facilitate cutaneous delivery of these poorly water soluble drugs. Methods: Almond oil, sesame oil and paraffin light were used to formulate nanoemulsions and screened for the stability. The solubility of fluconazole and curcumin in surfactants, co-surfactants and oils was screened to decide the various components of the nanoemulsion. The oil phase was light paraffin whereas tween 80 and span 80 were the surfactants and ethanol was used as a co-surfactant. To identify the area of nanoemulsion existence, a pseudoternary diagram was drawn and optimum systems were developed. Drug-loading efficiency was assessed and the developed nanoemulsions were characterized for globule size, stability, robustness to dilution and pH. The optimized nanoemulsion was further evaluated for drug content, viscosity, skin permeation study (ex vivo) and assay of antifungal activity. Results: The globule size was below 200 nm and uniform for the optimized nanoemulsion formulation. It showed enhanced skin permeation (ex vivo) and better antifungal efficacy as compared to the native form of fluconazole and curcumin suspensions. Antimicrobial assay confirmed the synergistic effect of fluconazole and curcumin combination against multiple drug resistance Trychophytum rubrum and Trichophyton metagrophytes as compared to the fluconazole alone. Conclusion: The results clearly indicate an optimized delivery of fluconazole and curcumin in a synergistic way from the nanoemulsion formulation. This resulted in better penetration of these poorly soluble molecules and overall enhanced antifungal activity as compared to these drugs as such against multiple drug resistance dermatophytes.

New, Biocompatible, Chitosan-Gelled Microemulsions Based on Essential Oils and Sucrose Esters as Nanocarriers for Topical Delivery of Fluconazole

Biocompatible gel microemulsions containing natural origin excipients are promising nanocarrier systems for the safe and effective topical application of hydrophobic drugs, including antifungals. Recently, to improve fluconazole skin permeation, tolerability and therapeutic efficacy, we developed topical biocompatible microemulsions based on cinnamon, oregano or clove essential oil (CIN, ORG or CLV) as the oil phase and sucrose laurate (D1216) or sucrose palmitate (D1616) as surfactants, excipients also possessing intrinsic antifungal activity. To follow up this research, this study aimed to improve the adhesiveness of respective fluconazole microemulsions using chitosan (a biopolymer with intrinsic antifungal activity) as gellator and to evaluate the formulation variables’ effect (composition and concentration of essential oil, sucrose ester structure) on the gel microemulsions’ (MEGELs) properties. All MEGELs were evaluated for drug content, pH, rheological behavior, viscosity, spreadability, in vitro drug release and skin permeation and antifungal activity. The results showed that formulation variables determined distinctive changes in the MEGELs’ properties, which were nevertheless in accordance with official requirements for semisolid preparations. The highest flux and release rate values and large diameters of the fungal growth inhibition zone were produced by formulations MEGEL-FZ-D1616-CIN 10%, MEGEL-FZ-D1216-CIN 10% and MEGEL-FZ-D1616-ORG 10%. In conclusion, these MEGELs were demonstrated to be effective platforms for fluconazole topical delivery.

Investigating the potential of Quercetin enthused nano lipoidal system for the management of dermatitis

Objective: The present research work was undertaken to develop quercetin enthused nanolipoidal systems and its characterization. The objective was to investigate potential of prepared system in the management of DNCB induced dermatitis. Method: Nanolipoidal system was prepared in different combinations with quercetin, L-α phosphatidylcholine (SPC) and ethanol and characterized for particle size, polydispersity index (PDI), zeta potential, drug entrapment efficiency, percentage drug release, skin retention and skin permeation. Selected batches were further incorporated into Carbopol 934 base gel. The vesicles were in size range 324.19-359 nm while polydispersity index (PDI) ranges from 0.241-0.554 and for zeta potential, it was from -26.33 to -39.3 nm. Entrapment efficiency was from 23.77-94.68 %. Confocal laser scanning microscopy showed penetration depth of rhodamine enthused ethosome across rat skin up to 45.23 µm which was significantly higher than the rhodamine solution (10 µm). In dinitrochlorobenzene (DNCB) induced mice dermatitis model histopathology study showed a marked decrease in amount of inflammatory cell nucleus in mice treated with quercetin loaded ethosomal gel followed by 76.13% decrease in-ear swelling and ear mass respectively in morphology study. The conventional marketed formulation showed a nominal decrease in epidermal thickness. Further Primary irritation index was less than 0.4 indicating negligible irritation in all the groups. Results: The optimized formulation F6 with SPC and ethanol in the ratio of 20:80 displayed the highest drug content and entrapment efficiency of 94.68±1.14%. PDI was 0.241±0.11 and skin retention 7.7%. Batch F6 with vesicle size and zeta potential of 324.9±19 nm and -26.33 mV, respectively, was incorporated in Carbopol 934 base gel and the prepared gel was evaluated for morphology, spreadability, in vitro, ex vivo release study, and kinetics study and in vivo studies. Conclusion: The present study revealed that the developed ethosomal gel can be used for enhanced delivery of Quercetin via skin. The in vitro studies indicated that the gel serves as an efficient carrier for Quercetin. It showed its effectiveness in the management of dermatitis. Further, Quercetin loaded nanoethosomal gel formulation can be viewed as a promising drug delivery system for the management of dermatitis.

N-Alkylmorpholines: Potent Dermal and Transdermal Skin Permeation Enhancers

Transdermal drug delivery is an attractive non-invasive method offering numerous advantages over the conventional routes of administration. The main obstacle to drug transport is, however, the powerful skin barrier that needs to be modulated, for example, by transdermal permeation enhancers. Unfortunately, there are still only a few enhancers showing optimum properties including low toxicity and reversibility of enhancing effects. For this reason, we investigated a series of new N-alkylmorpholines with various side chains as potential enhancers in an in vitro permeation study, using three model permeants (theophylline, indomethacin, diclofenac). Moreover, electrical impedance, transepidermal water loss, cellular toxicity and infrared spectroscopy measurements were applied to assess the effect of enhancers on skin integrity, reversibility, toxicity and enhancers’ mode of action, respectively. Our results showed a bell-shaped relationship between the enhancing activity and the hydrocarbon chain length of the N-alkylmorpholines, with the most efficient derivatives having 10–14 carbons for both transdermal and dermal delivery. These structures were even more potent than the unsaturated oleyl derivative. The best results were obtained for indomethacin, where particularly the C10-14 derivatives showed significantly stronger effects than the traditional enhancer Azone. Further experiments revealed reversibility in the enhancing effect, acceptable toxicity and a mode of action based predominantly on interactions with stratum corneum lipids.

Ion-Pair Compounds of Strychnine for Enhancing Skin Permeability: Influencing the Transdermal Processes In Vitro Based on Molecular Simulation

This research aimed to explore how Strychnine (Str) ion-pair compounds affect the in vitro transdermal process. In order to prevent the influence of different functional groups on skin permeation, seven homologous fatty acids were selected to form ion-pair compounds with Str. The in vitro permeation fluxes of the Str ion-pair compounds were 2.2 to 8.4 times that of Str, and Str-C10 had the highest permeation fluxes of 42.79 ± 19.86 µg/cm2/h. The hydrogen bond of the Str ion-pair compounds was also confirmed by Fourier Transform Infrared (FTIR) Spectroscopy, Nuclear Magnetic Resonance (NMR) Spectroscopy and molecular simulation. In the process of molecular simulation, the intercellular lipid and the viable skin were represented by ceramide, cholesterol and free fatty acid of equal molar ratios and water, respectively. It was found by the binding energy curve that the Str ion-pair compounds had better compatibility with the intercellular lipid and water than Str, which indicated that the affinity of Str ion-pair compounds and skin was better than that of Str and skin. Therefore, it was concluded that Str ion-pair compounds can be distributed from the vehicle to the intercellular lipid and viable skin more easily than Str. These findings broadened our knowledge about how Str ion-pair compounds affect the transdermal process.

Enhanced Transdermal Delivery of Pranoprofen Using a Thermo-Reversible Hydrogel Loaded with Lipid Nanocarriers for the Treatment of Local Inflammation

A biocompatible topical thermo-reversible hydrogel containing Pranoprofen (PF)-loaded nanostructured lipid carriers (NLCs) was studied as an innovative strategy for the topical treatment of skin inflammatory diseases. The PF-NLCs-F127 hydrogel was characterized physiochemically and short-time stability tests were carried out over 60 days. In vitro release and ex vivo human skin permeation studies were carried out in Franz diffusion cells. In addition, a cytotoxicity assay was studied using the HaCat cell line and in vivo tolerance study was performed in humans by evaluating the biomechanical properties. The anti-inflammatory effect of the PF-NLCs-F127 was evaluated in adult male Sprague Daw-ley® rats using a model of inflammation induced by the topical application of xylol for 1 h. The developed PF-NLCs-F127 exhibited a heterogeneous structure with spherical PF-NLCs in the hydrogel. Furthermore, a thermo-reversible behaviour was determined with a gelling temperature of 32.5 °C, being close to human cutaneous temperature and thus favouring the retention of PF. Furthermore, in the ex vivo study, the amount of PF retained and detected in human skin was high and no systemic effects were observed. The hydrogel was found to be non-cytotoxic, showing cell viability of around 95%. The PF-NLCs-F127 is shown to be well tolerated and no signs of irritancy or alterations of the skin’s biophysical properties were detected. The topical application of PF-NLCs-F127 hydrogel was shown to be efficient in an inflammatory animal model, preventing the loss of stratum corneum and reducing the presence of leukocyte infiltration. The results from this study confirm that the developed hydrogel is a suitable drug delivery carrier for the transdermal delivery of PF, improving its dermal retention, opening the possibility of using it as a promising candidate and safer alternative to topical treatment for local skin inflammation and indicating that it could be useful in the clinical environment.